Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies analyzing mtDNA have established to elucidate the molecular pathology of mitochondrial encephalomyopathies. The human mitochondrial genome is 16,569 bp circular double-stranded molecule that is maternally inherited. Since the first report on large deletions of mtDNA in patients with progressive external ophthalmoplegia (PEO) by Holt et al in 1988, various mtDNA mutations were found. On the basis of the recent findings of mtDNA mutations, genetic classification of mitochondrial diseases has been proposed by S DiMauro in 1991. (1) large deletions or duplications of mtDNA were found in PEO and Pearson disease. (2) A single base substitution were reported in several mitochondrial encephalomyopathies as follows: (a) At nucleotide position 11778, 4136 or 4160......Leber's hereditary optic neuritis, (b) 8344......MERRF, (c) 3243 or 3271......MELAS, (d) 8993......Holt's disease.
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PMID:[Mitochondrial encephalomyopathies: pleomorphism of the mitochondrial DNA mutations and clinical features]. 841 14

A 17-year old girl presented with recurrent seizures, strokes, fatigue, vomiting, cerebellar ataxia, dementia and hypertrichosis. Further examinations showed jerking left-sided arm reflexes, partial internal deafness and myopathy. CT and MR of the skull revealed radiolucencies within the cerebral matter of the cortex and the medulla. Laboratory tests showed increased levels of lactate and pyruvate in serum and cerebro-spinal fluid. Microscopic examination of muscular tissue showed "ragged red fibers". Electron microscopy yielded crystal inclusions in mitochondria. The symptoms represented the complete picture of the so-called MELAS/MERRF-complex, which can be easily misdiagnosed as strokes and seizures of unknown cause.
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PMID:[Stroke, epilepsy and abdominal pain as leading symptoms in a case of mitochondrial encephalomyopathy]. 844 77

A number of human diseases are caused by inherited mitochondrial DNA mutations. Two of these diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres), are commonly caused by point mutations to tRNA genes encoded by mitochondrial DNA. Here we report on how these mutations affect mitochondrial function in primary fibroblast cultures established from a MELAS patient containing an A to G mutation at nucleotide 3243 in the tRNA(Leu(UUR) gene and a MERRF patient containing an A to G mutation at nucleotide 8344 in the tRNA(Lys) gene. Both mitochondrial membrane potential and respiration rate were significantly decreased in digitonin-permeabilized MELAS and MERRF fibroblasts respiring on glutamate/malate. A similar decrease in mitochondrial membrane potential was found in intact MELAS and MERRF fibroblasts. The mitochondrial content of these cells, estimated by stereological analysis of electron micrographs and from measurement of mitochondrial marker enzymes, was similar in control, MELAS and MERRF cells. Therefore, in cultured fibroblasts, mutation of mitochondrial tRNA genes leads to assembly of bioenergetically incompetent mitochondria, not to an alteration in their amount. However, the cell volume occupied by secondary lysosomes and residual bodies in the MELAS and MERRF cells was greater than in control cells, suggesting increased mitochondrial degradation in these cells. In addition, fibroblasts containing mitochondrial DNA mutations were 3-4-fold larger than control fibroblasts. The implications of these findings for the pathology of mitochondrial diseases are discussed.
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PMID:Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. 880 26

A study of mitochondrial DNA disease was carried out on 12 members belonging to three generations of a family from northern Sardinia. On the basis of the diagnostic criteria currently used in the classification of mitochondrial diseases a typical MERRF-MELAS overlap phenotype was seen in 11 patients with the mtDNA tRNA(lys) mutation at nucleotide position 8356. Clinical and instrumental investigations (EEG in particular) were made. Patients were divided into two groups: severely and mildly affected cases. The follow-up was reported. The aim of this study was to identify, through EEG, the early signs of the disease. The EEG findings recorded during the clinical evolution allowed us to recognize four degrees of cerebral involvement, and could also suggest the prognosis.
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PMID:Clinical and EEG findings in eleven patients affected by mitochondrial encephalomyopathy with MERRF-MELAS overlap. 883 98

