Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 describe a 15-year-old boy with full-blown mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO). He presented with visual disturbance, hearing impairment, continuous partial epilepsy on the right aspect of the face, and right hemiparesis since the age of 13. Four months later, he experienced another strokelike episode with continuous partial epilepsy on the left hand. Serial computed tomographic scans revealed bilateral parieto-occipital hypodense lesions with gyral enhancement and an additional low-density lesion in the right frontal area 4 months later, respectively. Results of laboratory examinations disclosed lactic acidosis and mitochondrial myopathy with many ragged-red fibers. To identify the defective gene in mitochondrial DNA, a simple molecular test was performed by using restriction endonuclease Apa I. A transition from A to G was found at nucleotide position 3243 of the tRNA(Leu) gene. Interestingly, the patient also had marked external ophthalmoplegia and ptosis commonly found in patients with CPEO. Therefore, we suggest that ophthalmoplegia also occurs in the MELAS syndrome.
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PMID:Ophthalmologic manifestations in MELAS syndrome. 836 52

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 performed a comparative analysis of the clinical, morphological and molecular characteristics of 62 patients affected with progressive external ophthalmoplegia with ragged-red fibres in muscle. Twenty-seven patients had only muscular disease, and 35 had a multisystemic disease with neurological, cardiac, sensory, or endocrine symptoms. Quantitation of mitochondrial accumulation and numbering of cytochrome c oxidase deficient muscle fibres were done in 43 patients. Muscle mitochondrial DNA deletions were detected, quantitated and localised by Southern Blot analysis. Point mutations were screened in five mitochondrial DNA transfer RNA genes by denaturing gradient gel electrophoresis technique. This study further emphasized the relationships between progressive external ophthalmoplegia and mitochondrial DNA mutations that were present in 46/62 patients (40 deletions, 4 h point mutations in the tRNA leucine gene and 2 further families with maternal inheritance but no mutation identified to-date). Family history was positive in 12 patients: 4 with a maternally inherited disease (2 of whom had an identified mitochondrial DNA mutation), and 4 with an autosomal dominant inherited disease, none of which was associated with multiple mitochondrial DNA deletions. Interestingly, 2 of our patients with an identified mitochondrial DNA mutation appeared as sporadic cases. No morphological or molecular parameters was correlated with the tissular extension of the disease. However, mitochondrial DNA deletions were significantly associated with ocular symptoms which had an earlier onset and were more severe. Clinical features of the patients with a multisystemic disease and a mitochondrial DNA deletion were essentially related to Kearns-Sayre syndrome. In particular, a cardiac conduction defect was present in 12 patients out of 18 with a multisystemic disease associated with a mitochondrial DNA deletion; it was never encountered in 17 patients with a multisystemic disease but no mitochondrial DNA deletion.
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PMID:[Progressive external ophthalmoplegia of mitochondrial origin: contribution of morphological and molecular studies]. 929 56

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

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

Autosomal dominant progressive external ophthalmoplegia (adPEO) is caused by mutations in at least three different genes: ANT1 (chromosome 4q34-35), TWINKLE, and POLG. The ANT1 gene encodes the adenine nucleotide translocator-1 (ANT1). We identified a heterozygous T293C mutation of the ANT1 gene in a Greek family with adPEO. The resulting leucine to proline substitution likely modifies the secondary structure of the ANT1 protein. ANT1 gene mutations may account for adPEO in families with different ethnic backgrounds.
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PMID:A novel missense adenine nucleotide translocator-1 gene mutation in a Greek adPEO family. 1175 13

