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)

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.
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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

Sixteen members of a family with a history of autosomal dominant progressive external ophthalmoplegia (adPEO) with hypogonadism were examined. The muscular involvement commenced cranially and descended in relation to increasing disease duration. The neuromuscular signs were PEO, dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss. The electromyogram (EMG) was myopathic in facial and proximal limb muscles. Neurogenic involvement was suspected in a few tibial anterior muscles. Neurography showed signs of axonal neuropathy correlated to clinical signs. F-responses were reduced in number or absent in peroneal nerves, and did not correlate to clinical signs or disease duration. Muscle biopsies in advanced cases had structural abnormalities of mitochondria, ragged-red fibers, and focal cytochrome c oxidase deficiency. A combination of muscle-nerve involvement with PEO, Achilles tendon areflexia, distal vibration sensory impairment, myopathic EMG, and abnormally low sural nerve responses seems to be typical of this type of mitochondrial disorder.
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PMID:Muscle-nerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism. 860 26

Inclusion body myositis (IBM) is a sporadic progressive myopathy, which is morphologically characterized by inflammatory cell infiltrates and rimmed vacuoles in muscle fibers. Mitochondrial changes are regularly present with ragged-red fibers showing deficiency of cytochrome c oxidase. In these muscle fiber segments, there is accumulation of mitochondria with mitochondrial DNA (mtDNA) deletions. There are different deletions in different muscle fibers. In this study, we have sequenced for the first time the multiple mtDNA deletions in muscle from four patients with IBM. The deletion breakpoints were sequenced from cloned polymerase chain reaction (PCR)-amplified mtDNA fragments. The sequencing was performed directly from the bacterial colonies used for cloning. Of 122 analyzed clones, 33 different deletions were identified. The majority of these have not previously been described. There was a marked predominance of deletion breakpoints in certain regions of mtDNA. These predominant breakpoint regions are similar to those described in other conditions with multiple deletions, such as autosomal dominant progressive external ophthalmoplegia (adPEO) and normal aging, but different from those described in diseases due to single deletions such as Kearns-Sayre syndrome and sporadic PEO. These findings indicate that common factors are involved in the development of multiple mtDNA deletions in IBM, adPEO, and aging.
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PMID:Analysis of multiple mitochondrial DNA deletions in inclusion body myositis. 937 54

Multiple mitochondrial DNA (mtDNA) deletions have been described in patients with autosomal dominant progressive external ophthalmoplegia (AD-PEO) and in autosomal recessive disorders including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). The pathogenic bases of these disorders are unknown. We studied three patients with AD-PEO and three patients with autosomal recessive (AR)-PEO (two patients with MNGIE and one patient with ARCO). Histochemistry and Southern blot analyses of DNA were performed in skeletal muscle from the patients. Muscle mtDNA was used to characterize the pattern and amounts of the multiple mtDNA rearrangements; PCR analysis was performed to obtain finer maps of the deleted regions in both conditions. The patients with AD-PEO had myopathic features; the patients with AR-PEO had multisystem disorders. The percentage of ragged-red and cytochrome c oxidase-negative fibers tended to be higher in muscle from the patients with AD-PEO (19% +/- 13.9, 29.7 +/- 26.3) than in muscle from the patients with AR-PEO (1.4% +/- 1.4, 3.3% +/- 3.2; p < 0.10). The sizes of the multiple mtDNA deletions ranged from approximately 4.0 to 10.0 kilobases in muscle from both groups of patients, and in both groups, we identified only deleted and no duplicated mtDNA molecules. Patients with AD-PEO harbored a greater proportion of deleted mtDNA species in muscle (31% +/- 5.3) than did patients with AR-PEO (9.7% +/- 9.1; p < 0.05). In the patients with AD-PEO, we identified a deletion that included the mtDNA heavy strand promoter (HSP) region, which had been previously described as the HSP deletion. The HSP deletion was not present in the patients with AR-PEO. Our findings show the clinical, histologic, and molecular genetic heterogeneity of these complex disorders. In particular, the proportions of multiple mtDNA deletions were higher in muscle samples from patients with AD-PEO than in those from patients with AR-PEO.
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PMID:Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses. 944 65

An expanding number of autosomal diseases has been associated with mitochondrial DNA (mtDNA) depletion and multiple deletions. These disorders have been classified as defects of intergenomic communication because mutations of the nuclear DNA are thought to disrupt the normal cross-talk that regulates the integrity and quantity of mtDNA. In 1989, autosomal dominant progressive external ophthalmoplegia with multiple deletions of mitochondrial DNA was the first of these disorders to be identified. Two years later, mtDNA depletion syndrome was initially reported in infants with severe hepatopathy or myopathy. The causes of these diseases are still unclear, but genetic linkage studies have identified three chromosomal loci for AD-PEO. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder associated with both mtDNA depletion and multiple deletions, is now known to be due to loss-of-function mutations in the gene encoding thymidine phosphorylase. Increased plasma thymidine levels in MNGIE patients suggest that imbalanced nucleoside and nucleotide pools in mitochondria may lead to impaired replication of mtDNA. Future research will certainly lead to the identification of additional genetic causes of intergenomic communication defects and will likely provide insight into the normal "dialogue" between the two genomes.
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PMID:Defects of intergenomic communication: where do we stand? 1088 64

