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pmcid
string | text
string | Vitals_Hema
sequence | GI
sequence | History
sequence | Neuro
sequence | Lab_Image
sequence | CVS
sequence | ENDO
sequence | GU
sequence | RESP
sequence | MSK
sequence | EENT
sequence | DERM
sequence | Pregnancy
sequence | LYMPH
sequence | Age (at case presentation)
sequence | Age (of onset)
sequence | Confirmed_Diagnosis(IEM)
sequence | IEM_Treatment
sequence |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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."} | [
"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 ℃"
] | [
"acute appendicitis",
"nausea, and vomiting"
] | [
"laparoscopic appendectomy",
"no abnormalities in her pediatric medical history",
"Type I DM"
] | [
"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"
] | [
"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."
] | [
"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."
] | [
"Type I DM.",
"hyperglycemia ( 257 mg / dl ),",
"her blood sugar was 176 mg / dl.",
"her blood sugar level was 120 mg / dl."
] | [] | [] | [] | [] | [] | [] | [] | [
"23 year - old"
] | [
"age 18"
] | [
"MELAS syndrome"
] | [] |
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.'} | [] | [
"slightly increased levels of serum aspartate aminotransferase,",
"vomiting, and diarrhea",
"increased serum aspartate and alanine aminotransferase levels,"
] | [
"previously healthy girl",
"Two months earlier, the patient 's elder sister had died of acute encephalopathy",
"previously healthy"
] | [
"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."
] | [
"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. ' }"
] | [] | [] | [] | [
"cough, and rhinorrhea,"
] | [] | [] | [] | [] | [] | [
"6 - month - old",
"10 - month - old"
] | [
"6 - month - old",
"10 - month - old"
] | [] | [] |
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'} | [] | [] | [
"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 )"
] | [
"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."
] | [
"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"
] | [
"Holter monitoring revealed high - frequency premature contractions."
] | [
"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,"
] | [] | [] | [
"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."
] | [
"bilateral cataracts, and hearing loss",
"eye movements were normal",
"Pure - tone audiometry indicated sensorineural and high - frequency hearing loss."
] | [] | [] | [] | [
"84 - year - old",
"73 - year - old"
] | [
"age of 60",
"age of 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'} | [] | [
"swallowing problems and gastroesophageal reflux"
] | [
"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 )"
] | [
"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"
] | [
"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 )"
] | [] | [
"recurrent hypoglycemic episodes."
] | [] | [] | [
"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"
] | [
"low - set ears, hypermetropia"
] | [
"Dysmorphic features included brachyturricephaly, facies myopathica"
] | [
"born after an uneventful pregnancy of 42 weeks"
] | [] | [
"At birth"
] | [] | [
"RYR1"
] | [] |
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."} | [] | [] | [
"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 ). \""
] | [
"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 )."
] | [
"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 )."
] | [] | [] | [] | [] | [] | [
"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 ),"
] | [] | [] | [] | [
"37 - year - old"
] | [
"10 years of age"
] | [
"LHON plus olivocerebellar degeneration"
] | [] |
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."} | [
"162 centimeters tall and 30 kilograms in weight.",
"Her vital signs were stable"
] | [] | [
"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"
] | [
"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"
] | [
"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 )."
] | [
"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 )."
] | [] | [] | [] | [
"general muscle weakness and gait disturbance",
"decreased muscle tone and strength, and atrophic muscle mass.",
"consistent muscle weakness",
"mitochondrial myopathy of the pleoconial type"
] | [] | [] | [
"She was born after a normal pregnancy and delivery."
] | [] | [
"27 - year - old"
] | [] | [
"MELAS syndrome"
] | [] |
3242024 | {'Case': "A 21-year-old woman was admitted to the hospital for a seizure-like episode lasting for approximately five minutes and subsiding spontaneously. The patient had frequent and insidious onset of seizure-like episodes, dysarthria, gait disturbance and a right-sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia. The patient initially presented with blood pressure of 111/59 mm Hg, pulse rate of 109 beats/min, respiratory rate of 20/min, and body temperature of 36.0℃. Laboratory results were raised cerebrospinal fluid (CSF) lactate of 5.2 mmol/L. Electroencephalography (EEG) showed diffuse cerebral dysfunction. Electromyography revealed sensorimotor polyneuropathy and chronic myopathy. Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ). Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria ( Fig. 2 ). Based on these clinical findings, the patient was diagnosed with MELAS syndrome. Ten years later, she went to a dentist for treatment of dental caries. Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly and she was urgently transferred to the emergency room of our institution. On arrival, she was stuporous with blood pressure of 209/147 mm Hg, pulse rate of 140 beats/min, respiratory rate of 25/min, and body temperature of 36.5℃. At that time, her electrocardiography (ECG) showed supraventricular tachycardia. After intravenous injections of 300 mg amiodarone, she recovered consciousness, and follow-up ECG showed sinus rhythm with pre-excitation ( Fig. 3 ). Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity (E' velocity) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy. Considering her bedridden status due to underlying MELAS syndrome, medical treatment with propafenone was started. The patient was discharged and has been followed up without tachycardia attack."} | [
"blood pressure of 111/59 mm Hg, pulse rate of 109 beats / min, respiratory rate of 20 / min, and body temperature of 36.0 ℃.",
"blood pressure of 209/147 mm Hg, pulse rate of 140 beats / min, respiratory rate of 25 / min, and body temperature of 36.5 ℃"
] | [] | [
"frequent and insidious onset of seizure - like episodes, dysarthria, gait disturbance and a right - sided visual field defect that had started four years ago without any history of essential hypertension, diabetes mellitus and dyslipidemia."
] | [
"seizure - like episode lasting for approximately five minutes and subsiding spontaneously",
"frequent and insidious onset of seizure - like episodes, dysarthria, gait disturbance and a right - sided visual field defect that had started four years ago",
"Laboratory results were raised cerebrospinal fluid ( CSF ) lactate of 5.2 mmol / L.",
"Electroencephalography ( EEG ) showed diffuse cerebral dysfunction",
"Electromyography revealed sensorimotor polyneuropathy and chronic myopathy",
"Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ).",
"Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria",
"Five minutes after local anesthesia with lidocaine, her consciousness changed suddenly",
"stuporous",
"recovered consciousness"
] | [
"Laboratory results were raised cerebrospinal fluid ( CSF ) lactate of 5.2 mmol / L.",
"Brain MRI showed infarction in the right temporal lobe, ischemia in the left posterior frontoparietal cortex and basal ganglia, and cystic lesion in the pineal gland with brainstem and cerebellar atrophy ( Fig. 1 ).",
"Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity ( E ' velocity ) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy"
] | [
"electrocardiography ( ECG ) showed supraventricular tachycardia",
"follow - up ECG showed sinus rhythm with pre - excitation",
"Transthoracic echocardiography revealed decreased early diastolic mitral annulus velocity ( E ' velocity ) and abnormal myocardial texture which were possibly associated with the initial phase of restrictive cardiomyopathy",
"followed up without tachycardia attack."
] | [] | [] | [] | [
"Electromyography revealed sensorimotor polyneuropathy and chronic myopathy",
"Biopsy of left vastus lateralis showed neurogenic atrophy and slightly increased lipid vacuoles without paracrystalline inclusion in the mitochondria"
] | [] | [] | [] | [] | [
"21 - year - old"
] | [] | [
"MELAS syndrome"
] | [] |
4750557 | {'Case report': 'SH is a 44-year-old female diagnosed with mitochondrial myopathy, encephalopathy and stroke-like episodes (MELAS) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure. After her diagnosis was made, she was initially followed by Neurology; however she was subsequently referred to our cardiomyopathy clinic secondary to progressive left ventricular hypertrophy (LVH) on echocardiogram and the known association between MELAS and cardiac disease. Prior to evaluation by our clinic, she had a clinical diagnosis of MELAS but evaluation by our cardiovascular genetics team yielded positive results for the A-to-G transition at nucleotide 3243 (m.3243A > G) of the mitochondrial genome, with 25% heteroplasmic deleterious mutation in MT-TL1, a mitochondrial leucine transfer RNA gene, the most common mutation underlying MELAS. At the time of presentation to our clinic, SH had carried the diagnosis of MELAS for 11 years and her symptoms had progressed significantly so that she was no longer able to be employed and her husband became her primary caretaker. Her clinical status included multiple medical problems related to her MELAS diagnosis: sensorineural hearing loss, myopathy, bilateral ophthalmoplegia, ptosis, seizures and stroke-like episodes with concern for dementia. Her family history is significant for a 12-year-old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss. In addition to a clinical exam and genetic evaluation, cardiac work-up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non-sustained atrial tachycardia ( Fig. 1 ). From a cardiac imaging perspective, an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub-epicardium of approximately 25–50% in thickness in the inferior segment at the base, inferior to lateral segments at the mid-ventricle and lateral segment of the apex, with sparing of the endocardium and septum ( Fig. 1 A and 1 B). Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes (R > L), and moderate cerebellar atrophy with extensive white matter disease. Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 (normal < 200 ng/L). Her liver and kidney functions were normal and there was no hyperglycemia. From a cardiac management perspective, she has been maintained on Atenolol 25 mg twice daily and aspirin 325 mg once daily.'} | [] | [] | [
"diagnosed with mitochondrial myopathy, encephalopathy and stroke - like episodes ( MELAS ) at age 32 after suffering a fall at her job that was thought to be secondary to a seizure.",
"Her family history is significant for a 12 - year - old daughter who is currently asymptomatic and a sister who also carries the diagnosis of MELAS but is less severely affected with symptoms mainly of diabetes mellitus and hearing loss"
] | [
"a fall at her job that was thought to be secondary to a seizure",
"she was no longer able to be employed and her husband became her primary caretaker",
"sensorineural hearing loss",
"bilateral ophthalmoplegia, ptosis, seizures and stroke - like episodes with concern for dementia",
"Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes ( R > L ), and moderate cerebellar atrophy with extensive white matter disease."
] | [
"positive results for the A - to - G transition at nucleotide 3243 ( m.3243A > G ) of the mitochondrial genome, with 25 % heteroplasmic deleterious mutation in MT - TL1, a mitochondrial leucine transfer RNA gene",
"an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub - epicardium of approximately 25–50 % in thickness in the inferior segment at the base, inferior to lateral segments at the mid - ventricle and lateral segment of the apex, with sparing of the endocardium and septum",
"Her brain MRI demonstrated extensive cerebral atrophy especially involving the temporal lobes ( R > L ), and moderate cerebellar atrophy with extensive white matter disease",
"Monitoring laboratory evaluation yielded no significant abnormalities with the exception of a slightly elevated brain natriuretic peptide of 305 ( normal < 200 ng / L ). Her liver and kidney functions were normal and there was no hyperglycemia."
] | [
"progressive left ventricular hypertrophy ( LVH ) on echocardiogram",
"cardiac work - up included an EKG which showed sinus rhythm with frequent normally conducted premature atrial contractions and a Holter monitor that demonstrated episodes of non - sustained atrial tachycardia",
"an echocardiogram demonstrated symmetric left ventricular hypertrophy with normal ventricular systolic function, and her cardiac MRI showed extensive positive late gadolinium enhancement in the sub - epicardium of approximately 25–50 % in thickness in the inferior segment at the base, inferior to lateral segments at the mid - ventricle and lateral segment of the apex, with sparing of the endocardium and septum",
"slightly elevated brain natriuretic peptide of 305 ( normal < 200 ng / L )."
] | [
"no hyperglycemia."
] | [] | [] | [
"myopathy",
"bilateral ophthalmoplegia, ptosis"
] | [
"sensorineural hearing loss,",
"bilateral ophthalmoplegia, ptosis,"
] | [] | [] | [] | [
"44 - year - old"
] | [
"age 32"
] | [
"mitochondrial myopathy , encephalopathy and stroke - like episodes ( MELAS )"
] | [] |
4369985 | {'CASE REPORT': "In 1986, a previously healthy 18-year-old male presented to our hospital with a 1-week history of fever, headache and vomiting. Meningism, but no focal neurological signs, was noted on examination. Lumbar puncture was performed, revealing slight elevation of protein in the cerebrospinal fluid (CSF) but no increased cell count. Over the next few days, right-sided weakness developed. Electroencephalogram demonstrated left parieto-occipital focal slowing. Results of T1/T2-weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area. The patient was commenced on acyclovir, but herpes serology came back negative. When generalized tonic-clonic seizures ensued, anticonvulsant therapy with carbamazepine was established. The patient was finally discharged with a provisional diagnosis of viral encephalitis, although no causative agent was found. No residual neurological deficits persisted. In 1989, hearing impairment was first documented and ascribed to the previous encephalitis. The following years saw recurrent admissions for seizures, and sodium valproate was added. The patient's functional status deteriorated progressively. In 1999, he was diagnosed with diabetes mellitus, requiring insulin straightaway. The patient's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness (MIDD). The 3243A>G mutation in the MT-TL1 gene of the mitochondrial DNA (mtDNA) was subsequently demonstrated in blood leucocytes, confirming the diagnosis. When her brother was admitted in October 2011 for anorexia, we re-evaluated his past medical notes. In the initial CSF analysis, no lactate levels had been checked. Electrocardiogram showed Wolff–Parkinson–White syndrome. Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy. CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto-occipital hypodensity, likely representing a previous stroke-like event (Fig. 1 ). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was deemed a likely explanation for his multi-systemic disease and was confirmed by demonstration of the 3243A>G transition in blood and urine. The heteroplasmy rate (the mixture of normal and mutated mitochondrial DNA) was 50 and 90%, respectively. Anticonvulsant therapy was switched to levetiracetam and treatment with coenzyme Q 10 was started. The patient now lives in a nursing home. Follow-up at our unit has been arranged. Figure 1: Cerebral computed tomography of a 40-year-old man showing generalized cerebral atrophy, bilateral basal ganglia calcification (asterisks) and a left parieto-occipital hypodensity (arrow)."} | [] | [
"vomiting.",
"anorexia"
] | [
"previously healthy",
"generalized tonic - clonic seizures",
"In 1989, hearing impairment was first documented and ascribed to the previous encephalitis",
"recurrent admissions for seizures,",
"In 1999, he was diagnosed with diabetes mellitus",
"The patient 's sister was admitted to our department in October 2010 with gross oedema of the legs. Her medical history included diabetes and sensorineural deafness. Advanced renal impairment was noted. In view of her phenotype, we suspected maternally inherited diabetes and deafness ( MIDD ). The 3243A > G mutation in the MT - TL1 gene of the mitochondrial DNA ( mtDNA ) was subsequently demonstrated in blood leucocytes, confirming the diagnosis",
"The patient now lives in a nursing home"
] | [
"headache",
"Meningism, but no focal neurological signs, was noted on examination",
"slight elevation of protein in the cerebrospinal fluid ( CSF ) but no increased cell count",
"right - sided weakness developed",
"Electroencephalogram demonstrated left parieto - occipital focal slowing",
"Results of T1 / T2 - weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area",
"generalized tonic - clonic seizures",
"No residual neurological deficits persisted",
"recurrent admissions for seizures",
"patient 's functional status deteriorated progressively",
"In the initial CSF analysis, no lactate levels had been checked.",
"CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto - occipital hypodensity, likely representing a previous stroke - like event",
"Cerebral computed tomography of a 40 - year - old man showing generalized cerebral atrophy, bilateral basal ganglia calcification ( asterisks ) and a left parieto - occipital hypodensity ( arrow )"
] | [
"slight elevation of protein in the cerebrospinal fluid ( CSF ) but no increased cell count",
"Results of T1 / T2 - weighted brain magnetic resonance imaging were reported to be in keeping with an inflammatory process in the left occipital area.",
"herpes serology came back negative",
"In the initial CSF analysis, no lactate levels had been checked",
"CT scan of the brain showed diffuse cerebral atrophy, bilateral basal ganglia calcification and a left parieto - occipital hypodensity, likely representing a previous stroke - like event",
"demonstration of the 3243A > G transition in blood and urine. The heteroplasmy rate ( the mixture of normal and mutated mitochondrial DNA ) was 50 and 90 %, respectively",
"Cerebral computed tomography of a 40 - year - old man showing generalized cerebral atrophy, bilateral basal ganglia calcification ( asterisks ) and a left parieto - occipital hypodensity ( arrow"
] | [
"Electrocardiogram showed Wolff – Parkinson – White syndrome"
] | [
"diagnosed with diabetes mellitus, requiring insulin straightaway."
