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listlengths 0
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|---|---|---|---|---|---|---|
test-1
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[
"blood pressure 115/65 mmHg, heart rate 100 beats / min, oxygen saturation rate 97 %",
"blood pressure at 120 - 140/60 - 80 mmHg, heart rate 80 - 100 beats / min, oxygen saturation 100 %, body temperature 37.0 - 37.4 ℃"
] |
test-2
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Gastrointestinal-System
|
GI
|
[
"acute appendicitis",
"nausea, and vomiting"
] |
test-3
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Patient-History
|
History
|
[
"laparoscopic appendectomy",
"no abnormalities in her pediatric medical history",
"Type I DM"
] |
test-4
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Neurology
|
Neuro
|
[
"headaches in her left temporal lobe",
"generalized convulsions and aphasia",
"In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found.",
"patient was able to read but had auditory aphasia such that she could not understand spoken words",
"no signs of hypotonia or amyotrophy of the limbs"
] |
test-5
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered ( 7.54 mM / L ).",
"adenosine - to - guanine transition at t - RNA nucleotide 3243 in PCR sequencing",
"The laboratory results showed hyponatremia ( 126 mEq / L ), hyperglycemia ( 257 mg / dl ), and light metabolic acidosis ( pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM / L, BE -5.3 mM / L )",
"There were no abnormal findings in the chest X - ray",
"Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM / L, BE -2.1 mM / L; her electrolytes were Na + 125 mEq / L, K + 3.8 mEq / L, Cl - 88 mEq / L; and her blood sugar was 176 mg / dl",
"The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM / L, and BE -3.6 mM / L; her electrolyte levels were Na + 128 mEq / L, K + 4.1 mEq / L, and Cl - 90 mEq / L; and her blood sugar level was 120 mg / dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM / L."
] |
test-6
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Cardiovascular-System
|
CVS
|
[
"In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found.",
"There were no abnormal findings in the chest X - ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67 % and no abnormal findings",
"ECG results appeared normal."
] |
test-7
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Endocrinology
|
ENDO
|
[
"Type I DM.",
"hyperglycemia ( 257 mg / dl ),",
"her blood sugar was 176 mg / dl.",
"her blood sugar level was 120 mg / dl."
] |
test-8
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Genitourinary-System
|
GU
|
[] |
test-9
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Respiratory-System
|
RESP
|
[] |
test-10
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Musculoskeletal-System
|
MSK
|
[] |
test-11
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[] |
test-12
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Dermatology
|
DERM
|
[] |
test-13
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Pregnancy
|
Pregnancy
|
[] |
test-14
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Lymphatic-System
|
LYMPH
|
[] |
test-15
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"23 year - old"
] |
test-16
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Age-of-Onset
|
Age (of onset)
|
[
"age 18"
] |
test-17
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"MELAS syndrome"
] |
test-18
|
2876866
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
{'Case Report': "A 23 year-old female patient, 160 cm tall and 48 kg, was diagnosed with acute appendicitis and admitted for a laparoscopic appendectomy. She had no abnormalities in her pediatric medical history, but from the age 18, she had slowly begun experiencing headaches in her left temporal lobe, nausea, and vomiting. In June of that year, she experienced generalized convulsions and aphasia. In a brain MRI and MRA, an infarction in the posterior divisions of the left mesencephalic arteries was found. Also, in a blood test, an increase in lactic acid was discovered (7.54 mM/L). The patient was suspected to have MELAS syndrome. She was diagnosed with MELAS after testing (adenosine-to-guanine transition at t-RNA nucleotide 3243 in PCR sequencing). After she turned 21, she was diagnosed with Type I DM. The patient had to orally ingest 200 mg of carbamazepine and 100 mg of aspirin per day and subcutaneously inject 30 units of insulin in the morning and 20 units in the evening. She had no history of total anesthesia. In a physical examination before the anesthesia, the patient was able to read but had auditory aphasia such that she could not understand spoken words. In the physical examination, there were no signs of hypotonia or amyotrophy of the limbs. The laboratory results showed hyponatremia (126 mEq/L), hyperglycemia (257 mg/dl), and light metabolic acidosis (pH 7.346, PaCO 2 36.3 mmHg, HCO 3 20.1 mM/L, BE -5.3 mM/L). There were no abnormal findings in the chest X-ray and electrocardiogram. One year prior to her admission to the hospital, she had an ECG that revealed a cardiac index of 67% and no abnormal findings. For sugar control, 4 units of shortacting insulin were injected, and 0.9% normal saline was administered to control hyponatremia. No other pre-operative measures were performed. After the patient was taken to the operating room, we attached ECG standard leads II, noninvasive monitors for blood pressure, heart rate, arterial oxygen saturation, capnogram, and bispectral index (BIS), and a nerve stimulator to the patient using the Multi Channel Anesthesia Monitor S/5™ (Datex-Ohmeda, USA). Preliminary vital signs were as follows: blood pressure 115/65 mmHg, heart rate 100 beats/min, oxygen saturation rate 97%, and the ECG results appeared normal. The patient underwent 3 minutes of denitrogenation with 100% oxygen through a face mask. Afterwards, we administered lidocaine (40 mg) with the Master TCI (Fresenius Vial S.A., France); we then injected 2% propofol (Fresofol®, Fresenius Kabi, Austria) and remifentanil (Ultiva™, GlaxoSmithKline, UK) at target concentrations of 4 µg/ml (Marsh-model) and 5 ng/ml (Minto-model), respectively. After roughly 90 seconds had passed, we checked lid reflexes and found that the patient had lost consciousness. We administered atracurium (0.5 mg/kg), the BIS was 50, and we saw that there was no response to TOF stimulation with the nerve stimulator placed on the ulnar nerve. Endotracheal intubation was then performed without complications. We started mechanical respiration with air (1.5 L/min), oxygen (1.5 L/min), respiratory volume of 450 ml, and respiratory rate of 12 breaths per minute. To control ventilation, the capnogram was kept at 35-40 mmHg. We used spirometry to measure the respiratory volume and pulmonary compliance. We started invasive blood pressure monitoring through the radial artery and measured the esophageal temperature with a body temperature monitor. During the operation, we used a forced-air warming blanket (Bair Hugger™, Austine Medical, USA) to stabilize the patient's body temperature. For fluid maintenance, we administered 0.9% normal saline at 200 ml per hour. During the operation, the patient's vitals were kept stable with blood pressure at 120-140/60-80 mmHg, heart rate 80-100 beats/min, oxygen saturation 100%, body temperature 37.0-37.4℃, and BIS 40-60. Thirty minutes after inducing anesthesia, the arterial blood gas study showed pH 7.44, PaCO 2 32 mmHg, PaO 2 299 mmHg, HCO 3 23.3 mM/L, BE -2.1 mM/L; her electrolytes were Na + 125 mEq/L, K + 3.8 