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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seven patients with mitochondrial encephalomyopathies were studied for peripheral neuropathy by clinical, electrophysiological and pathological examinations. The clinical manifestation of neuropathy varied from asymptomatic to mild and moderate sensorimotor symptoms with painful paresthesia. Five patients (2 with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, and 3 with myoclonic epilepsy and ragged-red fibers, MERRF) had clinical symptoms and signs of polyneuropathy associated mainly with decreased amplitudes of the compound muscle or nerve action potentials in an electrophysiological study indicating axonal degeneration. Sural nerve biopsy from 1 MERRF patient, also confirmed an axonal degeneration with reduction of large myelinated fibers. Mitochondrial DNA analysis of the sural nerve from this patient showed a point mutation from A to G transition at the nucleotide position 8344 with 80% mtDNA mutation. The results of this study suggest that peripheral neuropathy is not uncommon in mitochondrial encephalomyopathies and is predominantly due to axonal degeneration.
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PMID:Peripheral neuropathy in mitochondrial encephalomyopathies. 905 67

Since the first identification in 1988 of pathogenic mitochondrial DNA (mtDNA) mutations, the mitochondrial diseases have emerged as a major clinical entity. The most striking feature of these disorders is their marked heterogeneity, which extends to their clinical, biochemical, and genetic characteristics. The major mitochondrial encephalomyopathies include MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), KSS/CPEO (Kearns-Sayre syndrome/chronic progressive external ophthalmoplegia), and NARP/MILS (neuropathy, ataxia, and retinitis pigmentosum/maternally inherited Leigh syndrome) and they typically present highly variable multisystem defects that usually involve abnormalities of skeletal muscle and/or the CNS. The primary emphasis here is to review recent investigations of these mitochondrial diseases from the standpoint of how the complexities of mitochondrial genetics and biogenesis might determine their varied features. In addition, the mitochondrial encephalomyopathies are compared and contrasted to Leber hereditary optic neuropathy, a mitochondrial disease in which the pathogenic mtDNA mutations produce a more uniform and focal neuropathology. All of these disorders involve, at some level, a mitochondrial respiratory chain dysfunction. Because mitochondrial genetics differs so strikingly from the Mendelian inheritance of chromosomes, recent research on the origin and subsequent segregation and transmission of mtDNA mutations is reviewed.
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PMID:Human mitochondrial diseases: answering questions and questioning answers. 977 Feb 97

The majority of pathogenic mitochondrial DNA (mtDNA) mutations are heteroplasmic, with both mutant and wild-type alleles present within the same individual. MtDNA is transmitted only from females to their offspring but a single female can bear offspring who harbour different levels of mutant mtDNA and have a variable phenotype. In single families, this complex genetic and phenotypic variability has confounded the identification of any relationship between the level of mutant mtDNA (mutation load) in the mother and the clinical features of her offspring. To obtain a more accurate description of the inheritance of pathogenic mtDNA mutations, we studied a large number of pedigrees that carried either the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (A3243G MELAS) or the myoclonic epilepsy with ragged-red fibres (A8344G MERRF) mutations. We made two principal observations. First, for both mutations, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Secondly, at any one level of maternal mutation load there was a greater frequency of affected offspring for the A3243G MELAS mutation than for the A8344G MERRF mutation. Although these results should not be used to give absolute risks to a female contemplating pregnancy, they suggest that the outcome of pregnancy is related to the level of mutant mtDNA in the mother and that the risks of having affected offspring may differ between different mtDNA mutations.
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PMID:MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. 979 44

We review the mitochondrial diseases in which cerebrovascular changes are seen, such as the MERRF syndrome (myoclonic epilepsy and ragged red fibers) or the Kearns-Sayre syndrome (progressive external ophthalmoplegia, retinitis pigmentaria, cerebellar disorders and disorders of cardiac conduction), focusing on the syndrome involving mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). We consider the different clinical aspects, diagnostic methods, pathophysiological mechanisms of the cerebrovascular involvement as well as therapeutic approaches.
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PMID:[Mitochondrial diseases and stroke]. 981 May 97

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

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR))gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the A8344G substitution in the tRNA(Lys)gene neither the relative abundance nor the aminoacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNA(Leu), the A8344G mutation does not affect tRNA(Lys)function in the same way.
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PMID:Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. 1069 70

