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)

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

Analysis of mitochondrial DNA (mtDNA) in muscle and blood from 72 patients with mitochondrial myopathy showed that 30 had major deletions of a variable proportion of muscle mtDNA. All of these 30 patients presented with progressive external ophthalmoplegia and limb weakness, and 8 had the additional features of the Kearns-Sayre syndrome. Of the 42 patients without detectable muscle mtDNA deletions, 10 had progressive external ophthalmoplegia and limb weakness, 2 had the Kearns-Sayre syndrome, 11 had limb weakness without extraocular involvement, and 19 had multisystem disorders predominantly affecting the central nervous system. Only 2 patients with mtDNA deletions had clinically affected relatives, compared with 10 of those without deletions. In the 4 patients with polarographic defects exclusively involving complex I (NADH coenzyme Q reductase), the deleted protein-coding genes were confined to those for complex I subunits. Thirteen other patients with apparently identical deletions had variable clinical and biochemical features. Immunoblots of complex I polypeptides from patients with deletions were either indistinguishable from controls or showed only a mild generalized decrease in all identifiable subunits.
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PMID:Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. 260 80

The mitochondrial myopathies give rise to a diverse group of clinical syndromes, variably involving skeletal muscle and the central nervous system, with onset in childhood or adult life. In vitro studies of mitochondrial metabolism have identified a variety of functional defects of the respiratory chain, predominantly affecting complex I or complex III in adults, and complex IV in children. The increased incidence of maternal, as opposed to paternal, transmission in familial mitochondrial myopathy has led to the suggestion that these disorders may be caused by mutations of mitochondrial (mt) DNA. This hypothesis is derived from observations that mtDNA encodes subunits of the respiratory chain proteins and is exclusively maternally transmitted. Analysis of muscle mtDNA shows two populations, one normal and the other deleted by up to nearly half its length, in about 40% of cases of mitochondrial myopathy. Only a single normal length population of mtDNA is seen in blood from these patients, and in blood and muscle from control subjects. Patients with muscle mtDNA deletions reported to date have all presented with progressive external ophthalmoplegia, including some with the Kearns-Sayre syndrome. They rarely have affected relatives. Deletions are not detected in cases of proximal myopathy alone, or those with adult onset syndromes predominantly affecting the central nervous system. There is no clear correlation between the deleted coding regions and the biochemical defects; even patients with seemingly identical muscle mtDNA deletions may be clinically and biochemically heterogeneous.
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PMID:Mitochondrial myopathies. 268 27

The clinical features of 66 patients with histologically defined mitochondrial myopathy are described. The age of onset of symptoms ranged from birth to 68 years, but was before 20 years in 61%. Nineteen patients had similarly affected relatives. Three groups of cases could be identified clinically: a combination of progressive external ophthalmoplegia and weakness of the limbs induced or increased by exertion (55%); such limb weakness alone (18%); and those with clinical features, such as ataxia, dementia, deafness, involuntary movements and seizures, predominantly or exclusively arising from the CNS (27%). There was considerable overlap between these groups, and pigmentary retinopathy, present in 36% of patients, occurred in all three. At a mean disease duration of twenty years, 9 patients (all from Group 3) were severely disabled but 42 were still able to work. In vitro studies of mitochondrial metabolism, performed in 33 cases, most commonly showed deficiencies of the mitochondrial respiratory chain localized to complex I (18 patients) or complex III (9). No typical clinical picture emerged for any of the identifiable biochemical defects.
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PMID:The clinical features of mitochondrial myopathy. 377 73

We studied 22 subjects carrying the A3243G point mutation of human mitochondrial DNA (mtDNA). In 14 cases the clinical phenotype was characterized by mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), while 8 patients had chronic progressive external ophthalmoplegia (CPEO). The proportion of A3243G heteroplasmy in muscle was determined by two methods; densitometry on a diagnostic restriction-fragment length polymorphism and solid-phase mini-sequencing. We found a highly significant inverse correlation between the percentage of A3243G mutation and the specific activity of complex I, the respiratory complex with the highest number of mtDNA-encoded subunits, suggesting a direct effect of the mutation on mtDNA translation. No correlation was observed between the percentage of mutated mtDNA and the presence or absence of specific clinical features, such as stroke, ophthalmoplegia and diabetes mellitus. However, in the MELAS group the percentage of mutated mtDNA molecules was strongly correlated with the age of onset, while no such correlation was found in the CPEO group, suggesting a different time-dependent evolution of the mutation in the two groups. Finally, in contrast with other mtDNA mutations associated with ragged-red fibres (RRF), in both MELAS3243 and CPEO3243 we observed a high proportion of RRF that were positive to the histochemical reaction to cytochrome c oxidase, a morphological feature that seems to be specific for the neuromuscular phenotypes associated with mutations affecting the tRNA(Leu(UUR)) gene.
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PMID:Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA. 764 39

