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

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is a disease mainly due to a mutation at position 3243 (A --> G) in the leucine tRNA gene in mitochondrial DNA. Symptoms of the disorder are complex and the exact pathogenesis is not understood. A review of the literature on the subject is presented.
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PMID:MELAS as an example of a mitochondrial disease. 1456 41

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) is typically associated with a single point mutation in the mitochondrial genome (mtDNA). Because mtDNA is known to have a higher mutation rate than nuclear DNA, we speculate that some patients with MELAS syndrome may harbor more than one mutation in mtDNA. For this purpose, mtDNA extracted from muscle containing dysmorphic mitochondria from a 32-year-old man with MELAS was sequenced in its entirety to identify all possible mutations. The result showed a homoplasmic A14693G and a heteroplasmic A3243G. The A14693G transition was not present in 205 unrelated control individuals, was not seen in 76 species randomly selected from GenBank, and appears to disrupt the base pairing within the T-loop of mtDNA tRNA(Glu). His asymptomatic siblings' blood showed wild-type at these positions, whereas the blood of the patient's oligosymptomatic diabetic mother had a heteroplasmic A14693G and an apparent homoplasmic wild-type A3243, suggesting an association of A14693G with diabetes mellitus. This case demonstrates the importance of sequencing the mtDNA in its entirety to evaluate the molecular basis of mitochondriopathy.
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PMID:Melas with point mutations involving tRNALeu (A3243G) and tRNAGlu(A14693g). 1457 59

Point mutations in mitochondrial tRNAs can cause severe multisystemic disorders such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonus epilepsy with ragged-red fibers (MERRF). Some of these mutations impair one or more steps of tRNA maturation and protein biosynthesis including 5'-end-processing, post-transcriptional base modification, structural stability, aminoacylation, and formation of tRNA-ribosomal complexes. tRNALeu(UUR), an etiologic hot spot for such diseases, harbors 20 of more than 90 disease-associated mutations described to date. Here, the pathogenesis-associated base substitutions A3243G, T3250C, T3271C, A3302G and C3303T within this tRNA were tested for their effects on endonucleolytic 3'-end processing and CCA addition at the tRNA 3'-terminus. Whereas mutations A3243G, A3302G and C3303T reduced the efficiency of 3'-end cleavage, only the C3303T substitution was a less efficient substrate for CCA addition. These results support the view that pathogenesis may be elicited through cumulative effects of tRNA mutations: a mutation can impede several pre-tRNA processing steps, with each such reduction contributing to the overall impairment of tRNA function.
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PMID:A pathogenesis-associated mutation in human mitochondrial tRNALeu(UUR) leads to reduced 3'-end processing and CCA addition. 1501 75

Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing protein with antioxidant properties. GPx-3 deficiency has been associated with cardiovascular disease and stroke. The regulation of GPx-3 expression remains largely uncharacterized, however, and we studied its transcriptional and translational determinants in a cultured cell system. In transient transfections of a renal cell line (Caki-2), the published sequence cloned upstream of a luciferase reporter gene produced minimal activity (relative luminescence (RL) = 0.6 +/- 0.4). Rapid amplification of cDNA ends was used to identify a novel transcription start site that is located 233 bp downstream (3') of the published site and that produced a >25-fold increase in transcriptional activity (RL = 16.8 +/- 1.9; p < 0.0001). Analysis of the novel GPx-3 promoter identified Sp-1- and hypoxia-inducible factor-1-binding sites, as well as the redox-sensitive metal response element and antioxidant response element. Hypoxia was identified as a strong transcriptional regulator of GPx-3 expression, in part through the presence of the hypoxia-inducible factor-1-binding site, leading to an almost 3-fold increase in expression levels after 24 h compared with normoxic conditions (normalized RL = 3.5 +/- 0.3 versus 1.2 +/- 0.1; p < 0.001). We also investigated the role of the translational cofactors tRNA(Sec), SECIS-binding protein-2, and SelD (selenophosphate synthetase D) in GPx-3 protein expression. tRNA(Sec) and SelD significantly enhanced GPx-3 expression, whereas SECIS-binding protein-2 showed a trend toward increased expression. These results demonstrate the presence of a novel functional transcription start site for the human GPx-3 gene with a promoter regulated by hypoxia, and identify unique translational determinants of GPx-3 expression.
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PMID:Determinants of human plasma glutathione peroxidase (GPx-3) expression. 1509 16