Many different pathogenic mutations in the mitochondrial (mt) transfer RNA (tRNA) genes have been reported for patients with mitochondrial encephalomyopathy. Although some of them are recurrent, most have only been described once and appear to be restricted to one patient or to one family. The incidence of mt tRNA gene alterations is not known, even though the frequency of some recurrent mutations has been analysed both in patients and in the general population. In this study, we describe the results of stepwise screening for sequence variations in the mt tRNA genes of 166 patients selected according to several criteria. Extensive sequence analysis of the tRNA genes was performed using denaturing gradient gel electrophoresis. A total of 31 patients (19%) were found to harbour significant levels of a pathogenic mutation, thus confirming the importance of mt tRNA mutations in human pathology. Forty-three different sequence variations were found, illustrating the great diversity of the mtDNA sequence in humans. The functional assessment of all these sequence variations represented a difficult task; it was mostly based on indirect data, such as the phylogenetic conservation of modified nucleotides and the proportions of variant species in different tissues of the index case or in blood of maternal relatives. Direct demonstration of a correlation between the proportion of heteroplasmic sequence variations and the cytochrome c oxidase defect was performed at the single muscle-fibre level. Eleven heteroplasmic sequence variations were found, six of which are new mutations. One is a known Caucasian polymorphism but the other 10 are pathogenic. Two of them are the well-known pathogenic MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (A3243G) and MERRF (myoclonic epilepsy with ragged-red fibres) (A8344G) point mutations. They were found in 23 patients. The eight other mutations were restricted to one patient. The pathogenic nature of these mutations was demonstrated directly for five of them and hypothesized from indirect arguments for the other three. Thirty-two homoplasmic sequence variations were found. Twenty-nine were considered to be polymorphisms, even though 15 of these were found for the first time in our patients and two others had been reported previously as pathogenic. The pathogenic nature of three homoplasmic variants remains questionable.
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PMID:Mitochondrial DNA transfer RNA gene sequence variations in patients with mitochondrial disorders. 1133

The mitochondrial cytopathies are genetically and phenotypically heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria. To the best of our knowledge, there are very few studies published from India till date. Selected and confirmed fourteen cases of neurological mitochondrial cytopathies with different clinical syndromes admitted between 1997 and 2000 are being reported. There were 8 male and 6 female patients. The mean age was 24.42+/-11.18 years (range 4-40 years). Twelve patients could be categorized into well-defined syndromes, while two belonged to undefined group. In the defined syndrome categories, three patients had MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes), three had MERRF (myoclonic epilepsy and ragged red fibre myopathy), three cases had KSS (Kearns-Sayre Syndrome) and three were diagnosed to be suffering from mitochondrial myopathy. In the uncategorized group, one case presented with paroxysmal kinesogenic dystonia and the other manifested with generalized chorea alone. Serum lactic acid level was significantly increased in all the patients (fasting 28.96+/-4.59 mg%, post exercise 41.02+/-4.93 mg%). Muscle biopsy was done in all cases. Succinic dehydrogenase staining of muscle tissue showed subsarcolemmal accumulation of mitochondria in 12 cases. Mitochondrial DNA study could be performed in one case only and it did not reveal any mutation at nucleotides 3243 and 8344. MRI brain showed multiple infarcts in MELAS, hyperintensities in putaminal areas in chorea and bilateral cerebellar atrophy in MERRF.
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PMID:Neurological mitochondrial cytopathies. 1213 80

We report an unusual case of encephalo-entero-myopathy associated with the A8344G mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). This patient had mitochondrial myopathy, multiple lipomatosis, mild hearing loss, stroke-like episodes, and paralytic ileus, but she lacked the canonical clinical features of MERRF, myoclonus, epilepsy, or ataxia. We conducted genetic, biochemical, histochemical, and immunohistochemical studies in skeletal muscle, brain, intestine, and lipoma tissue. The mutation was abundant in all tissues, and cytochrome c oxidase (COX) activity was selectively decreased in brain and small intestine. COX deficiency was also documented histochemically and immunohistochemically in the small intestine, suggesting that mitochondrial dysfunction played a role in the pathogenesis of paralytic ileus. This case illustrates an unusual and dramatic clinical phenotype of the A8344G mutation, characterized by stroke-like episodes and acute ileus.
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PMID:The A8344G mutation in mitochondrial DNA associated with stroke-like episodes and gastrointestinal dysfunction. 1247 64


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