] | [] | [] | [] | [
"hearing impairment",
"Macular dystrophy, but no signs of diabetic retinopathy, was found on fundoscopy"
] | [] | [] | [] | [
"18 - year - old"
] | [
"18 - year - old"
] | [
"Mitochondrial encephalopathy with lactic acidosis and stroke - like episodes ( MELAS )"
] | [
"treatment with coenzyme Q 10 was started"
] |
4776051 | {'CASE REPORT': 'A 17-year-old Venezuelan male with a 5-year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup (Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non-significant. On examination, he had a short stature one standard below the mean with a BMI within normal limits. Ophthalmologic examination revealed bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism. On funduscopic examination, bilateral atypical pigmentary retinopathy was seen (Fig. 2 ). The differential diagnosis included KSS, chronic progressive external ophthalmoplegia, MELAS syndrome, myasthenia gravis, Pearson syndrome and retinitis pigmentosa. MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal except for EKG, which unveiled complete right branch block, and a left anterior hemiblock (Fig. 3 ). The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization. His CSF protein and lactate levels were elevated. A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests (Fig. 4 ). The diagnosis of KSS was made from the following findings: onset of disease before 20 years of age with chronic external ophthalmoplegia, cardiac conduction defects, pigmentary retinopathy and muscle biopsy. Figure 1: Bilateral ptosis. Figure 2: ( a and b ) Funduscopic examination showing atypical pigmentary retinitis. Figure 3: Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock. Figure 4: Electron microscopy of the skeletal muscle tissue revealing abnormal disposition of mitochondrial crests, higher concentration of mitochondria with notable abnormalities in size and shape.'} | [
"he had a short stature one standard below the mean with a BMI within normal limits."
] | [] | [
"A 17 - year - old Venezuelan male with a 5 - year past medical history of bilateral ptosis came for his regular ophthalmic and general health checkup ( Fig. 1 ). He had diplopia, decreased visual acuity and nyctalopia. He was diagnosed with diplopia by a general practitioner 5 years ago since then the patient has not seen any physician for any eye examination or general health checkup. His personal and family history was non - significant.",
"5 - year past medical history of bilateral ptosis",
"His personal and family history was non - significant"
] | [
"bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions;",
"MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"His CSF protein and lactate levels were elevated",
"chronic external ophthalmoplegia",
"Bilateral ptosis"
] | [
"MRI brain, echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"His CSF protein and lactate levels were elevated",
"A biopsy of the anterior right tibial muscle showed a higher concentration of mitochondria with notable abnormalities in size, form and disposition of mitochondrial crests"
] | [
"echo, audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"EKG, which unveiled complete right branch block, and a left anterior hemiblock",
"The Holter monitor recorded supraventricular extrasystoles and a defect in ventricular repolarization",
"cardiac conduction defects",
"Electrocardiogram revealing a complete right bundle branch block and a left anterior hemiblock"
] | [] | [] | [] | [] | [
"He had diplopia, decreased visual acuity and nyctalopia",
"bilateral and partial external ophthalmoplegia with mild limitations in gaze in all directions; visual acuity was four bilaterally with evidence of hypermetric astigmatism.",
"On funduscopic examination, bilateral atypical pigmentary retinopathy was seen",
"audiometry, urine analysis, serum creatinine kinase, lactate and pyruvate levels, basic metabolic panel, calcium, magnesium, plasma cortisol levels and thyroid profile were normal",
"chronic external ophthalmoplegia",
"pigmentary retinopathy",
"Bilateral ptosis",
"Funduscopic examination showing atypical pigmentary retinitis"
] | [] | [] | [] | [
"17 - year - old"
] | [
"onset of disease before 20 years of age"
] | [
"The diagnosis of KSS was made from the following findings"
] | [] |
4831400 | {'Case Description': 'Polyhydramnios in the second and third trimester of pregnancy is defined by (semiquantative) measurements such as a maximum vertical pocket (MVP) >8 cm, or an amniotic fluid index (AFI) >24 cm. Approximately 90% of cases are idiopathic or caused by gestational diabetes (GDM) 1 . However, 10% of cases are associated with fetal structural abnormalities 2 . Most frequent causes are impaired swallowing from any cause (gastrointestinal, facial, musculoskeletal, or brain abnormalities), cardiac failure, hydrops, and renal abnormalities. Metabolic diseases, such as congenital disorders of glycogen storage, are also incidentally reported to present with polyhydramnios in pregnancy 3 . The usual diagnostic work‐up of polyhydramnios is to exclude GDM and maternal infections, and to perform an extensive structural assessment to rule out fetal anomalies. The presence of structural anomalies, involves increased risk of aneuploidy or other chromosomal and syndromic disorders. In isolated polyhydramnios, the risk of perinatal adverse outcome is, however, still increased when compared with uneventful pregnancies 4 . A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios. Aside from a spontaneously closed ventricular septal defect (VSD) in her own infancy, both parents were healthy. A maternal uncle of the mother had died postnatally of an unknown cause. First‐trimester combined test revealed a low risk for trisomies (NT 1.1 mm). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios (uterine size that outpaced gestational age) and premature contractions. She received tocolytics and corticosteroids for fetal lung maturation. Ultrasound showed polyhydramnios (MVP 9.9 cm, AFI 27.5 cm) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles (11 mm). Amniotic fluid drainage (1.8 L) was performed in an attempt to cease the premature contractions. More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna (12 mm) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm (slightly below p3, with head circumference p50, Fig. 1 A). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD. QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 (11q22.1), including exon 1 of the contactine 5 ( CNTN5 ) gene. This variant is not reported as genomic variant in the normal population, neither known to be associated with a genetic disorder or malformation. A relation with the clinical signs appears unlikely. Maternal serum infection testing (TORCHES) was also normal. Two days later (26 + 0), she spontaneously delivered a boy of 835 g (−0.5 SDS), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively. At birth, he was started on CPAP and transported to the neonatal intensive care unit. Physical examination showed a hypotonic infant with a lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus (Fig. 1 B). He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges. The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels. Testes were not palpable in the scrotum. Postnatal cardiac ultrasound confirmed the presence of a small VSD. Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy. A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome. He developed hypotension and was treated with fluid boluses and inotropic support and antibiotics. Despite stabilization of blood pressure and systemic circulation, he developed a progressive lactate acidosis with extremely high plasma lactate: 19.1 mmol/L and high pyruvate: 269 μ mol/L. The L/P (lactate/pyruvate) ratio was 71, which is strongly increased (normal <20). Organic acid analysis in urine showed a strong increase of lactate (56540 μ mol/mmol creatinine) and increases of 3‐OH‐butyrate, pyruvate, fumarate, malate, and 4‐OH‐phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very long‐chain fatty acids in plasma were normal. In the absence of secondary causes, these findings are consistent with primary lactic acidosis, caused by a disorder of the pyruvate metabolism or a mitochondrial respiratory chain defect. Due to the severity of the cumulative problems, the neonate died 2 days after birth. Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst (Figure S1C), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst (Figure S1D). DNA analysis of the PDHA1 ‐gene (most frequent genetic cause of pyruvate‐dehydrogenase complex deficiency) showed no pathogenic mutations. Large deletions, point mutations, and small insertions/deletions in mitochondrial DNA (mtDNA) derived from blood were excluded by next‐generation sequencing (NGS) using the Illumina MiSeq platform and a dedicated bioinformatics pipeline (available on request). For whole exome sequencing, exome enrichment was performed by the Agilent SureSelectXT exome enrichment kit version 4, including the UTR regions. Sequencing was performed by an Illumina HiSeq2000 (San Diego, CA) using a 2 × 100 bp paired‐end recipe. Basecalling, and demultiplexing was done using bcl2fastq 1.8.4.,(Illumina, San Diego, CA) reads were aligned onto the human reference genome (hg19) using BWA 0.5.9., duplicates marked using the PICARD software suite 1.77 (GitHub Enterprise, San Francisco, CA), and variants were called using GATK 2.1‐8. Annotations were added using an in‐house build annotation database, according to UCSC RefGene track, dbSNP137, and the dbNSFP (v2.0). Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing: c.292C>T (p.(Arg98*))and c.1303C>T (p.(Arg435*)). Both are nonsense mutations resulting in a premature stop codon at position p.98 and p.435 of the FBXL4 protein, respectively. The location of these mutations on different alleles (compound heterozygosity) was confirmed by testing the parents. Missense and stop mutations in the FBXL4 gene were reported recently to be associated with severe autosomal recessively inherited mitochondrial encephalomyopathy 5, 6, 7, 8 . Our case is the first case demonstrating a premature prenatal onset of symptoms of FBXL4‐ related mitochondrial encephalomyopathy. The polyhydramnios was the primary sign, leading to the detection of brain abnormalities on more detailed fetal ultrasound examination. This early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements. The cases of FBXL4 ‐related encephalopathy reported so far are characterized by increased serum lactate level, psychomotor delay, hypotonia, failure to thrive, swallowing difficulty, and muscle wasting 6 . Onset of symptoms varied from neonatal onset after term birth, to the age of 14 months 5, 6, 8 . Other reported cases were born at term or premature due to medical intervention for intrauterine growth retardation or reduced fetal movements 5, 6 . The FBXL4 gene is situated on nuclear DNA on chromosome 6q16.1. The FBXL4 mitochondrial protein contains an F‐box in its N‐terminal half, followed by 11 leucine‐rich repeats 9, and is expressed in heart, kidney, liver, lung, pancreas, and placenta 10 . Evidence of the pathogenetic effect of FBXL4 mutations was provided by skeletal muscle biopsies and fibroblasts showing defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion 5 . The nonsense mutation p.Arg435* in the FBXL4 gene, present in our patient, was earlier reported in homozygous form in a child of consanguineous parents with early onset mitochondrial encephalopathy, severe hypotonia, cardiomyopathy, MRI abnormalities, increased serum lactate, and premature death 5 . The second mutation detected in our patient (p.Arg98* mutation) has not been reported previously. However, like the other mutation reported, this nonsense mutation leads to nonsense‐mediated decay (NMD, RNA degradation) or a truncated protein 5, 6 . As a result, our patient would have been unable to produce a normal FBXL4 gene product. The mother was pregnant again before exome sequencing had started. Within the prenatal timeframe, exome sequencing lead to the diagnosis of the first child, consequently enabling prenatal diagnosis for the second child. Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child. The VSD in our patient is considered to be a separate finding (familial trait), which is not related to the syndrome. Our case demonstrated a prenatal onset of mitochondrial encephalomyopathy presenting with polyhydramnios, causing premature delivery, and cerebellar atrophy. The neonate was hypotonic and in a poor condition with need for mechanical ventilation, inotropic support, and persistent lactate acidosis. Targeted exome sequencing using a mitochondrial gene panel proved its benefit by revealing compound heterozygous mutations in the FBXL4 gene. Prenatal testing was successfully carried out in the current pregnancy. Direct testing for mutations in the FBXL4 gene should be considered in patients with severe encephalomyopathy with high levels of serum lactate.'} | [
"835 g ( −0.5 SDS ),"
] | [] | [
"A 30‐year‐old primigravid woman, with a so far uneventful pregnancy, was referred to our clinic with polyhydramnios",
"Aside from a spontaneously closed ventricular septal defect ( VSD ) in her own infancy, both parents were healthy",
"A maternal uncle of the mother had died postnatally of an unknown cause",
"The mother was pregnant again before exome sequencing had started",
"Amniocentesis with sequence analysis of the FBXL4 gene confirmed that the fetus was unaffected. The pregnancy resulted in the birth of a healthy child.",
"The VSD in our patient is considered to be a separate finding ( familial trait )"
] | [
"mild dilatation of both lateral ventricles ( 11 mm ).",