A 30-year-old man was hospitalized with dysarthria and weakness of his right arm and leg. Three months previously, he had noticed numbness and weakness of his right shoulder, which spread to involve his left leg but which improved after 8 months. On admission, neurological examination revealed limb kinetic apraxia and constructive apraxia of the right hand, motor aphasia, dysarthria, and spastic quadriplegia. Sensory examination revealed hyperalgesia and dysesthesia in the right arm and left leg. Deep tendon reflexes were hyperactive in all four extremities. And he had bilateral Babinski signs. Laboratory examination revealed pH 7.38, PCO2 46.1 Torr, PO2 93.4 Torr, BE 1.7, and blood lactate, 9.0 mg/dl (normal 5-20 mg/dl). Cerebrospinal fluid lactate level was 20.0 mg/dl. pyruvate 1.34 mg/dl. and protein 83 mg/dl. Blood lactate and pyruvate values were markedly elevated after aerobic exercise. T2WI brain MRI showed scattered high signal lesions in the left precentral and postcentral gyrus, right paracentral lobes, both superior frontal gyri, and right superior temporal gyrus. Right biceps brachi biopsy showed almost complete cytochrome c oxidase (COX) deficiency. There were no ragged-red fibers. There was marked decrease of COX activity: 2.7 nmol/min/mg-mitochondrial protein (normal range: 33.0 +/- 16.1, n = 7) in the biopsied muscle. Open brain biopsy (after permission from the patient and his family) revealed gliosis and perivascular infiltration of lymphocytes and macrophages without vascular proliferation. There was no mitochondrial DNA mutations, deletion or duplication, including tRNA-Leu 3243, 8993, 3271, 9176, 3291, and tRNA-Lys 8344, 8356, and 8363. From these findings, a diagnosis of COX deficiency presenting as MELAS-like episodes was done. His mother also showed abnormality on aerobic exercise test, but she had no episode of stroke or neurological dysfunction. Six months later, his aphasia and apraxia of the right hand had resolved, and at discharge he was able to ambulate with a cane. Ten months later, he returned to his work. There has been no recurrence of neurologic symptoms over the next 3 years and 10 months. This patient appears to represent a rare case of adult onset COX deficiency presenting as MELAS-like episodes.
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PMID:[MELAS-like episodes in an adult case with cytochrome c oxidase deficiency]. 1523 72

Point mutations in the mitochondrial (mt) tRNA(Leu(UUR)) gene are responsible for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a subgroup of mitochondrial encephalomyopathic diseases. We previously showed that mt tRNA(Leu(UUR)) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurine-containing modification (taum5U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of the mutant tRNA due to the wobble modification deficiency independent of the pathogenic point mutation itself, we used a molecular surgery technique to construct an mt tRNA(Leu(UUR)) molecule lacking the taurine modification but without the pathogenic mutation. This "operated" mt tRNA(Leu(UUR)) without the taurine modification showed severely reduced UUG translation but no decrease in UUA translation. We thus concluded that the UUG codon-specific translational defect of the mutant mt tRNAs(Leu(UUR)) is the primary cause of MELAS at the molecular level. This result could explain the complex I deficiency observed clinically in MELAS.
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PMID:Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. 1547 92

Mutations in mtDNA are responsible for a variety of mitochondrial diseases, where the mitochondrial tRNA(Leu(UUR)) gene has especially hot spots for pathogenic mutations. Clinical features often depend on the tRNA species and/or positions of the mutations; however, molecular pathogenesis elucidating the relation between the location of the mutations and their leading phenotype are not fully understood. We report here that mitochondrial tRNAs(Leu(UUR)) harboring one of five mutations found in tissues from patients with symptoms of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (A3243G, G3244A, T3258C, T3271C, and T3291C) lacked the normal taurine-containing modification (5-taurinomethyluridine) at the anticodon wobble position. In contrast, mitochondrial tRNAs(Leu(UUR)) with different mutations found in patients that have mitochondrial diseases but do not show the MELAS symptoms (G3242A, T3250C, C3254T, and A3280G) had the normal 5-taurinomethyluridine modifications. These observations were made by using a modified primer extension technique that can detect the modification deficiency in the extremely limited quantities of mutant tRNAs obtainable from patient tissues. These results strongly suggest deficient wobble modification could be a key molecular factor responsible for the phenotypic features of MELAS, which can explain why the different MELAS-associated mutations result in indistinguishable clinical features.
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PMID:Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. 1587 Feb 3