mEq/L, Cl - 88 mEq/L; and her blood sugar was 176 mg/dl. Twenty minutes prior to the end of the operation, we administered ondansetron (4 mg) to prevent post-operative nausea and vomiting. After suturing the peritoneum, we stopped injecting remifentanil, kept the level of propofol in the target effect site at 2 µg/ml, and restored spontaneous breathing. After the operation was over, we stopped injecting propofol and stabilized spontaneous breathing at 300 ml per breath on the spirometer. On the nerve stimulator, the TOF rate was kept at 0.95. To reverse the muscle relaxant effects, we administered glycopyrrolate (0.4 mg) and pyridostigmine (15 mg). Afterwards, the patient responded to voice commands and opened her eyes. With stabilized spontaneous breathing, she was extubated. The operation lasted around 1 hour, and during the operation, 350 ml of 0.9% normal saline were used. We then moved the patient to the recovery room and kept her under observation with blood pressure, electrogram, and oxygen saturation monitors. In the recovery room, we gave her oxygen at 5 L/min through the facial mask. The arterial blood gas study showed pH 7.32, PaCO 2 43 mmHg, PaO 2 219 mmHg, HCO 3 21.2 mM/L, and BE -3.6 mM/L; her electrolyte levels were Na + 128 mEq/L, K + 4.1 mEq/L, and Cl - 90 mEq/L; and her blood sugar level was 120 mg/dl. We then moved the patient to the ward where we performed a lactic acid test, which measured 3.6 mM/L. Three days after the operation, the patient showed no complications from the operation or anesthesia, so she was released from the hospital."}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-19
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-20
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Gastrointestinal-System
|
GI
|
[
"slightly increased levels of serum aspartate aminotransferase,",
"vomiting, and diarrhea",
"increased serum aspartate and alanine aminotransferase levels,"
] |
test-21
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Patient-History
|
History
|
[
"previously healthy girl",
"Two months earlier, the patient 's elder sister had died of acute encephalopathy",
"previously healthy"
] |
test-22
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Neurology
|
Neuro
|
[
"generalized tonic - clonic seizure and mental change, as well as increased rigidity of the extremities",
"generalized tonic - clonic seizure.",
"drowsy and showed decerebrate rigidity, without focal neurologic signs",
"His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained."
] |
test-23
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"symmetric low - density lesions in the thalami and external capsules",
"symmetric T1- and T2 - prolonged areas were present in the thalami and external capsules. T2 * -weighted gradient - echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium - diethylene triamine penta - acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo - acquisition mode sequence ( TR / TE=3000/30, 96 acquisitions, volume of interest=7 mL ) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA.",
"symmetric low - density thalamic lesions",
"symmetric distribution of T1- and T2 - prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2 * -weighted gradient - echo images ( TR / TE = 800/30, flip angle = 20 ° ) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium - diethylene triamine penta - acetic acid, the lesions showed no abnormal enhancement. Diffusion - weighted MR imaging ( b value=1000 sec / mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient ( ADC ) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo - acquisition mode sequence ( TR / TE=3000/30, 96 acquisitions, volume of interest=7 mL ) showed that compared with an age - matched control subject, peak intensities were higher, occurring at 2.0 - 2.5 and 0.8 - 1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid ( CSF ) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid ( DNA ) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA",
"residual atrophic change in the previously observed lesions; both T1- and T2 - weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage. ' }"
] |
test-24
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Cardiovascular-System
|
CVS
|
[] |
test-25
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Endocrinology
|
ENDO
|
[] |
test-26
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Genitourinary-System
|
GU
|
[] |
test-27
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Respiratory-System
|
RESP
|
[
"cough, and rhinorrhea,"
] |
test-28
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Musculoskeletal-System
|
MSK
|
[] |
test-29
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[] |
test-30
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Dermatology
|
DERM
|
[] |
test-31
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Pregnancy
|
Pregnancy
|
[] |
test-32
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Lymphatic-System
|
LYMPH
|
[] |
test-33
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"6 - month - old",
"10 - month - old"
] |
test-34
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Age-of-Onset
|
Age (of onset)
|
[
"6 - month - old",
"10 - month - old"
] |
test-35
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[] |
test-36
|
2698060
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
{'Case 2': "Four days after the development of fever, cough, and rhinorrhea, a 6-month-old, previously healthy girl was admitted with generalized tonic-clonic seizure and mental change, as well as increased rigidity of the extremities. CT images of the brain, obtained at another hospital, depicted symmetric low-density lesions in the thalami and external capsules. Two months earlier, the patient's elder sister had died of acute encephalopathy. Conventional brain MR imaging performed on the second day of hospitalization indicated that symmetric T1- and T2-prolonged areas were present in the thalami and external capsules. T2*-weighted gradient-echo images clearly showed that within the thalamic lesions, acute hemorrhage had occurred. After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement and ADC mapping revealed areas of low signal intensity within them ( Fig. 2A ). Localized proton MR spectroscopy using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed a small doublet at 1.33 ppm ( Fig. 2B ). Laboratory findings indicated slightly increased levels of serum aspartate aminotransferase, lactate, and ammonia, though the lactate level rapidly returned to normal. CSF analysis revealed increased protein content without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for DNA of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA. The patient was thought to be suffering from acute necrotizing encephalopathy, and was treated with mannitol, acyclovir, and steroid. Her mental state improved and on the second day of hospitalization her level of alertness was almost normal. The extremities gradually became less rigid, and follow-up brain MR imaging and MR spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( Fig. 2C ).", 'Case 1': 'Two days after the onset of fever, vomiting, and diarrhea, a 10-month-old previously healthy boy was admitted with generalized tonic-clonic seizure. Brain CT, performed elsewhere, revealed the presence of symmetric low-density thalamic lesions. On admission, he was drowsy and showed decerebrate rigidity, without focal neurologic signs. Conventional brain MR images obtained using a 1.5-T system on the second day of hospitalization depicted symmetric distribution of T1- and T2-prolonged