To clarify the importance of deleted protein and tRNA genes on the impairment of mitochondrial function, we performed a quantitative analysis of biochemical, genetic and morphological findings in skeletal muscles of 16 patients with single deletions and 5 patients with multiple deletions of mtDNA. Clinically, all patients showed chronic progressive external ophthalmoplegia (CPEO). The size of deletions varied between 2.5 and 9 kb, and heteroplasmy between 31% and 94%. In patients with single deletions, the citrate synthase (CS) activity was nearly doubled. Decreased ratios of pyruvate- and succinate-dependent respiration were detected in fibers of all patients in comparison to controls. Inverse and linear correlations without thresholds were established between heteroplasmy and (i) CS referenced activities of the complexes of respiratory chain, (ii) CS referenced maximal respiratory rates, (iii) and cytochrome-c-oxidase (COX) negative fibers. In patients with single and multiple deletions, all respiratory chain complexes as well as the respiratory rates were decreased to a similar extent. All changes detected in patients with single deletions were independent of deletion size. In one patient, only genes of ND5, ND4L as well as tRNA(Leu(CUN)), tRNA(Ser(AGY)), and tRNA(His) were deleted. The pronounced decrease in COX activity in this patient points to the high pathological impact of these missing tRNA genes. The activity of nuclear encoded SDH was also significantly decreased in patients, but to a lesser extent. This is an indication of secondary disturbances of mitochondria at CPEO. In conclusion, we have shown that different deletions cause mitochondrial impairments of the same phenotype correlating with heteroplasmy. The missing threshold at the level of mitochondrial function seems to be characteristic for large-scale deletions were tRNA and protein genes are deleted.
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PMID:Mitochondrial respiratory rates and activities of respiratory chain complexes correlate linearly with heteroplasmy of deleted mtDNA without threshold and independently of deletion size. 1235 Dec 17

A 21-year-old woman described proximal muscle weakness since early childhood. At age 16, she developed bilateral ptosis, progressive external ophthalmoplegia, and exercise intolerance. She harbored a heteroplasmic G12315A mutation in the mitochondrial DNA tRNA(Leu(CUN)) gene, which disrupts a highly conserved G-C base pair in the TPsiC stem of the molecule. Mutant mitochondrial DNA was 62% of total in muscle and 17% in blood. The mutation was undetectable in blood, urinary sediment, and hair follicles from the patient's mother. This second patient with G12315A and progressive external ophthalmoplegia confirms the pathogenicity of the mutation and helps to define the correlation between genotype and phenotype.
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PMID:Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the G12315A mutation in mitochondrial DNA. 1239 39

The authors report on a family with dominantly inherited progressive external ophthalmoplegia and a diagnostic and statistical manual (fourth revised edition) diagnosis of bipolar psychiatric disorder in several members. Skeletal muscle biopsy from the proposita showed decreased cytochrome c oxidase staining, several ragged-red fibers, and multiple mtDNA deletions. The authors identified a missense mutation (leucine 98-->proline) in the adenine nucleotide translocator 1 gene. The presence of bipolar affective disorder expands the phenotype of adenine nucleotide translocator 1 allelic variants.
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PMID:Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. 1256 15

Although neuropsychological deficits have been reported in mitochondrial cytopathies, patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) have not been studied systematically using a comprehensive test battery. The aim of our study was to assess the range and extent of putative cognitive dysfunction in 22 patients with CPEO or KSS, and to compare cognitive performance of patients with healthy control subjects matched for age, sex and years of education. Genetic analysis of skeletal muscle tissue from 22 patients with CPEO or KSS included screening for mitochondrial DNA (mtDNA) point mutations (3243/8344) and mtDNA deletions. All patients were examined by a neuropsychological test battery covering verbal skills, verbal and visual memory, visuo-spatial perception, visual construction, attention, abstraction and flexibility, and Quality of Life. Molecular genetic analysis of mtDNA revealed single large-scale deletions in 15 out of 22 patients and the tRNA (Leu) A3243G point mutation in two out of 22 patients. In five out of 22 patients none of the frequently encountered mtDNA mutations could be detected. Neuropsychological testing did not reveal general intellectual deterioration, but specific cognitive deficits, particularly in visual construction, attention and abstraction/flexibility. Subgroup analysis of 15 patients with mtDNA deletions showed similar results when compared with the full group. In our series of patients with CPEO or KSS neuropsychological testing did not reveal signs that would suggest general intellectual decline or dementia, but provided evidence of specific focal neuropsychological deficits, suggesting particular impairment of visuospatial perception associated to parieto-occipital lobes and executive deficits associated to the prefrontal cortex.
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PMID:Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. 1269 61


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