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 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

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

A comparative histochemical analysis of the prevalence and cytochrome oxidase staining characteristics of ragged-red fibres in limb skeletal muscles was performed in 19 patients spanning four distinct mitochondrial syndromes: chronic progressive external ophthalmoplegia; myoclonus epilepsy with ragged-red fibres; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and pure limb myopathy. The percentage occurrence of non-ragged red but cytochrome oxidase negative fibres was additionally noted. Ragged-red fibres and cytochrome oxidase-negative fibres were generally more prevalent in the chronic progressive external ophthalmoplegia syndrome than in myoclonus epilepsy ragged-red fibres syndrome or mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes syndrome. Isolated cytochrome oxidase-negative fibres were a common finding in each phenotypic syndrome except pure limb myopathy and could involve any of the major fibre types non-specifically. Ragged-red fibres were devoid of cytochrome oxidase activity in chronic progressive external ophthalmoplegia, but commonly displayed activity in the other three syndromes providing a clue to syndromal differentiation on a histochemical basis.
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PMID:Contrasting histochemical features of various mitochondrial syndromes. 762 56

Subacute necrotizing encephalomyelopathy (Leigh's syndrome) is a rare neurodegenerative disease in the adult. The precise metabolic defect is unknown, but abnormalities of a mitochondrial enzyme system related to cytochrome-c oxidase or pyruvate dehydrogenase are described. The clinical picture usually consists of an altered breathing pattern, oculomotor paralysis, other signs of cranial nerve dysfunction, ataxia, myoclonic jerks, nystagmus, generalized seizures, optic atrophy and demyelinating peripheral neuropathy. Hypopnea leads to CO2-retention with consecutive loss of consciousness demanding mechanical ventilation. Respiratory failure is the most frequent cause of death. Here we describe two patients with adult onset Leigh's syndrome and we discuss the longterm treatment strategies including vitamin B1 and CPAP mask.
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PMID:[Adult Leigh syndrome. A rare differential diagnosis of central respiratory insufficiency]. 771 56

The mode of inheritance of Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) have not yet been established, since most cases are sporadic. We studied skeletal muscle pathology and mitochondrial DNA (mtDNA) in a sporadic KSS patient (proband) and examined mitochondrial function of the muscle in his asymptomatic family members. The proband was a 56-year-old male with bilateral ptosis, external ophthalmoplegia, retinal degeneration and cardiac conduction disturbance. Biopsied deltoid muscle showed 9.7% of ragged red fibers without cytochrome oxidase (COX) activity and abnormal mitochondria on electron microscopy. Analysis of muscle mtDNA revealed a 4,977 bp deletion between nt. 8,483 and 13,459. None of the family members had symptoms similar to those of the proband. However, an aerobic exercise test of 15W for 15 minutes with an ergometer induced a marked increase in serum lactate levels in the proband's mother. Histology of her biopsied deltoid muscle showed 0.3% of ragged red fibers without COX activity and morphologically abnormal mitochondria. These findings indicate that the abnormal mitochondria of the proband were transmitted from his asymptomatic mother. This also suggests that some of the sporadic KSS/CPEO cases are inherited one.
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PMID:[A case of Kearns-Sayre syndrome whose asymptomatic mother had abnormal mitochondria in skeletal muscle]. 778 Dec 38

Monoclonal antibodies recognizing the mitochondrially encoded subunits I and II, and the nuclear-encoded subunits IV, Va, Vb and VIc of human cytochrome-c oxidase were generated. These antibodies are highly specific and allow the assessment of subunit steady-state levels in crude cell extracts and tissue sections. In the experimental human cell line 143B206, which is devoid of mitochondrial DNA, immunovisualization with the antibodies revealed that the nuclear-encoded subunits IV and Va were present in amounts close to that of the parental cell line despite the absence of the mitochondrially encoded subunits. In contrast, the nuclear-encoded subunits Vb and VIc were severely reduced in cell line 143B206, suggesting that unassembled nuclear-encoded subunits are degraded at different rates. In skeletal muscle sections of a patient with chronic progressive external ophthalmoplegia known to harbor the 'common deletion' in a subpopulation of her mitochondrial DNA, most cytochrome-c oxidase activity negative fibers had greatly reduced levels of subunits I, II, Va, Vb and VIc of cytochrome-c oxidase. The steady-state level of subunit IV, however, was less affected. This was particularly evident in cytochrome-c oxidase activity negative fibers with accumulated mitochondria ('ragged-red' fibers) where immunodetection with anti-subunit IV resulted in intense staining. The data presented in this paper demonstrate that the battery of monoclonal antibodies can be employed for diagnostic purposes to analyze steady-state levels of mitochondrially and nuclear-encoded subunits of cytochrome-c oxidase.
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PMID:Subunit specific monoclonal antibodies show different steady-state levels of various cytochrome-c oxidase subunits in chronic progressive external ophthalmoplegia. 861 60