areas in the thalami ( Fig. 1A ), tegmentum of the pons, and periventricular white matter. T2*-weighted gradient-echo images (TR/TE = 800/30, flip angle = 20°) demonstrated low signal intensities within the thalamic lesions, suggesting acute hemorrhage ( Fig. 1B ). After the intravenous administration of gadolinium-diethylene triamine penta-acetic acid, the lesions showed no abnormal enhancement. Diffusion-weighted MR imaging (b value=1000 sec/mm 2 ) demonstrated high signal intensity in all the lesions, though this was absent in the central portion of thalamic lesions, and other than in this same area, apparent diffusion coefficient (ADC) mapping revealed low signal intensity ( Fig. 1C ). Localized proton MR spectroscopy of the thalami using a stimulated echo-acquisition mode sequence (TR/TE=3000/30, 96 acquisitions, volume of interest=7 mL) showed that compared with an age-matched control subject, peak intensities were higher, occurring at 2.0-2.5 and 0.8-1.5 ppm ( Figs. 1D, E ). Laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels, though those of blood ammonium and lactate were normal. Cerebrospinal fluid (CSF) analysis showed slightly increased protein content, without pleocytosis. Polymerase chain reaction analysis of the CSF was negative for deoxynucleic acid (DNA) of herpes simplex virus and enterovirus, and similar analysis of peripheral blood was negative for major mutations in mitochondrial DNA, which would indicate mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome. The patient was treated with acyclovir, an antiviral agent, and steroid. His mental state improved, and on the fourth day of hospitalization he was almost alert. Cognitive functions gradually improved, though severe motor deficits remained. Follow-up brain MR imaging performed three months later revealed residual atrophic change in the previously observed lesions; both T1- and T2-weighted images depicted small areas of high signal intensity at the center of the thalami, indicating residual subacute hemorrhage.'}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-37
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-38
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Gastrointestinal-System
|
GI
|
[] |
test-39
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Patient-History
|
History
|
[
"she died at the age of 84",
"CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy",
"She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis ( Fig. 1 )",
"hypothyroidism",
"family history of bent spine, i.e., in her elder sister ( patient 2, Fig. 1, III-5 ), mother ( Fig. 1, II-3 ), and maternal aunt ( Fig. 1, II-4 )"
] |
test-40
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Neurology
|
Neuro
|
[
"presenting with tremors since the age of 60",
"she started walking with the aid of a walking stick",
"At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness",
"Brain MRI revealed hyperintense lesions around the white matter ( Fig. 2 f );",
"gait disturbance.",
"she started using a walking stick because of her unstable gait",
"gradually became more difficult for her to climb the stairs.",
"right ptosis, dysarthria,",
"eye movements were normal.",
"Tendon reflexes were symmetrical, and Babinski ’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg ’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini - Mental State Examination ( score : 25 points )",
"Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter",
"Brain magnetic resonance imaging ( MRI ) with fluid - attenuated inversion recovery imaging showed moderate cerebellar and temporo - parieto - occipital lobe atrophy ( Fig. 2 d ). MR spectroscopy revealed the absence of increased lactate peaks. 123I - IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions."
] |
test-41
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles ( Fig. 2 e ). Brain MRI revealed hyperintense lesions around the white matter ( Fig. 2 f ); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS ( m.3243A > G ) or MERRF ( m.8344A > G ) mutations",
"Sixty - nine of the 609 Gomori trichrome stained muscle fibers ( 11.3 % ) were ragged - red fibers ( Fig. 3 a ). Cytochrome c oxidase ( COX ) activity was deficient in many of the ragged - blue fibers that were stained with succinate dehydrogenase ( SDH ) and COX ( 233 of 881 muscle fibers, 26.4 % ) ( Fig. 3 b, c ), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase - reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate ( AMP ) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase - reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions ( Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged - red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged - blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions",
"m.602C > T in the tRNA Phe gene and m.16111C > G in the D - loop. The variant m.16111C > G is listed as a polymorphism, but the variant m.602C > T is not reported in either database. The m.602C > T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C > T transition in the muscle homogenate mitochondrial tRNA Phe gene ( Fig. 5 a ). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2 % ( mean ± SD; the operation was performed thrice ). Mutant mitochondrial DNA was not detected in the blood lymphocytes",
"elevated serum CK levels",
"Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows : serum CK level was 290 IU / l ( normal range 45–163 IU / l ), resting blood and cerebrospinal fluid ( CSF ) lactate levels were normal, thyroid - stimulating hormone levels were slightly low at 0.47 μIU / ml ( normal range 0.5–5.0 μIU / ml ). Under the administration of 50 μg / day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U / ml ( normal range < 0.3 U / ml ), antithyroid peroxidase antibody levels were high at 46.5 U / ml ( normal range < 0.3 U / ml ), rheumatoid factor levels were high at 152.3 IU / ml ( normal value < 15.0 IU / ml ), antinuclear antibody levels were mildly elevated ( titer of 1:80 ). Autoimmune analyses, including anti - Jo-1, anti - RNP, anti - SS - A, and anti - SS - B, were negative. The oral glucose tolerance test ( 75 g ) was within normal limits",
"Computed tomography ( CT ) of the thoracic spinal nerve 10 ( T10 ) revealed severe atrophy and fatty degeneration of the paraspinal muscles ( Fig. 2 c ). Brain magnetic resonance imaging ( MRI ) with fluid - attenuated inversion recovery imaging showed moderate cerebellar and temporo - parieto - occipital lobe atrophy ( Fig. 2 d ). MR spectroscopy revealed the absence of increased lactate peaks. 123I - IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions. ',",
"All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20 % ( Table 1 ). BN - PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity ( CI / CS ) CII activity ( CII / CS ) CIII activity ( CIII / CS ) CIV activity ( CIV / CS ) CS activity Patient 1 0.1938 ( 0.7027 ) 0.2723 ( 0.9874 ) 1.2737 ( 4.6192 ) 0.0579 ( 0.21 ) 0.2757 Control 0.3194 ( 1.6183 ) 0.2751 ( 1.3444 ) 1.3132 ( 6.5512 ) 0.0826 ( 0.3840 ) 0.2151 Patient 1 / control ratio 60.7 % ( 43.4 % ) 98.9 % ( 73.4 % ) 97.0 % ( 70.5 % ) 70.1 % ( 54.7 % ) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol / min protein, and represent percentage of normal control ( n = 10 ) mean relative to a reference enzyme of citrate synthase ( CS ) The activities are relatively low in complex I and complex IV compared with other complexes"
] |
test-42
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Cardiovascular-System
|
CVS
|
[
"Holter monitoring revealed high - frequency premature contractions."
