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)

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.
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PMID:Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype. 759 99

The paper describes Kearns-Sayre's syndrome, a rare hereditary neuromuscular disease, in a patient aged 17 years. The clinical picture of the disease had a classical triad: external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction disturbances. This triad was supplemented with other polymorphous symptoms characteristic of the syndrome, such as moderate myopathic syndrome, hemeralopia, physical infantilism, hypogonadism, pyramidal syndrome. Bifascicular block in the His-Purkinje system was accompanied by mitral prolapse. The problems of early diagnosis of the syndrome and choice of adequate therapeutical methods are discussed.
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PMID:[The Kearns-Sayre syndrome]. 815 11

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease.
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PMID:Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot? 825 46

Eye movement tests (saccade tests: reaction time, peak velocities and accuracy, and the eye tracking test) were studied in 53 insulin-dependent diabetic (IDDM) patients and 42 randomly selected non-diabetic control subjects, aged between 20 and 40 years. All subjects had central visual acuity of at least 0.1 in one eye, and none had ophthalmoplegia. The reaction time was longer and the accuracy decreased in the saccade test in diabetic patients as compared to control subjects. Peak velocities tended to be slower in diabetic patients, but no significant differences between diabetic and non-diabetic subjects were observed. The maximum eye movement velocities were reduced at all target velocities in diabetic patients as compared to control subjects. These findings can be explained on the basis of many potential disturbances in the central nervous system. Only the duration of diabetes had a clear association with maximum smooth pursuit eye movement velocities in the eye tracking test. Microvascular complications (retinopathy, nephropathy), autonomic neuropathy or metabolic control (high fasting blood glucose and glycated hemoglobin A1c) had no clear association with the results of eye movement tests. In conclusion, insulin dependent diabetes mellitus deteriorates the visuomotor responses.
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PMID:Voluntary eye movement tests in patients with insulin-dependent diabetes mellitus. 847 25

We describe a two-generation family with combined clinical features of myoclonic epilepsy, progressive external ophthalmoplegia (PEO), proximal myopathy, pigmentary retinopathy, progressive deafness, basal ganglia calcification, and ragged-red fibers in a muscle biopsy specimen. One family member died unexpectedly at age 22 years. The molecular tests revealed an A-to-G transition at nucleotide position 3243 of the mitochondrial tRNA(Leu(UUR)) gene. No one in this family had stroke-like episodes. Although the propositus (a 28-year-old woman) had a significant number of white hairs, the percentage of mutant mtDNA in white-hair roots was not different from that in the colored-hair roots. Our findings suggest that the 3243 mutation can be associated with mixed clinical features of myoclonic epilepsy with ragged-red fibers (MERRF) and PEO and that a preferential increase in the levels of the mutant mtDNA is not related to graying of hair, and hence to the hypothesized production of premature aging of cells.
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PMID:A MERRF/PEO overlap syndrome associated with the mitochondrial DNA 3243 mutation. 862 77

We analysed the mitochondrial genome of one patient with chronic and progressive bilateral ophthalmoplegia. This patient also had abnormal EKG showing cardiac conduction defects and pigmentary retinopathy, suggestive of the Kearns-Sayre syndrome. On muscle biopsy, with Gomori trichrome stain, the fibers showed an increase in red-staining material in the intermyofibrillary network and the subsarcolemmal region. On electron microscopy, aggregations of abnormal mitochondria were demonstrated, confirming the diagnosis of mitochondrial myopathy. Analysis of mitochondrial DNA (mtDNA) from the patient and her mother showed no deleted mtDNA.
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PMID:Mitochondrial genome analysis in Kearns-Sayre syndrome. 862 98

Kearns Sayre Syndrome (KSS) belongs to the group of so called 'mitochondrial encephalopathies'. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may have the potential to noninvasively detect and monitor disease specific cerebral involvement, as we wish to demonstrate in a patient whom we have followed for 3.5 years. At first presentation with incomplete external ophthalmoplegia, ptosis, pigmentary retinopathy and impaired hearing MRI demonstrated ill defined areas of symmetric T2-prolongation in the dorsal parts of the mesencephalon, the pons and in both cerebellar hemispheres. While the patients clinical symptoms deteriorated, including the onset of dysphagia, signal abnormalities spread downwards into the medulla oblongata involving the glossopharyngeal nuclei and supratentorially into the white matter. Proton MRS performed with the PRESS sequence (TR/TE 1500/136 ms) in the area of white matter damage showed a doublet at 1.33 ppm, which is characteristic for the presence of lactate. Our findings suggest MRI abnormalities to increase in parallel with neurologic progression of KSS and confirm the utility of 1H-MRS in supporting mitochondrial respiratory chain insufficiency as the underlying cause of parenchymal alterations.
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PMID:Magnetic resonance imaging and spectroscopy of progressive cerebral involvement in Kearns Sayre Syndrome. 886 68

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.
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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

Six children are presented with an isolated complex III deficiency in muscle tissue. More specifically, oxidation rates and ATP+CrP production rates from both pyruvate and succinate as substrates and/or the activity of decylubiquinol:cytochrome c oxidoreductase were all markedly reduced. Complex III deficiency was also present in liver of two patients tested, but could not be demonstrated in cultured fibroblasts of four patients tested. Mitochondrial DNA, extracted from muscle, was analyzed; no deletions or common point mutations were found. Four patients presented with a multi-organ disorder. Among these patients three presented at neonatal age with neurological signs and lactate elevation in blood and CSF, of whom two had severe neonatal Fanconi syndrome. One child, aged seven years, had encephalomyopathy, ophthalmoplegia, retinopathy and Wolff-Parkinson-White syndrome. The remaining two patients exhibited myopathy only, within the first year of life. Thus, like in other respiratory chain disorders, patients with complex III deficiency may present at any age and show variable symptoms and outcome, ranging from neonatal death to failure to thrive only. Apparently there are no clinical findings which are specific for complex III deficiency.
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PMID:Clinical heterogeneity in respiratory chain complex III deficiency in childhood. 916 75

We report a 47-year-old female patient showing clinical features of chronic progressive external ophthalmoplegia (CPEO) without stroke-like episodes. Large scale deletion of mitochondrial DNA (mtDNA) was not found in her biopsied muscle, whereas the A-->G transition at position 3243 (A3243G) was detected. The patient's mother had diabetes mellitus, suggesting maternal inheritance. This mutation is usually associated with MELAS, but wide clinical variety of the mutation has been recognized. Although several patients of CPEO with A3243G mutation (CPEO3243) have been found in the Western countries, only one case has been reported in detail in Japan. The CPEO3243 patients, including ours, show retinopathy less frequently, but diabetes mellitus and hearing loss more frequently than CPEO patients with deletions of mtDNA (CPEO delta). CPEO3243 is usually inherited maternally, but almost all CPEO delta is sporadic. With regard to COX activity of biopsied muscles, CPEO3243 resembles CPEO delta more than MELAS3243. This suggests that how the mutant mtDNA is distributed among cells or tissues may have more significant effect on clinical phenotype than what type of mtDNA mutation exists. The presence of such a CPEO3243 patient like ours could be an important suggestion toward further understanding of mitochondrial diseases.
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PMID:[A case of mitochondrial encephalomyopathy showing ophthalmoplegia, diabetes mellitus and hearing loss associated with the A3243G mutation of mitochondrial DNA]. 924 43


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