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 report a new mutation, a G to A transition at nucleotide position 4298 within the mitochondrial tRNA(Ile) gene in a patient with chronic progressive external ophthalmoplegia and multiple sclerosis. The mutation, which alters an evolutionary conserved nucleotide within the anticodon stem, was heteroplasmic in skeletal muscle but was not present in the patient's blood. Single fibre PCR analysis revealed significantly higher levels of the G4298A mutation in cytochrome c oxidase (COX) negative fibres than in COX-positive fibres. This mutation represents the seventh pathogenic nucleotide substitution to be found in this gene and as such confirms the tRNA(Ile) gene as a susceptible "hot spot" for mitochondrial DNA point mutations. Of particular interest is that this patient has the clinical features of both multiple sclerosis and a mitochondrial DNA disorder.
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PMID:A novel mitochondrial DNA point mutation in the tRNA(Ile) gene: studies in a patient presenting with chronic progressive external ophthalmoplegia and multiple sclerosis. 947 77

Kearns-Sayre syndrome (KSS) is a progressive neuromuscular disease characterized by ophthalmoplegia, cardiac conduction block, and pigmentary retinopathy associated with abnormal mitochondrial structure and function. Usually mitochondrial DNA (mtDNA) deletions have been associated with Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia. Size and position of the deletions differ markedly among these patients. The present study confirms this observation for a patient with KSS by a muscle and nerve biopsy in which we detected a 1.2 kb mtDNA deletion. The location of the deletion, however, is unusual in this case: its position comprises nucleotides 14952 to 15739. The defect is heteroplasmic and concerns the cytochrome b and tRNA genes. Complex I and IV of the respiratory chain were intact in this case, indicating that below a threshold of tRNA formation, the impaired biosynthesis and membrane integration of one respiratory complex may cause the phenotypical appearance of the KSS syndrome associated with a subclinical neuropathy.
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PMID:Mitochondrial cytochrome b gene deletion in Kearns-Sayre syndrome associated with a subclinical type of peripheral neuropathy. 983 55

We compared clinical pictures of a case of mitochondrial encephalomyopathy with tRNA(Leu(UUR)) point mutation at nucleotide position 3254 of mitochondrial DNA with those at position 3243. The mutation 3254 was a 19-year-old male patient with cardiomyopathy accompanied with muscle atrophy. The first mutant 3243 was a 31-year-old female patient showing clinical features of MELAS and endocrinological abnormalities. The second 3243 mutant was a 27-year-old male patient who had an external ophthalmoplegia and slight mental decline. In all cases, muscle biopsy specimen showed ragged red fibers and strongly SDH-reactive blood vessels, but their limb weakness were unremarkable. These results suggest that tRNA(Leu(UUR)) point mutation 3254 exhibits similar clinical phenotypes as those observed in 3243 mutant.
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PMID:[Comparison of clinical pictures of mitochondrial encephalomyopathy with tRNA(Leu(UUR)) mutation in 3243 with that in 3254]. 998 53

Multiple mitochondrial DNA (mtDNA) deletions have been reported in patients with autosomal dominant and recessive disorders. We studied several affected and one non-affected individuals belonging to a pedigree in which the inheritance of the pathological trait was compatible with an autosomique dominant transmission. Affected members had late-onset multisystem disorders with multiple mtDNA deletions in skeletal muscle. But this family presented a striking difference from previously described cases, because none of the patients had progressive external ophthalmoplegia (PEO). We also studied one young boy with a no contributary family history. He had a cerebellar ataxia with PEO and multiple mtDNA deletions in muscle. Molecular analysis revealed that in the first family, repeated sequences were present at the breakpoint junctions, whereas such motifs were not found in the young patient's case. In the first family, we evidenced mtDNA point mutations in clones containing breakpoint junctions and a 9-bp motif triplication in the intergenic COII/tRNA(Lys) region, whereas this sequence is repeated twice in the wild type mtDNA. Our results suggest that multiple deletions observed in the two pedigrees result from different molecular mechanisms and point out the role of repeated sequences in the first pedigree. No mtDNA repair system has been described in mammals so far, but the molecular abnormalities found in the first family suggest that a defect in an mtDNA repair system, homologous to the E. coli MutHLS pathway, could be responsible for such a phenotype.
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PMID:Importance of searching for associated mitochondrial DNA alterations in patients with multiple deletions. 1085 92