] |
test-43
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Endocrinology
|
ENDO
|
[
"She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis ( Fig. 1 ).",
"hypothyroidism",
"thyroid - stimulating hormone levels were slightly low at 0.47 μIU / ml ( normal range 0.5–5.0 μIU / ml ).",
"Under the administration of 50 μg / day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U / ml ( normal range < 0.3 U / ml ), antithyroid peroxidase antibody levels were high at 46.5 U / ml ( normal range < 0.3 U / ml ),",
"The oral glucose tolerance test ( 75 g ) was within normal limits,"
] |
test-44
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
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Genitourinary-System
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GU
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[] |
test-45
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3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Respiratory-System
|
RESP
|
[] |
test-46
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Musculoskeletal-System
|
MSK
|
[
"with a stooping posture",
"she started walking with the aid of a walking stick",
"abnormal posture and gait disturbance",
"slight stooping posture and a pushed - out waist",
"she started using a walking stick because of her unstable gait.",
"gradually became more difficult for her to climb the stairs",
"prominent paraspinal muscle atrophy and mild proximal weakness of limbs",
"marked atrophy of the paraspinal muscles and abnormal posture",
"right ptosis, dysarthria",
"moderate weakness of the neck flexion and mild weakness of the proximal limb muscles",
"pushed - out waist",
"marked atrophy of the paraspinal muscles",
"Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features."
] |
test-47
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[
"bilateral cataracts, and hearing loss",
"eye movements were normal",
"Pure - tone audiometry indicated sensorineural and high - frequency hearing loss."
] |
test-48
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Dermatology
|
DERM
|
[] |
test-49
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Pregnancy
|
Pregnancy
|
[] |
test-50
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Lymphatic-System
|
LYMPH
|
[] |
test-51
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"84 - year - old",
"73 - year - old"
] |
test-52
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Age-of-Onset
|
Age (of onset)
|
[
"age of 60",
"age of 63"
] |
test-53
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[] |
test-54
|
3098999
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
{'Patient 2': 'The elder sister of patient 1 was an 84-year-old woman with a stooping posture presenting with tremors since the age of 60. In her 70s she started walking with the aid of a walking stick. At 82 years of age, she was hospitalized for generalized seizures and disturbed consciousness. CT of T10 revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 e). Brain MRI revealed hyperintense lesions around the white matter (Fig. 2 f); elevated serum and CSF lactate levels were also noted at this time. The mitochondrial DNA analysis of the lymphocytes did not indicate MELAS (m.3243A>G) or MERRF (m.8344A>G) mutations. The patient’s condition remained undiagnosed and she died at the age of 84. CK levels in all her four sons were found to be elevated and her third son was diagnosed with epilepsy. She and her fourth son had also been previously diagnosed with Hashimoto thyroiditis (Fig. 1 ). Patient 1 was examined using pathological, biochemical, and genetic analyses. The Institutional Review Board of Kagoshima University approved this study. Patient 1 gave the written and informed consent for her participation in this study.', 'Histochemical and immunohistochemical studies': 'Frozen biopsies of the biceps brachii muscle specimens were obtained from patient 1. The specimens were sliced into 8 μm sections and placed on aminosilane-coated slides. Histochemical and immunohistochemical procedures were performed as previously described.', 'Histological and immunohistochemical characterizations': 'The muscle fibers ranged from 10 to 80 μm in diameter. Sixty-nine of the 609 Gomori trichrome stained muscle fibers (11.3%) were ragged-red fibers (Fig. 3 a). Cytochrome c oxidase (COX) activity was deficient in many of the ragged-blue fibers that were stained with succinate dehydrogenase (SDH) and COX (233 of 881 muscle fibers, 26.4%) (Fig. 3 b, c), and no blood vessels showing strong SDH reactivity were observed. In NADH dehydrogenase-reactive sections, focal decreases and increases in oxidative enzyme activities were observed. Adenosine monophosphate (AMP) deaminase activity was normal. The random checkerboard distribution of the histochemical fiber types was preserved as shown in the ATPase-reactive sections. Acid phosphatase activity was slightly high in some fibers. Muscle fiber glycogen contents appeared normal and the lipid contents were slightly high in some fibers. Electron microscopy showed abnormal proliferation of mitochondria with paracrystalline inclusions (Fig. 4 ). Fig. 3 Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm Fig. 4 Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm', 'Mitochondrial DNA analysis': 'In case of patient 1, the total DNA was extracted from the peripheral blood leukocytes and the frozen muscle specimens using the DNeasy Blood & Tissue kit (Qiagen). MitoChip v2.0 (The GeneChip ® Human Mitochondrial Resequencing Array 2.0), which provides a standard assay for the complete sequence analysis of human mitochondrial DNA, was obtained from Affymetrix. The patient’s entire mitochondrial DNA was sequenced using MitoChip v2.0 as previously described. Analysis of the microarray data obtained with MitoChip v2.0 was performed using GeneChip Sequence Analysis Software v4.0 (Affymetrix). In order to reveal the mutations that were confirmed by MitoChip v2.0, a 465-base pair PCR product that spanned all of the mutation sites was screened by DNA sequencing. In brief, 50 ng of the patient’s genomic DNA was amplified using the hot-start PCR method and a forward (5′-CACCATTCTCCGTGAAATCA-3′) and reverse primer (5′-AGGCTAAGCGTTTTGAGCTG-3′). Each PCR product was generated under the following conditions: 15 min at 95°C, 42 cycles of amplification (95°C for 30 s, 61°C for 30 s, and 72°C for 1 min), and 30 min at 72°C. Using a presequencing kit (USB, Cleveland, OH, USA), the patient’s PCR products with abnormal elution profiles were purified, and the appropriate PCR products from relatives and control chromosomes were obtained and sequenced by dye-terminator chemistry using an ABI Prism 377 sequencer (Applied Biosystems, Foster City, CA, USA). The resulting sequences were then aligned and any mutations were evaluated using the Sequencher sequence alignment program (Gene Codes, Ann Arbor, MI, USA). The polymorphic and pathogenic natures of the confirmed mutations were checked against two databases: the MITOMAP ( http://www.mitomap.org/ ) and GiiB-JST mtSNP database ( http://mtsnp.tmig.or.jp/mtsnp/index.shtml ). Using MitoChip v2.0, 37 missense variants were detected in the mitochondrial DNA of the peripheral blood lymphocytes. All of these variants show polymorphisms and are listed in the MITOMAP and GiiB-JST mtSNP databases. Two additional missense variants were detected in the mitochondrial DNA of the muscle homogenate; the variants were m.602C>T in the tRNA Phe gene and m.16111C>G in the D-loop. The variant m.16111C>G is listed as a polymorphism, but the variant m.602C>T is not reported in either database. The