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)

Mitochondrial (mt)DNA haplogroups in a German control group (n = 67) were characterized by screening mitochondrial coding regions encompassing most of the ND, tRNA and cyt b genes. We used a PCR-SSCP screening approach followed by direct sequencing of polymorphic mtDNA fragments. Five major mtDNA lineages, diverging in at least nine different haplogroups, could be defined by characteristic polymorphic sites in mitochondrial genes. Additional sequencing of two hypervariable segments (HVS-I and II) of the non-coding displacement (D) loop in all control subjects revealed that certain D loop variants were strongly correlated with lineages and haplogroups, while others represented hotspots occurring frequently in different haplogroups. The existence of identified lineages and haplogroups received support from data in the literature, obtained by use of different approaches. Subsequently, we investigated four disease groups for association with these haplogroups: (i) LHON patients (n = 55) carrying at least one of the primary/intermediate LHON mutations at nt 3460, 11778, 14484 and/or 15257; (ii) patients suffering from Wolfram or DIDMOAD syndrome (n = 8); (iii) MELAS patients (n = 9); (iv) a group of children, who died from 'sudden infant death syndrome' (SIDS) (n = 9). The distribution patterns among the haplogroups of the disease groups (LHON, DIDMOAD and SIDS) differed considerably from the control population. LHON and DIDMOAD were significantly under-represented in the most frequent German haplogroup DC, but were concentrated in a mtDNA lineage defined by polymorphisms at nt 4216 + 11251 + 16126. As this lineage diverged into two precisely defined haplogroups, LHON and DIDMOAD could be assigned to the two haplogroups separately. Strikingly, SIDS was often found in association with two rare German haplogroups. MELAS patients were equally distributed among German haplogroups and, moreover, did not reveal any accumulation of specific D loop variants. We conclude that certain European mtDNA haplogroups define a genetic susceptibility basis for various disorders.
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PMID:Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease. 930 61

The mitochondrial DNA (mtDNA) codes for essential hydrophobic components of the system of oxidative phosphorylation. Diseases caused by mtDNA defects are manifested as variable clinical phenotypes and the symptoms represent the involvement of tissues with high energy demand. Various approaches have been taken to treat mitochondrial diseases by administration of redox compounds, enzyme activators, vitamins and coenzymes or dietary measures. The MELAS mutation at the base pair 3243 of mitochondrial DNA demolishes a transcription termination sequence located within the tRNA(Leu)[UUR] gene, resulting in synthesis of an abnormally large derivative of 16 S rRNA and defective translation. The activity of NADH:Q oxidoreductase (complex I) is often decreased and lactic acidosis is a typical clinical finding. We hypothesized that defective translation of the seven mitochondrially coded subunits (of the total 41) of complex I may alter its affinity to the NADH substrate in which case the activity decrease may be compensated for by increasing the NADH concentration. A MELAS patient was treated with oral nicotinamide for 5 months. The blood NAD content representing the NAD + NADH pool of erythrocytes rose 24 fold and the blood lactate + pyrovate concentration fell by 50%. All these metabolic alterations suggested an improvement of the function of complex I or the whole mitochondrial respiratory chain. However, the kinetic properties of the patient's complex I were similar to the reference values. A tempting explanation is that the free NADH concentration in mitochondria is normally at the level of K(m), so that the decreased activity of the respiratory chain can be compensated for by increased mitochondrial [NADH]. Another possibility would be that the substrate shuttles for transport of reducing power of cytosolic NADH into mitochondria (the malate aspartate or glycerol-3-phosphate shuttles) may be enhanced by increased total NAD + NADH. Because the malate-aspartate shuttle is actually a pump for reducing equivalents driven by the mitochondrial membrane energization, it is proposed that the exacerbations of the MELAS syndrome be partly due to a vicious circle initiated by a defect of complex I and affecting the active transport of the hydrogen from cytosolic NADH into the mitochondrion.
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PMID:Metabolic interventions against complex I deficiency in MELAS syndrome. 930 2

