Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel feature of demyelinating polyneuropathy was observed in a patient with the tRNA(Leu(UUR)) mutation at base pair 3243 of the mitochondrial DNA. Based on electrodiagnostic examination, the polyneuropathy was defined as being of the demyelinating, mixed (motor more than sensory) type. In a 1-year follow-up we observed approximately 7% reduction in both the motor and sensory conduction velocities. The other clinical features of the proband included a mild to moderate cognitive impairment and a combined hearing loss with a moderate sensorineural component. The proportion of the mutant genome found in the muscle of the proband was 29%, but the mutation was not found in his blood. A wide variability of the clinical phenotype was observed in the family of the proband. Heteroplasmic mutation was detected in the blood of most family members. The proportion of abnormal mitochondrial DNA was highest in the proband's brother, who had clinically definite mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, while the mutant genome was less frequent or absent in the subjects with less severe phenotypes and in healthy individuals. The findings on this pedigree emphasize the need for studies of complete families in the search for new clinical phenotypes of mutations in mitochondrial DNA.
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PMID:Demyelinating polyneuropathy in a patient with the tRNA(Leu)(UUR) mutation at base pair 3243 of the mitochondrial DNA. 862 19

Enzymatic and molecular analyses were conducted on the muscular tissue of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Significant decreases in activity of complexes I and IV were found and three nucleotide substitutions in the mitochondrial tRNA genes were detected. Two of the substitutions were detected in unaffected members of the family and in some healthy controls. A C-to-T transition mutation at the nucleotide position 3,256 in the mitochondrial tRNA(Leu)(UUR) gene was detected only in the patient and not in unaffected members of the family or 100 healthy controls. The data strongly suggest that this mutation at nucleotide position 3,256 in the mitochondrial tRNA(Leu)(UUR) gene is associated with MELAS.
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PMID:A mitochondrial tRNA(Leu)(UUR) mutation at 3,256 associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). 780 30

The investigation of pathogenic mitochondrial DNA (mtDNA) mutations has revealed a complex relation between patient genotype and phenotype. For unknown reasons, some mtDNA mutations produce specific clinical manifestations such as chronic progressive external ophthalmoplegia; myoclonic epilepsy and ragged-red fiber disease (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). To enhance our understanding of the association between genotype and phenotype, we investigated a patient with mitochondrial encephalomyopathy and severe cerebral calcifications for a mtDNA mutation. There was a deletion of one of three T:A nucleotide pairs in the tRNALeu(UUR) gene of the mtDNA involving positions 3271 to 3273. Pedigree analysis suggested that this mutation may have occurred spontaneously in the proband. This analysis represents the smallest mtDNA deletion observed to date and is the first deletion identified within a mitochondrial tRNA. This observation emphasizes the importance of delineating the precise mutation responsible for an oxidative phosphorylation disease for patient diagnosis as well as for genetic counseling of maternal lineage relatives.
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PMID:Mitochondrial encephalomyopathy associated with a single nucleotide pair deletion in the mitochondrial tRNALeu(UUR) gene. 785 27

The amount of oxidative phosphorylation enzymes in mitochondrial encephalomyopathy patients has been studied by two-dimensional electrophoresis (blue native PAGE/Tricine-SDS-PAGE). Only 20 mg muscle was required to identify and analyse complexes I, III, IV, and V after Coomassie staining. In most cases reduced amounts of the involved complex(es) correlated well with decreased enzyme activities. The reliability of the method was reflected by the constant mutual ratio of the complexes found in all controls. Deviations from normal ratios were found to be more sensitive indicators for a defect than the absolute quantities, which varied considerably within the control group both in the enzymic and in the electrophoretic analysis. The effect of the mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes on the amount of oxidative phosphorylation complexes was demonstrated for the first time directly on the protein level. In patients without known DNA mutations, specific defects of single complexes were identified. The new technique is a sensitive method for the identification of oxidative phosphorylation defects, complementary to enzymic measurements.
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PMID:Human diseases with defects in oxidative phosphorylation. 1. Decreased amounts of assembled oxidative phosphorylation complexes in mitochondrial encephalomyopathies. 786 54

We have recently reported an A to G transition at nucleotide position 3243 in the mitochondrial DNA (mtDNA) tRNA(Leu(UUR)) gene in a large family with non-insulin-dependent diabetes mellitus (NIDDM). Characteristic was its maternal transmission and an associated sensorineural hearing loss. In a screening of a Dutch and French NIDDM population for the presence of the tRNA(Leu(UUR)) mutation we identified two new pedigrees in which NIDDM is present in combination with deafness. The mode of inheritance agrees with a maternal one. This result shows that patients with a phenotype of NIDDM and deafness can be identified within groups of NIDDM patients based on the tRNA(Leu(UUR)) mutation. The same mutation has also been linked to the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). How the same mutation can give rise to different clinical phenotypes is not clear. We obtained the complete mtDNA sequence from our initial pedigree and identified a number of additional mutations that could confer the phenotype of the tRNA(Leu(UUR)) mutation to diabetes. We examined the presence of these additional, potentially pathogenic mutations in the mtDNA from the two new pedigrees and from a previously described British pedigree. The absence of these mutations in all three pedigrees shows that the tRNA(Leu(UUR)) mutation alone associates with the phenotype of NIDDM and deafness. We conclude that maternally inherited diabetes and deafness is a distinct subtype of diabetes that is associated with a single mitochondrial tRNA(Leu(UUR)) mutation. We propose the abbreviation MIDD for this particular subtype.
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PMID:Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA(Leu(UUR)) gene. 791 Aug