"showing an enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm ( slightly below p3, with head circumference p50, Fig. 1 A ).",
"hypotonic infant",
"Cranial ultrasound on first postnatal day showed bilateral peri‐ and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy.",
"Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra‐ and periventricular hemorrhage with adjacent cyst ( Figure S1C ), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst ( Figure S1D )",
"brain abnormalities on more detailed fetal ultrasound examination",
"hypotonia and diminished fetal movements",
"mitochondrial encephalomyopathy",
"cerebellar atrophy",
"hypotonic",
"poor condition with need for mechanical ventilation,"
] | [
"Firstâ€trimester combined test revealed a low risk for trisomies ( NT 1.1 mm ).",
"The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50.",
"More detailed fetal intracranial assessment was possible afterwards, showing an enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm ( slightly below p3, with head circumference p50, Fig. 1 A ). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD",
"QF PCR and a CytoScan HD Array were performed, showing a small de novo duplication on chromosome 11 ( 11q22.1 ), including exon 1 of the contactine 5 ( CNTN5 ) gene.",
"Maternal serum infection testing ( TORCHES ) was also normal",
"Postnatal cardiac ultrasound confirmed the presence of a small VSD.",
"Cranial ultrasound on first postnatal day showed bilateral peri†and intraventricular hemorrhages with dilatation of the ventricles, periventricular pseudocysts, and confirmed the presence of cerebellar atrophy.",
"progressive lactate acidosis with extremely high plasma lactate : 19.1 mmol / L and high pyruvate : 269 μ mol / L. The L / P ( lactate / pyruvate ) ratio was 71, which is strongly increased ( normal < 20 ). Organic acid analysis in urine showed a strong increase of lactate ( 56540 μ mol / mmol creatinine ) and increases of 3â€OHâ€butyrate, pyruvate, fumarate, malate, and 4â€OHâ€phenyllactate. The amino acids proline and lysine were increased in both urine and plasma. Oligosaccharides in urine and acylcarnitines and very longâ€chain fatty acids in plasma were normal",
"Postmortem cranial MRI confirmed the findings on ultrasound, showing extensive bilateral intra†and periventricular hemorrhage with adjacent cyst ( Figure S1C ), vermian and cerebellar hypoplasia with a retrocerebellar pseudocyst ( Figure S1D )",
"DNA analysis of the PDHA1 â€gene ( most frequent genetic cause of pyruvateâ€dehydrogenase complex deficiency ) showed no pathogenic mutations",
"Targeted exome analyses of a panel of 447 nuclear genes were performed, containing known mitochondrial disease genes and functionally or clinically related genes. Two heterozygous mutations in the FBXL4 gene were detected and confirmed by Sanger sequencing : c.292C > T ( p.(Arg98*))and c.1303C > T ( p.(Arg435 * ) ).",
"brain abnormalities on more detailed fetal ultrasound examination",
"persistent lactate acidosis"
] | [
"spontaneously closed ventricular septal defect ( VSD ) in her own infancy,",
"The myocardium was hypertrophic with a small perimembraneous VSD",
"Postnatal cardiac ultrasound confirmed the presence of a small VSD",
"hypotension",
"The VSD in our patient is considered to be a separate finding ( familial trait )"
] | [] | [
"Testes were not palpable in the scrotum"
] | [
"respiratory distress syndrome.",
"poor condition with need for mechanical ventilation"
] | [
"He had relatively long and slender arms and legs, large hands, long fingers, small fingernails and somewhat broad distal phalanges",
"The lower extremities showed bilateral pes cavus with broad metatarsals and prominent heels",
"mitochondrial encephalomyopathy"
] | [] | [
"lack of subcutaneous fat. The muscles and bones were clearly visible. He had mild dysmorphic features with high and arched eyebrows, a hairy forehead, triangular face, a slight upslant of palpebral fissures, down turned corners of the mouth, mild hypoplastic alae nasi, prominent pointed chin, deep incisura between tragus and antitragus providing a clear view into the external meatus",
"small fingernails"
] | [
"First‐trimester combined test revealed a low risk for trisomies ( NT 1.1 mm ). The anomaly scan was performed at 20 weeks GA and showed no abnormalities. Transverse cerebellar diameter was normal at p50. At 25 + 5 weeks of gestation, she presented with signs of polyhydramnios ( uterine size that outpaced gestational age ) and premature contractions.",
"Ultrasound showed polyhydramnios ( MVP 9.9 cm, AFI 27.5 cm ) with normal fluid‐filled stomach and mild dilatation of both lateral ventricles ( 11 mm ).",
"enlarged cisterna magna ( 12 mm ) and a dysplastic and small cerebellum. The transcerebellar diameter measured 25.4 mm ( slightly below p3, with head circumference p50, Fig. 1 A ). Further intracranial assessment was not possible due to maternal habitus, fetal position, and uterine contractions. The myocardium was hypertrophic with a small perimembraneous VSD",
"Two days later ( 26 + 0 ), she spontaneously delivered a boy of 835 g ( −0.5 SDS ), Apgar scores were 4/4/7 after 1.5 and 10 min, respectively.",
"A few hours after birth, the neonate required mechanical ventilation and surfactant treatment for respiratory distress syndrome.",
"the neonate died 2 days after birth",
"polyhydramnios",
"early presentation of polyhydramnios is most likely caused by hypotonia and diminished fetal movements",
"polyhydramnios, causing premature delivery"
] | [] | [
"30‐year‐old"
] | [] | [
"FBXL4 ‐related encephalopathy"
] | [] |
4750615 | {'Case report': 'The patient presented at age seven years with intermittent vomiting, diarrhea, constipation, weight loss and fatigue that has persisted for over 18 months. Routine work-up showed significant metabolic acidosis with low serum bicarbonate concentrations. He was started on oral sodium citrate and admitted for evaluation, which revealed low serum glucose of 3.05 mmol/L (55 mg/dL) and very low plasma l -carnitine (total carnitine:7 μmol/L, reference range: 25–69). Serum creatine phosphokinase (CK) and transaminases were elevated and continued to increase as he clinically deteriorated, with CK peaking at 202 μkat/L (12,086 U/L), AST at 341 U/L and ALT at 190 U/L. Ophthalmologic and audiologic exams were normal. Differential diagnoses included fatty acid oxidation defects, GSDs, and mitochondrial oxidative phosphorylation disorders. The patient had started on carnitine and cornstarch but continued to deteriorate, with multiple admissions for ketotic hypoglycemia and severe lactic acidosis. Brain magnetic resonance imaging was normal, while brain magnetic resonance spectroscopy (MRS) showed lactate peaks in the left basal ganglion and lateral ventricle. As this finding was suggestive of a mitochondrial disorder, treatment with coenzyme Q10, riboflavin, creatine monohydrate, alpha-lipoic acid, and medium chain triglyceride (MCT) oil was initiated, while continuing carnitine supplementation. Leucovorin was later added due to a low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate level. At age eight, he required a gastric feeding tube (G-tube) placement for malnutrition and continued weight loss. The urine organic acid profile was notable for elevations of lactate, ethylmalonate, 3-methylglutaconate, and branched-chain ketoacids, suggestive of mitochondrial dysfunction. Cultured skin fibroblast testing was performed for suspected defects in fatty acid oxidation, pyruvate carboxylase (EC 6.4.1.1), and pyruvate dehydrogenase complex (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4) with normal results . Analysis of acylcarnitines in cultured skin fibroblasts incubated with palmitic acid and l -carnitine (in vitro probe assay) showed marked elevations of long-chain species, suggestive of carnitine palmitoyltransferase II or carnitine–acylcarnitine translocase deficiency. CSF analysis showed mild elevation of lactate of 3.1 mmol/L (< 2.8), and a low normal level of 5-methyltetrahydrofolate. Transaminitis was initially attributed to a possible GSD; glycogen content was elevated in both liver (10%; control range 3.3 +/− 1.7%) and muscle (3.0%; control range 0.94 +/− 0.55). However, sequencing of PHKA1 and PHKG2 genes (GSD IX) and AGL gene (GSD III) was normal. Activities of debranching enzyme (EC 2.4.1.25 GSD III) and hepatic phosphorylase kinase (GSD IX, EC 2.7.11.19) in the liver and muscle, and glucose-6-phosphatase (GSD Ia, EC 3.1.3.9) in the liver were also normal. Further evaluation for a suspected mitochondrial disorder revealed normal electron transporter chain (ETC) activity in cultured skin fibroblasts. Muscle histopathology demonstrated prominent granular red staining of the fibers with a trichrome stain and numerous mitochondria aggregates by electron microscopy, characteristic of a mitochondrial myopathy ( Fig. 1 ). ETC testing on frozen muscle revealed deficient complex III activity of 455 (mean 1461, standard deviation 473); mtDNA sequencing of the muscle sample revealed a 9 basepair deletion with loss of 3 amino acids Leu-Ala-Thr (m.15319_15327delCCTAGCAAC; p.Leu192_Thr194del, Fig. 2 ) in the MT-CYB gene encoding cytochrome b subunit of complex III, with > 90% mutant load, confirming complex III deficiency. MtDNA sequencing in the liver and blood did not reveal the mutation, although low heteroplasmy for the mutation was detected in uncultured skin fibroblasts. Since the diagnosis, ongoing cardiac evaluations to monitor for cardiomyopathy or rhythm disturbance have been normal. The child dramatically improved with the start of G-tube feeding and dietary supplements, with increased energy level, improved exercise tolerance and progress in academic performance. Previously confined to a wheel chair, he started to walk independently and actively. Lactic acid, transaminases and CK levels have stabilized, although lactate showed occasional elevations as high as 11 mmol/L without symptoms of metabolic decompensation. His G-tube was removed at age 12 years and he stopped taking supplements, and he continues to do remarkably well physically.'} | [] | [
"intermittent vomiting, diarrhea, constipation, weight loss"
] | [
"The patient presented at age seven years with intermittent vomiting, diarrhea, constipation, weight loss and fatigue that has persisted for over 18 months",
"multiple admissions for ketotic hypoglycemia and severe lactic acidosis"
] | [
"fatigue that has persisted for over 18 months"
] | [
"significant metabolic acidosis with low serum bicarbonate concentrations",
"low serum glucose of 3.05 mmol / L ( 55 mg / dL ) and very low plasma l -carnitine ( total carnitine:7 μmol / L, reference range : 25–69 ). Serum creatine phosphokinase ( CK ) and transaminases were elevated and continued to increase as he clinically deteriorated, with CK peaking at 202 μkat / L ( 12,086 U / L ), AST at 341 U / L and ALT at 190 U / L.",
"multiple admissions for ketotic hypoglycemia and severe lactic acidosis. Brain magnetic resonance imaging was normal, while brain magnetic resonance spectroscopy ( MRS ) showed lactate peaks in the left basal ganglion and lateral ventricle",
"a low cerebrospinal fluid ( CSF ) 5 - methyltetrahydrofolate level",
"urine organic acid profile was notable for elevations of lactate, ethylmalonate, 3 - methylglutaconate, and branched - chain ketoacids, suggestive of mitochondrial dysfunction. Cultured skin fibroblast testing was performed for suspected defects in fatty acid oxidation, pyruvate carboxylase ( EC 6.4.1.1 ), and pyruvate dehydrogenase complex ( EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4 ) with normal results. Analysis of acylcarnitines in cultured skin fibroblasts incubated with palmitic acid and l -carnitine ( in vitro probe assay ) showed marked elevations of long - chain species, suggestive of carnitine palmitoyltransferase II or carnitine – acylcarnitine translocase deficiency. CSF analysis showed mild elevation of lactate of 3.1 mmol / L ( < 2.8 ), and a low normal level of 5 - methyltetrahydrofolate. Transaminitis was initially attributed to a possible GSD; glycogen content was elevated in both liver ( 10 %; control range 3.3 + /− 1.7 % ) and muscle ( 3.0 %; control range 0.94 + /− 0.55 ). However, sequencing of PHKA1 and PHKG2 genes ( GSD IX ) and AGL gene ( GSD III ) was normal. Activities of debranching enzyme ( EC 2.4.1.25 GSD III ) and hepatic phosphorylase kinase ( GSD IX, EC 2.7.11.19 ) in the liver and muscle, and glucose-6 - phosphatase ( GSD Ia, EC 3.1.3.9 ) in the liver were also normal. Further evaluation for a suspected mitochondrial disorder revealed normal electron transporter chain ( ETC ) activity in cultured skin fibroblasts. Muscle histopathology demonstrated prominent granular red staining of the fibers with a trichrome stain and numerous mitochondria aggregates by electron microscopy, characteristic of a mitochondrial myopathy ( Fig. 1 ). ETC testing on frozen muscle revealed deficient complex III activity of 455 ( mean 1461, standard deviation 473 ); mtDNA sequencing of the muscle sample revealed a 9 basepair deletion with loss of 3 amino acids Leu - Ala - Thr ( m.15319_15327delCCTAGCAAC; p. Leu192_Thr194del, Fig. 2 ) in the MT - CYB gene encoding cytochrome b subunit of complex III, with > 90 % mutant load, confirming complex III deficiency. MtDNA sequencing in the liver and blood did not reveal the mutation, although low heteroplasmy for the mutation was detected in uncultured skin fibroblasts."
] | [
"ongoing cardiac evaluations to monitor for cardiomyopathy or rhythm disturbance have been normal."
] | [] | [] | [] | [
"improved exercise tolerance",
"Previously confined to a wheel chair, he started to walk independently and actively"
] | [
"Ophthalmologic and audiologic exams were normal."
