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)

In an attempt to elucidate the pathogenesis of focal cytochrome c-oxidase (COX) deficiency in skeletal muscle from patients with chronic progressive external ophthalmoplegia (CPEO), we examined the longitudinal distribution of COX activity in single muscle fibers from 6 CPEO patients with muscle mitochondrial DNA (mtDNA) deletions. A new method for teasing single muscle fibers, recently developed in our laboratory, revealed fibers with COX-positive and -negative segments in all 6 patients. The borders between the enzyme-positive and -negative segments in these fibers were sharply delineated, so that the length of each COX-negative segments could be accurately measured. The proportion of the sum of the lengths of the enzyme-negative segments to the total length of the muscle fibers correlated well with the proportion of deleted mtDNA, suggesting that abnormal mitochondria harboring mutant mtDNA may be responsible for the focal loss of COX activity.
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PMID:Segmental cytochrome c-oxidase deficiency in CPEO: teased muscle fiber analysis. 131 76

Some aspects of the contractile properties of skeletal muscle in patients with progressive external ophthalmoplegia (PEO), mitochondrial myopathy and focal cytochrome c-oxidase deficiency were investigated by studying the twitch response (TR) of the tibialis anterior muscle both at rest and after maximum isometric contraction. The results of needle electromyography were normal in four of the six examined patients, and myopathic in the remaining two. A slowing in muscle relaxation was the most frequently observed abnormality; significantly prolonged muscle contraction times and reduced twitch torque potentiation values after isometric contraction were also detected. TR abnormalities in PEO patients may be due either to a dysfunction of the contractile machinery depending upon impaired muscle energy supply or to altered muscle fiber characterized by the predominance of type I slow fiber. In addition to conventional electromyographic investigations, TR study may be a useful diagnostic tool in PEO patients.
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PMID:Twitch response of striated muscle in patients with progressive external ophthalmoplegia, mitochondrial myopathy and focal cytochrome c-oxidase deficiency. 755 70

We report extensive deletion of muscle mitochondrial DNA and ophthalmological findings in a patient with progressive external ophthalmoplegia. The patient was a twenty-nine-year-old female who had suffered from slowly progressive external ophthalmoplegia for ten years. No abnormal finding was observed in the funduscopic examination, but fluorescein angiography showed mottled hyperfluorescence. The final rod threshold for the dark adaptation testing was slightly elevated. The flash electroretinogram showed a slightly attenuated b wave. Ragged-red fibers were observed in muscle biopsies. A biochemical and histochemical study showed that cytochrome c oxydase activity was reduced. The length of deletion of the mitochondrial DNA, determined by polymerase chain reaction, was 4977 base pairs, flanked by a 13-base pair direct repeat.
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PMID:[Progressive external ophthalmoplegia with extensive mitochondrial DNA deletion]. 797 25

Cardiocrome, containing cytochrome c, flavin mononucleotide and thiamine diphosphate, was administered intravenously for 22 months to a patient with Kearns-Sayre syndrome. This combined therapy alleviated the patient's easy fatigability, motor disability, corneal edema and chilblains, but was not effective for his ophthalmoplegia, blepharoptosis or hearing loss. Truncal ataxia, dysphagia and an atrioventricular block appeared even with this therapy. Although the abnormal distribution of cerebral blood flow demonstrated by single photon emission computed tomography was improved, serial cranial magnetic resonance imaging and electrophysiological examination revealed progressive changes. In conclusion, this therapy was favorably effective for impaired skeletal muscle function and corneal edema, but not for ocular movements, central nervous system symptoms or cardiac conduction abnormalities, because irreversible degeneration had probably occurred in these organs.
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PMID:Long-term therapy with cytochrome c, flavin mononucleotide and thiamine diphosphate for a patient with Kearns-Sayre syndrome. 890 47

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

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

Much interest has recently been shown in apoptosis-mediated roles in the pathophysiology of mitochondrial diseases, because mitochondrial defects are implicated in a wide variety of degenerative diseases. We investigated whether apoptotic events occurred in skeletal muscles of patients with mitochondrial diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayer syndrome (KSS), and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). In a immunohistochemical study, stainings for 8-hydroxy-deoxyguanosine (8-OH-dG), 4-hydroxy-nonenal (4-HNE), Mn-SOD, Bcl-2, cytochrome c, DNase I and Bcl-x L showed a pronounced granular distribution in the cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs). On the other hand, the signals for Bax, p53, Fas and caspase 3 were not obviously increased in RRFs. In situ labeling of DNA breaks demonstrated preferential signals not only in myonuclei but also in subsarcolemmal regions of RRFs, indicating that mitochondrial as well as myonuclear DNA is fragmented in RRFs. An immunoblotting study demonstrated that cytochrome c was increased in the cytosol of diseased muscles and that DNase I was increased in mitochondria, compared to that of normal muscles. No difference was observed between protein bands at 20 kDa corresponding to caspase 3 in diseased and normal muscles. These findings demonstrate that these mitochondrial diseases harbor unique apoptosis-related changes that differ from caspase 3-dependent apoptosis. It is thought that these changes are induced by superoxide overproduction and cytochrome c release resulting from an inherent mitochondrial defect and that the events are associated with DNase I activation.
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PMID:Apoptosis-related changes in skeletal muscles of patients with mitochondrial diseases. 1181 Jan 83