m.602C>T variant was also confirmed by direct sequencing. The sequence chromatogram showed a heteroplasmic m.602C>T transition in the muscle homogenate mitochondrial tRNA Phe gene (Fig. 5 a). The proportion of mutant mitochondrial DNA in the muscle was 64.7 ± 1.2% (mean ± SD; the operation was performed thrice). Mutant mitochondrial DNA was not detected in the blood lymphocytes when measured using real-time amplification refractory mutation system quantitative PCR analysis (RT-ARMS qPCR), as previously described. Healthy Japanese controls ( n = 100) did not show these mutations in their blood lymphocytes, at least not within the limits of Sanger’s method for DNA sequencing. Fig. 5 a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration ( asterisk ) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes', 'Patient 1': 'A 73-year-old woman (Fig. 1, III-8) presenting with abnormal posture and gait disturbance. Since the age of 63, the patient had a slight stooping posture and a pushed-out waist. At 68 years of age, she started using a walking stick because of her unstable gait. She was diagnosed with hypothyroidism by her family physician and administrated with 25 μg/day levothyroxine; however, her symptoms did not improve. At 70 years of age, it gradually became more difficult for her to climb the stairs. At 71 years of age, she was admitted to another hospital. Doctors suspected myopathy because of elevated serum CK levels. She visited our hospital presenting with prominent paraspinal muscle atrophy and mild proximal weakness of limbs. Hypothyroidism-related myopathy was suspected in her, and hence, the levothyroxine dose was increased to 50 μg/day; however, her symptoms did not improve. She had a family history of bent spine, i.e., in her elder sister (patient 2, Fig. 1, III-5), mother (Fig. 1, II-3), and maternal aunt (Fig. 1, II-4). Physical examination on arrival revealed a marked atrophy of the paraspinal muscles and abnormal posture (Fig. 2 a, b). She also presented with right ptosis, dysarthria, bilateral cataracts, and hearing loss. Her eye movements were normal. But there was moderate weakness of the neck flexion and mild weakness of the proximal limb muscles. Tendon reflexes were symmetrical, and Babinski’s sign was absent. She had poor balance with tandem gait without limb ataxia. Sensory systems were intact and Romberg’s sign was negative. She scored poorly on the attention and calculation tests that are a part of the Mini-Mental State Examination (score: 25 points). Fig. 1 Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols ; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels Fig. 2 a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter Laboratory data were as follows: serum CK level was 290 IU/l (normal range 45–163 IU/l), resting blood and cerebrospinal fluid (CSF) lactate levels were normal, thyroid-stimulating hormone levels were slightly low at 0.47 μIU/ml (normal range 0.5–5.0 μIU/ml). Under the administration of 50 μg/day levothyroxine; antithyroglobulin antibody levels were high at 7.0 U/ml (normal range <0.3 U/ml), antithyroid peroxidase antibody levels were high at 46.5 U/ml (normal range <0.3 U/ml), rheumatoid factor levels were high at 152.3 IU/ml (normal value <15.0 IU/ml), antinuclear antibody levels were mildly elevated (titer of 1:80). Autoimmune analyses, including anti-Jo-1, anti-RNP, anti-SS-A, and anti-SS-B, were negative. The oral glucose tolerance test (75 g) was within normal limits, but Holter monitoring revealed high-frequency premature contractions. Pure-tone audiometry indicated sensorineural and high-frequency hearing loss. Needle electromyographic findings of the biceps brachii and rectus femoris muscles indicated mild myopathic features. Computed tomography (CT) of the thoracic spinal nerve 10 (T10) revealed severe atrophy and fatty degeneration of the paraspinal muscles (Fig. 2 c). Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery imaging showed moderate cerebellar and temporo-parieto-occipital lobe atrophy (Fig. 2 d). MR spectroscopy revealed the absence of increased lactate peaks. 123I-IMP single photon emission CT revealed hypoperfusion that was indicative of atrophic brain lesions.', 'Biochemical studies': 'Enzyme activity levels, blue native polyacrylamide gel electrophoresis (BN-PAGE), and other biochemical measurements of the frozen muscle specimens from patient 1 were performed as previously described. All respiratory chain enzyme activities, which are expressed as a percentage of the normal control values relative to the citrate synthase activity, were greater than 20% (Table 1 ). BN-PAGE revealed no abnormalities in either the respiratory chain complexes or their molecular assembly structures. Table 1 Enzymatic activities for mitochondrial respiratory complexes in patient 1 CI activity (CI/CS) CII activity (CII/CS) CIII activity (CIII/CS) CIV activity (CIV/CS) CS activity Patient 1 0.1938 (0.7027) 0.2723 (0.9874) 1.2737 (4.6192) 0.0579 (0.21) 0.2757 Control 0.3194 (1.6183) 0.2751 (1.3444) 1.3132 (6.5512) 0.0826 (0.3840) 0.2151 Patient 1/control ratio 60.7% (43.4%) 98.9% (73.4%) 97.0% (70.5%) 70.1% (54.7%) Enzymatic activities for individual mitochondrial respiratory complexes are given in nmol/min protein, and represent percentage of normal control ( n = 10) mean relative to a reference enzyme of citrate synthase (CS) The activities are relatively low in complex I and complex IV compared with other complexes CI complex I, CII complex II, CIII complex III, CIV complex IV'}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-55
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-56
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Gastrointestinal-System
|
GI
|
[
"swallowing problems and gastroesophageal reflux"
] |
test-57
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Patient-History
|
History
|
[
"second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks",
"positive family history of minicore myopathy ( his sister died with this condition at age 5 due to aspiration )",
"The parents were heterozygous carriers ( Wortmann et al. 2009 )"
] |
test-58
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Neurology
|
Neuro
|
[
"congenital hypotonia, low facial expression, and inverted feet.",
"facies myopathica",
"the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees"
] |
test-59
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"chronic lactic acidemia ( lactate 2.3–4 mmol / l, C : < 2.1 mmol / l ), 3 - methylglutaconic aciduria ( 80 μmol / l, C : < 18 μmol / mmol creatinine ), and recurrent hypoglycemic episodes. Serum alanine levels ( 610 μmol / l, C : < 450 μmol / l ) and creatine kinase ( CK ) levels ( 500–800 U / l, C : 180 U / l ) were moderately increased",
"The biopsy results showed the characteristic picture of central core disease : electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction ( Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear - coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA ( cDNA ) was found.",
"Biochemistry ATP production nmol / h / mUCS ( N 42–81 ) 4 Complex I mU / UCS ( N 70–251 ) 58 Complex II mU / UCS ( N 335–749 ) 312 Complex III mU / UCS ( N 2200–6610 ) 725 Complex IV mU / UCS ( N 810–3120 ) 483 Complex deficiencies I, II, III, IV",
"Genetics Paternal mutation p. His581GlnfsX29 ( exon 16 ) Maternal mutation p. Val14849Ile ( exon 101 )"
] |
test-60
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Cardiovascular-System
|
CVS
|
[] |
test-61
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Endocrinology
|
ENDO
|
[
"recurrent hypoglycemic episodes."
