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)

Mitochondria are unique among intracellular organelles because they contain their own DNA, which can be transcribed and translated to form proteins. Mitochondrial diseases include myopathies and multisystem disorders. The case of a patient showing bilateral ophthalmoplegia with proximal limb weakness, severe dysphagia and short stature, without family history, is described. The analysis of mitochondrial DNA of the patient muscle revealed a deleted form accounting for 65% of the total mitochondrial DNA. The Southern Blot Analysis of mtDNA allows a rather precise localization of deletions giving new insights in the pathogenesis of mitochondrial myopathies and representing a new precious diagnostic tool in these diseases.
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PMID:[Mitochondrial DNA deletion in a case of progressive ophthalmoplegia]. 227 55

Large-scale deletions of mitochondrial DNA (mtDNA) have been described in patients with progressive external ophthalmoplegia (PEO) and ragged red fibers. We have determined the exact deletion breakpoint in 28 cases with PEO, including 12 patients already shown to harbor an identical deletion; the other patients had 16 different deletions. The deletions fell into two classes. In Class I (9 deletions; 71% of the patients), the deletion was flanked by perfect direct repeats, located (in normal mtDNA) at the edges of the deletion. In Class II (8 deletions; 29% of patients), the deletions were not flanked by any obviously unique repeat element, or they were flanked by repeat elements which were located imprecisely relative to the breakpoints. Computer analysis showed a correlation between the location of the deletion breakpoints and sequences in human mtDNA similar to the target sequence for Drosophila topoisomerase II. It is not known how these deletions originate, but both slipped mispairing and legitimate recombination could be mechanisms playing a major role in the generation of the large mtDNA deletions found in PEO.
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PMID:Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. 230 45

A 43-year-old woman with progressive external ophthalmoplegia developed a bifascicular block and dilatation of the right ventricle during 4 years of follow-up. Histochemical and electron microscopy studies detected mitochondrial abnormalities in ocular, skeletal muscle and cardiac biopsies. This case registers disease progression from the external ocular to the skeletal and cardiac muscles. Mitochondrial DNA was deleted in relation to the morphological abnormality.
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PMID:Evolution of cardiac involvement in progressive ophthalmoplegia with deleted mitochondrial DNA. 233 42

Two clinico-pathological cases of Kearns-Sayre syndrome are reported. In both cases the typical triad (progressive external ophthalmoplegia, heart block, retinitis pigmentosa) was present and spongiosis was the main pathological finding. In one case there was also a marked capillary proliferation, significance of which is discussed. A deletion of the mitochondrial DNA was found in the muscle, spinal cord and brain of this last case.
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PMID:Kearns-sayre syndrome. Two clinico-pathological cases. 235 83

By using a combination of Southern blot hybridization analysis, polymerase-chain reaction amplification, and direct nucleotide sequencing, we studied deletions of mitochondrial DNA (mtDNA) in several nonfamilial patients with progressive external ophthalmoplegia and Kearns-Sayre syndrome, and in some of their direct relatives. Results suggest that the heteroplasmic mtDNA populations are already present at a very early stage of development, and that there is no direct transmission of mtDNA heteroplasmy by maternal inheritance.
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PMID:Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies. 237 42

Deletions of mitochondrial DNA have been detected in skeletal muscle of some patients with mitochondrial encephalomyopathies, but their junctions have been defined only approximately. We developed a procedure, using widely spaced primers for the polymerase chain reaction, that amplifies preferentially the sequences bracketing the deletion. This procedure permits detection of minor proportions, not detectable by Southern analysis, of deleted mitochondrial DNA species in a heteroplasmic mixture. Different proportions of intact mitochondrial DNA and species deleted from nucleotide 8708 to 13,722 were found in skeletal muscle, blood, and urinary epithelial cells from a patient with chronic progressive external ophthalmoplegia. These data indicate that the mutation occurred at or before early embryonic development and provide the first definition at the nucleotide level of a human disease caused by a deletion of mitochondrial DNA.
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PMID:Preferential amplification and molecular characterization of junction sequences of a pathogenetic deletion in human mitochondrial DNA. 253 62

