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)

We identified two patients with progressive external ophthalmoplegia, a mitochondrial disease, who harbored a population of partially deleted mitochondrial DNA (mtDNA) with unusual properties. These molecules were deleted from mtDNA positions 548 to 4,442 and encompassed not only rRNA sequences but the heavy-strand promoter region as well. A 13-bp direct repeat was found flanking the breakpoint precisely, with the repeat at positions 535 to 547 located within the binding site for mitochondrial transcription factor 1 (mtTF1). This is the second mtDNA deletion involving a 13-bp direct repeat reported but is at least 10 times less frequent in the patient population than the former one. In situ hybridization studies showed that transcripts under the control of the light-strand promoter were abundant in muscle fibers with abnormal proliferation of mitochondria, while transcripts directed by the heavy-strand promoter, whether of genes residing inside or outside the deleted region, were not. The efficient transcription from the light-strand promoter implies that the major heavy-and light-strand promoters, although physically close, are functionally independent, confirming previous in vitro studies.
Mol Cell Biol 1991 Mar
PMID:Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region. 199 12

Multiple deletions of mitochondrial DNA have been detected by Southern blotting in the skeletal muscle of a 42-year-old woman with chronic progressive external ophthalmoplegia. A PCR method, using several combinations of primers covering the whole mtDNA as well as sequence analysis, disclosed the wide spectrum of these multiple deletions differing in size, location and sequence at the breakpoint junction. Most involved the major region between the two replication origins. However, three deletions affected the minor region and lacked either the light strand origin of replication or the heavy strand promoter. These data suggest an impairment of mtDNA replication leading to illegitimate recombination and extensive damage of mtDNA.
Mol Cell Probes 1995 Jun
PMID:Fine mapping of randomly distributed multiple deletions of mitochondrial DNA in a case of chronic progressive external ophthalmoplegia. 747 15

A single mtDNA point mutation at nt 3243 has been associated with two different clinical phenotypes: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes ('MELAS3243') and progressive external ophthalmoplegia ('PEO3243'). It has been shown that there is a much higher proportion of ragged-red fibers (RRF) with cytochrome c oxidase (COX) deficiency in PEO3243 than in MELAS3243. Using PCR/RFLP analysis of isolated individual skeletal muscle fibers from patients with both syndromes, we found a direct correlation between the localized concentration of the nt 3243 mutation and impairment of COX function at the single muscle fiber level: we found relatively low levels of mutant mtDNAs (56 +/- 21%) in 'normal' fibers; high levels (90 +/- 6%) in COX-positive RRF; and an almost complete segregation of mutant mtDNAs (95 +/- 3%) in COX-negative RRF. Thus, the differential distribution of fibers with extremely high concentrations of mutant mtDNAs characterizes, and probably distinguishes, the skeletal muscle of PEO and MELAS patients harboring the same nt-3243 mutation.
Hum Mol Genet 1994 Mar
PMID:Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. 791 29

The phenotypes of Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) are closely associated with deletions of mitochondrial DNA (mtDNA). Recent evidence suggesting that more than one type of rearrangement may be present in KSS led us to reinvestigate 18 patients with KSS or CPEO for the presence of mtDNA rearrangements other than deletion. mtDNA duplication was detectable in 10 of 10 patients with KSS, while deletion monomers were the only recombinant mtDNA easily detectable in eight of eight patients with CPEO. Deletion dimers were found only in cases having duplications. Thus, duplications of mtDNA seem to be a hallmark of KSS, including a patient where Pearson's syndrome was the first manifestation. We suggest that duplication of mtDNA is characteristic of the early-onset disease KSS, and that the balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.
Hum Mol Genet 1994 Jun
PMID:Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome? 795 Dec 43

We report an application of multiprimed polymerase chain reaction (PCR) which allows a rapid, nonradioactive detection of deletions in mitochondrial DNA using EDTA-blood and muscle samples. The use of two primer sets consisting of three forward and five reverse primers, respectively, allows a competitive PCR resulting in significant amplification products only in the presence of deletion-harbouring DNA species. Under the conditions described, deletions causing Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia (PEO) have been successfully detected. The location of the primers on mitochondrial DNA used in this study should allow identification and localization of most of the large-scale deletions (i.e. more than 1 kb) of mitochondrial DNA reported so far.
Mol Cell Probes 1994 Feb
PMID:Deletion screening of mitochondrial DNA via multiprimer DNA amplification. 802 7

For quantitative elucidation of maximal mitochondrial oxidation capacities in human mononuclear cells, cultured human skin fibroblasts and human thrombocytes the optimal amount of digitonin for plasma membrane permeabilization was determined to be 5, 10, and 0.1 micrograms/10(6) cells, respectively. Using these concentrations the rate of respiration of permeabilized cells with the mitochondrial substrates succinate (+ rotenone) or glutamate + malate can be stimulated between two- and fourfold by ADP and inhibited by carboxyatractyloside. The maximal respiratory activities of well-characterized preparations of permeabilized mononuclear cells of five patients with chronic progressive external ophthalmoplegia were compared to healthy controls and a 30 to 50% decrease of the ADP-stimulated respiration rates with glutamate + malate and succinate + rotenone was detected. This is an indication for the presence of the mitochondrial defect in respiratory active blood cells. Additionally, for two of these patients the mitochondrial defects were proven to be detectable by the determination of maximal oxygen consumption rates of digitonin-permeabilized cultured skin fibroblasts. Therefore, the determination of maximal oxidation capacities of a well-defined cell population using strictly standardized conditions of digitonin permeabilization is judged as a useful and sensitive method for the elucidation of mitochondrial function in extramuscular tissue.
Biochem Mol Med 1995 Apr
PMID:Oxygraphic evaluation of mitochondrial function in digitonin-permeabilized mononuclear cells and cultured skin fibroblasts of patients with chronic progressive external ophthalmoplegia. 858 54