] |
test-62
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Genitourinary-System
|
GU
|
[] |
test-63
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Respiratory-System
|
RESP
|
[] |
test-64
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Musculoskeletal-System
|
MSK
|
[
"congenital hypotonia, low facial expression, and inverted feet.",
"swallowing problems",
"hyperlaxity with arachnodactyly",
"initial histological findings suggested a possible multi / minicore disease",
"creatine kinase ( CK ) levels ( 500–800 U / l, C : 180 U / l ) were moderately increased",
"No motor development was observed with regular physiotherapy",
"The biopsy results showed the characteristic picture of central core disease : electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction ( Table 1 ).",
"At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures",
"bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees",
"He had no extraocular muscle anomalies and no exercise - induced myalgia"
] |
test-65
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[
"low - set ears, hypermetropia"
] |
test-66
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Dermatology
|
DERM
|
[
"Dysmorphic features included brachyturricephaly, facies myopathica"
] |
test-67
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Pregnancy
|
Pregnancy
|
[
"born after an uneventful pregnancy of 42 weeks"
] |
test-68
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Lymphatic-System
|
LYMPH
|
[] |
test-69
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"At birth"
] |
test-70
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Age-of-Onset
|
Age (of onset)
|
[] |
test-71
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"RYR1"
] |
test-72
|
3757256
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
{'Patient': 'The patient was the second child of nonconsanguineous parents who was born after an uneventful pregnancy of 42 weeks. At birth, early findings comprised congenital hypotonia, low facial expression, and inverted feet. He was diagnosed with swallowing problems and gastroesophageal reflux. Dysmorphic features included brachyturricephaly, low-set ears, hypermetropia, facies myopathica, and hyperlaxity with arachnodactyly. Due to positive family history of minicore myopathy (his sister died with this condition at age 5 due to aspiration), an early muscle biopsy was performed. The initial histological findings suggested a possible multi/minicore disease. The patient developed chronic lactic acidemia (lactate 2.3–4 mmol/l, C: <2.1 mmol/l), 3-methylglutaconic aciduria (80 μmol/l, C: <18 μmol/mmol creatinine), and recurrent hypoglycemic episodes. Serum alanine levels (610 μmol/l, C: <450 μmol/l) and creatine kinase (CK) levels (500–800 U/l, C: 180 U/l) were moderately increased. No motor development was observed with regular physiotherapy; for further clarification of the diagnosis, a second muscle biopsy was performed at the age of 6 years. The biopsy results showed the characteristic picture of central core disease: electron microscopy detected abnormal, large mitochondria with crystalline inclusions and biochemical evidence of severe mitochondrial dysfunction (Table 1 ). Genetic studies including mitochondrial DNA sequencing, sequencing of the nuclear-coded structural complexes I and III genes, and POLG mutation analysis were all normal. A compound heterozygous RYR1 mutation in complementary DNA (cDNA) was found. The parents were heterozygous carriers (Wortmann et al. 2009 ). At age 9 years, while receiving regular physiotherapy, the boy could not sit up, raise his arms above the level of the hips, hold a pen, or stand due to his severe, generalized muscle weakness and contractures. Further physical signs were bilateral ptosis, facies myopathica with open mouth, and kyphoscoliosis in addition to joint contractures, presenting foremost in his hips and knees. He had no extraocular muscle anomalies and no exercise-induced myalgia. Table 1 Abnormal biochemical and genetic features Analyses performed Results Biochemistry ATP production nmol/h/mUCS (N 42–81) 4 Complex I mU/UCS (N 70–251) 58 Complex II mU/UCS (N 335–749) 312 Complex III mU/UCS (N 2200–6610) 725 Complex IV mU/UCS (N 810–3120) 483 Complex deficiencies I, II, III, IV Genetics Paternal mutation p. His581GlnfsX29 (exon 16) Maternal mutation p.Val14849Ile (exon 101) ATP adenosine triphosphate, UC unconditioned stimulus, N normal'}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-73
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[] |
test-74
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Gastrointestinal-System
|
GI
|
[] |
test-75
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Patient-History
|
History
|
[
"The patient 's mother ( II-2 ) and uncle ( II-3 ) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient 's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F - H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F - H ). We were unable to confirm the detailed clinical information of the proband 's grandmother ( I-2 ). \""
] |
test-76
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Neurology
|
Neuro
|
[
"gait disturbances",
"horizontal gaze palsy, gaze - evoked nystagmus, dysarthria, and cerebellar ataxia",
"Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus",
"severe dizziness and double vision",
"gait disturbances",
"mild disturbance of cognitive function ( Revised Wechsler Adult Intelligence Scale : total IQ=73, performance IQ=58, verbal IQ=91 )",
"Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze - evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system.",
"Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ),",
"brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1 - weighted imaging, and high signal intensities on T2 - weighted imaging, suggesting degeneration ( Fig. 2C and D )."