The majority of patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) have an A-->G mutation at nucleotide 3243 in mitochondrial transfer (t)RNA. To date there have only been 10 reported cases of MELAS syndrome in patients with a T-->C mutation at position 3271 of mitochondrial tRNA. Although many of the clinical features are similar between patients with these different mutations, it appears that the age at onset is later for the 3271 mutation. This report provides information from a North American kindred with the 3271 mutation (n = 6 proven; n = 2 probable; n = 3 possible) that adds clinical, physiological, histological, and molecular information to the pool of information on this rare disorder. Many of these features were similar to previous reports of both 3243 and 3271 patients. We conclude that the phenotypic expression of these different mutations are similar, but the age of onset for 3271 patients is later than for 3243 patients.
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PMID:Clinical, physiological, and histological features in a kindred with the T3271C melas mutation. 942 20

We studied a patient with the diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) for mitochondrial DNA mutations in muscle. Established MELAS mutations were excluded. Mitochondrial DNA was further analyzed for mutations in the 22 tRNA genes by single-strand conformation polymorphism (SSCP) analysis; a tRNA(Val) mutation (G1642A) was found. The structure of the altered tRNA, the heteroplasmy, and the absence of the mutation in the mother and in 100 control subjects suggests that the tRNA(Val) mutation is associated with the MELAS syndrome.
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PMID:A mitochondrial tRNA(Val) gene mutation (G1642A) in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes. 944 99

A mitochondrial tRNA mutation at nucleotide 3,243 is known to be found in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). We report a 30 year-old female patient of MELAS, diagnosed 5 years ago, who presented herself to our ENT outpatient department because of her bilateral tinnitus and progressive hearing impairment since 4 years ago. Two sequential pure tone audiograms showed bilateral symmetrical progressive sensorineural hearing loss, especially in the high frequency area in 1993 and 1996. The pure tone average was R-45 dB, L-47 dB in 1993 and R-62 dB, L-67 dB in 1996. Hearing loss is an important feature in MELAS syndrome and reported to be seen in about 30% of patients. It is often the first clinical symptom, too. In any case, mitochondrial cytopathies need to be considered by the otologist in forming a diagnosis of sensorineural hearing loss (SNHL), particularly in cases, which present adult-onset progressive hearing loss and neurologic symptoms before 50 years of age.
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PMID:Sensorineural hearing loss in MELAS syndrome--case report. 978 Jun 3

Autopsy reports of patients with mitochondrial encephalopathy with lactic acidosis and strokelike episode (MELAS) are rare. This report documents the clinical and autopsy findings of a 47-year-old woman with MELAS syndrome. The diagnosis was corroborated by documenting a mitochondrial DNA mutation tRNA-Leu (UUR) at position 3243. The patient's clinical history was marked by schizophrenia, peptic ulcer disease, constipation requiring hemicolectomy, migraine headaches, deafness, and a left temporal lobe infarct. At autopsy, a muscle biopsy demonstrated numerous ragged red fibers and a partial cytochrome C oxidase deficiency. By electron microscopy, increased numbers of slightly hypertrophic mitochondria were observed focally within myocytes and vessel walls; paracrystalline mitochondrial inclusions were not seen. The brain at autopsy showed mild cerebral atrophy and diffuse cortical gliosis. Prominent bilateral basal ganglia calcifications and vascular sclerosis were present, and a small remote left temporal lobe infarct was seen.
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PMID:Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. 982 26

Post-transcriptional modifications are characteristic features of tRNAs and have been shown in a number of cases to influence both their structural and functional properties, including structure stabilization, amino-acylation and codon recognition. We have developed an approach which allows the investigation of the post-transcriptional modification patterns of human mitochondrial wild-type and mutant tRNAs at both the qualitative and the quantitative levels. Specific tRNA species are long-term labeled in vivo with [32P]orthophosphate, isolated in a highly selective way, enzymatically digested to mononucleotides and then subjected to two-dimensional thin layer chromatographic analysis. The wild-type tRNALysand the corresponding tRNALyscarrying the A8344G mutation associated with the MERRF (Myoclonic Epilepsy with Ragged Red Fibers) syndrome exhibit the same modified nucleotides at the same molar concentrations. By contrast, a quantitatively different modification pattern was observed between the wild-type tRNALeu(UUR)and its counterpart carrying the A3243G mutation associated with the MELAS (Mitochondrial Myopathy, Encephalopathy with Lactic Acidosis and Stroke-like episodes) syndrome, the latter exhibiting a 50% decrease in m2G content. Complementary sequencing of tRNALeu(UUR)has allowed the localization of this modification at position 10 within the D-stem of the tRNA. The decreased level of this modification may have important implications for understanding the molecular mechanism underlying the MELAS-associated mitochondrial dysfunction.
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PMID:Search for differences in post-transcriptional modification patterns of mitochondrial DNA-encoded wild-type and mutant human tRNALys and tRNALeu(UUR). 988 70