Point mutations in mitochondrial DNA, as found in MELAS, MERRF, NARP and other syndromes, are inherited via the maternal lineage. Genetic counselling can be beneficial, but prenatal diagnosis is not advantageous in these syndromes. Empirical data about the recurrence risk can be applied in Leber disease (LHON). Mitochondrial disorders not associated with a point mutation have a sporadic nature (large deletions/duplications in mitochondrial DNA) or are transmitted according to Mendelian laws. Autosomal dominant inheritance is likely to be found in disorders with depletion of mitochondrial DNA. X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E1 alpha subunit of the pyruvate dehydrogenase complex. Mutation analysis or linkage studies can be applied for carrier detection and prenatal diagnosis in these three types of mitochondriopathies. The majority of the disorders with a disturbed mitochondrial energy metabolism are likely inherited in an autosomal recessive mode. Prenatal diagnosis can be performed in the cases of cytochrome c oxidase and NADH dehydrogenase deficiencies in chorionic villi in selected families.
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PMID:Genetic counselling and prenatal diagnosis in disorders of the mitochondrial energy metabolism. 888 81

Because Wolfram (or DIDMOAD) syndrome is supposed to be a mitochondrial (mt)-mediated disease, we investigated a group of eight DIDMOAD patients with respect to point mutations of the mtDNA thus far described as being associated with defined mitochondrial disorders such as MELAS, MERRF, and LHON. Furthermore, to screen DIDMOAD patients for other mtDNA defects we used Southern blot analysis to detect mtDNA length mutations and rearrangements as well as PCR-SSCP and direct sequencing to screen all ND genes (complex I of the respiratory chain), the 22 tRNAs, and a part of the cyt b gene for unknown mutations. As a disease control group, 17 LHON patients (harboring one of the primary LHON mutations) were included in this study because of the overlapping clinical symptoms (optic atrophy) in both syndromes. We compared mtDNA variants identified in DIDMOAD patients with those found in LHON patients as well as in a control group consisting of 67 healthy German blood donors. In total, the control group was characterized by 29 polymorphic sites in ND and tRNA genes that define certain major Caucasian haplotypes. We found that a cluster of nucleotide exchanges at nucleotide positions (nps) 4216 and 11,251 roughly discriminates controls (12/67 controls, 18%) from the disease groups (6/8 DIDMOAD patients, 75%; 10/17 LHON patients, 59%). All 4216-positive LHON patients (10 patients) were concentrated in a haplogroup defined by additional exchanges at nps 10,398, 12,612, and 13,708 (haplogroup A), while the bulk of 4216-positive DIDMOAD patients (5 patients) were found in a distinct haplogroup consisting of nucleotide exchanges at nps 4917, 10,463, 13,368, 14,233, and 15,928. The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. A more detailed analysis was performed by sequencing the two hypervariable regions of the non-coding D-loop region from patients and controls and corroborated the ranging in the two major haplogroups. Thus, the different clinical features of the mitochondrial disease groups investigated here corresponded to different clusters of mtDNA variants, which might act as predisposing haplotypes, increasing the risk for disease.
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PMID:Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. 902 81

Defects of the mitochondrial energy production cab be expressed in many tissues and may lead to various types of diseases. Since defects can occur on many sites of the oxidative phosphorylation system, molecular diagnosis can be difficult. In typical mitochondrial syndromes, like MELAS- or MERRF-syndrome, diagnosis can be suspected already on clinical grounds. Lactate measured in various body fluids is still the best selective screening parameter. Loading tests, respectively ergometry is only necessary in the milder clinical forms of diseases or possibly in older children. The in vivo lactate determination e.g. In the CNS by 1H NMR spectroscopy can be helpful in evaluating prognosis. The diagnosis of a mitochondriopathy is usually confirmed enzymatically by tissue biopsies; skeletal muscle is still the tissue of the first choice because some enzyme deficiencies are not sufficiently expressed in cultured fibroblasts. If possible, intact mitochondria should be investigated polarografically along with histology and histochemistry. Finally several parts of the respiratory chain and pyruvate dehydrogenase complex are analyzed by single enzyme measurement. Also combined deficiencies have been described. Polypeptide subunits of respiratory chain complexes can be investigated by means of immunoblotting. The investigations of the mitochondrial DNA from the end of the diagnostic scale. The application of various new therapeutic agents, such as antioxidants, radical scavangers and cofactors have not come to any persuasive clinical result. But there is a number of reports about some successful treatment with coenzyme Q10, vitamin K3, vitamin C, riboflavin, thiamine, dichloroacetate and in PDHC -deficiency with ketogenic diet. Mitochondrial gene therapy appears only theoretical and speculative. Because of the enormous heterogeneity even on the DNA-level genetic counselling is reserved for some cases with exact molecular diagnosis.
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PMID:[Diagnosis and therapy of mitochondriopathies]. 913 66