] |
test-77
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus",
"Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations.",
"Blood and cerebrospinal fluid analyses were normal",
"Ergometer exercise did not up - regulate his serum lactate and pyruvate",
"Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1 - weighted imaging, and high signal intensities on T2 - weighted imaging, suggesting degeneration ( Fig. 2C and D ).",
"The G11778A and T3394C mutations were identified, while the A3243 G mutation was not detected.",
"Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr - to - His amino acid substitution in ND1. PCR - RFLP data revealed that the T3394C mutation present in both the proband ( III-1 ) and his mother ( II-2 ) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg - to - His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR - RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92 % heteroplasmic G11778A mutation, and II-2 had a 70 % heteroplasmic G11778A mutation ( Fig. 4C )."
] |
test-78
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Cardiovascular-System
|
CVS
|
[] |
test-79
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Endocrinology
|
ENDO
|
[] |
test-80
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Genitourinary-System
|
GU
|
[] |
test-81
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Respiratory-System
|
RESP
|
[] |
test-82
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Musculoskeletal-System
|
MSK
|
[] |
test-83
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Eyes-Ears-Nose-Throat
|
EENT
|
[
"visual and gait disturbances",
"horizontal gaze palsy, gaze - evoked nystagmus",
"atrophy of the optic nerve",
"severe dizziness and double vision",
"visual and gait disturbances",
"bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze - evoked nystagmus",
"The light reflex was prompt.",
"atrophy of the optic nerve",
"no pigmentation changes of the retina",
"Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ),"
] |
test-84
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Dermatology
|
DERM
|
[] |
test-85
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Pregnancy
|
Pregnancy
|
[] |
test-86
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Lymphatic-System
|
LYMPH
|
[] |
test-87
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Age-at-Presentation
|
Age (at case presentation)
|
[
"37 - year - old"
] |
test-88
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Age-of-Onset
|
Age (of onset)
|
[
"10 years of age"
] |
test-89
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
Confirmed-Diagnosis-IEM
|
Confirmed_Diagnosis(IEM)
|
[
"LHON plus olivocerebellar degeneration"
] |
test-90
|
3469805
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
{'Case Report': "The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. The proband (III-1) ( Fig. 1 ) was a 37-year-old man with severe dizziness and double vision. He had first experienced visual and gait disturbances at 10 years of age. The neurological examination performed on admission revealed mild disturbance of cognitive function (Revised Wechsler Adult Intelligence Scale: total IQ=73, performance IQ=58, verbal IQ=91). Neurological disturbances were observed including bilateral exotropia, double vision, incomplete horizontal movement of the eyes to the bilateral side, horizontal, and vertical gaze-evoked nystagmus, and dysarthria. The light reflex was prompt. No disturbances in cranial nerves I, VII, VIII, and XII were detected. Tremor appeared in his neck, but other involuntary movements including palatal myoclonus were not observed. While his upper and lower limbs showed no paralysis, they exhibited severe cerebellar ataxia and hypotonia. No abnormal findings were detected in his deep tendon reflex and sensory system. Ophthalmological examination revealed atrophy of the optic nerve, but there were no pigmentation changes of the retina. Blood and cerebrospinal fluid analyses were normal. Ergometer exercise did not up-regulate his serum lactate and pyruvate. Orbital MRI revealed atrophy of the optic nerve ( Fig. 2A ), and brain MRI disclosed severe atrophy of the cerebellum and mild atrophy of the brain stem ( Fig. 2B ). The bilateral inferior olivary nucleus exhibited low signal intensities on T1-weighted imaging, and high signal intensities on T2-weighted imaging, suggesting degeneration ( Fig. 2C and D ). The patient was diagnosed as having LHON plus olivocerebellar degeneration. Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness. The patient's mother (II-2) and uncle (II-3) also had optic neuropathy, but other neurological abnormalities such as ataxia and dystonia were not observed. The patient's mother has a history of subarachnoid hemorrhage. MRI of his mother disclosed mild atrophy of the optic nerve ( Fig. 2E ), pons, and cerebellum ( Fig. 2F-H ). No signal changes were observed in the inferior olivary nucleus ( Fig. 2F-H ). We were unable to confirm the detailed clinical information of the proband's grandmother (I-2).", 'Mutation analyses of mtDNA': "Blood samples were obtained from the patient and his mother with their informed consent, and the methods used were approved by the institutional review board of Tottori University Hospital. Both mtDNA and genomic DNA were extracted by standard procedures. The polymerase chain reaction (PCR) was carried out using the primers 5'-CCTCCCTACTATGCCTAGAAGGA-3' and 5'-TTTGGGTTGTGGCTCAGTGT-3' for ND4, including 11778G analysis, and 5'-AGTTCAGACCGGAGTAATCCAG-3' and 5'-AGGGTTGTAGTAGCCCGTAG-3' for ND1 . The primer set for ND4 was designed to identify G11778A mutations, which is the main mutation for LHON. The primer set for ND1 was designed to detect not only the T3394C mutation as a minor mutation for LHON but also an A3243G mutation that is frequently detected in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. PCR products that included the previously reported candidate abnormal points were analyzed by capillary electrophoresis using an automated DNA sequencer. The G11778A and T3394C mutations were identified, while the A3243G mutation was not detected. The mutations in the mtDNA were confirmed by performing PCR-restriction fragment length polymorphism (RFLP), in which the PCR products were digested using either HaeIII (for T3394C) or Tsp45I (for G11778A). In order to quantify the heteroplasmic mutation of G117 78A, we prepared vector constructs including 11778G or 11 778A, and semiquantitative analyses of G11778A were performed using a mixture of each with several rate standards (described in Fig. 4 ). Sequence analysis revealed the homoplasmic T3394C mutation of the mtDNA ( Fig. 3A ). This mutation causes a Tyr-to-His amino acid substitution in ND1. PCR-RFLP data revealed that the T3394C mutation present in both the proband (III-1) and his mother (II-2) was homoplasmic; differences between the patient and his mother were not observed for this mutation ( Fig. 3B ). The G11778A mutation, which causes an Arg-to-His amino acid substitution in ND4, was also observed ( Fig. 4A ). PCR-RFLP data showed that this mutation in the patient and his mother was heteroplasmic ( Fig. 4B ). The semiquantitative analysis performed to determine the effect of this mutation on disease severity revealed that III-1 had a 92% heteroplasmic G11778A mutation, and II-2 had a 70% heteroplasmic G11778A mutation ( Fig. 4C ). Established genetic abnormalities associated with cerebellar ataxia including polyglutamine diseases were not found."}
