Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular lesions in two patients exhibiting classical clinical manifestations of MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) syndrome have been investigated. A recently reported disease-related A----G base substitution at nt 3243 of the mtDNA, in the DHU loop of tRNA(Leu), was detected by restriction-enzyme analysis of the relevant PCR-amplified segment of the mtDNA of one patient but was not observed, by either restriction-enzyme analysis or nucleotide sequencing, in the other. To define the molecular lesion in the patient who does not have the A----G base substitution at nt 3243, the total mitochondrial genome of the patient has been sequenced. An A----G base substitution at nt 11084, leading to a Thr-to-Ala amino acid replacement in the ND4 subunit of the respiratory complex I, is suggested to be a disease-related mutation.
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PMID:A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I. 821 27

Mitochondrial DNA is a unique, maternally inherited molecule encoding several subunits of the respiratory enzyme chain. In several mitochondrial cytopathies mutations have been described in this genome viz. large-scale heteroplasmic deletions in syndromes with progressive external ophthalmoplegia and point mutations in MELAS and MERRF encephalomyopathies. We here report Southern blot analyses in the cases of CPEO we have seen and describe the search for point mutations in MELAS and MERRF. Mitochondrial genetic sequencing in normal and disease controls as well as in patients has confirmed the pathogenic nature of a tRNA Lys point mutation in MERRF. We propose a novel mitochondrial structural gene mutation in a MELAS--like encephalomyopathy: an A-->G substitution at position 11084 leading to a Thr to Ala replacement in the ND4 subunit of complex I.
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PMID:The molecular genetics of mitochondrial cytopathies: the Melbourne experience. 134 60

A T-to-C transition mutation at nucleotide position 3,250 in the mitochondrial tRNA(Leu)(UUR) gene was present in a family with mitochondrial myopathy. Two of three muscle biopsies examined had complex I (NADH-ubiquinone oxidoreductase) deficiency. Heteroplasmy of wild and mutant mitochondrial DNA was detected by Nae I digestion of the polymerase chain reaction products with a modified primer. This was found in blood or muscle samples or both from all seven members examined. Similar to the 3,243 mutation in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), the new mutation site was located in the dihydrouridine loop and embedded in the binding region of mitochondrial transcription termination factor. Elucidation of the effects of this mutation may help clarify the role of mitochondrial tRNAs and transcription termination.
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PMID:A novel point mutation in the mitochondrial tRNA(Leu)(UUR) gene in a family with mitochondrial myopathy. 151 79

We studied 40 MELAS patients (21 male and 19 female) to characterize the clinical features and biochemical and muscle biopsy findings related to the mtDNA mutation at the nucleotide position of 3,243, the most common genetic defect in MELAS. The most frequent symptom was episodic sudden headache with vomiting and convulsions, which commonly affected patients aged 5 to 15 years (80%). Biochemical defects in the muscle were variable; 13 patients had complex I, seven complex IV, and four complexes I + IV deficiencies. In four muscle biopsies without ragged-red fibers or any enzyme defect, we based the diagnosis on the identification of strongly SDH-reactive blood vessels, which occurred in 87.5% of the biopsies. The mtDNA mutation was present in 32 of 40 patients (80%). We conclude that there are no clinical and pathologic differences between the patients with and without this mtDNA mutation.
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PMID:Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. 154 15

A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, in which a pituitary growth hormone (GH) secretion deficiency of hypothalamic origin was revealed through neuro-endocrinological examinations, was described. The case was a 10-year-old girl, who had been suffering from generalized tonic seizures since age 5, four episodes of alternating hemiplegia since age 6, stunted growth since age 7, and simple partial motor seizures as well as gelastic seizures since age 8. Marked elevation of lactate and pyruvate in both serum and CSF, abundant ragged red fibers in biopsied muscle, and low density areas in the left occipital lobe and bilateral globus pallidus in addition to diffuse brain atrophy on CT scan and MRI of the head were demonstrated, although the activities of muscle enzymes complex I-IV were within normal ranges. Pituitary GH secretion was deficient under the loadings with insulin, L-DOPA, sleep, and a single growth hormone releasing factor (GRF) administration, but normal GH response was registered under the repetitive stimulation with GRF. Activities of other hormonal axes were normal. It is likely that short stature commonly observed in MELAS patients is due to hypothalamic dysfunction, which might be brought out by chronic ischemia and energy deficiency of the diencephalon based upon mitochondrial abnormality of that region. It is likely that gelastic seizure in this case is due to hypothalamic dysfunction.
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PMID:[Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS]. 187 57

Neuropathological studies were carried out in two patients with mitochondrial encephalomyopathies in whom the underlying lesions in muscle mitochondrial DNA (mtDNA) and respiratory enzyme complexes have been investigated. The first, a man with Kearns-Sayre syndrome, died at the age of 49 years. Autopsy showed an old parietal lobe infarct, diffuse spongiform leukoencephalopathy of cerebral and cerebellar white matter and mild spongiform change in deep grey matter and brainstem nuclei. Heteroplasmy of skeletal muscle mitochondrial DNA with a 3.5 kb mtDNA deletion in one of two mtDNA populations was found. The second case, a woman, suffering from myoclonic epilepsy, cerebellar ataxia, bilateral sensorineural deafness, several 'stroke-like' episodes died at age 52. At autopsy, an old infarct was seen in the L internal capsule. Severe loss of neurons and gliosis were found in the dentate nuclei, moderate changes in the red nuclei and inferior olivary nuclei and mild changes in the substantial nigra and locus coeruleus. In both patients, skeletal muscle biopsy showed numbers of ragged-red fibres and intramitochondrial paracrystalline inclusions at electron microscopy. A defect in the synthesis of the ND5 subunit of the respiratory complex I was suggested in the second patient in whom a diagnosis of MELAS was made.
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PMID:Mitochondrial encephalomyopathies: a correlation between neuropathological findings and defects in mitochondrial DNA. 190 31