A 60-year-old woman had developed ptosis, progressive external ophthalmoplegia and action tremor over the last ten years. Physical examination also revealed short stature and retinal pigmentation. Anaerobic forearm exercise test showed increase of basal lactate and rise of lactate/piruvate index. Biceps biopsy displayed numerous ragged red fibers. Respiratory chain studies were consistent with complex I deficiency. Point mutations or deletions in mitochondrial DNA were not found. MR identified a diffuse leukoencephalopathy over both cerebral hemispheres, mesencephalon, pons and cerebellum. The late and sporadic onset of a progressive external ophthalmoplegia outlining a Kearns-Sayre syndrome is striking. A leukoencephalopathy associated with mitochondrial encephalomyopathy is an infrequent finding. The action tremor of this patient could be symptomatic of her mitochondrial disfunction.
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PMID:[Mitochondrial encephalomyopathy of late presentation with progressive ophthalmoplegia, tremor and diffuse leukoencephalopathy]. 1061 22

We report on 3 siblings (2 females and 1 male) with chronic progressive external ophthalmoplegia (CPEO), compatible with inherited mitochondrial cytopathy. The younger of the two sisters died at the age of 37 due to progressive respiratory failure. The older one presented with a status epilepticus at the age of 39 and was treated with valproate. Five months after the start of treatment, she developed fulminant liver failure and died. The brother has suffered from CPEO since early childhood but has had so far no other symptoms of a mitochondrial disease. A muscle biopsy from the younger sister revealed ragged-red fibers and decreased activities of complex I and IV of the respiratory chain but no pathogenic mutations in the mitochondrial tRNA genes or in several locations in the coding region of the mitochondrial genome. In the older sister's liver (obtained post-mortem), mitochondrial DNA was fragmented and could not be investigated. The clinical presentation and the biochemical findings suggest that all 3 siblings suffered from a mitochondrial cytopathy. Since mitochondrial cytopathies and valproate-induced fulminant liver failure are both rare events, an association between them is likely. Mitochondrial diseases should therefore be considered as a risk factor for valproate-induced liver failure and be excluded before treatment with valproate.
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PMID:Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. 1095 15

In mammalian cells, mitochondria provide energy from aerobic metabolism. They play an important regulatory role in apoptosis, produce and detoxify free radicals, and serve as a cellular calcium buffer. Neurodegenerative disorders involving mitochondria can be divided into those caused by oxidative phosphorylation (OXPHOS) abnormalities either due to mitochondrial DNA (mtDNA) abnormalities, e.g., chronic external ophthalmoplegia, or due to nuclear mutations of OXPHOS proteins, e.g., complex I and II associated with Leigh syndrome. There are diseases caused by nuclear genes encoding non-OXPHOS mitochondrial proteins, such as frataxin in Friedreich ataxia (which is likely to play an important role in mitochondrial-cytosolic iron cycling), paraplegin (possibly a mitochondrial ATP-dependent zinc metalloprotease of the AAA-ATPases in hereditary spastic paraparesis), and possibly Wilson disease protein (an abnormal copper transporting ATP-dependent P-type ATPase associated with Wilson disease). Huntingon disease is an example of diseases with OXPHOS defects associated with mutations of nuclear genes encoding non-mitochondrial proteins such as huntingtin. There are also disorders with evidence of mitochondrial involvement that cannot as yet be assigned. These include Parkinson disease (where a complex I defect is described and free radicals are generated from dopamine metabolism), amyotrophic lateral sclerosis, and Alzheimer disease, where there is evidence to suggest mitochondrial involvement perhaps secondary to other abnormalities.
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PMID:Mitochondria and degenerative disorders. 1157 22

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
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PMID:Primary and secondary defects of the mitochondrial respiratory chain. 1213 29

Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.
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PMID:Multiple mtDNA deletions with features of MNGIE. 1229 82


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