] | [] | [] | [] | [
"The patient presented at age seven years"
] | [] | [
"complex III deficiency"
] | [
"coenzyme Q10 , riboflavin , creatine monohydrate , alpha - lipoic acid , and medium chain triglyceride ( MCT ) oil was initiated , while continuing carnitine supplementation . Leucovorin was later added"
] |
5301300 | {'CASE REPORT': 'The patient is a 45y Caucasian male, height 182cm, weight 80kg, with a previous history of divergence of the ocular bulbs with double vision since age 6y, bilateral ptosis since age 23y, which was surgically corrected at age 30y, ophthalmoparesis since at least age 27y, a syncope at age 30y, and anterocollis since at least age 40y. At age 27y he had undergone muscle biopsy from the left deltoid muscle showing mild myopathic lesions with increased accumulation of intrafusal glycogen and lipid droplets. Electroneurography at age 27y revealed axonal polyneuropathy. 24h-ECG at age 30y disclosed an intermittent AV-block II and electroencephalography generalized poly-spike waves in the absence of seizures. Clinical neurologic investigation at age 40y revealed, in addition to the above mentioned abnormalities, bilateral proximal weakness of the upper limbs, a winging scapula bilaterally, and reduced tendon reflexes. Cerebrospinal fluid (CSF) investigations at age 40y revealed elevated protein (1008mg/l, n: 150-450mg/l) exclusively. Needle-(electromyography) EMG of the right anterior tibial muscle at age 40y showed neurogenic alterations. A Guillain-Barre-syndrome (GBS) was suspected and immunoglobulins administered with a beneficial effect. Transthoracic echocardiography at age 40y revealed mild myocardial thickening. At late age 40y mild weakness of the lower limbs (M5-/M4+) and an abnormal respiratory pattern were noted for the first time. Radioscopy of the lungs did not reveal abnormal mobility of the diaphragm. Lactate stress testing under 40W resulted in a lactate increase to 9.5mmol/l after 8 minutes. Upon supra-maximal stimulation of the phrenic nerve at age 41y no answer could be evoked and needle-EMG of the rectus abdominis muscle revealed abnormal spontaneous activity. Muscle biopsy from the right deltoid muscle at age 41y showed myopathic features, ragged-red fibers, regenerating fibers, increased number of lipid droplets, glycogen depositions, and some COX-negative fibers. Biochemical investigations of the muscle homogenate revealed a combined complex I+IV defect. The activity of the NADH-CoQ-oxidoreductase was 7.4 U/g NCP (n, 15.8-42.84 U/g NCP) and the activity of the cytochrome-c-oxidase 89 U/g NCP (n, 112-351 U/g NCP). Investigation for mtDNA deletions or insertions by long-range PCR was normal. Southern blot could not be carried out because of insufficient material. nDNA located genes responsible for mitochondrial myopathy were not tested. The family history was positive for diabetes (grandmother from the mother’s side) and cardiac abnormalities (mother). At age 45y he was admitted for acute respiratory dysfunction in the absence of recent pulmonary infection or embolism with hypercapnia but normal oxygenation due to weakness of the respiratory muscles (Table 2 ). There was no indication for heart failure. Though he was awake with normal oxygenation, he required intubation and mechanical ventilation because of hypercapnia due to muscular respiratory insufficiency. Clinical neurologic examination revealed ptosis, ophthalmoparesis, weak head anteflexion and retroflexion (M5-), weakness of the upper limbs with distal predominance (M4 to M5-), proximal weakness of the lower limbs (M5-) absent tendon reflexes, generalized wasting, and stocking-type sensory disturbances. Blood tests revealed hyponatriemia (129mmol/l, n: 135-150mmol/l) and slight anemia (Table 1 ). The diaphragm was moving normally. Cerebral CT was normal. Under controlled ventilation elevated CO 2 decreased to near normal values within 3 days (Table 2 ). On hospital day (hd) 3 he was extubated but respiratory insufficiency with hypercapnia recurred, why he required re-intubation and ventilatory support on hd5 (Table 2 ). One day after re-intubation, tracheostomy was carried out. Blood gases normalized (Table 2 ) and from hd8 ventilatory support could be discontinued during daytime. Since a GBS was additionally suspected upon the history and the elevated CSF-protein, immunoglobulins were given. Under this regimen respiratory function further improved and he was able to sit with support during daytime. Unsupported sitting was impossible due to affected truncal muscles.', 'Case Report:': 'A 45y male was admitted for hypercapnia due to muscular respiratory insufficiency. He required intubation and mechanical ventilation. He had a previous history of ophthalmoparesis since age 6y, ptosis since age 23y, and anterocollis since at least age 40y. Muscle biopsy from the right deltoid muscle at age 41y was indicative of mitochondrial myopathy. Biochemical investigations revealed a combined complex I+IV defect. Respiratory insufficiency was attributed to mitochondrial myopathy affecting not only the extra-ocular and the axial muscles but also the shoulder girdle and respiratory muscles. In addition to myopathy, he had mitochondrial neuropathy, abnormal EEG, and elevated CSF-protein. Possibly, this is why a single cycle of immunoglobulins was somehow beneficial. For muscular respiratory insufficiency he required tracheostomy and was scheduled for long-term intermittent positive pressure ventilation.'} | [
"height 182 cm, weight 80 kg"
] | [] | [
"with a previous history of divergence of the ocular bulbs with double vision since age 6y, bilateral ptosis since age 23y, which was surgically corrected at age 30y, ophthalmoparesis since at least age 27y, a syncope at age 30y, and anterocollis since at least age 40y.",
"The family history was positive for diabetes ( grandmother from the mother ’s side ) and cardiac abnormalities ( mother )",
"admitted for acute respiratory dysfunction in the absence of recent pulmonary infection or embolism with hypercapnia but normal oxygenation due to weakness of the respiratory muscles",
"A 45y male was admitted for hypercapnia due to muscular respiratory insufficiency.",
"He had a previous history of ophthalmoparesis since age 6y, ptosis since age 23y, and anterocollis since at least age 40y."
] | [
"bilateral ptosis since age 23y,",
"ophthalmoparesis since at least age 27y,",
"Electroneurography at age 27y revealed axonal polyneuropathy",
"electroencephalography generalized poly - spike waves in the absence of seizures",
"bilateral proximal weakness of the upper limbs, a winging scapula bilaterally, and reduced tendon reflexes",
"Cerebrospinal fluid ( CSF ) investigations at age 40y revealed elevated protein ( 1008mg / l, n : 150 - 450mg / l ) exclusively",
"Needle-(electromyography ) EMG of the right anterior tibial muscle at age 40y showed neurogenic alterations.",
"mild weakness of the lower limbs ( M5-/M4 + )",
"Upon supra - maximal stimulation of the phrenic nerve at age 41y no answer could be evoked",
"needle - EMG of the rectus abdominis muscle revealed abnormal spontaneous activity",
"was awake with normal oxygenation",
"ptosis, ophthalmoparesis, weak head anteflexion and retroflexion ( M5- ), weakness of the upper limbs with distal predominance ( M4 to M5- ), proximal weakness of the lower limbs ( M5- ) absent tendon reflexes, generalized wasting, and stocking - type sensory disturbances",
"Cerebral CT was normal.",
"ophthalmoparesis since age 6y, ptosis since age 23y",
"mitochondrial neuropathy, abnormal EEG, and elevated CSF - protein"
] | [
"muscle biopsy from the left deltoid muscle showing mild myopathic lesions with increased accumulation of intrafusal glycogen and lipid droplets",
"Cerebrospinal fluid ( CSF ) investigations at age 40y revealed elevated protein ( 1008mg / l, n : 150 - 450mg / l ) exclusively",
"Transthoracic echocardiography at age 40y revealed mild myocardial thickening",
"Radioscopy of the lungs did not reveal abnormal mobility of the diaphragm",
"Lactate stress testing under 40W resulted in a lactate increase to 9.5mmol / l after 8 minutes",
"Muscle biopsy from the right deltoid muscle at age 41y showed myopathic features, ragged - red fibers, regenerating fibers, increased number of lipid droplets, glycogen depositions, and some COX - negative fibers. Biochemical investigations of the muscle homogenate revealed a combined complex I+IV defect. The activity of the NADH - CoQ - oxidoreductase was 7.4 U / g NCP ( n, 15.8 - 42.84 U / g NCP ) and the activity of the cytochrome - c - oxidase 89 U / g NCP ( n, 112 - 351 U / g NCP ). Investigation for mtDNA deletions or insertions by long - range PCR was normal.",
"Blood tests revealed hyponatriemia ( 129mmol / l, n : 135 - 150mmol / l ) and slight anemia",
"Cerebral CT was normal.",
"Blood gases normalized",
"elevated CSF - protein",
"Biochemical investigations revealed a combined complex I+IV defect"
] | [
"syncope at age 30y",
"24h - ECG at age 30y disclosed an intermittent AV - block II",
"Transthoracic echocardiography at age 40y revealed mild myocardial thickening",
"no indication for heart failure"
] | [] | [] | [
"abnormal respiratory pattern",
"Radioscopy of the lungs did not reveal abnormal mobility of the diaphragm",
"acute respiratory dysfunction in the absence of recent pulmonary infection or embolism with hypercapnia but normal oxygenation due to weakness of the respiratory muscles",
"hypercapnia due to muscular respiratory insufficiency",
"The diaphragm was moving normally.",
"respiratory insufficiency with hypercapnia recurred",
"Under this regimen respiratory function further improved",
"hypercapnia due to muscular respiratory insufficiency",
"Respiratory insufficiency was attributed to mitochondrial myopathy affecting not only the extra - ocular and the axial muscles but also the shoulder girdle and respiratory muscles.",
"muscular respiratory insufficiency"
] | [
"bilateral ptosis since age 23y,",
"anterocollis since at least age 40y.",
"bilateral proximal weakness of the upper limbs, a winging scapula bilaterally",
"Needle-(electromyography ) EMG of the right anterior tibial muscle at age 40y showed neurogenic alterations",
"mild weakness of the lower limbs ( M5-/M4 + )",
"needle - EMG of the rectus abdominis muscle revealed abnormal spontaneous activity",
"acute respiratory dysfunction in the absence of recent pulmonary infection or embolism with hypercapnia but normal oxygenation due to weakness of the respiratory muscles",
"hypercapnia due to muscular respiratory insufficiency.",
"ptosis, ophthalmoparesis, weak head anteflexion and retroflexion ( M5- ), weakness of the upper limbs with distal predominance ( M4 to M5- ), proximal weakness of the lower limbs ( M5- )",
"generalized wasting,",
"The diaphragm was moving normally.",
"respiratory insufficiency with hypercapnia recurred",
"he was able to sit with support during daytime",
"Unsupported sitting was impossible due to affected truncal muscles.",
"muscular respiratory insufficiency.",
"ophthalmoparesis since age 6y, ptosis since age 23y, and anterocollis since at least age 40y.",
"mitochondrial myopathy affecting not only the extra - ocular and the axial muscles but also the shoulder girdle and respiratory muscles",
"muscular respiratory insufficiency"
] | [
"divergence of the ocular bulbs with double vision since age 6y",
"bilateral ptosis since age 23y,",
"ophthalmoparesis since at least age 27y",
"ptosis, ophthalmoparesis,",
"ophthalmoparesis since age 6y, ptosis since age 23y,"
] | [] | [] | [] | [
"45y",
"45y"
] | [
"age 6y"
] | [] | [] |
5402823 | {'Case Report': 'A 52-year-old man presented at the National Hospital with 5 years history of progressive imbalance of gait, speech and memory impairment, and occasional urinary incontinence. He has never smoked tobacco or taken alcohol. His parents were first cousins from the Hausa ethnic group. His 78-year-old father is alive and well. His 70-year-old mother developed unsteady gait and dysphagia at age 55 years and is now bedridden and blind. His maternal aunt had died of a similar illness at age 39 years. Of his 12 siblings, all four sisters are alive and well, but five of eight brothers died. Three brothers died of unrelated causes, but one died at age 19 years following speech and swallowing difficulties while another one developed frequent falls, dementia, and blindness at age 27 years and died at 45 years. One brother is apparently healthy at age 54 years, but two others aged 42 and 43 years both suffer progressive imbalance of gait. The patient is married to one wife and has had seven children, of whom three have died. One son had frequent falls, seizures, abnormal speech, and blindness at age 8 years and died 3 years later. A daughter died of neonatal sepsis, while another daughter had unsteady gait and speech and swallowing difficulties at 2 years and died at 6 years. On examination, the patient was oriented and scored 28/30 on the Mini-Mental State Examination Scale. He had dysarthria and slow saccades on eye movement. Visual acuity was 6/18 in both eyes, and fundoscopy showed bilateral peripapillary atrophy. He had global hyperreflexia, bilateral ankle clonus, and extensor plantar responses. Muscle power was 5/5 in all limbs. He had a glove-and-stocking sensory loss and bilateral cerebellar signs and scored 16/40 on the Scale for the Assessment and Rating of Ataxia. His mother and 42-year-old brother both had visual impairment, ataxia, and sensory loss on examination. Investigations performed on the patient including a full blood count, serum chemistry, fasting glucose, lipid profile, thyroid function tests, serum Vitamins E and B12 levels, and electrocardiogram were all normal. We suspected a mitochondrial encephalopathy to keep in view SCA7 and von-Hippel–Lindau syndrome. When brain magnetic resonance imaging revealed brainstem atrophy with normal spinal cord, cerebellum, and cerebral hemispheres, we diagnosed SCA7 and tested for CAG repeat expansions at the SCA1, 2, 3, 6, and 7 loci on the proband, his mother and his 42-year-old brother. DNA was extracted from peripheral blood and analyzed by polymerase chain reaction and capillary electrophoresis at the Molecular Diagnostics Laboratory of the National Health Laboratory Service in Cape Town, South Africa. Each of the three samples tested showed expansion mutations of 39 repeats at the SCA7 (ATXN7) gene locus, where one normal allele and one fully expanded allele (10/39) were observed.'} | [] | [] | [
"A 52 - year - old man presented at the National Hospital with 5 years history of progressive imbalance of gait, speech and memory impairment, and occasional urinary incontinence",
"He has never smoked tobacco or taken alcohol",
"His parents were first cousins from the Hausa ethnic group. His 78 - year - old father is alive and well. His 70 - year - old mother developed unsteady gait and dysphagia at age 55 years and is now bedridden and blind. His maternal aunt had died of a similar illness at age 39 years. Of his 12 siblings, all four sisters are alive and well, but five of eight brothers died. Three brothers died of unrelated causes, but one died at age 19 years following speech and swallowing difficulties while another one developed frequent falls, dementia, and blindness at age 27 years and died at 45 years. One brother is apparently healthy at age 54 years, but two others aged 42 and 43 years both suffer progressive imbalance of gait. The patient is married to one wife and has had seven children, of whom three have died. One son had frequent falls, seizures, abnormal speech, and blindness at age 8 years and died 3 years later. A daughter died of neonatal sepsis, while another daughter had unsteady gait and speech and swallowing difficulties at 2 years and died at 6 years.",
"His mother and 42 - year - old brother both had visual impairment, ataxia, and sensory loss on examination"
] | [
"patient was oriented and scored 28/30 on the Mini - Mental State Examination Scale",
"dysarthria and slow saccades on eye movement",
"global hyperreflexia, bilateral ankle clonus, and extensor plantar responses",
"Muscle power was 5/5 in all limbs",
"glove - and - stocking sensory loss and bilateral cerebellar signs and scored 16/40 on the Scale for the Assessment and Rating of Ataxia",
"brain magnetic resonance imaging revealed brainstem atrophy with normal spinal cord, cerebellum, and cerebral hemispheres,"
] | [
"full blood count, serum chemistry, fasting glucose, lipid profile, thyroid function tests, serum Vitamins E and B12 levels, and electrocardiogram were all normal",
"brain magnetic resonance imaging revealed brainstem atrophy with normal spinal cord, cerebellum, and cerebral hemispheres",
"Each of the three samples tested showed expansion mutations of 39 repeats at the SCA7 ( ATXN7 ) gene locus, where one normal allele and one fully expanded allele ( 10/39 ) were observed. '"
] | [] | [] | [] | [] | [
"Muscle power was 5/5 in all limbs."