Biochemical results concerning 64 patients suspected of mitochondrial myopathies are presented. Four clinical groups were studied including 21 encephalomyopathies, 42 ocular myopathies, 8 isolated myopathies and 3 cardiomyopathies. In 26 cases, the coexistence of a normal mitochondrial DNA and a mutated mitochondrial DNA (heteroplasmy) was found (19 simple deletions, 4 multiple deletions and 3 punctual mutations) and all cases presented with ocular disorders (excepted 2 cases with MERRF). Furthermore, 1 complex I deficiency (1 ocular myopathy), 1 complex IV deficiency (1 adult encephalomyopathy type Leigh), 3 complexes I + IV deficiencies (2 cases with a cardiomyopathy and 1 familial MELAS) and 2 pyruvate (1 adult from of Leigh's encephalomyopathy) dehydrogenase deficiencies (clinically and genetically different) did not show evidence of mitochondrial DNA mutation.
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PMID:[Mitochondrial function and mitochondrial DNA in a series of 64 patients suspected of having mitochondrial myopathy]. 196 51

The NADH-quinone oxidoreductases of the bacterial respiratory chain could be divided in two groups depending on whether they bear an energy-coupling site. Those enzymes that bear the coupling site are designated as NADH dehydrogenase 1 (NDH-1) and those that do not as NADH dehydrogenase 2 (NDH-2). All members of the NDH-1 group analyzed to date are multiple polypeptide enzymes and contain noncovalently bound FMN and iron-sulfur clusters as prosthetic groups. The NADH-ubiquinone-1 reductase activities of NDH-1 are inhibited by rotenone, capsaicin, and dicyclohexylcarbodiimide. The NDH-2 enzymes are generally single polypeptides and contain noncovalently bound FAD and no iron-sulfur clusters. The enzymatic activities of the NDH-2 are not affected by the above inhibitors for NDH-1. Recently, it has been found that both of these types of the NADH-quinone oxidoreductase are present in a single strain of bacteria. The significance of the occurrence of these two types of enzymes in a single organism has been discussed in this review.
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PMID:Bacterial NADH-quinone oxidoreductases. 205 Jun 55

We reported a case of mitochondrial encephalomyopathy with repeated stroke-like episodes. A 33-year-old single male was admitted to our hospital because of stroke-like episodes with visual field defect, hemiplegia and convulsion repeated seven times for the past seven years. There were no abnormalities on the physical examination. He was hallucinative and perseverative and had mental deficiency. Muscle weakness and atrophy were not prominent, and generalized hyporeflexia were present without pathological reflexes. Myoclonus was not observed. Serum CK and blood gas analysis were normal (pH 7.398). Although blood levels of lactate and pyruvate were almost within normal limit, lactate was elevated by 20WATT-15 minutes exercises. On the contrary, the CSF levels of lactate and pyruvate were elevated markedly. CT of the brain revealed the presence of the low density areas in the right occipital and the left frontal lobes. Cranial 4 vessels studies were unremarkable. EEG showed the diffuse slowness with spike and wave complex. CT of the muscles were normal. A specimen obtained from the left biceps brachii muscle showed ragged-red fibers without obvious myogenic or neurogenic changes, and accumulations of abnormal mitochondria with paracrystalline inclusion bodies were observed by electron microscopy. However, mitochondrial abnormalities were not seen in the vessel walls in the biopsied muscle. Activities of complex I + III, II + III, IV in mitochondria were normal. Clinical features of this case were consistent with MELAS. However, this case showed no muscle weakness, short stature and lactic acidosis which characterize MELAS, and the onset of this case was later than those cases that were reported before.
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PMID:[A case of mitochondrial encephalomyopathy characterized by repeated stroke-like episodes]. 250 53

A 29-year-old man with mitochondrial encephalomyopathy caused by partial deficiency of mitochondrial NADH-ubiquinone oxidoreductase (Complex I) is described. Clinical manifestations were characterized by generalized convulsion, dementia and stroke-like episodes consisting of hemianopsia, Gerstmann's syndrome and visual hallucination. Blood and cerebrospinal fluid lactate and pyruvate levels were elevated. Biochemical studies on a muscle biopsy specimen revealed partial deficiency of Complex I activity, and decreases in the 75-kDa and the 20-kDa subunits of Complex I by immunoblotting analysis. Serial brain CT scans revealed multiple low-density areas with fluctuating densities. Single photon emission tomographic study revealed preservation of blood circulation where CT scans showed diminished density in acute stage, suggesting the presence of abnormal cellular metabolism rather than vascular occlusion as the basic mechanism of his stroke-like episodes. Pathogenesis of neurological manifestations in MELAS is discussed with reference to the possible involvement of free radicals in inducing brain damage.
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PMID:Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with special reference to the mechanism of cerebral manifestations. 251 13


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