Mutations in the tRNA genes of mitochondrial DNA (mtDNA) cause the debilitating MELAS (mitochondrial, myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres) syndromes. These mtDNA mutations affect respiratory chain function, apparently without decreasing cellular ATP concentration [Moudy et al. (1995) PNAS, 92, 729-733]. To address this issue, we investigated the role of mitochondrial ATP synthesis in fibroblasts from MELAS and MERRF patients. The maximum rate of mitochondrial ATP synthesis was decreased by 60-88%, as a consequence of the decrease in the proton electrochemical potential gradient of MELAS and MERRF mitochondria. However, in quiescent fibroblasts neither ATP concentration or the ATP/ADP ratio was affected by the lowered rate of ATP synthesis. We hypothesized that the low ATP demand of quiescent fibroblasts masked the mitochondrial ATP synthesis defect and that this defect might become apparent during higher ATP use. To test this we simulated high energy demand by titrating cells with gramicidin, an ionophore that stimulates ATP hydrolysis by the plasma membrane Na+/K+-ATPase. We found a threshold gramicidin concentration in control cells at which both the ATP/ADP ratio and the plasma membrane potential decreased dramatically, due to ATP demand by the Na+/K+-ATPase outstripping mitochondrial ATP synthesis. In MELAS and MERRF fibroblasts the corresponding threshold concentrations of gramicidin were 2-20-fold lower than those for control cells. This is the first demonstration that cells containing mtDNA mutations are particularly sensitive to increased ATP demand and this has several implications for how mitochondrial dysfunction contributes to disease pathophysiology. In particular, the increased susceptibility to plasma membrane depolarization will render neurons with dysfunctional mitochondria susceptible to excitotoxic cell death.
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PMID:Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. 991 28

We compared clinical pictures of a case of mitochondrial encephalomyopathy with tRNA(Leu(UUR)) point mutation at nucleotide position 3254 of mitochondrial DNA with those at position 3243. The mutation 3254 was a 19-year-old male patient with cardiomyopathy accompanied with muscle atrophy. The first mutant 3243 was a 31-year-old female patient showing clinical features of MELAS and endocrinological abnormalities. The second 3243 mutant was a 27-year-old male patient who had an external ophthalmoplegia and slight mental decline. In all cases, muscle biopsy specimen showed ragged red fibers and strongly SDH-reactive blood vessels, but their limb weakness were unremarkable. These results suggest that tRNA(Leu(UUR)) point mutation 3254 exhibits similar clinical phenotypes as those observed in 3243 mutant.
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PMID:[Comparison of clinical pictures of mitochondrial encephalomyopathy with tRNA(Leu(UUR)) mutation in 3243 with that in 3254]. 998 53

Out of 90 Portuguese patients with mitochondrial cytopathy, six harbored the A3243G mutation in the mtDNA tRNA(Leu(UUR)) gene ('MELAS mutation'). They had heterogeneous clinical features, including myopathy with stroke-like episodes, progressive external ophthalmoparesis, diabetes mellitus, and subacute encephalopathy. Histochemical and biochemical analyses of muscle biopsies showed abundant ragged-red fibers reacting positively with the cytochrome oxidase stain, and decreased respiratory chain enzyme activities. On average, the proportion of mutated mtDNA was 67% (20-88%) in tissues from patients and 21% (0-49%) in blood from 20 maternal relatives. The proportion of mutated mitochondrial genomes in muscle did not correlate with clinical presentation or duration of disease. This study, the first in Portuguese patients, confirms the frequent occurrence of the A3243G mutation in patients with mitochondrial diseases, and emphasises the usefulness of genetic testing in reaching a correct diagnosis.
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PMID:The mitochondrial DNA A3243G mutation in Portugal: clinical and molecular studies in 5 families. 1037 Oct 79


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