We report a clinically heterogeneous, multigenerational pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with a mutation at nucleotide 3243 in the mitochondrial DNA tRNA(Leu)(UUR) gene. Our findings suggest that the mutation at nucleotide 3243 is not always associated with the classic MELAS phenotype and that other symptoms (notably cardiac and gastrointestinal abnormalities) should raise the suspicion of a mitochondrial disorder.
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PMID:Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). 796 31

Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNA(LEU(UUR)) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 min after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50%) and 12 (85.7%) of 14 mutant diabetic subjects, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNA(LEU(UUR)) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). 798 84

MELAS is a mitochondrial cytopathy characterized by encephalopathy with stroke-like episodes and lactic acidosis. Most patients exhibit an A-G transition mutation at np 3243 of mitochondrial DNA (tRNA(Leu)(UUR)). We present a family of four in which the mutation was discovered in blood and in muscle mt DNA. Two patients had the classic MELAS syndrome with multiple stroke-like episodes. Some episodes were precipitated by metabolic stress. The remaining two patients had an oligosymptomatic disease with mild chronic encephalopathy, small stature and hearing loss. MRI was followed over a period of 4-8 years, during which the MELAS patients showed progression from nonspecific multifocal signal change to typical extensive cortico-subcortical parieto-occipital lesions and progressive cerebral atrophy. MRI in the oligosymptomatic cases was normal, or showed non-progressive cerebellar atrophy. Biochemical findings were non-specific, indicating increased mitochondrial volume in all cases, and a relatively complex IV defect in one case. All patients were treated with coenzyme Q with varying clinical response. The percentage of mutant mt DNA in blood and muscle did not correlate with clinical severity. Pathogenetic theories based on molecular genetics, and the therapeutic regimen in terms of the underlying biochemical concepts are discussed.
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PMID:[MELAS syndrome. Clinical aspects, MRI, biochemistry and molecular genetics]. 801 33

Non-insulin-dependent diabetes mellitus (NIDDM) has a strong genetic component and maternal factors have recently been implicated in disease inheritance. The mitochondrial myopathies are a group of diseases which often show maternal inheritance as a result of mtDNA defects; some patients have impaired glucose tolerance. Occasional families with maternally inherited diabetes and deafness associated with a deletion or point mutation of mtDNA have been reported. To assess the importance of mitochondrial gene defects in NIDDM, 150 unrelated diabetic subjects from Wales, UK and 68 unrelated patients with diabetes and at least one affected sibling from England, UK were studied. Southern blot analysis did not show any large mtDNA deletions or duplications. One patient had a mutation in the mitochondrial tRNAleu(UUR) gene at bp 3243. This mutation is commonly associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes (MELAS). Study of this patient and his siblings showed a distinct form of late-onset diabetes associated with nerve deafness but no clinical features of the MELAS syndrome. No diabetic subject was shown to have the mtDNA mutation at position 8344 (tRNA(lys)) which has previously been described in the syndrome of mitochondrial encephalomyopathy and red-ragged fibres (MERRF). The role of other mitochondrial gene defects in diabetes and the pathophysiological basis of glucose intolerance in patients with the MELAS mutation requires further elucidation.
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PMID:Mitochondrial gene defects in patients with NIDDM. 926 98

Several members of a three-generation kindred from Sardinia were affected by a maternally inherited syndrome characterized by features of both myoclonus epilepsy with ragged-red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Clinically, symptoms such as myoclonus epilepsy, neural deafness and ataxia were variably associated with stroke-like episodes and/or migrainous attacks. Morphologically, numerous MELAS-associated SDH-stained vessels were observed in muscle biopsies, either alone or in combination with ragged-red fibers, the morphological hallmark of MERRF. Sequence analysis of the mtDNA tRNA genes revealed the presence of a single, heteroplasmic T-->C transition at nt 8356, in the region of the tRNA(Lys) gene corresponding to the T-psi-C stem. The T-->C(8356) transition was exclusively found in the maternal lineage of our family, and the relative amount of the mutant mtDNA species in muscle was correlated with the severity of the clinical presentation. Therefore, we propose that the T-->C(8356) transition is responsible for the mitochondrial encephalomyopathy found in our family, and must be added to the expanding list of the pathogenetically relevant mutations of human mtDNA.
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PMID:A MERRF/MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNA(Lys) gene. 806 54


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