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)

We studied multiple different postmortem tissue samples from a woman and two of her daughters with the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) tRNA(Leu(UUR)) mutation at nucleotide 3243 in mitochondrial DNA (mtDNA). All tissues examined were heteroplasmic for the mutation. The mean proportion of mutant mtDNAs in the mother's tissues (0.30 +/- 0.10) was significantly lower than that of each of her daughters' (0.76 +/- 0.11, p < 0.03, and 0.72 +/- 0.13, p < 0.001); there was no difference in the fraction of mutant mtDNAs between the daughters (p < 0.71). This difference in the mean proportion of mtDNA mutants between family members correlates with their clinical profiles; the mother had the latest onset of disease and lived longest, while the two daughters had a strikingly similar clinical course. In individual patients, the mean proportion of mutant mtDNAs was not different in tissues deriving from ectodermal, mesodermal, and endodermal germ layers. Variance in the mutant:wild-type mtDNA ratio was normally distributed about the mean, both when all tissues were considered together and when different regions of the CNS were considered separately. Thus, the proportion of mtDNAs carrying the tRNA(Leu(3243)) mutation was not uniform in members of this pedigree and did not undergo rapid mitotic segregation along germ-layer divisions. These findings are consistent with the hypothesis that the overall proportion of mtDNAs carrying this mutation is primarily determined by segregation during oogenesis or early embryologic development and that random replicative (mitotic) segregation, subsequent to the establishment of primary germ layers, is responsible for the variation between tissues.
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PMID:Variable distribution of mutant mitochondrial DNAs (tRNA(Leu[3243])) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation. 835 Oct 17

We describe a 15-year-old boy with full-blown mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO). He presented with visual disturbance, hearing impairment, continuous partial epilepsy on the right aspect of the face, and right hemiparesis since the age of 13. Four months later, he experienced another strokelike episode with continuous partial epilepsy on the left hand. Serial computed tomographic scans revealed bilateral parieto-occipital hypodense lesions with gyral enhancement and an additional low-density lesion in the right frontal area 4 months later, respectively. Results of laboratory examinations disclosed lactic acidosis and mitochondrial myopathy with many ragged-red fibers. To identify the defective gene in mitochondrial DNA, a simple molecular test was performed by using restriction endonuclease Apa I. A transition from A to G was found at nucleotide position 3243 of the tRNA(Leu) gene. Interestingly, the patient also had marked external ophthalmoplegia and ptosis commonly found in patients with CPEO. Therefore, we suggest that ophthalmoplegia also occurs in the MELAS syndrome.
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PMID:Ophthalmologic manifestations in MELAS syndrome. 836 52

A family with maternally-transmitted deafness and diabetes mellitus is described. Although the proband clinically exhibited MELAS-like symptoms such as sudden-onset cerebellar ataxia and weakness of the proximal portion of the limbs in addition to deafness and diabetes mellitus, the other three members of the family had only deafness and diabetes mellitus and no neurological manifestations. The analysis of mitochondrial DNA of the two members revealed an A-->G mutation of tRNA(leu(UUR)), a mutation commonly seen in patients with MELAS. According to the clinical histories and endocrinological investigations, the type of the diabetes mellitus in this family was considered to be IDDM, which may be attributed to the dysfunction of mitochondrial of the pancreas islet cells, resulting from the mutation of the mitochondrial DNA.
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PMID:[A family with MELAS whose main manifestations are maternally-transmitted deafness and diabetes mellitus]. 840 88

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is one of the clinically-defined mitochondrial diseases, characterized by early onset and stroke-like symptoms. A point mutation at nucleotide pair 3243 within the tRNA-Leu (UUR) gene is found in 80% of MELAS patients and another mutation at nucleotide pair 3271 in 10%. In vitro and in vivo expression studies on 3243 mutant genome show that it affects both the transfer RNA and transcription termination functionally. By virtue of further analyses on relationship between the mutations and phenotypes, a new approach to deal with the disease could be obtainable.
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PMID:[MELAS (mitochondrial myopathy, encephalopathy lactic acidosis, and stroke-like episodes): clinical features and mitochondrial DNA mutations]. 841 15

