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)

Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of inherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect. Marked variation in the level of mutant mtDNA among tissues is thought to be responsible for the diverse clinical phenotypes associated with the same pathogenic mtDNA mutation. This study was designed to determine whether the percentage level of a pathogenic mtDNA molecule is determined by a purely random process. The tissue distribution of the A3243G MELAS point mutation was analyzed in five individuals who were members of a family with maternally inherited diabetes and deafness. The level of mutant mtDNA was measured in four tissues in three individuals and three tissues in two individuals. The highest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocyte/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 x 10(-5). These results indicate that the distribution of the A3243G mutation is not solely determined by random processes.
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PMID:Nonrandom tissue distribution of mutant mtDNA. 1040 50

We report the unusual features of a female patient who had MELAS-specific A3243G mutation in mitochondrial DNA (mtDNA) and diabetes mellitus (DM). The patient showed mitochondrial myopathy, encephalopathy, lactic acidosis, and deafness but lacked the stroke-like episode. Acute hyperglycemia was noted after one attack of status epilepticus. Molecular genetic analysis demonstrated a heteroplasmic A3243G point mutation in the mtDNAs of muscle, blood cells and hair follicles. Glucagon stimulation test exhibited marked depression of pancreatic beta-cell function. However, in a further study neither this mutation, nor MELAS syndrome or DM, was found in all of her maternal relatives. A series of follow-up studies for beta-cell function also showed gradual improvement. The pedigree study led us to believe that this A3243G mutation arose from the germ line cells or occurred later in somatic tissues of the patient. We also suggest that the A3243G mutation of mtDNA may elicit the pathogenesis of a subtype of DM. Nevertheless, environmental stress may be another important factor for provocation of the disease.
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PMID:Absence of maternal A3243G mtDNA mutation and reversible hyperglycemia in a patient with MELAS syndrome. 1066 Jan 56

MELAS is a mitochondrial encephalomyopathy characterized clinically by recurrent stroke-like episodes, seizures, sensorineural deafness, dementia, hypertrophic cardiomyopathy, and short stature. The majority of patients are heteroplasmic for a mutation (A3243G) in the tRNAleu(UUR) gene in mitochondrial DNA (mtDNA). In cells cultured in vitro, the mutation produces a severe mitochondrial translation defect only when the proportion of mutant mtDNAs exceeds 95% of total mtDNAs. However, most patients are symptomatic well below this threshold, a paradox that remains unexplained. We studied the relationship between the level of heteroplasmy for the mutant mtDNA and the clinical and biochemical abnormalities in a large pedigree that included 8 individuals carrying the A3243G mutation, 4 of whom were asymptomatic. Unexpectedly, we found that brain lactate, a sensitive indicator of oxidative phosphorylation dysfunction, was linearly related to the proportion of mutant mtDNAs in all individuals carrying the mutation, whether they were symptomatic or not. There was no evidence for threshold expression of the metabolic defect. These results suggest that marked tissue-specific differences may exist in the pathogenic expression of the A3243G mutation and explain why a neurological phenotype can be observed at relatively low levels of heteroplasmy.
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PMID:Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree. 1066 88

Though mitochondria have been a major source of energy production in eukaryotae since 15-20 billion years previously, existence of disorders due to primary abnormalities of their DNA has not been known until very recent years. In 1962, Luft et al reported the first case of such myopathy, and another case reported in 1967 by Shy et al was also the first case of generalized disorder with mitochondrial abnormalities. Since then, many case reports have followed including MELAS and other encephalomyopathies. Finally, in 1989, deletion of mitochondria DNA was found by Folt et al. Today, these disorders were able to be classified as follows: 1) LHON and A1555G type deafness as strictly limited non-syndromic type, 2) encephalomyopathies and their incomplete forms due to common and other deletions of mitochondria DNA, 3) encephalomyopathies and their incomplete forms including MIDD, diabetes mellituis, cardiomyopathy, deafness due to point mutations of mitochondria DNA related MELAS and others, 4) Neurodegenerative types including Parkinson's disease, Alzheimer's disease, cerebellar degeneration, and amyotrophic lateral sclerosis, or neurologic disorders mimic to such diseases, 5) Mitochondrial involvement not due to primary abnormalities of mitochondria DNA. Possible mechanisms were discussed, but sufficient knowledge is lacking so far to clarify pathophysiology of these disorders and the role of deleterious DNA in aging. Possible effective therapeutic strategies were also discussed, but further development of research works on these disorders in the 21st century are needed to answer these questions.
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PMID:[Current and future aspects of mitochondrial diseases]. 1079 Oct 75

We report the case of fifty-two year-old mentally deficient female who presented with diabetes mellitus, deafness, stroke-like episodes, cardiomyopathy, and macular pattern dystrophy of the retina. Her brain exhibited calcification within basal ganglia, lactacidaemia was not increased. Although her skeletal muscles had never been clinically impaired, a quadriceps biopsy led to the diagnosis of mitochondrial disease because it exhibited ragged red fibers and heteroplasmic point-mutation at position 3243 of the mitochondrial DNA, although not any detectable respiratory chain complex deficiency was found. The mutant percentage in muscle was 70 p.100 and 5 to 10 p.100 in leukocytes. The question of whether a diabetic microangiopathy may be responsible stroke-like episodes is discussed. We suggest it was rather a complicated form of diabetes-deafness than a incomplete MELAS syndrome associated with mitochondrial diabetes.
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PMID:[Mitochondrial diabetes complicated by or associated with "MELAS" syndrome?]. 1103 19

