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)

A thirty-two year old female had chronic progressive external ophthalmoplegia (CPEO), exertional fatigue, dysarthria, dysphagia, and bilateral hearing impairment. Histochemical stains, obtained from the right vastus lateralis, showed ragged-red fibers and wide-spread abnormalities in the number, size, and the structure of mitochondria under electronomicroscopic examination. A biochemical analysis showed a low activity of NADH-cytochrome C reductase, NADH dehydrogenase and a normal activity of succinate cytochrome C reductase and cytochrome C oxidase. This data suggests a specific defect in the NADH dehydrogenase of complex I (NADH CoQ reductase). We believe that this is the first biochemically defined mitochondrial myopathy reported in Taiwan and provides additional evidence for the existence of biochemical heterogeneity in mitochondrial disorders of CPEO.
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PMID:Chronic progressive external ophthalmoplegia with NADH-CoQ reductase deficiency: report of a case. 132 93

The association of chronic intestinal pseudoobstruction with ophthalmoplegia has been reported previously in visceral myopathies. We report a case of this association in which muscle mitochondria had a crystalline appearance, a dense core, and decreased cytochrome c oxidase and succinate cytochrome c reductase activities. The absence of evident mitochondrial DNA deletion in the skeletal muscle of this patient does not exclude the possibility of localized deletion or mutation of mitochondrial DNA in digestive muscle.
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PMID:Chronic intestinal pseudoobstruction with myopathy and ophthalmoplegia. A muscular biochemical study of a mitochondrial disorder. 173 70

Two sisters with chronic progressive external ophthalmoplegia (CPEO) and their in all 7 healthy children were investigated. Both ophthalmoplegic patients had histopathological changes typical of mitochondrial myopathy. The same type of muscular pathology was also found among the healthy children. The most common muscular changes were subsarcolemmal accumulation of pathological mitochondria, including vacuoles, abnormal cristae and sometimes also inclusion bodies. Biochemical studies showed partial complex III deficiency, with low succinate-cytochrome c reductase activity in 1 of the ophthalmoplegic patients. These findings suggest that CPEO is a slowly progressive muscle disease, starting early in life. The widespread occurrence among the children may indicate maternal inheritance.
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PMID:Early mitochondrial changes in chronic progressive ocular myopathy. 196 42

A patient with chronic progressive external ophthalmoplegia (CPEO) who had abundant cytoplasmic bodies in muscle fibers and a deletion of mitochondrial DNA is reported. The patient was a 26-year-old male suffering from ophthalmoplegia from age 21. He had a marfanoid skeletal abnormality and perceptive hearing loss, but had neither retinopathy, ataxia, nor dementia. In the mitochondria isolated from the biopsied skeletal muscle, NADH-ubiquinone oxidoreductase activity was slightly decreased, succinate-cytochrome c reductase activity was slightly increased, and cytochrome c oxidase activity remained normal. Southern blot analysis of the muscle DNA identified heteroplasmy composed of a normal-sized mitochondrial DNA and a mutant mitochondrial DNA with a 4.2-kilobase deletion. The PCR plus S1 analysis showed that the deletion extended from nucleotide position 7860 +/- 60 to 12,090 +/- 70. The histological studies of the biopsied muscle revealed ragged-red fibers and cytochrome c oxidase-negative fibers in 15.7% and 18.6% of the muscle fibers, respectively. Other conspicuous histological change was abundant cytoplasmic bodies surrounded by clusters of abnormal mitochondria. The cytoplasmic bodies were found preferentially in type 1 fibers, and exclusively in cytochrome c oxidase-negative fibers and in ragged-red fibers. Focal existence of cytoplasmic bodies in muscle fibers with abnormal mitochondria suggests that segregated distribution of the abnormal mitochondria with deleted mitochondrial DNA is involved in the pathogenesis of cytoplasmic bodies.
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PMID:Cytoplasmic body and mitochondrial DNA deletion. 196 59

