Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0029089 (ophthalmoplegia)
3,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past few years several syndromes have been associated with lesions of the human mitochondrial DNA. MtDNA is a small, circular extra-nuclear chromosome encoding essential components of the respiratory chain. MtDNA-related syndromes can be divided into two groups: mitochondrial encephalomyopathies, characterized by the presence of ragged-red fibres (RRF) as the morphological hallmark, or "pure" encephalopathies with no gross morphological abnormalities in muscle. The first group includes myoclonic epilepsy with ragged-red fibres (MERRF), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO) and a new entity, maternally inherited myopathy and cardiomyopathy. The second group includes Leber's Hereditary Optic Neuroretinopathy (LHON) and the newly described ataxia-retinitis pigmentosa-dementia complex. Three kinds of molecular lesions have been identified: point mutations of protein encoding mtDNA-genes (similar to yeast mit- mutations); point mutations of mtDNA-tRNA genes (similar to yeast syn- mutations); and large-scale rearrangements of mtDNA (similar to yeast rho- mutations). In general, "mit-" mutations are responsible for non-RRF encephalopathies, while "syn-" and "rho-" mutations are associated with mitochondrial encephalomyopathies with RRF. Furthermore, point mutations (mit- and syn-) are usually maternally- inherited, while large-scale mtDNA rearrangements are either sporadic or inherited as mendelian traits. In most cases, the molecular detection of the known defects of mtDNA can be carried out by non-invasive techniques, thus making it an easy and relatively inexpensive procedure in the differential diagnosis of the mitochondrial disorders, a rapidly expanding area of clinical neurology.
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PMID:Defects of mitochondrial DNA. 134 53

With the discovery of mitochondrial DNA (mtDNA) mutations in different neuromuscular disorders, investigations now seek to clarify how the mutant mtDNA induces biochemical and morphologic defects. In one of the most important approaches human mutant mtDNA is transferred into cells that lack mtDNA to examine the relationship between the amount of mutant mtDNA and defects in cell growth, respiration and enzyme activities. The resulting cells are 'cybrids'; these clonal cells contain the heteroplasmic mutant and normal mtDNA from patients with mitochondrial diseases. The mitochondria become functionally defective when the amount of mutant mtDNA exceeds a certain threshold, which differs from mutation to mutation: 60 to 70% in chronic progressive external ophthalmoplegia (CPEO) and probably 95% in the syndromes of mitochondrial encephalopathy, myopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged red fibers (MERRF). This threshold effect may explain the tissue-specific patterns of clinical expression.
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PMID:Mitochondrial diseases. 139 36

The strongly succinate dehydrogenase-reactive blood vessels (SSV) are shown to have increased numbers of enlarged mitochondria in smooth muscle cells of the vessel wall on electron microscopy. They are seen in biopsied skeletal muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) at high frequency. The present study was done to examine the incidence of SSV in biopsied muscles from various neuromuscular diseases. Among 107 patients with mitochondrial encephalomyopathies (MEM) including 50 with chronic progressive external ophthalmoplegia (CPEO), 7 with myoclonus epilepsy with ragged-red fibers (MERRF), and 50 with MELAS, SSV were seen in nearly a half of the patients, and comprised approximately 24% of small arteries. On the other hand, SSV in 100 patients with various neuromuscular diseases other than MEM were exceptional, and only one of 8 patients with myotonic dystrophy had SSV. These findings suggest that the SSV are induced by functional abnormality of mitochondria in smooth muscle cells, and that an identification of the SSV is an additional crucial evidence to make a pathological diagnosis of MEM.
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PMID:[Strongly succinate dehydrogenase-reactive blood vessels (SSV) in various neuromuscular diseases]. 142 48

Among various mitochondrial encephalomyopathies, there are three distinct clinical entities, including chronic progressive external ophthalmoplegia (CPEO), myoclonus epilepsy associated with ragged-red fibers (MERRF), and mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS). They are now clearly demonstrated to have the respective specific mitochondrial (mt) DNA mutations, which facilitate us to analyse mtDNA for practical diagnosis. With molecular analysis on 40 CPEO, 6 MERRF and 40 MELAS patients, most patients in the individual disorders had the disease-specific mutations. In CPEO, 31 of 40 patients had deleted mtDNA in a heteroplasmic distribution; the mutant mtDNA were present in a large amount in the skeletal muscle and other symptomatically affected organs as observed on Southern blotting and polymerase chain reaction (PCR). In MERRF (6 out of 6 patients) and MELAS (32 out of 40 patients), mutant mtDNA was easily detectable with PCR not only in skeletal muscle but also in blood cells from several patients examined. The results lead us to conclude that molecular analysis helps to obtain definite diagnosis of the diseases without loss of time.
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PMID:[Clinical application of molecular diagnosis for mitochondrial encephalomyopathies]. 155 59