We report on 3 siblings (2 females and 1 male) with chronic progressive external ophthalmoplegia (CPEO), compatible with inherited mitochondrial cytopathy. The younger of the two sisters died at the age of 37 due to progressive respiratory failure. The older one presented with a status epilepticus at the age of 39 and was treated with valproate. Five months after the start of treatment, she developed fulminant liver failure and died. The brother has suffered from CPEO since early childhood but has had so far no other symptoms of a mitochondrial disease. A muscle biopsy from the younger sister revealed ragged-red fibers and decreased activities of complex I and IV of the respiratory chain but no pathogenic mutations in the mitochondrial tRNA genes or in several locations in the coding region of the mitochondrial genome. In the older sister's liver (obtained post-mortem), mitochondrial DNA was fragmented and could not be investigated. The clinical presentation and the biochemical findings suggest that all 3 siblings suffered from a mitochondrial cytopathy. Since mitochondrial cytopathies and valproate-induced fulminant liver failure are both rare events, an association between them is likely. Mitochondrial diseases should therefore be considered as a risk factor for valproate-induced liver failure and be excluded before treatment with valproate.
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PMID:Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. 1095 15

A current hypothesis claims that an increase of blood flow is required for oxygen consumption to rise during neuronal excitation (activation). Chronic progressive external ophthalmoplegia is a mitochondrial disease associated with deletions of mtDNA or by point mutation of tRNA genes. We tested the hypothesis that the cerebral metabolic rate of oxygen (CMRO2) may not rise in this disorder if the accompanying cerebral blood flow increase is insufficient. Two patients with progressive external ophthalmoplegia were visually stimulated with a colored checkerboard pattern reversing as different frequencies. When stimulated, Patient 1 had a small increase of cerebral blood flow, while Patient 2 had no cerebral blood flow increase. In the visually active state, the patients had no significant change of CMRO2, while healthy subjects had a pronounced increase of CMRO2 in the pericalcarine visual cortex at 4 Hz and a further slight increase at 8 Hz during activation.
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PMID:Impaired activation of oxygen consumption and blood flow in visual cortex of patients with mitochondrial encephalomyopathy. 1102 55

Mitochondrial DNA (mtDNA) mutations have been causally linked with cardiomyopathies, both dilated (DCM) and hypertrophic. We identified the T12297C mutation in the mtDNA-tRNA(Leu(CUN)) of a 36-year-old male patient diagnosed with DCM. The mutation was heteroplasmic, with high amount (88%) of mutant DNA in the myocardium, and was absent in normal (n = 120) and disease (n = 150) controls. It affects a highly conserved nucleotide (adjacent to the anticodon triplet) that allows the phospho-ribose backbone to turn and form the loop. The potential pathological role of T12297C mutation is further supported by its recent identification in another unrelated Italian family with DCM associated with endocardial fibroelastosis. In the variable loop of the same tRNA, our patient also carried the A12308G transition that is debated as pathological mutation or neutral polymorphism in progressive external ophthalmoplegia: the two defects could exert a synergistic effect on the tRNA structure and function. The endomyocardial biopsy study showed abnormal ring-like mitochondria and occasional cytochrome c oxydase negative myocytes. Overall, the heteroplasmy, the highly conserved position of the mutated nucleotide, the absence of the mutation in large series of diseased and normal controls, and the cardiac mitochondrial changes support a causative link of the mutation with the disease.
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PMID:The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy. 1131 76

We describe a new mutation in the tRNA(Ala) gene, a T-->C transition at nucleotide position 5628, in a 62-year-old woman with late onset chronic progressive external ophthalmoplegia, dysphagia and mild proximal myopathy. The mutation is heteroplasmic and disrupts a highly conserved A-U base pair within the anticodon stem of the tRNA(Ala). Cytochrome c oxidase-negative fibers harbor a significantly higher level of mutated mtDNA than cytochrome c oxidase-positive fibers. This is the first mutation in the tRNA(Ala) gene which satisfies accepted criteria for pathogenicity.
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PMID:A new mutation in the mitochondrial tRNA(Ala) gene in a patient with ophthalmoplegia and dysphagia. 1140 21

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.
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PMID:Mouse models for mitochondrial disease. 1157 27

In the muscle biopsy of a female patient with chronic progressive external ophthalmoplegia (CPEO), myopathy, and exercise intolerance, the heteroplasmic deletion of a single nucleotide (DeltaT5885) in the mitochondrial tRNA tyrosine gene (tRNA(Tyr)) was found. The mutation was associated with the mitochondrial phenotype of individual muscle fibers, suggesting a causal association of DeltaT5885 with the mitochondrial disease phenotype. The microdeletion was absent from the patient's and her relatives' blood, indicating a spontaneous somatic origin.
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PMID:CPEO associated with a single nucleotide deletion in the mitochondrial tRNA(Tyr) gene. 1175 14


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