We investigated the correlations of deletions of mitochondrial DNA in skeletal muscle with clinical manifestations of mitochondrial myopathies, a group of disorders defined either by biochemical abnormalities of mitochondria or by morphologic changes causing a ragged red appearance of the muscle fibers histochemically. We performed genomic Southern blot analysis of muscle mitochondrial DNA from 123 patients with different mitochondrial myopathies or encephalomyopathies. Deletions were found in the mitochondrial DNA of 32 patients, all of whom had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome, a multisystem disorder characterized by ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia. The deletions ranged in size from 1.3 to 7.6 kilobases and were mapped to different sites in the mitochondrial DNA, but an identical 4.9-kilobase deletion was found in the same location in 11 patients. Biochemical analysis showed decreased activities of NADH dehydrogenase, rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase, four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA. We conclude that deletions of muscle mitochondrial DNA are associated with ophthalmoplegia and may result in impaired mitochondrial function. However, the precise relation between clinical and biochemical phenotypes and deletions remains to be defined.
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PMID:Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. 230

Ragged-red fibers (RRFs) are mainly seen in mitochondrial myopathy and related to biochemical defects in electron transfer chain on some occasions. Recently, some papers reported the occurrence of RRFs in the biopsied muscle of myotonic dystrophy (MyD). To examine whether the mitochondrial function is disturbed in MyD, we have studied the biopsied muscles of 12 cases with MyD (10 males and 2 females averaging 38 years of age) morphologically and mainly biochemically. RRFs, ranging from 2--20% of the muscle fibers, were identified in 5 out of 12 cases. On electron microscopy, these fibers had aggregated abnormally enlarged mitochondria with dene bodies, concentrically whirled membranous cristae and paracrystalline inclusions. Clinically, 4 of 5 cases with RRFs had mild to moderate and only 2 of 7 without RRFs had ophthalmoplegia. Bicycle ergometer exercise test showed abnormal increase of lactate/pyruvate ratio in three cases with RRFs. Histochemically, cytochrome c oxidase (CCO) activity was absent selectively in all of the RRFs. Immunohistochemical staining showed the presence of CCO protein by using monoclonal antibody which was specific to CCO subunit IV. Biochemical study with crude muscle extract of 11 cases of MyD showed decreases in NADH dehydrogenase, NADH CoQ reductase, succinate CoQ reductase (SCR), CCO, carnitine actyl transferase activities in most of cases regardless RRFs. To avoid the influence possibly derived from the various stages of muscle degeneration in the biopsied specimens, we calculated the ratio of the enzyme activities compared with succinate dehydrogenase which was located in the electron transfer chain and did not show any statistical difference regardless of RRFs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[A study of mitochondrial electron transfer chain in myotonic dystrophy]. 259 36

Clinical, histochemical and ultrastructural findings concerning 14 cases with diagnosis of Chronic Progressive External Ophthalmoplegia are described. According to the clinical features the patients have been rated in two groups: the first including subjects with isolated ptosis or ptosis with external ophthalmoplegia and the second including subjects with a spreading of the muscular deficit and involvement of the neck and limbs. The most frequent histological and histochemical features are type I fibre atrophy, ragged-red fibres, DPNH-diaphorase reaction disorders and abnormal accumulation of lipids into the fibres. Electron microscopy reveal myofibrillar disorganization and clusters of polymorphous, abnormal mitochondria. In five cases mitochondria contain a variety of crystalline inclusions. Correlations between clinical data and histochemical and ultrastructural findings are discussed. Mitochondrial abnormalities are postulated to be a characteristic physiopathological pattern in CPEO.
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PMID:Chronic progressive external ophthalmoplegia. Clinical, electrophysiological, histochemical and ultrastructural studies of 14 cases. 629 31