|
IEM-Treatment
|
IEM_Treatment
|
[] |
test-91
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Vitals-and-Hematology
|
Vitals_Hema
|
[
"162 centimeters tall and 30 kilograms in weight.",
"Her vital signs were stable"
] |
test-92
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Gastrointestinal-System
|
GI
|
[] |
test-93
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Patient-History
|
History
|
[
"no family history of neurological diseases",
"Motor and intellectual development was normally attained during infancy.",
"hospitalized for general muscle weakness and gait disturbance when she was 6 years old.",
"24 years old she had sudden syncope",
"when the patient was 26, she had another stroke"
] |
test-94
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Neurology
|
Neuro
|
[
"left hemiplegia and aphasia",
"Motor and intellectual development was normally attained during infancy",
"general muscle weakness and gait disturbance",
"decreased muscle tone and strength, and atrophic muscle mass",
"sudden syncope",
"An magnetic resonance imaging ( MRI ) revealed acute infarction of the left basal ganglia and the left frontal lobe.",
"another stroke and presented with general weakness, aphagia, and dysarthria",
"An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia.",
"presented with another stroke with associated left sided weakness",
"An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ).",
"The patient 's mental status and general condition improved"
] |
test-95
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Laboratory-and-Imaging
|
Lab_Image
|
[
"The biopsy showed mitochondrial myopathy of the pleoconial type",
"Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems.",
"An magnetic resonance imaging ( MRI ) revealed acute infarction of the left basal ganglia and the left frontal lobe",
"An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia",
"The plasma lactate level was 21.8 mg / dL ( normal range 4.5 - 19.8 mg / dL ). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng / dL ( normal range 0.89 - 1.76 ng / dL ) and TSH was 0.04 µIU / mL. Levels of complement component 3 and 4 were 13 mg / dL ( normal range 75 - 145 mg / dL ) and 18 mg / dL ( normal range 12 - 72 mg / dL ) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti - double stranded DNA was 1.6 ( normal range 0 - 6 ). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation : m.3303C > T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome.",
"no specific findings in chest X - rays",
"Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25 %. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 )."
] |
test-96
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Cardiovascular-System
|
CVS
|
[
"Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems.",
"no specific findings in chest X - rays or electrocardiography",
"An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ).",
"An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25 %. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 )."
] |
test-97
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Endocrinology
|
ENDO
|
[] |
test-98
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Genitourinary-System
|
GU
|
[] |
test-99
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Respiratory-System
|
RESP
|
[] |
test-100
|
3629250
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
{'Case': "A 27-year-old female was admitted to the hospital because of left hemiplegia and aphasia. She was 162 centimeters tall and 30 kilograms in weight. She was born after a normal pregnancy and delivery. There was no family history of neurological diseases. Motor and intellectual development was normally attained during infancy. She was hospitalized for general muscle weakness and gait disturbance when she was 6 years old. A neurologic exam showed decreased muscle tone and strength, and atrophic muscle mass. She had consistent muscle weakness, so a muscle biopsy was performed from the calf muscle when she was 8 years old. The biopsy showed mitochondrial myopathy of the pleoconial type. Her first echocardiography was completed afterwards and showed marked hypertrophy of both ventricles without any regional wall problems. Follow-up procedures were performed in an outpatient clinic once or twice a year. When she was 24 years old she had sudden syncope. An magnetic resonance imaging (MRI) revealed acute infarction of the left basal ganglia and the left frontal lobe. Two years later, when the patient was 26, she had another stroke and presented with general weakness, aphagia, and dysarthria. An MRI showed old multifocal infarctions at the basal ganglia, thalamus, left pons and left periventricular white matter area. An MR spectroscopy showed a positive lactate peak in both basal ganglia. These clinical and radiological findings suggested brain involvement of MELAS syndrome. Thus, further evaluation was done for MELAS syndrome including blood lactate and genetic analysis. The plasma lactate level was 21.8 mg/dL (normal range 4.5-19.8 mg/dL). CBC, electrolyte, blood urea nitrogen, and creatinine were in the normal range. Thyroid function was also measured. The free T4 was 1.76 ng/dL (normal range 0.89-1.76 ng/dL) and TSH was 0.04 µIU/mL. Levels of complement component 3 and 4 were 13 mg/dL (normal range 75-145 mg/dL) and 18 mg/dL (normal range 12-72 mg/dL) respectively. Antistreptolysin O antibody was negative, rheumatoid factor was negative, and anti-double stranded DNA was 1.6 (normal range 0-6). Lupus anticoagulants and anti cytoplasmic antibody, which were measured to rule out vasculitis, were normal. A DNA gene sequencing study showed a mutation: m.3303C>T mutation in the mitochondrially encoded tRNA leucine 1 gene, which confirmed the diagnosis of MELAS syndrome. She was treated with supportive care and rehabilitation for a month and was then discharged. Warfarin was used during the hospital stay, but was stopped when she was discharged, because MELAS syndrome causes nonvascular infarct and there is no report about the related risk of thromboembolism. One year later, she presented with another stroke with associated left sided weakness, and was subsequently admitted to the hospital. Her vital signs were stable and there were no specific findings in chest X-rays or electrocardiography. Her MRI revealed infarction in the right middle cerebral territory ( Fig. 1 ). An magnetic resonance angiography showed an occluded right distal internal carotid artery and right middle cerebral artery ( Fig. 2 ). An echocardiography was performed to identify the cardiac origin of the ischemic stroke, and it showed concentrically hypertrophied left ventricle with globally hypokinetic wall motion and ejection fraction of 25%. An intracardiac thrombus attached to the left ventricular apex was noted ( Fig. 3 ). The patient's mental status and general condition improved after she was treated with mannitol and anticoagulation therapy. Rehabilitation and supportive care, including warfarin, were followed and maintained. The patient was discharged after a month."}
|
Musculoskeletal-System
|
MSK
|
[
"general muscle weakness and gait disturbance",
"decreased muscle tone and strength, and atrophic muscle mass.",
"consistent muscle weakness",
"mitochondrial myopathy of the pleoconial type"
] |
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