] | [
"and slow saccades on eye movement. Visual acuity was 6/18 in both eyes, and fundoscopy showed bilateral peripapillary atrophy"
] | [] | [] | [] | [
"52 - year - old"
] | [] | [
"SCA7"
] | [] |
5128397 | {'Case report': "A 48-year-old woman of Palestine origin presented to a local hospital with subacute onset of confusion and word-finding difficulties. Her symptoms had started 2 weeks earlier with a headache, nausea, and dizziness. Her medical history was significant for essential hypertension, poorly controlled type 2 diabetes mellitus, and bilateral hearing loss of unknown etiology requiring hearing aids since age 46 years. Computed tomography (CT) revealed a hypodense lesion within the left temporal lobe (edema) involving gray matter and white matter ( Fig. 1 ). Magnetic resonance imaging (MRI) demonstrated left temporal lobe diffusion signal abnormality and fluid-attenuated inversion recovery (FLAIR) hyperintensity predominantly involving the cortex, with cortical and leptomeningeal contrast enhancement. The apparent diffusion coefficient (ADC) map showed preserved, isointense signal in the temporal cortex ( Fig. 2 ). The ventricular system and remaining parenchyma were grossly normal. Normal patent vessels without stenosis were seen on MR angiogram ( Fig. 3 ). Clinically, her symptoms initially stabilized, but in the following week, the patient's confusion worsened, and she developed clumsiness and stiffness of her right arm. At that point, she was referred to our institution for further evaluation. On admission, she had moderate expressive aphasia, mild dysarthria, and apraxia with paratonia of her right upper extremity. Imaging showed partial resolution of the left temporal lobe lesion, and new cortical diffusion weighted imaging abnormality in the left temporal and occipital lobes with corresponding FLAIR hyperintensity ( Fig. 2 ). Normal ADC signal and postcontrast leptomeningeal enhancement were similarly seen in these regions. Positron emission tomography (PET) showed no evidence of malignancy but demonstrated reduced metabolic activity in the regions of signal abnormality with adjacent metabolic hyperactivity involving the left superior parietal and medial occipital lobes in a gyriform distribution. Lumbar puncture ruled out infection but was significant for elevated lactate to 5.1 mmol/L. Serum lactate was elevated to 4.6 mmol/L. Serum inflammatory markers (dsDNA, anti-Hu, anti-Ri, anti-Yo, SS-A, SS-B, C3, C4) were normal. On day 4 of hospitalization, the patient reported feeling better, and her family took her home against medical advice. She then suffered 2 generalized tonic–clonic seizures associated with severe headache and blurred vision, and she was readmitted to our institution the same night. Continuous electroencephalogram showed left hemispheric slowing and frequent seizures originating from the left occipital lobe. Subsequent MRI demonstrated extension of the occipital lesion to involve more of the parietal and occipital lobes ( Fig. 4 ). MR spectroscopy showed elevated lactate peak at 1.3 ppm diffusely throughout the brain ( Fig. 5 ). A clinical diagnosis of MELAS syndrome was made. The patient recovered without further complications on anticonvulsants and high-dose intravenous arginine then oral citrulline at 0.5 mg/kg. At 2-month follow-up, her cognition including language and activities of daily living had greatly improved. Genetic testing of patient's serum confirmed m.3243 A→G mutation (heteroplasmy 22%) in the MT-TL1 gene that encodes leucine transfer RNA, consistent with MELAS syndrome. A detailed 3-generation family history revealed no known neurologic, muscular, cardiac, or vision problems. Genetic counseling is ongoing."} | [] | [
"nausea,"
] | [
"A 48 - year - old woman of Palestine origin presented to a local hospital with subacute onset of confusion and word - finding difficulties. Her symptoms had started 2 weeks earlier with a headache, nausea, and dizziness.",
"Her medical history was significant for essential hypertension, poorly controlled type 2 diabetes mellitus, and bilateral hearing loss of unknown etiology requiring hearing aids since age 46 years",
"moderate expressive aphasia, mild dysarthria, and apraxia with paratonia of her right upper extremity.",
"On day 4 of hospitalization, the patient reported feeling better, and her family took her home against medical advice. She then suffered 2 generalized tonic – clonic seizures associated with severe headache and blurred vision, and she was readmitted to our institution the same night.",
"A detailed 3 - generation family history revealed no known neurologic, muscular, cardiac, or vision problems"
] | [
"presented to a local hospital with subacute onset of confusion and word - finding difficulties. Her symptoms had started 2 weeks earlier with a headache, nausea, and dizziness.",
"her symptoms initially stabilized, but in the following week, the patient 's confusion worsened, and she developed clumsiness and stiffness of her right arm. At that point, she was referred to our institution for further evaluation. On admission, she had moderate expressive aphasia, mild dysarthria, and apraxia with paratonia of her right upper extremity",
"She then suffered 2 generalized tonic – clonic seizures associated with severe headache and blurred vision, and she was readmitted to our institution the same night. Continuous electroencephalogram showed left hemispheric slowing and frequent seizures originating from the left occipital lobe.",
"her cognition including language and activities of daily living had greatly improved."
] | [
"Computed tomography ( CT ) revealed a hypodense lesion within the left temporal lobe ( edema ) involving gray matter and white matter ( Fig. 1 ). Magnetic resonance imaging ( MRI ) demonstrated left temporal lobe diffusion signal abnormality and fluid - attenuated inversion recovery ( FLAIR ) hyperintensity predominantly involving the cortex, with cortical and leptomeningeal contrast enhancement. The apparent diffusion coefficient ( ADC ) map showed preserved, isointense signal in the temporal cortex ( Fig. 2 ). The ventricular system and remaining parenchyma were grossly normal. Normal patent vessels without stenosis were seen on MR angiogram ( Fig. 3 )",
"Imaging showed partial resolution of the left temporal lobe lesion, and new cortical diffusion weighted imaging abnormality in the left temporal and occipital lobes with corresponding FLAIR hyperintensity ( Fig. 2 ). Normal ADC signal and postcontrast leptomeningeal enhancement were similarly seen in these regions. Positron emission tomography ( PET ) showed no evidence of malignancy but demonstrated reduced metabolic activity in the regions of signal abnormality with adjacent metabolic hyperactivity involving the left superior parietal and medial occipital lobes in a gyriform distribution. Lumbar puncture ruled out infection but was significant for elevated lactate to 5.1 mmol / L. Serum lactate was elevated to 4.6 mmol / L. Serum inflammatory markers ( dsDNA, anti - Hu, anti - Ri, anti - Yo, SS - A, SS - B, C3, C4 ) were normal.",
"Subsequent MRI demonstrated extension of the occipital lesion to involve more of the parietal and occipital lobes ( Fig. 4 ). MR spectroscopy showed elevated lactate peak at 1.3 ppm diffusely throughout the brain",
"Genetic testing of patient 's serum confirmed m.3243 A→G mutation ( heteroplasmy 22 % ) in the MT - TL1 gene that encodes leucine transfer RNA, consistent with MELAS syndrome"
] | [
"essential hypertension"
] | [
"poorly controlled type 2 diabetes mellitus"
] | [] | [] | [] | [
"dizziness",
"bilateral hearing loss of unknown etiology requiring hearing aids since age 46 years",
"blurred vision,"
] | [] | [] | [] | [
"48 - year - old"
] | [] | [
"MELAS syndrome"
] | [
"high - dose intravenous arginine then oral citrulline at 0.5 mg / kg"
] |
5313432 | {'Case Report': 'The patient was a 41-year-old man who had experienced generalized convulsions, insomnia, and depression since 20 years of age. He had been diagnosed with ischemic stroke at 33 years of age and epileptic seizure with epileptic encephalopathy at 37 years of age. He had no other systemic signs of mitochondrial disorder, such as short stature, diabetes mellitus, deafness or heart failure. His family history was not remarkable. He developed myoclonus in the distal extremities, gait disturbance, and dysarthria at 41 years of age. Three months later, he was admitted to our hospital due to impaired consciousness and vomiting. A neurological examination showed gaze nystagmus, cerebellar ataxia, and myoclonic movement in his distal extremities. However, no ophthalmoplegia, hearing loss, or muscle weakness were detected. His mini-mental status examination score was 15/30, and his frontal assessment battery score was 5/18. The findings from routine blood tests including blood sugar and autoimmune antibodies were normal. A laboratory examination showed slightly increased serum pyruvic acid levels (1.2 mg/dL), but his serum lactate levels were normal (14.2 mg/dL). The cerebrospinal fluid lactate (34.8 mg/dL) and pyruvic acid (1.6 mg/dL) levels were elevated. Electrocardiogram and echocardiogram were normal. Brain magnetic resonance imaging (MRI) showed bilateral cortical and subcortical high-intensity lesions on T2-weighted imaging (T2WI) and fluid attenuated inversion recovery (FLAIR), distributed bilaterally and almost symmetrically. Bilateral red nuclei, mesencephalic tectum, vermis and cerebellar flocculus were also involved ( Fig. 1A and C ). Some of the cortical and subcortical lesions gave a high signal on diffusion-weighted imaging (DWI) ( Fig. 1B ). These lesions appeared as high or iso signal intensity on the apparent diffusion coefficient (ADC) map. Two weeks later, the high signal on DWI had diminished, and four weeks later, the high signal on T2WI and FLAIR had diminished ( Fig. 2 ). 1 H-MRS revealed elevated lactate concentrations in the lesions ( Fig. 1D ). 99m Tc-Ethylcysteinate dimer single photon emission computed tomography (SPECT) imaging revealed bilateral multifocal increase of perfusion in the MRI lesions ( Fig. 1E ). We suspected mitochondrial encephalopathy, such as MELAS. A histopathological study of the biopsied right biceps branchii muscle revealed mild variation in the fiber size, measuring from 30 to 90 microns in diameter, which was thought to be a non-specific change. No necrotic or regenerating fibers were seen. On modified Gomori-trichrome stain, ragged red fibers (RRFs) were not observed. Succinate dehydrogenase (SDH) stain revealed no strongly SDH-reactive blood vessels. Cytochrome c oxidase staining revealed no abnormalities ( Fig. 1F ). However, the complete sequencing of mitochondrial DNA samples extracted from the biopsied muscle revealed a heteroplasmic m.10158T>C mutation, with a level of mutant heteroplasmy of 69.5%, in the mitochondrial complex I subunit gene, MT-ND3 ( Fig. 1G ). Because his family had no clinical symptoms suggestive of mitochondrial diseases, we could not conduct a complete mtDNA sequence analysis of his family. Over a two-month period, he experienced two stroke-like episodes with simple partial seizure and vomiting. Each time the stroke-like episodes ended within four days with drip infusion of edaravone and supportive care. To control epileptic seizure, we added levetiracetam (1,000 mg/day) to zonisamide (400 mg/day) and carbamazepine (400 mg/day). Because he had not yet been diagnosed with MELAS-like encephalopathy at that time, we did not administer L-arginine. His higher brain dysfunction and myoclonus worsened with each stroke-like episode.'} | [] | [
"vomiting"
] | [
"The patient was a 41 - year - old man who had experienced generalized convulsions, insomnia, and depression since 20 years of age",
"He had been diagnosed with ischemic stroke at 33 years of age and epileptic seizure with epileptic encephalopathy at 37 years of age. He had no other systemic signs of mitochondrial disorder, such as short stature, diabetes mellitus, deafness or heart failure.",
"His family history was not remarkable",
"He developed myoclonus in the distal extremities, gait disturbance, and dysarthria at 41 years of age",
"Three months later, he was admitted to our hospital due to impaired consciousness and vomiting",
"his family had no clinical symptoms suggestive of mitochondrial diseases",
"Over a two - month period, he experienced two stroke - like episodes with simple partial seizure and vomiting. Each time the stroke - like episodes ended within four days"
] | [
"generalized convulsions, insomnia, and depression",
"ischemic stroke at 33 years of age",
"epileptic seizure with epileptic encephalopathy at 37 years of age.",
"myoclonus in the distal extremities, gait disturbance, and dysarthria at 41 years of age.",
"impaired consciousness",
"gaze nystagmus, cerebellar ataxia, and myoclonic movement in his distal extremities",
"no ophthalmoplegia, hearing loss, or muscle weakness",
"His mini - mental status examination score was 15/30, and his frontal assessment battery score was 5/18",
"The cerebrospinal fluid lactate ( 34.8 mg / dL ) and pyruvic acid ( 1.6 mg / dL ) levels were elevated.",
"Brain magnetic resonance imaging ( MRI ) showed bilateral cortical and subcortical high - intensity lesions on T2 - weighted imaging ( T2WI ) and fluid attenuated inversion recovery ( FLAIR ), distributed bilaterally and almost symmetrically. Bilateral red nuclei, mesencephalic tectum, vermis and cerebellar flocculus were also involved ( Fig. 1A and C ). Some of the cortical and subcortical lesions gave a high signal on diffusion - weighted imaging ( DWI ) ( Fig. 1B ). These lesions appeared as high or iso signal intensity on the apparent diffusion coefficient ( ADC ) map. Two weeks later, the high signal on DWI had diminished, and four weeks later, the high signal on T2WI and FLAIR had diminished ( Fig. 2 ). 1 H - MRS revealed elevated lactate concentrations in the lesions ( Fig. 1D ).",
"99 m Tc - Ethylcysteinate dimer single photon emission computed tomography ( SPECT ) imaging revealed bilateral multifocal increase of perfusion in the MRI lesions",
"two stroke - like episodes with simple partial seizure and vomiting",
"Each time the stroke - like episodes ended within four days",
"epileptic seizure",
"His higher brain dysfunction and myoclonus worsened with each stroke - like episode"
] | [
"routine blood tests including blood sugar and autoimmune antibodies were normal. A laboratory examination showed slightly increased serum pyruvic acid levels ( 1.2 mg / dL ), but his serum lactate levels were normal ( 14.2 mg / dL ). The cerebrospinal fluid lactate ( 34.8 mg / dL ) and pyruvic acid ( 1.6 mg / dL ) levels were elevated. Electrocardiogram and echocardiogram were normal. Brain magnetic resonance imaging ( MRI ) showed bilateral cortical and subcortical high - intensity lesions on T2 - weighted imaging ( T2WI ) and fluid attenuated inversion recovery ( FLAIR ), distributed bilaterally and almost symmetrically. Bilateral red nuclei, mesencephalic tectum, vermis and cerebellar flocculus were also involved ( Fig. 1A and C ). Some of the cortical and subcortical lesions gave a high signal on diffusion - weighted imaging ( DWI ) ( Fig. 1B ). These lesions appeared as high or iso signal intensity on the apparent diffusion coefficient ( ADC ) map. Two weeks later, the high signal on DWI had diminished, and four weeks later, the high signal on T2WI and FLAIR had diminished ( Fig. 2 ). 1 H - MRS revealed elevated lactate concentrations in the lesions ( Fig. 1D ). 99 m Tc - Ethylcysteinate dimer single photon emission computed tomography ( SPECT ) imaging revealed bilateral multifocal increase of perfusion in the MRI lesions",
"histopathological study of the biopsied right biceps branchii muscle revealed mild variation in the fiber size, measuring from 30 to 90 microns in diameter, which was thought to be a non - specific change. No necrotic or regenerating fibers were seen. On modified Gomori - trichrome stain, ragged red fibers ( RRFs ) were not observed. Succinate dehydrogenase ( SDH ) stain revealed no strongly SDH - reactive blood vessels. Cytochrome c oxidase staining revealed no abnormalities ( Fig. 1F ). However, the complete sequencing of mitochondrial DNA samples extracted from the biopsied muscle revealed a heteroplasmic m.10158T > C mutation, with a level of mutant heteroplasmy of 69.5 %, in the mitochondrial complex I subunit gene, MT - ND3"
] | [] | [] | [] | [] | [] | [
"gaze nystagmus",
"no ophthalmoplegia, hearing loss"
] | [] | [] | [] | [
"41 - year - old"
] | [
"20 years of age"
] | [
"MELAS - like encephalopathy"
] | [] |
