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)

Kearns-Sayre syndrome is the triad of progressive external ophthalmoplegia, pigmentary retinopathy, and complete AV block. The etiology is unknown, but is thought to be due to a mitochondrial DNA deletion. Reported electrocardiographic abnormalities include first-degree AV block, fascicular blocks, and complete heart block, as well as non-specific S-T segment changes and T wave abnormalities, but has not included sinus node dysfunction. We report a case with episodes of sinus arrest in an asymptomatic patient with Kearns-Sayre syndrome resulting in pauses lasting up to 6 seconds.
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PMID:Sinus dysrhythmia in Kearns-Sayre syndrome. 751 37

We clinically characterized 18 diabetic patients in 7 families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and mitochondrial DNA mutations of tRNALEU(UUR) (3243), 5 diabetics in a family with myoclonic epilepsy and ragged red fiber (MERRF) and tRNALYS (8344) mutation and 11 diabetics in a family with chronic external ophthalmoplegia (CPEO) and multiple deletions. Insulin secretory capacities were significantly reduced in the mutant relatives, as compared with the non-mutant members. It is speculated that the mutation-induced OPHOS defects in the pancreatic beta- cells might result in insulin secretory defects.
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PMID:[Clinical characterization of diabetes mellitus in the families with mitochondrial encephalomyopathies]. 752 90

Deletions of muscle mitochondrial DNA are known in mitochondrial myopathy patients who have chronic progressive external ophthalmoplegia (CPEO). A 41-year-old patient with no apparent family history of this condition suffers from hypertrophic cardiomyopathy, slight muscle atrophy, and weakness of the extremities, but not from CPEO. A muscle biopsy showed the presence of ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. This combination of clinical features in our patient is atypical in mitochondrial myopathy with demonstrable deleted muscle mitochondrial DNA. Pleomorphic clinical expression is suggested.
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PMID:Multiple mitochondrial DNA deletions in a patient with mitochondrial myopathy and cardiomyopathy but no ophthalmoplegia. 756 30

We report two sisters (32 and 36 years old) with familial deaf-mutism, progressive external ophthalmoplegia, leukodystrophy and mitochondrial myopathy. T2-weighted brain MRI demonstrated diffuse symmetrical high intensity areas in the white matter. Their muscle biopsies showed ragged-red fibers and cytochrome c oxidase (CCO)-negative fibers. CCO activity in biopsied muscle decreased to about 20% of normal control. They had no deletions of the mitochondrial DNA and no point mutations in mitochondrial tRNA. Their brother was diagnosed as having Kugelberg-Welander disease, grand mal seizures and urinary dysfunction. Their parents and grandparents had consanguinity. Three relatives were found to have deaf-mutism without accompanying ophthalmoplegia. This rare combination of mitochondrial encephalomyopathy and familial deaf-mutism might be caused by a nuclear DNA mutation in these sisters.
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PMID:Familial mitochondrial encephalomyopathy with deaf-mutism, ophthalmoplegia and leukodystrophy. 757 54

Large-scale mitochondrial DNA deletion was found in a 5-year-old girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and Fanconi's syndrome. Muscle biopsy disclosed ragged-red fibers and cytochrome c oxidase negative fibers. Respiratory chain studies were normal. Southern blot analysis demonstrated a 10.5-Kb heteroplasmic deletion in both muscle and blood. Deleted genomes represented 40% of total mitochondrial DNA in muscle and 63% in blood. There was no evidence of point mutations characteristic of MELAS. We suggest that not only patients with progressive external ophthalmoplegia syndromes, but also those with defined syndromes [e.g., MELAS or myoclonic epilepsy and ragged-red fibers (MERRF)] without characteristic point mutations, be screened for mitochondrial DNA deletions.
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PMID:Mitochondrial DNA deletion in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) and Fanconi's syndrome. 757 54