In a 33-year-old man, mitochondriopathy was diagnosed upon short stature, auditory impairment, gynaecomastia, hypogonadism, vertical ophthalmoplegia, cerebral atrophy, leucencephalopathy, cataract, hypertrabeculated left ventricle, hypothyroidism, diabetes mellitus, glomerulonephritis necessitating kidney transplantation, general wasting, polyneuropathy, abnormally high lactate levels on exercise, partially reduced cytochrome-c oxidase staining and abnormally structured mitochondria on muscle biopsy. Mitochondrial DNA (mtDNA) analysis revealed 1 novel (A15662G) and 3 known mtDNA transition(s) (T3398C, T4216C, G15812A) affecting the cytb and ND1 gene, respectively. Three of the patient's transitions were also detected in blood leukocytes of the patient's maternal grandmother, mother and brother. Mutant mtDNA was heteroplasmic at >75% in the patient's skeletal muscle.
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PMID:Complex mitochondriopathy associated with 4 mtDNA transitions. 1089 93

We performed morphological, biochemical, and genetic studies, including single-fiber PCR (sf PCR), on muscle biopsies obtained from a mother and daughter with MELAS syndrome due to the A3243G transition of mitochondrial DNA (mtDNA). The severity of muscle involvement appeared quite distinct, in spite of the fact that both patients segregated similar mutant mtDNA levels on total muscle DNA. The daughter did not show any clinical muscle involvement: muscle biopsy revealed many ragged red fibers (RRFs) mostly positive for cytochrome-c oxidase (COX) activity. In contrast, her mother had developed a generalized myopathy without progressive external ophthalmoplegia (PEO), morphologically characterized by many COX-negative RRFs. Single-muscle fiber PCR demonstrated in both patients significantly higher percentages of wild-type mtDNA in normal fibers (daughter: 23.25 +/- 15.22; mother: 43.13 +/- 26.11) than in COX-positive RRFs (daughter: 11.25 +/- 5.22, P < 0.005; mother: 9.12 +/- 5.9, P < 0.001) and in COX-negative RRFs (daughter: 8.9 +/- 4.2, P < 0.001 mother: 4.8 +/- 2.8, P < 0.001). Wild-type mtDNA levels resulted higher also in COX-positive vs. COX-negative RRFs (daughter: P < 0.05; mother: P < 0.001). Our data confirm a direct correlation between A3243G levels and impairment of COX function at the single-muscle fiber level. Moreover, the evidence of a clinical myopathy in the patient with higher amounts of COX-negative RRFs bolsters the concept that a differential distribution of mutant mtDNAs at the cellular level may have effects on the clinical involvement of individual tissues. However, the occurrence of a similar morphological and biochemical muscle phenotype also in PEO(3243) patients suggests that other genetic factors involved in the interaction between mitochondrial and nuclear DNA, rather than the stochastic distribution of mtDNA genomes during embryogenesis, are primarily implicated in determining the various clinical expressions of the A3243G of mtDNA.
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PMID:Single-fiber PCR in MELAS(3243) patients: correlations between intratissue distribution and phenotypic expression of the mtDNA(A3243G) genotype. 1099 6

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

We report on 2 adult patients presenting with choreic movements as the main clinical feature of mitochondrial cytopathy. One patient exhibited a sensory neuronopathy and ophthalmoplegia. The other had ptosis, a proximal myopathy, and a sensory neuropathy. The diagnosis of mitochondrial cytopathy was established by the presence of ragged red fibers, cytochrome C oxydase-negative fibers, and a defect of the complex IV of the respiratory chain in muscle biopsy. No mutations in mitochondrial DNA were detected. The choreic movements observed in juvenile forms of mitochondrial cytopathy are rarely observed in adults. Although striatal vulnerability is commonly reported in patients with mitochondrial disorders, the mechanism by which the mitochondrial dysfunction leads to chorea is not known.
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PMID:Adult-onset chorea and mitochondrial cytopathy. 1559 39


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