5721577 | {'Case report': "The patient was a 37-year-old female, of 157 cm in height and 45 kg in weight. She was transferred to our department from a local hospital due to psychiatric features (both agitated behavior and auditory hallucinations), alexia and apraxia that had begun 10 days ago, followed by disorientation and generalized tonic-clonic seizures. She had a long history of episodic migraine-like headaches and progressive bilateral hearing loss for 3 years. However, she did not take any medication. Her vital signs showed a normal body temperature of 36.8 °C, a hypotension of 90/56 mm Hg and pulse at 72 beats per minute. Because of the patient's psychiatric symptoms and application of sedative after seizure attacks, she could not cooperate with physical examination. The laboratory data showed high anion gap metabolic acidosis with elevated levels of lactate and pyruvate. Serum levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were decreased. Her TSH level was low at 0.26 mU/L (normal range 0.35–5.5 mU/L), and FT4 concentration was 7.56 pmol/L (normal range 10.2–31 pmol/L). Both serum free and total triiodothyronine (FT3 and TT3) were significantly lower than normal range. FT3 concentration was 2.28 pmol/L (normal range 3.5–6.5 pmol/L), and TT3 concentration was 0.6 nmol/L (normal range 1.2–3.4 nmol/L). Moreover, elevated titers of serum anti-thyroglobulin and anti-thyroid microsomal antibodies were detected. Cerebral spinal fluid (CSF) studies were normal for cell counts and biochemistry, and negative for culture. CSF IgG index was 0.48 (normal range ≤ 0.7), and oligoclonal bands (OB) was negative. Computed tomography (CT) scan showed lesions of hypodense in the left temporal and parietal lobe, with brainstem and cerebellar atrophy ( Fig. 1 A). No evidence of subarachnoid or intracerebral hemorrhage. Vascular imaging of the cervical and cerebral arteries by CT angiography excluded the possibility of cerebrovascular disease ( Fig. 1 B). However, CT images were not conclusive to differentiate between the infectious or metabolic lesion. On day 5, brain magnetic resonance imaging MRI (3.0 T) revealed a hypointensity lesion in the left temporal-parietal lobe on T1 weighted image ( Fig. 2 A), and increased signal intensity in the same region on FLAIR sequences ( Fig. 2 B) with a clearly restricted diffusion ( Fig. 2 C). The signal intensity on ADC sequence was mildly reduced ( Fig. 2 D). No obvious enhancement was found on Gd-DTPA enhanced images ( Fig. 2 E). MR spectroscopy was carried out as well. Compared to the ipsilateral normally appearing area ( Fig. 2 F), there was a significantly elevated lactate peak at 1.3 ppm in region of interest (ROI) with decreased NAA spectrum and reduced NAA/Cr ratio ( Fig. 2 G). The change of the spectrum reflected the severity of metabolic disorders, suggesting the local accumulation of lactic acid and disturbance of hypoxic processes. Fig. 1 CT scan showed lesions of hypodense in the left temporal and parietal lobe (Panel A). Three-dimensional reconstruction of CT vessel images (Panel B). Fig. 1 Fig. 2 Brain MRI (3.0 T) revealed a hypointense lesion in the left temporal and parietal lobe on T1 (Panel A), and increased signal intensity in the same region on Flair (Panel A) image with a clearly restricted diffusion (Panel C). The signal intensity on ADC sequence is mildly reduced (Panel D). No obvious enhancement was found on Gd-DTPA enhanced images (Panel E). Compared to the ipsilateral normally appearing area (Panel F), MR spectroscopy presented a significantly elevated lactate peak at 1.3 ppm in region of interest (ROI) (Panel G). Panels f and g are the molecular findings of metabolites respectively. Fig. 2 An electroencephalogram was performed on day 7 and displayed bilateral slow wave activities. Brainstem auditory evoked potential (BAEP) showed the bilateral sensorineural hearing loss. All the clinical and radiological findings were suggestive of mitochondrial disease. The final diagnosis of MELAS syndrome was confirmed by genetic analysis. The patient's peripheral blood leukocytes was detected by restriction fragment length polymorphism (RFLP) and revealed a mitochondrial DNA (mtDNA) mutation at A3242G point ( Fig. 3 ). Fig. 3 Mitochondrial DNA (mtDNA) mutation at A3242G point. Fig. 3 Her medications included L-arginine, phenobarbital, co-enzyme Q and levothyroxine substitution therapy. The patient's condition continuously improved, and was discharged on day 23. Six months following discharge, this patient had no further seizure."} | [
"157 cm in height and 45 kg in weight",
"normal body temperature of 36.8 ° C, a hypotension of 90/56 mm Hg and pulse at 72 beats per minute."
] | [] | [
"The patient was a 37 - year - old female, of 157 cm in height and 45 kg in weight. She was transferred to our department from a local hospital due to psychiatric features ( both agitated behavior and auditory hallucinations ), alexia and apraxia that had begun 10 days ago, followed by disorientation and generalized tonic - clonic seizures.",
"She had a long history of episodic migraine - like headaches and progressive bilateral hearing loss for 3 years."
] | [
"psychiatric features ( both agitated behavior and auditory hallucinations ), alexia and apraxia that had begun 10 days ago, followed by disorientation and generalized tonic - clonic seizures. She had a long history of episodic migraine - like headaches",
"An electroencephalogram was performed on day 7 and displayed bilateral slow wave activities."
] | [
"high anion gap metabolic acidosis with elevated levels of lactate and pyruvate. Serum levels of thyroid - stimulating hormone ( TSH ) and free thyroxine ( FT4 ) were decreased. Her TSH level was low at 0.26 mU / L ( normal range 0.35–5.5 mU / L ), and FT4 concentration was 7.56 pmol / L ( normal range 10.2–31 pmol / L ). Both serum free and total triiodothyronine ( FT3 and TT3 ) were significantly lower than normal range. FT3 concentration was 2.28 pmol / L ( normal range 3.5–6.5 pmol / L ), and TT3 concentration was 0.6 nmol / L ( normal range 1.2–3.4 nmol / L ). Moreover, elevated titers of serum anti - thyroglobulin and anti - thyroid microsomal antibodies were detected. Cerebral spinal fluid ( CSF ) studies were normal for cell counts and biochemistry, and negative for culture. CSF IgG index was 0.48 ( normal range ≤ 0.7 ), and oligoclonal bands ( OB ) was negative. Computed tomography ( CT ) scan showed lesions of hypodense in the left temporal and parietal lobe, with brainstem and cerebellar atrophy ( Fig. 1 A ). No evidence of subarachnoid or intracerebral hemorrhage. Vascular imaging of the cervical and cerebral arteries by CT angiography excluded the possibility of cerebrovascular disease ( Fig. 1 B ). However, CT images were not conclusive to differentiate between the infectious or metabolic lesion. On day 5, brain magnetic resonance imaging MRI ( 3.0 T ) revealed a hypointensity lesion in the left temporal - parietal lobe on T1 weighted image ( Fig. 2 A ), and increased signal intensity in the same region on FLAIR sequences ( Fig. 2 B ) with a clearly restricted diffusion ( Fig. 2 C ). The signal intensity on ADC sequence was mildly reduced ( Fig. 2 D ). No obvious enhancement was found on Gd - DTPA enhanced images ( Fig. 2 E ). MR spectroscopy was carried out as well. Compared to the ipsilateral normally appearing area ( Fig. 2 F ), there was a significantly elevated lactate peak at 1.3 ppm in region of interest ( ROI ) with decreased NAA spectrum and reduced NAA / Cr ratio ( Fig. 2 G ). The change of the spectrum reflected the severity of metabolic disorders, suggesting the local accumulation of lactic acid and disturbance of hypoxic processes. Fig. 1 CT scan showed lesions of hypodense in the left temporal and parietal lobe ( Panel A ). Three - dimensional reconstruction of CT vessel images ( Panel B ). Fig. 1 Fig. 2 Brain MRI ( 3.0 T ) revealed a hypointense lesion in the left temporal and parietal lobe on T1 ( Panel A ), and increased signal intensity in the same region on Flair ( Panel A ) image with a clearly restricted diffusion ( Panel C ). The signal intensity on ADC sequence is mildly reduced ( Panel D ). No obvious enhancement was found on Gd - DTPA enhanced images ( Panel E ). Compared to the ipsilateral normally appearing area ( Panel F ), MR spectroscopy presented a significantly elevated lactate peak at 1.3 ppm in region of interest ( ROI )",
"mitochondrial DNA ( mtDNA ) mutation at A3242 G point"
] | [] | [] | [] | [] | [] | [
"progressive bilateral hearing loss",
"Brainstem auditory evoked potential ( BAEP ) showed the bilateral sensorineural hearing loss."
] | [] | [] | [] | [
"37 - year - old"
] | [] | [
"The final diagnosis of MELAS syndrome was confirmed by genetic analysis ."
] | [
"L - arginine , phenobarbital , co - enzyme Q and levothyroxine substitution therapy ."
] |
5415296 | {'Case Report': 'A 7-month-old, entire female, domestic shorthair cat was referred to our behavioural service owing to house soiling and a play-related problem. The owners’ complaints were that the cat had never used the litter tray, and it did not know how to play. The environment consisted of two young adult humans with no children. They lived in a flat of 85 m 2, with two terraces of 5 m 2 each. There were three separated litter boxes at home, all of which were non-covered with low sides. The owners had used clumping, non-clumping, silica-based and soil-based litter during the months between the adoption (when the cat was 4 months old) and the first visit. One of the latrines always had clumping substrate. There were three food and three water troughs, all of them far from the latrines. The impression of the owners was that the cat eliminated where it was at any given moment. It eliminated many more times in front of the owner (90%) than when it was alone (10%). The cat never tried to cover its faeces or urine after depositions. Occasionally, the owners punished the cat verbally and physically, but only when it eliminated in front of them. The substrates used by the cat were ceramic tiles, the sofa and beds. It always adopted an emptying-body posture. Spots were always located on horizontal surfaces. The owners used bleach-based products in order to clean the spots, and just water in the case of the sofa and beds. Regarding the play-related problem, the owners said that the cat did not understand the body language of other cats and commonly crashed into other cats or people. It also ‘tried to bite, catch and scratch the air’ when playing. It did not find balls or other toys when the owners threw them to the cat to play. The rest of the cat’s behavioural history was unremarkable. The differential diagnoses of the house-soiling problem included problems with the litter trays, including insufficient number, incorrect type, competition with other cats for the latrines, incorrect location, acquired aversion, or inappropriate substrate; a preference for another location or substrate; a problem with preference acquisition (ie, because of a cognitive impairment, or a sensory impairment or an unavailability of appropriate latrines or substrate during the first few weeks of life); and marking behaviours. Finally, a medical illness can contribute to all of these problems or to be the main cause. 1, 2 We could rule out most of these problems after interviewing the owners. Firstly, it was unlikely that there was a problem with the litter tray because the number, type and location were correct. The locations were correct because the animal eliminated near the litter tray if it was there. Many different substrates had been used. Secondly, it was not a problem of preference because the cat eliminated in different locations and surfaces. The age of the animal, the distribution of the spots and the body posture during elimination ruled out marking behaviours. Alterations in play behaviours described by the owners could have been due to a cognitive impairment, and/or a sensory impairment (ie, blindness). Play behaviours depend on learning capability and sensory systems. 3 Additionally, an enriched environment is necessary to learn and display play behaviours in a proper manner. 4 In that case, the social and instrumental environment was good. Regarding elimination, a problem of substrate preferences acquisition was diagnosed. A cognitive impairment, a medical condition or both could have been the cause of the problem during the elimination habits acquisition. Moreover, cognitive impairment and some medical conditions also could explain the play-related behavioural problems. During the consultation, the physical examination was unremarkable; however, the neurological examination revealed a moderate and hypermetric ataxic gait, and a bilateral lack of menace response. A complete ophthalmological examination was performed by the ophthalmological service in order to rule out ocular diseases. No ophthalmological abnormalities were detected. Additionally, based on the behaviours at home described by the owners (the inability to find some toys, and the behaviour of ‘scratching and biting the air’), some degree of visual impairment was suspected but not confirmed with the neurological examination. The cat did not crash with objects either at home or at the consultation room. The problem was located in the central nervous system (CNS); specifically, an intracranial and multifocal problem was diagnosed. A complete blood count and a complete biochemistry panel were performed, and all of the results were within normal limits. The feline immunodeficiency virus/feline leukaemia virus test was negative. A thorax radiograph, abdominal ultrasound, brain magnetic resonance imaging (MRI; 0.2 T) and cerebrospinal fluid analysis showed no abnormalities. Although some small lesions could be missed with low-field MRI, we had to assume the absence of lesions obtained in the work-up. Thus, a degenerative condition such as a lysosomal storage disease, organic aciduria or mitochondrial encephalopathy was suspected. Samples of blood and urine were sent to the University of Pennsylvania School of Veterinary Medicine for metabolic screen tests. Amino acids, organic acids, carbohydrates, nitroprusside, ketone and mucopolysaccharide concentrations were analysed, as was α-mannosidase, β-mannosidase, fucosidase and hexosaminidase A and B activity. All of these were within normal limits. No treatment was prescribed for the neurological problem. The owners were given advice on correcting the soiling problem in the house using reward-based training with a clicker. During the first week, the clicker was conditioned by a food reward, and the entire floor was covered with newspaper. Each time that the cat eliminated, it was rewarded with a clicker and food. Newspaper was removed progressively. Three months later, the cat used a small newspaper-covered area to eliminate. This partial improvement suggests that there was a learning impairment during the acquisition of habits but not a total lack of learning capability. After 3 months, the cat was referred to the neurology service again, in status epilepticus. Neurological findings, after the postictal phase, included a lack of bilateral menace response and cerebellar ataxic gait. A bilateral carpal valgus that had already been found in the first visit and a visible suture line in the posterior capsule of both crystalline lenses were also detected. The owners reported progressive gait deficits over the previous month and compulsive running episodes with a partially impaired mental status (probably seizure activity). A symptomatic treatment with diazepam (1 mg/kg intrarectally only if seizures) and phenobarbital (2 mg/kg PO q24h) was started, with a very poor response. After 15 days of treatment, levetiracetam was added (10 mg/kg PO q8h) owing to an increase in seizure activity, with an initially good response. However, seizures reappeared after 2 months with 1–2 episodes every 15 days each lasting <2 mins. After 2 years of treatment and a progressive worsening, the cat was euthanased. A complete necropsy was immediately performed. No gross lesions were found, and based on the CNS histological lesions shown in Figures 1 – 4, a diagnosis of spongiform polioencephalomyelopathy was made. The spongiform degeneration of the grey matter was extensively distributed in the whole CNS. In order to rule out prion aetiology, a PrPsc inmunohistochemistry assay was performed, and the results were negative. Thus, congenital spongiform polioencephalomyelopathy (CSP) was diagnosed postmortem. Spongy vacuolation seen by light microscopy in the neural tissue is defined as spongy degeneration, and may take the form of vacuoles within processes of the neuropil, vesiculation of myelin sheaths, or swelling of astrocyte or oligodendrocyte cytoplasm. 5 A congenital problem, retrovirus infection and prion disease have been suggested as possible aetiologies. 6 – 10 Congenital spongiform degeneration of the grey matter has been previously described in a few cases of cats; 6 – 8 however, the cause remains still unknown. Common clinical signs include gait alteration, seizures, blindness, bilateral cataracts, behavioural changes and cranial nerve alterations. These signs appear during very early stages of development (just after birth), with a progressive fatal outcome in a few days or months. Behavioural signs are poorly described in animal science literature. 6 – 8 Although the degeneration usually affects diffusely all the grey matter, the behavioural alterations and the evolution of the clinical signs depend on the affected area of the brain in each case. Nevertheless, the clinical signs do not always correlate with the degree of the histological lesions. A spongy degenerative problem of grey matter has also been described in humans, and occurs in isolated cases and in sibs. 11 – 13 In all of human cases reported, the problem appears early in infancy and the outcome is always fatal. All the affected children show learning disabilities (ie, retarded speech development) during the early periods of infancy. Additionally, they rapidly develop neurological signs, especially seizures. The clinical findings and neuropathological changes are very similar in humans and the present case. There are no studies regarding degeneration of grey matter and its effect on learning ability in animals. However, other neurodegenerative problems (ie, lysosomal storage diseases) and problems that lead to structural abnormalities of the forebrain (ie, hydrocephaly) may be correlated with learning disabilities in animals and humans. 14 – 17 The acquisition of the elimination habits occurs during the first weeks of a kitten’s life. Most kittens naturally seek out sand-like materials for elimination purposes. However, the preference for a substrate needs to be learnt during those first weeks of age. Learning disabilities and/or sensory impairments could modify the acquisition of these habits.'} | [
"A complete blood count and a complete biochemistry panel were performed, and all of the results were within normal limits"
] | [] | [
"A 7 - month - old, entire female, domestic shorthair cat was referred to our behavioural service owing to house soiling and a play - related problem. The owners ’ complaints were that the cat had never used the litter tray, and it did not know how to play",
"After 3 months, the cat was referred to the neurology service again, in status epilepticus.",
"After 2 years of treatment and a progressive worsening, the cat was euthanased."