Brain single photon emission computed tomography (SPECT) studies were conducted in three patients with A3243G mutation of the mitochondrial (mt) DNA tRNA. All were born to mothers suffering from chronic progressive external ophthalmoplegia (CPEO) with the same A3243G point mutation of the mtDNA tRNA. The first case manifested clinically with MELAS, the second case manifested with CPEO, and third case was characterized by recurrent migraine-like headache, tremor, and epilepsy. Brain SPECT of all patients, regardless of whether they had or had not suffered from stroke-like episodes, showed multiple areas of asymmetrical decreased perfusion, particularly in the posterior and lateral head regions, especially the temporal lobes. Crossed-cerebellar diaschisis may occur. Conventional brain magnetic resonance images failed to show some of the lesions. Decreased regional cerebral blood flow, rather than previously proposed hyperemia, is likely to be the cause. We conclude that mitochondrial vasculopathy with regional cerebral hypoperfusion may be seen on brain SPECT in patients with mitochondrial disorders and A3243G mutations, regardless of whether they have or have not suffered from stroke-like episodes.
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PMID:Brain single photon emission computed tomography in patients with A3243G mutation in mitochondrial DNA tRNA. 1596 44

The COII/tRNA(Lys) intergenic 9-bp deletion (MIC9D) of mitochondrial DNA (mtDNA) has been established as a genetic polymorphism for Asian-Pacific populations. We investigated whether this small mtDNA deletion is co-transmitted with human diseases such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF) syndromes. Forty unrelated Taiwanese families, including 12 families with MERRF and A8344G mtDNA mutation and 28 families with MELAS and A3243G mutation of mtDNA, respectively, were recruited in this study. In addition, 199 healthy subjects were recruited as control. We found that the frequency of occurrence of mtDNA with the MIC9D polymorphism in healthy subjects was 21% (41/199). However, the incidence of the MIC9D polymorphism was 67% (8/12) among the probands of all the families with MERRF syndrome (P = 0.001; OR = 8) and 39% (11/28) among the probands of the families with MELAS syndrome (P = 0.038; OR = 2). This finding indicates that the frequency of occurrence of mtDNA with the MIC9D polymorphism in patients with MERRF or MELAS syndrome is higher than that of healthy subjects. The prevalence of mitochondrial encephalomyopathies in relation to the MIC9D polymorphism of mtDNA in Taiwanese population is discussed.
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PMID:High prevalence of the COII/tRNA(Lys) intergenic 9-bp deletion in mitochondrial DNA of Taiwanese patients with MELAS or MERRF syndrome. 1596 49

An increased concentration of homocysteine is an important risk factor of atherosclerosis; however, the mechanism of the proatherogenic effect of this amino acid is not yet known. Studies performed during the last two decades suggest that the atherogenic effect of homocysteine may be accounted for by homocysteine thiolactone (HCTL). Homocysteine is nonspecifically activated by methionyl-tRNA synthetase; however, it is not transferred to tRNA and incorporated into proteins, but is transformed to a cyclic thioester, homocysteine thiolactone. HCTL is highly reactive and acylates free amino groups of protein lysine residues, the process referred to as protein N-homocysteinylation. Various plasma proteins are homocysteinylated in vitro and in vivo. Homocysteinylation results in the incorporation of additional thiol groups which may alter the physicochemical properties and biological activity of proteins. In particular, homocysteinylation of low-density lipoproteins (LDLs) increases their susceptibility to oxidation and accelerates their uptake by macrophages. In addition, homocysteinylated LDL elicit humoral immune response. Anti-homocysteinyllysine antibodies are detected in plasma of healthy humans and their titer is elevated in patients with ischemic heart disease or ischemic cerebral stroke. Homocysteine thiolactone is hydrolyzed to homocysteine by paraoxonase (PON), a calcium-dependent esterase synthesized in the liver and contained in plasma high-density lipoproteins (HDLs). Protein homocysteinylation may contribute to accelerated atherogenesis in individuals with hyperhomocysteinemia.
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PMID:Protein homocysteinylation: a new mechanism of atherogenesis? 1610 41


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