Myocardial imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid (123I-BMIPP), a new radiopharmaceutical designed to evaluate myocardial fatty acid metabolism, was performed in 7 patients with mitochondrial myopathy to detect their myocardial damages in comparison with 201Tl myocardial imaging. These patients were divided into 4 chronic progressive external ophthalmoplegia (CPEO) cases, 2 mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) cases and 1 myoclonus epilepsy with ragged-red fibers (MERRF). In visual assessment, we observed more myocardial segments with decreased uptake of 123I-BMIPP compared to 201Tl in MELAS cases than in CPEO cases. The mean myocardial uptake of 123I-BMIPP was higher than that of 201Tl in CPEO cases. On the other hand, in MELAS and MERRF cases, the mean myocardial uptake of 123I-BMIPP was lower than that of 201Tl. Abnormal findings suggesting myocardial damages were observed in echocardiogram and/or in electrocardiogram in MELAS and MERRF cases, while no such abnormal findings were observed in CPEO cases. Along with the previously reported experimental result that the impairment of rat myocardial mitochondria decreased myocardial uptake of 125I-BMIPP, these results suggest that 123I-BMIPP may be useful to detect myocardial damages in patients with mitochondrial myopathy.
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PMID:[Clinical study on myocardial imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid in patients with mitochondrial myopathy]. 160 40

Vascular involvement in biopsied muscle specimens from 11 patients with chronic progressive external ophthalmoplegia (CPEO) with ragged-red fibers (RRF) was studied. Almost none of 69 intramuscular arteries examined were strongly stained with succinate dehydrogenase (SDH) except one patient who had 2 SSV (strongly SDH-reactive blood vessels) in his muscle biopsy. Although RRF and focal cytochrome c oxidase (CCO) deficiency in muscle fibers were the common histochemical changes in muscle biopsy specimens from CPEO patients, all mitochondria in both endothelial and smooth muscle cells of the arteries had normal morphology except for the two SSV and all mitochondria in the blood vessels had normal CCO activity by electron cytochemistry. The findings obtained from the present study were quite different from those in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged-red fibers (MERRF) in which the striking vascular involvement with SSV is the most common and major abnormality in muscle biopsy specimens. To study vascular involvement in mitochondrial encephalomyopathies is the one of very important clues to understand the pathophysiology of phenotypic expressions in mitochondrial encephalomyopathies.
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PMID:[Vascular pathology in chronic progressive external ophthalmoplegia with ragged-red fibers]. 161 73

To determine whether a mitochondrial mRNA deficiency exists in mitochondrial myopathies, muscle biopsies from a patient with chronic progressive external ophthalmoplegia (CPEO) and a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) were studied using in situ hybridization. Histochemistry and immunohistochemistry were performed along with hybridization. Hybridization reactions were widely distributed over the sarcoplasm of all muscle fibers in the patient with MELAS. In the patient with CPEO, 80% of the fibers showed a marked decrease in density of autoradiographic grains. This marked decrease corresponded to the histochemical and immunohistochemical findings of a very weak staining of cytochrome c oxidase (CCO). The isotope-labeled cDNA probe used in in situ hybridization in this study complements a part of subunit I of CCO and a part of subunit II of complex I in the mitochondrial gene. Our results suggest a defect in the mRNA in this CPEO patient.
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PMID:In situ hybridization of muscle mitochondrial mRNA in mitochondrial myopathies. 170 73

A 9-year-old girl and an 11-year-old boy had ptosis, progressive external ophthalmoplegia, pigmentary retinopathy, and sensorineural hearing loss. The girl had diabetes mellitus and the boy had hypoparathyroidism. Both children also developed recurrent vomiting and cerebral infarcts with lactic acidosis. Muscle biopsy specimens showed ragged-red fibers and Southern analysis demonstrated a distinct heteroplasmic deletion of muscle mitochondrial DNA in each patient but no evidence of the point mutation in the transfer RNALeu(UUR) gene recently identified in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). These 2 children had combined features of Kearns-Sayre syndrome and MELAS, suggesting that mitochondrial DNA deletions occasionally can have pleomorphic clinical expression.
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PMID:Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes. 189 71

We studied a large family with a dominantly inherited mitochondrial myopathy characterized by progressive external ophthalmoplegia, dysphagia, cataract, lactic acidosis, exercise intolerance, and early death. Morphologic studies of muscle biopsies suggested mitochondrial heteroplasmy and revealed ragged-red fibers and decreased histochemical reactions for cytochrome c oxidase and succinate dehydrogenase. Biochemistry showed a partial defect of cytochrome c oxidase and a mild generalized reduction of other mitochondrial enzymes requiring mitochondrial DNA-encoded subunits. Southern blot analysis and PCR amplification showed mitochondrial DNA deletions in muscle of all affected members, but not in lymphocytes or fibroblasts, suggesting a tissue-specific distribution. Deletions were multiple and seemed to increase with time and to correlate with the severity of the disease.
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PMID:Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA: clinical, morphologic, and biochemical studies. 206 33

Mitochondrial encephalomyopathies are usually divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibres (MERRF); and (3) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome. Large deletions of human mitochondrial DNA and a transition mutation at the mitochondrial transfer RNALys gene give rise to CPEO including Kearns-Sayre syndrome and MERRF, respectively. Here we report an A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNA(Leu)(UUR) that is specific to patients with MELAS. Because this mutation creates an ApaI restriction site, we could perform a simple molecular diagnostic test for the disease. The mutation was present in 26 out of 31 independent MELAS patients and 1 out of 29 CPEO patients, but absent in the 5 MERRF and 50 controls tested. Southern blot analysis confirmed that the mutant DNA always coexists with the wild-type DNA (heteroplasmy).
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PMID:A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. 171 Mar 18


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