We describe a family with three cases of "clinically incomplete mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome" in which heteroplasmic tRNA(Leu(UUR)) mutation at nucleotide 3243 of the mitochondrial DNA was present in three generations. The amount of mutant genome varied among tissues: it was 60% in the kidney, 72% in the cardiac muscle, and 91% in the liver of the female proband's affected brother and 63% in the kidney, 71% in the cardiac muscle, and 71% in the liver of the female proband's perinatally deceased son. The tRNA(Leu(UUR)) mutation was also carried by the siblings of the proband's affected mother. None of them had any clinical signs of MELAS syndrome. This syndrome has the new feature of being associated with adult-onset diabetes mellitus, neurosensory hearing loss, and short stature.
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PMID:Adult-onset diabetes mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with the tRNA(Leu(UUR)) mutation. 849 19

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.
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PMID:Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. 868 11

We describe a family which demonstrates and expands the extreme clinical variability now known to be associated with the A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus presented at birth with clinical manifestations consistent with diabetic embryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months of life, presented with intractable seizures later associated with developmental delay. The twins' mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Since age 19 years, the maternal aunt has had recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA(Leu(UUR)) A-->G mutation. A maternal uncle had diabetes mellitus type I, deafness, and normal intellect, and died at 35 years after recurrent strokes. This pedigree expands the known clinical phenotype associated with tRNA(Leu(UUR)) A-->G mutation and raises the possibility that, in some cases, diabetic embryopathy may be due to a mitochondrial cytopathy that affects both the mother's pancreas (and results in diabetes mellitus and the metabolic dysfunction associated with it) and the embryonic/fetal and placental tissues which make the embryo more vulnerable to this insult.
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PMID:The expanding clinical phenotype of the tRNA(Leu(UUR)) A-->G mutation at np 3243 of mitochondrial DNA: diabetic embryopathy associated with mitochondrial cytopathy. 872 72

In 79 South Indian nuclear pedigrees ascertained via probands with NIDDM and both parents living, parental diabetic status was established through previously diagnosed NIDDM (n = 97) or oral glucose tolerance testing (n = 61). There was no significant difference between diabetes prevalence in mothers and fathers (60 vs 53 (76% vs 67%), respectively, p = 0.22). 'Age at diabetes diagnosis' survival curves did differ according to parental gender (p = 0.02) but this may reflect gender differences in health provision rather than pathophysiology. No maternal excess effects of the magnitude evident in previous studies were detected, suggesting either ethnic differences or overestimation of the maternal effect when reported histories of parental diabetes have been used. The tRNA(Leu(UUR) gene region was studied for diabetes-associated variation given the role of mutations in this gene in some pedigrees displaying maternal transmission of NIDDM. None of 142 unrelated South Indian NIDDM subjects displayed the MELAS mutation at nt3243. However, sequencing identified two variants of potential importance: (a) at nt3290 in the tRNA(Leu(UUR) gene, seen in 7/142 diabetic and 1/85 control subjects (p = 0.11), (b) at nt3316 in the ND1 gene (4/142 vs 1/85 subjects, respectively (p = 0.51)). Further studies are needed to determine the relevance of these variants to the development of NIDDM.
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PMID:Evaluation of the importance of maternal history of diabetes and of mitochondrial variation in the development of NIDDM. 873 23

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 mitochondrial A 3243 G mutation in the tRNA(Leu(UUR)) gene was first described as a common cause of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome). This same mutation is also the cause of a totally different disorder, a subtype of diabetes mellitus which is inherited maternally and often associated with sensorineural hearing loss. In this paper, we report on a Japanese boy with A 3243 G who developed a previously undescribed combination of symptoms, nephropathy and growth hormone deficiency. The patient first presented with short stature and moderate mental retardation. Growth hormone (GH) provocation tests showed deficient growth hormone secretion. During the course of follow up, he presented with progressive nephropathy followed by the development of diabetes mellitus. The results of laboratory tests and renal biopsy were against incidental association of known types of nephropathy. On PCR-RFLP analysis, the percentage of mutated mtDNA was higher in the renal biopsy specimen than 12 peripheral blood leucocytes. Our case suggests that mitochondrial diseases should be taken into account when there is nephropathy of unknown cause. In addition, the presence of growth hormone deficiency may account for part of the mechanism leading to short stature commonly seen in these patients.
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PMID:Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation. 881 55


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