A partial deficiency of cytochrome oxidase has been found in 7 patients with chronic progressive external ophthalmoplegia and proximal myopathy or craniosomatic abnormalities. Muscle biopsies from all these patients showed morphological mitochondrial abnormalities ("ragged red" fibres) and cytochemical assay of cytochrome oxidase showed that these fibres contained no demonstrable enzyme activity. The incidence of cytochrome oxidase-negative fibres was greater than that of "ragged-red" fibres suggesting that the enzyme defect preceded the development of morphological mitochondrial changes. Biochemical analysis of skeletal muscle mitochondrial fractions from 3 patients revealed in 1 case a significantly lower concentration of cytochrome aa3 and a decreased ratio of cytochrome oxidase/succinate-cytochrome c reductase. Fasting blood metabolites were elevated in 2 patients. We suggest that partial cytochrome oxidase deficiency is the underlying defect in mitochondrial myopathy associated with the oculocraniosomatic syndromes.
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PMID:A partial deficiency of cytochrome c oxidase in chronic progressive external ophthalmoplegia. 630 77

Defects in complex I (NADH:ubiquinone oxidoreductase (EC 1.6.5.3)) are the most frequent cause of human respiratory disorders. The pathogenicity of a given human mitochondrial mutation can be difficult to demonstrate because the mitochondrial genome harbors large numbers of polymorphic base changes that have no pathogenic significance. In addition, mitochondrial mutations are usually found in the heteroplasmic state, which may hide the biochemical effect of the mutation. We propose that the unicellular green alga Chlamydomonas could be used to study such mutations because (i) respiratory complex-deficient mutants are viable and mitochondrial mutations are found in the homoplasmic state, (ii) transformation of the mitochondrial genome is feasible, and (iii) Chlamydomonas complex I is similar to that of humans. To illustrate this proposal, we introduced a Leu157Pro substitution into the Chlamydomonas ND4 subunit of complex I in two recipient strains by biolistic transformation, demonstrating that site-directed mutagenesis of the Chlamydomonas mitochondrial genome is possible. This substitution did not lead to any respiratory enzyme defects when present in the heteroplasmic state in a patient with chronic progressive external ophthalmoplegia. When present in the homoplasmic state in the alga, the mutation does not prevent assembly of whole complex I (950 kDa) and the NADH dehydrogenase activity of the peripheral arm of the complex is mildly affected. However, the NADH:duroquinone oxidoreductase activity is strongly reduced, suggesting that the substitution could affect binding of ubiquinone to the membrane domain. The in vitro defects correlate with a decrease in dark respiration and growth rate in vivo.
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PMID:Reconstruction of a human mitochondrial complex I mutation in the unicellular green alga Chlamydomonas. 2226 73

Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns-Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function. Myoclonus is a key feature of MERFF, but may also be encountered in mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), ARCA2, POLG1 mutations and Leigh syndrome. Dystonia is common in Leigh syndrome (which may be caused by 75 different genes) and in Leber hereditary ocular neuropathy (LHON) plus disease, due to mutations in mtDNA genes that encode subunits of NADH dehydrogenase, as well as in ARCA2, pantothenate kinase-associated neurodegeneration (PKAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and POLG1 mutations. Other movement disorders are rarer (such as parkinsonism, tremor, chorea). Although parkinsonism is more frequent in POLG1 mutations, and myoclonus in MERFF, most movement disorders are found either isolated or combined in numerous MIDs. The presence of associated neurological signs, whether central or peripheral, or of evocative magnetic resonance imaging (MRI) abnormalities (striatal necrosis) should prompt a search for MID. In cases of a particular clinical spectrum (LHON, MERFF, Kearns-Sayre, SANDO, SPG7, ARCA2, ARSACS), a search for the most frequently implicated mutation(s) is recommended. In other cases, muscle biopsies followed by metabolic and genetic studies may be useful for arriving at a diagnosis.
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PMID:Movement disorders in mitochondrial diseases. 2777 46


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