A woman affected by chronic progressive external ophthalmoplegia and muscle mitochondrial DNA deletion was studied by phosphorus magnetic resonance spectroscopy (31P-MRS) prior to and after 1 and 7 months of treatment with oral lipoic acid. Before treatment a decreased phosphocreatine (PCr) content was found in the occipital lobes, accompanied by normal inorganic phosphate (Pi) level and cytosolic pH. Based on these findings, we found a high cytosolic adenosine diphosphate concentration [ADP] and high relative rate of energy metabolism together with a low phosphorylation potential. Muscle MRS showed an abnormal work-energy cost transfer function and a low rate of PCr recovery during the post-exercise period. All of these findings indicated a deficit of mitochondrial function in both brain and muscle. Treatment with 600 mg lipoic acid daily for 1 month resulted in a 55% increase of brain [PCr], 72% increase of phosphorylation potential, and a decrease of calculated [ADP] and rate of energy metabolism. After 7 months of treatment MRS data and mitochondrial function had improved further. Treatment with lipoate also led to a 64% increase in the initial slope of the work-energy cost transfer function in the working calf muscle and worsened the rate of PCr resynthesis during recovery. The patient reported subjective improvement of general conditions and muscle performance after therapy. Our results indicate that treatment with lipoate caused a relevant increase in levels of energy available in brain and skeletal muscle during exercise.
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PMID:Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. 759 80

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 mitochondrial tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), usually associated with this mutation, 12 probands had other phenotypes including other encephalopathies, chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy and ragged red fibres (MERRF), myopathy alone and diabetes and deafness. Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with CPEO compared with those with MELAS. The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the tRNALys A-->G(8344) mutation. The proportion of mutant mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with mitochondrial myopathy. The family with this transition had high levels of mutant mtDNA A-->G(3243), with a unique phenotype of predominant skeletal myopathy, suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.
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PMID:The mitochondrial DNA transfer RNALeu(UUR) A-->G(3243) mutation. A clinical and genetic study. 760 89

Large-scale deletions of mitochondrial DNA (mtDNA) have been associated with a subgroup of mitochondrial encephalomyopathies, usually characterized by progressive external ophthalmoplegia (PEO) and mitochondrial proliferation in muscle fibers. We and others have shown that muscle from patients with mtDNA deletions have variable cytochrome c oxidase (COX) deficiency and reduction of mitochondrially-synthesized polypeptides in affected muscle fibers. The present work summarizes the phenotype-genotype correlations observed in patients' muscle. In situ hybridization revealed that, while most COX-deficient fibers had increased levels of mutant mtDNA, they almost invariably had reduced levels of normal mtDNA. PCR quantitation of both deleted and wild-type mtDNAs in normal and respiration-deficient muscle fibers from patients with the "common deletion" showed that deleted mtDNAs were present in normal fibers (31 +/- 26%), but their percentages were much higher in affected fibers (95% +/- 2%). Absolute levels of deleted mtDNA were also increased in affected fibers, whereas absolute levels of wild-type mtDNA were significantly reduced. Taken together, our results suggest that although a specific ratio between mutant and wild-type mitochondrial genomes is probably the major determinant of the respiratory chain deficiency associated with mtDNA deletions, the reduction in the absolute amounts of wild-type mtDNA may also play a significant pathogenetic role.
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PMID:Phenotype-genotype correlations in skeletal muscle of patients with mtDNA deletions. 760 17

The Kearns-Sayre syndrome (KSS) associates progressive external ophthalmoplegia initiating prior to the age of 20 years and pigmentary retinitis with a series of other heterogeneous clinical manifestations. The incomplete syndrome is usually denominated progressive external ophthalmoplegia (PEO)-plus which is a sporadically appearing mitochondrial cytopathy associated with large deletions of a variable proportion of mitochondrial DNA (mtDNA) molecules. Six patients with PEO-plus/KSS in whom muscle biopsy was performed following a complete clinical study are described. The muscle was processed by conventional histochemical techniques, electron microscopy, and genetic study (Southern transference, polymerase chain reaction, restriction cartography and both manual and automatic sequencing). The percentage of mutated mtDNA molecules for each patient was obtained by densitometry. The 6 patients presented multiorganic clinical manifestations characteristics of most mitochondrial diseases. The presence of destructured red fibers were observed in all the biopsies. All the patients presented a deletion in the mtDNA of a size between 4,861 to 7,437 base pairs (bp). All the deletions appeared flanked by direct repetitions from 4 to 13 bp and one also presented inverse repetitions from 5 to 6 bp in the zone next to the rupture point. In the 6 cases heteroplasmia was observed with a variable percentage of deleted molecules from 23 to 56%. The molecular basis of progressive external ophthalmoplegia-plus/Kearns-Sayre syndrome appears to be the existence of sole, large deletions in the mitochondrial DNA with the varying in location and percentage conditioning the appearance of different phenotypes similar among themselves. The 7,437 base pair deletion was the most frequently observed in the patients analyzed.
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PMID:[Progressive external ophthalmoplegia and the Kearns-Sayre syndrome: a clinical and molecular study of 6 cases]. 763 Feb 31


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