] | [
"house soiling and a play - related problem.",
"did not know how to play.",
"the cat did not understand the body language of other cats and commonly crashed into other cats or people. It also ‘ tried to bite, catch and scratch the air ’ when playing. It did not find balls or other toys when the owners threw them to the cat to play. The rest of the cat ’s behavioural history was unremarkable",
"moderate and hypermetric ataxic gait, and a bilateral lack of menace response",
"based on the behaviours at home described by the owners ( the inability to find some toys, and the behaviour of ‘ scratching and biting the air ’ ), some degree of visual impairment was suspected but not confirmed",
"The cat did not crash with objects either at home or at the consultation room",
"brain magnetic resonance imaging ( MRI; 0.2 T ) and cerebrospinal fluid analysis showed no abnormalities.",
"suggests that there was a learning impairment during the acquisition of habits but not a total lack of learning capability.",
"status epilepticus",
"lack of bilateral menace response and cerebellar ataxic gait",
"progressive gait deficits over the previous month and compulsive running episodes with a partially impaired mental status ( probably seizure activity )",
"seizures reappeared after 2 months with 1–2 episodes every 15 days each lasting < 2 mins",
"No gross lesions were found, and based on the CNS histological lesions shown in Figures 1 – 4, a diagnosis of spongiform polioencephalomyelopathy was made. The spongiform degeneration of the grey matter was extensively distributed in the whole CNS."
] | [
"A complete blood count and a complete biochemistry panel were performed, and all of the results were within normal limits. The feline immunodeficiency virus / feline leukaemia virus test was negative.",
"A thorax radiograph, abdominal ultrasound, brain magnetic resonance imaging ( MRI; 0.2 T ) and cerebrospinal fluid analysis showed no abnormalities.",
"Amino acids, organic acids, carbohydrates, nitroprusside, ketone and mucopolysaccharide concentrations were analysed, as was α - mannosidase, β - mannosidase, fucosidase and hexosaminidase A and B activity. All of these were within normal limits.",
"No gross lesions were found, and based on the CNS histological lesions shown in Figures 1 – 4, a diagnosis of spongiform polioencephalomyelopathy was made. The spongiform degeneration of the grey matter was extensively distributed in the whole CNS.",
"PrPsc inmunohistochemistry assay was performed, and the results were negative"
] | [] | [] | [] | [] | [
"bilateral carpal valgus"
] | [
"No ophthalmological abnormalities were detected",
"based on the behaviours at home described by the owners ( the inability to find some toys, and the behaviour of ‘ scratching and biting the air ’ ), some degree of visual impairment was suspected but not confirmed",
"visible suture line in the posterior capsule of both crystalline lenses were also detected"
] | [] | [] | [] | [
"7 - month - old"
] | [] | [
"congenital spongiform polioencephalomyelopathy ( CSP ) was diagnosed postmortem"
] | [] |
5680934 | {'Case Report': 'This boy was born to nonconsanguineous Chinese parents. He was born at term, weighed 3100 g with good Apgar scores. He had global developmental delay at 7 months of age with severe head lag and generalized hypotonia. He was brachycephalic with hypopigmented hair. He had poor weight gain with swallowing dysfunction and significant reflux disease requiring gastrostomy feeding. He started having orofacial and limb dyskinesias at 1.5 years of age and subsequently developed refractory multifocal epilepsy at 3 years of age requiring multiple antiepileptics and ketogenic diet to control his seizures. Electroencephalogram showed focal and diffuse slowing consistent with background encephalopathic state, with frequent multifocal epileptiform discharges bilaterally. He developed central and obstructive sleep apneas at 3.5 years of age and was initiated on night bilevel positive airway pressure. He was evaluated with magnetic resonance imaging brain scan and chromosomal microarray at 8 months of age, which was normal. Whole-exome sequencing and direct sequencing confirmed that he harbored compound heterozygous missense mutations c.3130C>T (p.Arg1044Cys), c.3430C>T (p.Arg1144Cys), and c.4078G>A (p.Ala1360Thr) in the LRPPRC gene mapped to chromosome 2p21-p16. Parents were carriers of the mutation. His muscle biopsy showed normal muscle architecture with no “ragged-red” fibers, necrotic fibers, or regenerating fibers seen. Cytochrome c-oxidase was positive in most of the fibers. There were no light microscopic or ultrastructural features to support mitochondrial myopathy. Respiratory chain enzymes in skeletal muscle were diagnostic for complex IV defect ( Table 1 ). He is currently 5 years of age, has generalized dystonia, and is mainly chair-bound. He has intermittent eye contact and minimal vocalization. His baseline lactates ranged from 1.5 to 3.6 mmol/L with mild intermittent metabolic acidosis. However, there were no episodes of acute ketosis, glycemic derangements, or any acute stroke-like episodes. The parents’ first child was diagnosed with steroid-resistant nephrotic syndrome at 18 months of age requiring tacrolimus treatment. Their second pregnancy was terminated at 22 weeks’ gestation due to antenatal diagnosis of Ebstein’s anomaly and multiple valvular abnormalities.'} | [] | [
"poor weight gain with swallowing dysfunction and significant reflux disease"
] | [
"This boy was born to nonconsanguineous Chinese parents. He was born at term, weighed 3100 g with good Apgar scores. He had global developmental delay at 7 months of age with severe head lag and generalized hypotonia.",
"He had poor weight gain with swallowing dysfunction and significant reflux disease",
"He started having orofacial and limb dyskinesias at 1.5 years of age and subsequently developed refractory multifocal epilepsy at 3 years of age",
"He developed central and obstructive sleep apneas at 3.5 years of age",
"Parents were carriers of the mutation",
"The parents ’ first child was diagnosed with steroid - resistant nephrotic syndrome at 18 months of age requiring tacrolimus treatment. Their second pregnancy was terminated at 22 weeks ’ gestation due to antenatal diagnosis of Ebstein ’s anomaly and multiple valvular abnormalities."
] | [
"He had global developmental delay at 7 months of age with severe head lag and generalized hypotonia",
"brachycephalic",
"swallowing dysfunction",
"started having orofacial and limb dyskinesias at 1.5 years",
"refractory multifocal epilepsy at 3 years of age",
"Electroencephalogram showed focal and diffuse slowing consistent with background encephalopathic state, with frequent multifocal epileptiform discharges bilaterally",
"magnetic resonance imaging brain scan and chromosomal microarray at 8 months of age, which was normal.",
"has generalized dystonia, and is mainly chair - bound. He has intermittent eye contact and minimal vocalization"
] | [
"magnetic resonance imaging brain scan and chromosomal microarray at 8 months of age, which was normal.",
"Whole - exome sequencing and direct sequencing confirmed that he harbored compound heterozygous missense mutations c.3130C > T ( p. Arg1044Cys ), c.3430C > T ( p. Arg1144Cys ), and c.4078G > A ( p. Ala1360Thr ) in the LRPPRC gene",
"His muscle biopsy showed normal muscle architecture with no “ ragged - red ” fibers, necrotic fibers, or regenerating fibers seen. Cytochrome c - oxidase was positive in most of the fibers. There were no light microscopic or ultrastructural features to support mitochondrial myopathy. Respiratory chain enzymes in skeletal muscle were diagnostic for complex IV defect",
"His baseline lactates ranged from 1.5 to 3.6 mmol / L with mild intermittent metabolic acidosis. However, there were no episodes of acute ketosis, glycemic derangements, or any acute stroke - like episodes"
] | [] | [] | [] | [
"central and obstructive sleep apneas at 3.5 years of age"
] | [
"brachycephalic"
] | [] | [
"hypopigmented hair"
] | [
"He was born at term, weighed 3100 g with good Apgar scores."