One form of familial progressive external ophthalmoplegia with multiple mitochondrial DNA deletions recently has been associated with mutations in POLG1, the gene encoding pol gammaA, the catalytic subunit of mitochondrial DNA polymerase. We screened the POLG1 gene in several PEO families and identified five different heterozygous missense mutations of POLG1 in 10 autosomal dominant families. Recessive mutations were found in three families. Our data show that mutations of POLG1 are the most frequent cause of familial progressive external ophthalmoplegia associated with accumulation of multiple mitochondrial DNA deletions, accounting for approximately 45% of our family cohort.
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PMID:Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. 1221 Jul 92

Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a severe autosomal recessively inherited neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy. We report here the molecular background of this disease based on the positional cloning/candidate approach of the defective gene. Having established the linkage to chromosome 10q24, we restricted the critical DNA region using single nucleotide polymorphism-based haplotypes. After analyzing all positional candidate transcripts, we identified two point mutations in the gene C10orf2 encoding Twinkle, a mitochondrial deoxyribonucleic acid (mtDNA)-specific helicase, and a rarer splice variant Twinky, underlying IOSCA. The founder IOSCA mutation, homozygous in all but one of the patients, leads to a Y508C amino acid change in the polypeptides. One patient, heterozygous for Y508C, carries a silent coding region cytosine to thymine transition mutation in his paternal disease chromosome. This allele is expressed at a reduced level, causing the preponderance of messenger RNAs encoding Y508C polypeptides and thus leads to the IOSCA disease phenotype. Previously, we have shown that different mutations in this same gene cause autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletions (MIM 606075), a neuromuscular disorder sharing a spectrum of symptoms with IOSCA. IOSCA phenotype is the first recessive one due to Twinkle and Twinky mutations, the dominant PEO mutations affecting mtDNA maintenance, but in IOSCA, mtDNA stays intact. The severe neurological phenotype observed in IOSCA, a result of only a single amino acid substitution in Twinkle and Twinky, suggests that these proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations.
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PMID:Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. 1613 56

The human POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase gamma (pol gamma). Mutations in pol gamma are associated with a spectrum of disease phenotypes including autosomal dominant and recessive forms of progressive external ophthalmoplegia, spino-cerebellar ataxia and epilepsy, and Alpers-Huttenlocher hepatocerebral poliodystrophy. Multiple deletions, or depletion of mtDNA in affected tissues, are the molecular hallmarks of pol gamma mutations. To shed light on the pathogenic mechanisms leading to these phenotypes, we have introduced in MIP1, the yeast homologue of POLG, two mutations equivalent to the human Y955C and G268A mutations, which are associated with dominant and recessive PEO, respectively. Both mutations induced the generation of petite colonies, carrying either rearranged (rho-) or no (rho0) mtDNA. Mutations in genes that control the mitochondrial supply of deoxynucleotides (dNTP) affect the mtDNA integrity in both humans and yeast. To test whether the manipulation of the dNTP pool can modify the effects of pol gamma mutations in yeast, we have overexpressed a dNTP checkpoint enzyme, ribonucleotide reductase, RNR1, or deleted its inhibitor, SML1. In both mutant strains, the petite mutability was dramatically reduced. The same result was obtained by exposing the mutant strains to dihydrolipoic acid, an anti-oxidant agent. Therefore, an increase of the mitochondrial dNTP pool and/or a decrease of reactive oxygen species can prevent the mtDNA damage induced by pol gamma mutations in yeast and, possibly, in humans.
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PMID:Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans. 1694 Mar 10

Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.
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PMID:Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances. 1748 96

Nuclear genes affecting mitochondrial genome stability were screened in an Italian family presenting with autosomal dominant progressive external ophthalmoplegia (adPEO) associated with multiple mitochondrial DNA (mtDNA) deletions. We report on a heterozygous c.907C>T (p.R303W) mutation found in the N-terminal domain of the human mitochondrial DNA helicase, Twinkle protein, in six members of a family, in which two individuals manifested late-onset PEO and morphological and molecular signs of mitochondrial dysfunction along with two carriers who are presently free of disease manifestation. We also investigated if the p.R303W mutation in PEO1 gene affected the relative copy number of mitochondrial DNA genomes.
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PMID:Molecular analysis in a family presenting with a mild form of late-onset autosomal dominant chronic progressive external ophthalmoplegia. 1942 52


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