We investigated the correlations of deletions of mitochondrial DNA in skeletal muscle with clinical manifestations of mitochondrial myopathies, a group of disorders defined either by biochemical abnormalities of mitochondria or by morphologic changes causing a ragged red appearance of the muscle fibers histochemically. We performed genomic Southern blot analysis of muscle mitochondrial DNA from 123 patients with different mitochondrial myopathies or encephalomyopathies. Deletions were found in the mitochondrial DNA of 32 patients, all of whom had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome, a multisystem disorder characterized by ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia. The deletions ranged in size from 1.3 to 7.6 kilobases and were mapped to different sites in the mitochondrial DNA, but an identical 4.9-kilobase deletion was found in the same location in 11 patients. Biochemical analysis showed decreased activities of NADH dehydrogenase, rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase, four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA. We conclude that deletions of muscle mitochondrial DNA are associated with ophthalmoplegia and may result in impaired mitochondrial function. However, the precise relation between clinical and biochemical phenotypes and deletions remains to be defined.
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PMID:Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. 230

The muscle mitochondria of a patient with Kearns-Sayre/chronic external ophthalmoplegia plus syndrome were found to be completely deficient in respiratory complex I activity and partially deficient in complex IV and V activities. Treatment of the patient with coenzyme Q10 and succinate resulted in clinical improvement of respiratory function, consistent with the respiratory deficiencies. Restriction enzyme analysis of the muscle mtDNA revealed a 4.9-kilobase deletion in 50% of the mtDNA molecules. Polymerase chain reaction analysis demonstrated that the deletion was present in the patient's muscle but not in her lymphocytes or platelets. Furthermore, the deletion was not present in the muscle or platelets of two sisters. Hence, the mutation probably occurred in the patient's somatic cells. Direct sequencing of polymerase chain reaction-amplified DNA revealed a 4977-base-pair deletion removing four genes for subunits of complex I, one gene for complex IV, two genes for complex V, and five genes for tRNAs, which paralleled the respiratory enzymes affected in the disease. A 13-base-pair direct repeat was observed upstream from both breakpoints. Relative to the direction of heavy-strand replication, the first repeat was retained and the second repeat was deleted, suggesting a slip-replication mechanism. Sequence analysis of the human mtDNA revealed many direct repeats of 10 base pairs or greater, indicating that this mechanism could account for other reported deletions. We postulate that the prevalence of direct repeats in the mtDNA is a consequence of the guanine-cytosine bias of the heavy and light strands.
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PMID:Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. 255 97

A 19-year-old man with chronic progressive external ophthalmoplegia with deleted mitochondrial DNA was reported. Neurological examination revealed bilateral external ophthalmoplegia, hearing loss of sensorineural type, short stature, mental retardation, muscle atrophy and weakness in the proximal muscles. Lactate and pyruvate levels were elevated in both serum and cerebrospinal fluid (CSF). Protein concentration was slightly increased in CSF. Electromyogram showed myopathic changes on all the muscles examined. Ragged-red fibers were found in biopsied rectus femoris muscle, stained with modified Gomori trichrome. Scattered cytochrome c oxidase deficient fibers were encountered. The computed tomography of the brain showed mild cerebral and cerebellar atrophy without any abnormal calcification or hypo-lucency. Southern blot analysis of the mitochondrial DNA (mtDNA) extracted from the patient's muscle revealed mixed population of mtDNA, consisting of the normal one and partially deleted one. The size of the deletion was about 4.5-kilobase. The region included the sequences coding for at least four subunits of Complex I, one subunit of Complex IV, two subunits of Complex V and five tRNAs. There may be a "hot area" on the mitochondrial genome that is more prone to be deleted than other regions of mtDNA. Southern blot analysis is usefull for the diagnosis of KSS or CPEO.
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PMID:[Chronic progressive external ophthalmoplegia (CPEO) with deleted mitochondrial DNA]. 259 47

Analysis of mitochondrial DNA (mtDNA) in muscle and blood from 72 patients with mitochondrial myopathy showed that 30 had major deletions of a variable proportion of muscle mtDNA. All of these 30 patients presented with progressive external ophthalmoplegia and limb weakness, and 8 had the additional features of the Kearns-Sayre syndrome. Of the 42 patients without detectable muscle mtDNA deletions, 10 had progressive external ophthalmoplegia and limb weakness, 2 had the Kearns-Sayre syndrome, 11 had limb weakness without extraocular involvement, and 19 had multisystem disorders predominantly affecting the central nervous system. Only 2 patients with mtDNA deletions had clinically affected relatives, compared with 10 of those without deletions. In the 4 patients with polarographic defects exclusively involving complex I (NADH coenzyme Q reductase), the deleted protein-coding genes were confined to those for complex I subunits. Thirteen other patients with apparently identical deletions had variable clinical and biochemical features. Immunoblots of complex I polypeptides from patients with deletions were either indistinguishable from controls or showed only a mild generalized decrease in all identifiable subunits.
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PMID:Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. 260 80


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