Mitochondrial DNA (mtDNA) defects are associated with a number of human disorders. Although many occur sporadically, maternal transmission is the hallmark of diseases due to mtDNA point mutations. The same mutation may manifest strikingly different phenotypes; for example, the A to G substitution at np 3243 was first reported in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (the MELAS syndrome), but is also found in patients with diabetes and deafness. Here we present a case of gestational diabetes, deafness, premature greying, placenta accreta and Wolff-Parkinson-White (WPW) syndrome associated with a mtDNA mutation. Although this is the first report of such an association, study of 27 other patients with WPW syndrome failed to confirm that this mtDNA mutation is a common cause of such pre-excitation disorders.
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PMID:Identification of mtDNA mutation in a pedigree with gestational diabetes, deafness, Wolff-Parkinson-White syndrome and placenta accreta. 1109 78

The authors studied a 47-year-old patient who presented with an association of deafness, acute cerebral stroke-like episode, leukoencephalopathy, and extensive basal ganglia calcifications. Late onset and neuroradiologic findings were atypical for MELAS syndrome (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike episodes). A heteroplasmic G to A transition at nucleotide 4332 in the tRNA glutamine gene was identified in the patient's muscle mitochondrial DNA. The pathogenicity of the mutation was shown in single muscle fibers by the correlation between high mutation load and cytochrome c oxidase defect.
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PMID:Atypical MELAS syndrome associated with a new mitochondrial tRNA glutamine point mutation. 1117 12

This review provides a compact overview on the contribution of mutations in mtDNA to the pathogenesis of diabetes mellitus, with emphasis on the A3243G mutation in the tRNA(Leu, UUR) gene. This mutation associates in most individuals with maternally inherited diabetes and deafness (MIDD) whereas in some other carriers the MELAS syndrome or a progressive kidney failure is seen. Possible pathogenic mechanisms are discussed especially the question why particular mutations in mtDNA associate with distinct clinical entities. Mutations in mtDNA can affect the ATP production, thereby leading to particular clinical phenotypes such as muscle weakness. On the other hand mtDNA mutations may also alter the intracellular concentration of mitochondrial metabolites which can act as signalling molecules, such as Ca or glutamate. This situation may contribute to the development of particular phenotypes that are associated with distinct mtDNA mutations.
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PMID:Molecular and clinical aspects of mitochondrial diabetes mellitus. 1140 93

Four members of a family were found to carry the A3243G mtDNA mutation. Clinical features varied from typical MELAS to myoclonic epilepsy to simple deafness without neurological signs. Several other members of the family had symptoms consistent with a mitochondrial disease. Muscle biopsy in 3 of the 4 patients showed the most prominent mitochondrial alterations with partial deficiency of cytochrome c oxidase in the case with the mildest phenotype. Mitochondrial DNA analysis detected a variable percentage of A3243G mutation, roughly correlating with the phenotype. The interesting feature of the family lies in the great intrafamilial variability of the severity of clinical expression, encompassing MELAS and MERRF features, associated with the A3243G mtDNA mutation. A search for the most common mtDNA mutations is recommended in all patients featuring incomplete MELAS or MERRF syndromes and in all familial cases presenting minimal clinical signs.
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PMID:MERRF/MELAS overlap syndrome in a family with A3243G mtDNA mutation. 1200 55

Mutations in the mitochondrial tRNA(leu) (UUR) gene have been associated with diabetes mellitus and deafness. We screened for the presence of mtDNA mutations in the tRNA(leu) (UUR) gene and adjacent ND1 sequences in 12 diabetes mellitus pedigrees with a possible maternal inheritance of the disease. One patient carried a G to A substitution at nt 3243 (tRNA(leu) (UUR) gene) in heteroplasmic state. In a second pedigree a patient had an A to G substitution at nt 3397 in the ND1 gene. All maternal relatives of the proband had the 3397 substitution in homoplasmic state. This substitution was not present in 246 nonsymptomatic Caucasian controls. The 3397 substitution changes a highly conserved methionine to a valine at aa 31 and has previously been found in Alzheimer's (AD) and Parkinson's (PD) disease patients. Substitutions in the mitochondrial ND1 gene at aa 30 and 31 have associated with a number of different diseases (e.g. AD/PD, MELAS, cardiomyopathy and diabetes mellitus, LHON, Wolfram-syndrome and maternal inherited diabetes) suggesting that changes at these two codons may be associated with very diverse pathogenic processes. In a further attempt to search for mtDNA mutations outside the tRNAleu gene associated with diabetes, the whole mtDNA genome sequence was determined for two patients with maternally inherited diabetes and deafness. Except for substitutions previously reported as polymorphisms, none of the two patients showed any non-synonymous substitutions either in homoplasmic or heteroplasmic state. These results imply that the maternal inherited diabetes and deafness in these patients must result from alterations of nuclear genes and/or environmental factors.
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PMID:MtDNA mutations in maternally inherited diabetes: presence of the 3397 ND1 mutation previously associated with Alzheimer's and Parkinson's disease. 1203 16


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