A novel mtDNA point mutation was detected in the tRNAleu(CUN) gene (G to A at position 12315) in a sporadic patient with chronic progressive external ophthalmoplegia, ptosis, limb weakness, sensorineural hearing loss and a pigmentary retinopathy. The mutation disrupts base pairing in the T psi C stem at a site which has been conserved throughout evolution. Although the other mtDNA tRNAleu gene (UUR) is a hotspot for mutation, this is the first pathogenic mutation to be reported in the gene coding for tRNAleu(CUN). MtDNAs carrying the mutation constituted 94% of total mtDNAs in two separate muscle biopsies. Single fibre analysis showed that skeletal muscle fibres without detectable cytochrome c oxidase activity (COX-ve fibres) contained predominantly mutant mtDNAs (93-98%) while fibres with apparently normal COX activity had up to 90% mutant mtDNAs, demonstrating that the G12315A mutation is functionally recessive. Immunofluorescence studies with specific antibodies to mtDNA- or nuclear-encoded subunits of COX were consistent with a defect in mitochondrial protein translation. The mutation was not present in blood cells or cultured fibroblasts and surprisingly, it could not be detected in satellite cells cultured from the patient's muscle. This pattern, which may by typical of patients who have inherited new germline pathogenic mtDNA mutations, possibly reflects loss of the mutation by random genetic drift in mitotic tissues and proliferation of mitochondria containing the mutant mtDNA in post-mitotic cells. The absence of mtDNA carrying the mutation in satellite cells suggests that regeneration of skeletal muscle fibres from satellite cells could restore a wild-type mtDNA genotype and normal muscle function.
Hum Mol Genet 1996 Nov
PMID:A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy. 892 13

The expression of several mitochondrial and nuclear genes involved in ATP production was examined in cells cultured from muscle biopsies of patients harboring mitochondrial pathologies. The transcript patterns in muscle cells from the patients affected by carnitine palmitoyl transferase II or 2-ketoglutarate dehydrogenase deficiencies were almost similar to control patterns. In the opposite, patterns were strikingly abnormal in all the other cell cultures from patients with defects in enzymatic complexes involved in oxidative phosphorylation: mitochondrial complex II and III deficiencies, two MELAS syndromes (myopathy, encephalopathy, lactic acidosis and stroke like episodes), a case of Kearns-Sayre syndrome and a case of chronic progressive external ophthalmoplegia. In cultured muscle cells from patients with mtDNA mutations, the percentage of mutated mtDNA was low as compared with those determined in the corresponding skeletal muscle biopsy. Moreover, the complex II defect resulting of a nuclear mutation was not expressed in the cell cultures. Thus, an undetermined transcriptional event, transmitted from muscle biopsies to cultured muscle cells, should be involved to account for such abnormal transcript patterns.
Mol Cell Biochem 1997 Mar
PMID:Expression of oxidative phosphorylation genes in muscle cell cultures from patients with mitochondrial myopathies. 906 96

The mitochondrial function in skeletal muscle biopsies of three patients with chronic progressive external ophthalmoplegia, having deletions of the mitochondrial DNA, was studied by laser-excited fluorescence measurements of NAD(P)H and flavoproteins in saponin-skinned fibers. We detected substantially elevated steady state redox states of the mitochondrial NAD-system in the muscle fibers of these patients. Moreover, the respiratory chain-linked autofluorescence changes in the muscle fibers of these patients were larger in comparison to controls indicating substantial alterations of the mitochondrial content. These results are in line with the presence of elevated numbers of partially respiratory chain inhibited mitochondria in the skeletal muscle of chronic progressive external ophthalmoplegia patients.
Mol Cell Biochem 1997 Sep
PMID:Detection of mitochondrial defects by laser fluorimetry. 930 72

Nineteen patients (9 females, 10 males) with mitochondrial encephalomyopathies (ME) were studied. The diagnosis was established according to clinical and histopathological criteria. Leading clinical features were chronic progressive external ophthalmoplegia (CPEO) and muscle weakness in 95% of the patients. Pigmentary retinopathy was seen in 63%, and was always associated with CPEO. Hypacusis was present in 47% and cerebellar ataxia in 63% of patients. Clinical or electrophysiological signs of involvement of the central nervous system (CNS) were found in 21% of the patients. In muscle biopsy ragged red fibers were the predominant histopathological findings (100% of the patients), while COX-negative fibers were seen in 74%, deletions of the mitochondrial DNA in 42%, and defects of the respiratory chain in 32% of the patients. Increased blood lactate levels were found in 79% of the patients. Needle electromyography revealed myopathic features in 74%, features of denervation in 16%, and was normal in the remainder. Imaging studies showed cerebral atrophy in 58%, cerebellar atrophy in 16%, and hyperintense lesions of the white matter, pyramidal tract or extrapyramidal system in 16% of the cases. It is concluded that the clinical manifestations of ME can be very variable. Diagnosis of ME should be always considered in young patients presenting with CPEO and muscle weakness. In most cases, diagnosis can be made by a few selected investigations, while detection of genetic abnormalities may lead to the diagnosis in the remaining cases.
Mol Cell Biochem 1997 Sep
PMID:Clinical, morphological, biochemical, and neuroradiological features of mitochondrial encephalomyopathies. Presentation of 19 patients. 930 3


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