] | [] | [
"5 years of age"
] | [
"7 months of age"
] | [] | [] |
6511931 | {'Chief complaints': 'A 52-year-old female presented with a sudden onset of right-sided numbness and weakness that was accompanied by a left temporal cluster-like headache. No fever or prodromal infection was found at disease onset.', 'Imaging examinations and history of present illness': 'MRI demonstrated a lamellar left parietal lobe lesion predominantly involving the cortex, with hyperintensity on both diffusion-weighted imaging and fluid-attenuated inversion recovery (Figure 1 ). The apparent diffusion coefficient map revealed a preserved, isointense signal. No abnormalities were found by susceptibility weighted imaging or magnetic resonance angiography and venography (Figure 1 ). Due to the stroke-like onset pattern and MRI features, further thrombophilia screening was performed and showed decreased protein S activity. A diagnosis of cortical venous thrombosis was first proposed. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) was also considered but temporarily excluded because of the incomplete manifestation and lack of genetic evidence. Anticoagulation therapy was initiated, and follow-up was performed to maintain the international normalized ratio (INR) within the target range. Two months later, the patient was readmitted for subacute cognitive impairment. She was unable to identify and communicate with family members; she also had difficulty understanding questions or instructions and instead responded by repeating the word "nothing". During hospitalization, a secondary generalized seizure occurred, initially with eyes gazing to the right and then convulsion developing, which lasted for approximately 10 s before self-alleviation. Neurological examination suggested transcortical sensory aphasia, with fully covered limb strength. Blood tests and CSF examination were normal; INR was 2.21. On repeated MRI, new lesions were identified in the left temporal lobe and were also detected 10 days later in the right temporal lobe on radiological follow-up (Figures 1 and 2 ). Although the MRI signal characteristics are consistent with the initial findings, the original lesion in the left parietal lobe had been alleviated, with cortical atrophy. We further conducted magnetic resonance spectroscopy (MRS), which revealed markedly elevated lactate (Lac) concentrations in the regions of interest in the left temporal lesion (Figure 1 ). Mitochondrial encephalopathy was diagnosed, and genetic testing using peripheral blood was performed. However, DNA testing for frequent MELAS and myoclonic epilepsy with ragged red fibers syndrome mutations were negative. Because of the lack of symptoms of muscle weakness or pain, the patient declined our suggestion of performing a muscle biopsy. Anticoagulation therapy was terminated, and levetiracetam (1000 mg/d) was administered. At 3 mo after her second admission, the patient was experiencing involuntary movement in her left limbs, with repetitive flexion/extension. An MRI scan showed a hyperintense signal abnormality in the right parietal lobe (Figure 2 ). Brachial biceps biopsy was performed. Histopathology revealed no abnormalities, and no necrotic or regenerating fibers were observed; ragged-red fibers and intense succinate dehydrogenase activity were not detected. Nonetheless, complete sequencing of mitochondrial DNA samples extracted from the biopsied muscle revealed a heteroplasmic m.10158T>C mutation, with a heteroplasmy level of 69.6%, in the mitochondrial complex I subunit gene MT-ND3 . In contrast, this mutation was not found in her peripheral blood cells.', 'Personal and family history': 'The family and personal history was unremarkable.', 'Physical examination upon admission': 'On physical examination, the height and weight of the patient were 154 cm and 56 kg, respectively. Vital signs were normal, as were heart, lung and abdominal exami-nations. Neurological examination showed intact mental status, with normal speech and comprehension. Mild 4/5 right-sided hemiparesis was present with normal tone in both the arm and leg, though no other focal neurological deficits were found. After admission, she complained of discomfort and tingling in the right leg, after which a generalized tonic-clonic seizure for 3 min occurred before it was stopped by a bolus of intravenous diazepam.', 'CASE SUMMARY': 'We report a 52-year-old woman with recurrent stroke-like episodes carrying the m.10158T>C mutation in the MT-ND3 gene, which is also responsible for fatal infant-onset Leigh syndrome. Despite the common mutation, the present case featured a distinct clinical and neuroimaging manifestation from Leigh syndrome. This patient presented with sudden onset of right-sided hemiparesis and hemilateral sensory disturbance accompanied by a left temporal cluster-like headache and later developed epilepsy during hospitalization, with no other signs suggestive of myopathy, lactate acidosis, or other systemic symptoms. Brain magnetic resonance imaging revealed variable lesions involving multiple cortical and subcortical regions. Furthermore, a negative genetic test obtained from peripheral blood delayed the diagnosis of mitochondrial disease, which was eventually established through second-generation DNA sequencing using biopsied muscle.', 'Laboratory examinations': 'Laboratory tests, including D-dimer, lactic acid, and serum autoantibody levels, as well as thyroid function and tumor markers indicated no apparent abnormalities. Glucose tolerance and lactic acid movement tolerance tests were normal. A lumbar puncture was performed, and her open intracranial pressure was 180 mm H 2 O. Cerebrospinal fluid (CSF) testing showed that cell counts and protein, glucose, chloride, monoclonal antibody, adenosine deaminase, and lactate dehydrogenas levels were within normal ranges.'} | [
"' On physical examination, the height and weight of the patient were 154 cm and 56 kg, respectively. Vital signs were normal"
] | [] | [
"A 52 - year - old female presented with a sudden onset of right - sided numbness and weakness that was accompanied by a left temporal cluster - like headache. No fever or prodromal infection was found at disease onset.",
"Two months later, the patient was readmitted for subacute cognitive impairment. She was unable to identify and communicate with family members; she also had difficulty understanding questions or instructions and instead responded by repeating the word \" nothing \". During hospitalization, a secondary generalized seizure occurred, initially with eyes gazing to the right and then convulsion developing, which lasted for approximately 10 s before self - alleviation",
"At 3 mo after her second admission, the patient was experiencing involuntary movement in her left limbs, with repetitive flexion / extension.",
"The family and personal history was unremarkable.",
"After admission, she complained of discomfort and tingling in the right leg, after which a generalized tonic - clonic seizure for 3 min occurred",
"52 - year - old woman with recurrent stroke - like episodes"
] | [
"sudden onset of right - sided numbness and weakness that was accompanied by a left temporal cluster - like headache.",
"Two months later, the patient was readmitted for subacute cognitive impairment. She was unable to identify and communicate with family members; she also had difficulty understanding questions or instructions and instead responded by repeating the word \" nothing \". During hospitalization, a secondary generalized seizure occurred, initially with eyes gazing to the right and then convulsion developing, which lasted for approximately 10 s before self - alleviation. Neurological examination suggested transcortical sensory aphasia, with fully covered limb strength",
"At 3 mo after her second admission, the patient was experiencing involuntary movement in her left limbs, with repetitive flexion / extension.",
"Neurological examination showed intact mental status, with normal speech and comprehension. Mild 4/5 right - sided hemiparesis was present with normal tone in both the arm and leg, though no other focal neurological deficits were found. After admission, she complained of discomfort and tingling in the right leg, after which a generalized tonic - clonic seizure for 3 min occurred",
"recurrent stroke - like episodes",
"sudden onset of right - sided hemiparesis and hemilateral sensory disturbance accompanied by a left temporal cluster - like headache and later developed epilepsy during hospitalization"
] | [
"MRI demonstrated a lamellar left parietal lobe lesion predominantly involving the cortex, with hyperintensity on both diffusion - weighted imaging and fluid - attenuated inversion recovery ( Figure 1 ). The apparent diffusion coefficient map revealed a preserved, isointense signal. No abnormalities were found by susceptibility weighted imaging or magnetic resonance angiography and venography ( Figure 1 ). Due to the stroke - like onset pattern and MRI features, further thrombophilia screening was performed and showed decreased protein S activity.",
"Blood tests and CSF examination were normal; INR was 2.21. On repeated MRI, new lesions were identified in the left temporal lobe and were also detected 10 days later in the right temporal lobe on radiological follow - up ( Figures 1 and 2 ). Although the MRI signal characteristics are consistent with the initial findings, the original lesion in the left parietal lobe had been alleviated, with cortical atrophy. We further conducted magnetic resonance spectroscopy ( MRS ), which revealed markedly elevated lactate ( Lac ) concentrations in the regions of interest in the left temporal lesion",
"MRI scan showed a hyperintense signal abnormality in the right parietal lobe ( Figure 2 ). Brachial biceps biopsy was performed. Histopathology revealed no abnormalities, and no necrotic or regenerating fibers were observed; ragged - red fibers and intense succinate dehydrogenase activity were not detected. Nonetheless, complete sequencing of mitochondrial DNA samples extracted from the biopsied muscle revealed a heteroplasmic m.10158T > C mutation, with a heteroplasmy level of 69.6 %, in the mitochondrial complex I subunit gene MT - ND3. In contrast, this mutation was not found in her peripheral blood cells.",
"Brain magnetic resonance imaging revealed variable lesions involving multiple cortical and subcortical regions.",
"Laboratory tests, including D - dimer, lactic acid, and serum autoantibody levels, as well as thyroid function and tumor markers indicated no apparent abnormalities. Glucose tolerance and lactic acid movement tolerance tests were normal. A lumbar puncture was performed, and her open intracranial pressure was 180 mm H 2 O. Cerebrospinal fluid ( CSF ) testing showed that cell counts and protein, glucose, chloride, monoclonal antibody, adenosine deaminase, and lactate dehydrogenas levels were within normal ranges."
] | [] | [] | [] | [] | [
"lack of symptoms of muscle weakness or pain",
"no other signs suggestive of myopathy"
] | [] | [] | [] | [] | [
"52 - year - old"
] | [] | [
"m.10158T > C mutation in the MT - ND3 gene"
] | [] |
6971469 | {'Case Report': 'A 24‐year‐old woman was admitted to our hospital with mildly impaired consciousness and myoclonus in the extremities. She had been diagnosed with MELAS at 21 years of age. Genetic testing revealed a 3271 T>C transition in the MT‐TL1 gene, clinically confirming the diagnosis of MELAS. After admission to hospital, neurological examination showed myoclonic movement in the extremities, mandible, and trunk. Muscle weakness was detected in the upper and lower limbs bilaterally. A laboratory examination showed increased serum pyruvic acid (2.1 mg/dL) and lactate (75 mg/dL). Brain magnetic resonance imaging showed bilateral high‐intensity lesions in the temporal and parietal lobes of the cortical and subcortical areas in T2 weighted imaging (Fig. 1 ). Antiepileptic drugs levetiracetam, perampanel, lacosamide, and clobazam were initiated. L‐arginine, coenzyme Q10, and L‐carnitine aimed at supporting mitochondrial energy production were given simultaneously. As the impaired consciousness and myoclonus persisted for 2 weeks, we undertook brain magnetic resonance imaging again, which revealed high‐intensity lesions in the right cortical temporal lobe, and arterial spin labeling showed increased blood flow in the bilateral frontal and temporal cortex. Electroencephalography revealed high‐amplitude slow and spiked waves. We diagnosed the patient with non‐convulsive status epilepticus. To control the seizures, propofol was given at a dose of 2.7 mg/kg/h for 12 h and then increased to 5.4 mg/kg/h, with midazolam added at a dose of 2 mg/h. On day 5, the urine appeared brown and arterial blood gas revealed metabolic acidosis (pH 7.261, pCO 2 33.0 mmHg, HCO 3 - 14.4 mmol/L, and lactate 99 mg/dL). Creatinine kinase was elevated at 20,999 U/L. The patient was diagnosed with PRIS. She was transferred to the intensive care unit (ICU) on day 19 of hospitalization. On admission to the ICU, the vital signs were as follows: body temperature, 39°C; blood pressure, 150/80 mmHg; heart rate, 150 b.p.m.; respiratory rate, 30 breaths/min; and SpO2, 99% (FiO 2 40%). Laboratory findings showed metabolic acidosis (lactic acid, 99 mg/dL; pyruvic acid, 0.92 mg/dL), creatinine kinase 29,560 U/L, and myoglobin 9,845 ng/mL. We treated her with interruption of propofol and continuous hemodiafiltration for metabolic acidosis. We continued coenzyme Q10, L‐carnitine, and L‐arginine for mitochondrial support for MELAS and antiepileptic drugs including levetiracetam, perampanel, lacosamide, and clobazam. After concurrent treatment of PRIS and MELAS, metabolic acidosis and creatinine kinase gradually decreased after reaching 59,000 IU/L on day 2 of ICU admission. Continuous hemodiafiltration was discontinued on day 11. Tracheostomy was carried out because i.v. midazolam treatment was prolonged to control the status epilepticus. Mechanical ventilation was discontinued on day 25 (Fig. 2 ). After rehabilitation, the patient was discharged on foot.', 'Case Presentation': 'A 24‐year‐old woman who had been diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes was admitted to our hospital with impaired consciousness and myoclonus. To control the non‐convulsive status epilepticus, propofol was administered. Arterial blood gas revealed metabolic acidosis, and creatinine kinase was elevated. The patient was diagnosed with PRIS. We treated her with interruption of propofol. She required mechanical ventilation for 25 days. After rehabilitation, she recovered and was discharged.'} | [
"On admission to the ICU, the vital signs were as follows : body temperature, 39 ° C; blood pressure, 150/80 mmHg; heart rate, 150 b.p.m.; respiratory rate, 30 breaths / min; and SpO2, 99 % ( FiO 2 40 % )"
] | [] | [
"A 24â€yearâ€old woman who had been diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokeâ€like episodes was admitted to our hospital with impaired consciousness and myoclonus."
] | [
"mildly impaired consciousness and myoclonus in the extremities",
"myoclonic movement in the extremities, mandible, and trunk",
"Brain magnetic resonance imaging showed bilateral high‐intensity lesions in the temporal and parietal lobes of the cortical and subcortical areas in T2 weighted imaging",
"impaired consciousness and myoclonus persisted for 2 weeks",
"brain magnetic resonance imaging again, which revealed high‐intensity lesions in the right cortical temporal lobe, and arterial spin labeling showed increased blood flow in the bilateral frontal and temporal cortex.",
"Electroencephalography revealed high‐amplitude slow and spiked waves",
"non‐convulsive status epilepticus",
"impaired consciousness and myoclonus",
"non‐convulsive status epilepticus"
] | [
"Genetic testing revealed a 3271 T > C transition in the MT‐TL1 gene",
"A laboratory examination showed increased serum pyruvic acid ( 2.1 mg / dL ) and lactate ( 75 mg / dL )",
"Brain magnetic resonance imaging showed bilateral high‐intensity lesions in the temporal and parietal lobes of the cortical and subcortical areas in T2 weighted imaging",
"brain magnetic resonance imaging again, which revealed high‐intensity lesions in the right cortical temporal lobe, and arterial spin labeling showed increased blood flow in the bilateral frontal and temporal cortex",
"arterial blood gas revealed metabolic acidosis ( pH 7.261, pCO 2 33.0 mmHg, HCO 3 - 14.4 mmol / L, and lactate 99 mg / dL ). Creatinine kinase was elevated at 20,999 U / L.",
"Laboratory findings showed metabolic acidosis ( lactic acid, 99 mg / dL; pyruvic acid, 0.92 mg / dL ), creatinine kinase 29,560 U / L, and myoglobin 9,845 ng / mL.",
"metabolic acidosis and creatinine kinase gradually decreased after reaching 59,000 IU / L",
"Arterial blood gas revealed metabolic acidosis, and creatinine kinase was elevated."
] | [] | [] | [
"urine appeared brown",
"PRIS"
] | [] | [
"Muscle weakness was detected in the upper and lower limbs bilaterally",
"urine appeared brown",
"PRIS"
] | [] | [] | [] | [] | [
"24‐year‐old",
"24‐year‐old"
] | [] | [
"diagnosed with MELAS at 21 years of age . Genetic testing revealed a 3271 T > C transition in the MT‐TL1 gene , clinically confirming the diagnosis of MELAS",
"diagnosed with mitochondrial myopathy , encephalopathy , lactic acidosis , and stroke‐like episodes"
] | [
"L‐arginine , coenzyme Q10 , and L‐carnitine aimed at supporting mitochondrial energy production were given",
"We continued coenzyme Q10 , L‐carnitine , and L‐arginine for mitochondrial support for MELAS"
] |
End of preview. Expand
in Data Studio
CaseReportBench: Clinical Dense Extraction Benchmark
CaseReportBench is a curated benchmark dataset designed to evaluate how well large language models (LLMs) can perform dense information extraction from clinical case reports, with a focus on rare disease diagnosis.
It supports fine-grained, system-level phenotype extraction and structured diagnostic reasoning — enabling model evaluation in real-world medical decision-making contexts.
🔔 Note
This dataset accompanies our upcoming publication:
Zhang et al. CaseReportBench: An LLM Benchmark Dataset for Dense Information Extraction in Clinical Case Reports.
To appear in the Proceedings of the Conference on Health, Inference, and Learning (CHIL 2025), PMLR.
The official PMLR citation and link will be added upon publication.
Key Features
- Expert-annotated, system-wise phenotypic labels mimicking clinical assessments
- Based on real-world PubMed Central-indexed clinical case reports
- Format: JSON with structured head-to-toe organ system outputs
- Designed for: Biomedical NLP, IE, rare disease reasoning, and LLM benchmarking
- Metrics include: Token Selection Rate, Levenshtein Similarity, Exact Match
Dataset Structure
Each record includes:
id: Unique document IDtext: Full raw case reportextracted_labels: System-organized dense annotations (e.g., neuro, heme, derm, etc.)diagnosis: Final confirmed diagnosis (Inborn Error of Metabolism)source: PubMed ID or citation
Usage
from datasets import load_dataset
ds = load_dataset("cxyzhang/caseReportBench_ClinicalDenseExtraction_Benchmark")
print(ds["train"][0])
Citation
@inproceedings{zhang2025casereportbench,
title = {CaseReportBench: An LLM Benchmark Dataset for Dense Information Extraction in Clinical Case Reports},
author = {Zhang, Cindy and Others},
booktitle = {Proceedings of the Conference on Health, Inference, and Learning (CHIL)},
series = {Proceedings of Machine Learning Research},
volume = {vX}, % Update when available
year = {2025},
publisher = {PMLR},
note = {To appear}
}
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