We showed that humanin (HN), an endogenous peptide against Alzheimer disease-related insults, was expressed in muscles of patients with chronic progressive external ophthalmoplegia (CPEO), a major mitochondrial disease. Because HN was recently found to block proapoptotic Bax function and exert its versatile cytoprotective effects in association with an increase in ATP levels, HN expression may thus reflect a physiological response against degenerative changes in the muscles of patients with CPEO. We found HN expression in all four patients examined, each of whom had different mitochondrial DNA mutations including two different single DNA deletions, multiple deletions, and no major mutations detected. We also found that HN expression was not linked to focal cytochrome c deficiency, strongly associated with the subtype of CPEO with single deletions. These results suggest that HN expression is more closely related to degenerative changes in all types of CPEO. Notably, HN was also expressed in non-degenerative muscle fibers of patients with CPEO or Leigh syndrome, who had the 8993T>G mutation in the mitochondrial ATPase 6 gene known to be associated with impaired ATP synthesis. Collectively, our findings suggest that HN may be specifically expressed in response to defects in energy production in muscles with mitochondrial abnormalities.
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PMID:Humanin expression in skeletal muscles of patients with chronic progressive external ophthalmoplegia. 1663 4

The Kearns-Sayre syndrome, (characterized by its onset before the age of 20 years, chronic ophthalmoplegia, pigmentary retinal degeneration and at least one of the following symptoms: ataxia, heart block and high protein content in the cerebrospinal fluid) is a severe variant of chronic progressive external ophthalmoplegia with frequent rearrangements of the mitochondrial DNA (mtDNA). The aim of this paper is to report a sporadic paediatric case of Kearns-Sayre syndrome with mtDNA heteroplasmic deletion, absence of cytochrome c-oxidase in many muscle fibers, autoimmune thyroiditis, complete atrio-ventricular heart block in which the diagnosis of subclinical hypothyroiditis associated with autoimmune thyroid disease was made. The subclinical hypothyroidism, more severe in the presence of thyroid antibodies, may have contributed to the pathogenesis of cardiovascular disease. We hypothesized that in this patient, predisposed by mitochondrial deletion, anti-thyroid antibodies may have interfered with the mitochondrial function of conduction heart system, causing atrio-ventricular heart block. It seems important to study anti-thyroid antibodies in every case of Kearn-Sayre syndrome, specially if cardiac rhythm disturbances are present.
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PMID:A case of Kearns-Sayre sindrome with autoimmune thyroiditis and complete atrio-ventricular block. 1673 14

A 43-year-old female patient diagnosed with chronic progressive external ophthalmoplegia (CPEO) because of mitochondrial myopathy documented by muscle biopsy is presented. The chief complaints were represented by blepharoptosis and ophthalmoplegia. The muscle biopsy was evaluated by histology, using the appropriate histochemical and histoenzimological stains. Ragged red fibers with Gomori trichrome stain were seen, which showed cytochrome c oxydase deficiency and abnormal succinate dehydrogenase staining in around 20% of muscle fibres. Electron microscopy was also performed which demonstrated abnormal, hyperplastic, pleomorphic, and hypertrophic mitochondria, characterized by paracrystalline inclusions arranged in parallel rows ("parking-lot" inclusions), consisting of rectangular arrays of mitochondrial membranes in a linear or grid-like pattern. In conclusion, mitochondrial myopathy was definitely diagnosed. Although molecular analysis, which was subsequently carried out, failed to reveal mutations in the mitochondrial DNA or in selected nuclear genes, the pathologic diagnosis was not changed. The differential diagnosis of CPEO with other forms of ocular myopathies as well as the possible association of CPEO with systemic syndromes is discussed. Ophtalmologists and medical internists should always suspect CPEO when dealing with patients affected by ocular myopathy, either in its pure form or in association with other myopathic or systemic signs.
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PMID:Selected case from the Arkadi M. Rywlin International Pathology Slide Series: Mitochondrial myopathy presenting with chronic progressive external ophthalmoplegia (CPEO): a case report. 2529 15


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