The dynamics of oxygen delivery and utilization are examined in a variety of mitochondrial disorders during rest, exercise and post exercise. We used a non-invasive optical technique to measure the oxygen consumption in the exercising limb in normal subjects and 5 patients with cytochrome c oxidase deficiency. We also examined 6 patients with MELAS and MERRF syndrome. We measured near-infrared spectra of hemoglobin in the gastrocnemius muscle during treadmill exercise. Normal subjects demonstrated a sustained deoxygenation during exercise, indicating an efficient utilization of delivered oxygen. Patients with cytochrome c oxidase deficiency demonstrated consistent oxygenation during exercise indicating an under utilization of delivered oxygen. Patients with MELAS and MERRF syndrome showed similar under utilization of oxygen during exercise. Non-invasive tissue oximetry during exercise demonstrates specific abnormalities in a variety of mitochondrial disorders, indicating abnormal oxygen utilization, and will be a useful addition to the clinical investigation of such disorders.
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PMID:Diagnosis of defects in oxidative muscle metabolism by non-invasive tissue oximetry. 930 58

The complete mechanism by which pathogenic mtDNA mutations cause cellular pathophysiology and in some cases cell death is unclear. Oxidant stress is especially toxic to excitable nerve and muscle cells, cells that are often affected in mitochondrial disease. The sensitivity of cells bearing the LHON, MELAS, and MERRF mutations to oxidant stress was determined. All were significantly more sensitive to H2O2 exposure than their nonmutant cybrid controls, the order of sensitivity was MELAS > LHON > MERRF > controls. Depletion of Ca2+ from the medium protected all cell lines from oxidant stress, consistent with the hypothesis that death induced by oxidant stress is Ca(2+)-dependent. A potential downstream target of Ca2+ is the mitochondrial permeability transition, MPT, which is inhibited by cyclosporin A. Treatment of MELAS, LHON, and MERRF cells with cyclosporin A caused significant rescue from oxidant exposure, and in each case significantly greater rescue of mutant than control cells. The pronounced oxidant-sensitivity of mutant cells, and their protection by Ca2+ depletion and CsA, has potential implications for both the pathophysiological mechanism and therapy of these mitochondrial genetic diseases.
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PMID:mtDNA mutations confer cellular sensitivity to oxidant stress that is partially rescued by calcium depletion and cyclosporin A. 934 84

In most cases of the mitochondrial encephalomyopathies, the mutations of mtDNA usually appear in heteroplasmic states. The degree of mtDNA heteroplasmy has been suggested to play an important role in determining the clinical phenotype and the organ-specific defects. We had devised a novel method for quantitative analysis of heteroplasmy using PCR-SSCP, this method is useful to accurately quantitate heteroplasmy of very small amount of samples. Using this method, we analyzed the heteroplasmy of skeletal muscle or leucocyte from 12 cases of MERRF and 5 cases of MELAS. And we analyzed autopsied cases (2 MERRF and 2 MELAS patients), and the cellular or organellar distributions of heteroplasmy of CNS in MERRF patients, and discussed the correlation of heteroplasmy of mtDNA and clinicopathological findings.
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PMID:[The correlation of the heteroplasmy of mtDNA and clinicopathological findings in the patients with mitochondrial encephalomyopathies]. 943 49


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