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: EC:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Subacute necrotizing encephalopathy (Leigh syndrome) is characterized by lactacidosis, seizures, ataxia, multiple cerebral hypervascularized lesions and mitochondrial oxidation defects. This is a report on a 21-year-old patient with proven Leigh syndrome, mild central and provokable peripheral lactacidosis, an extra-erythrocyte complex II defect, functionally reduced myokinase adenylate deaminase activity, but no ultrastructural mitochondrial changes. Determination of lactate, pyruvate and ammonia under ischemic conditions plus a pyruvate loading test were particularly useful. Oral flunarizine (Sibelium 30 mg/d) proved to be therapeutically effective.
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PMID:Diagnosis and treatment in a case of juvenile subacute necrotizing encephalopathy Leigh without cytochrome c oxidase deficiency. 132 78

A 25-year-old woman with Kearns-Sayre syndrome (KSS) had complete external ophthalmoplegia, short stature, ataxia, cardiac conduction defects, and pigmentary retinopathy. Muscle biopsy revealed ragged-red fibers. Electron microscopy showed increased numbers of mitochondria with disordered structure and paracrystalline inclusions. Enzymatic analysis revealed a deficiency of complex II of the mitochondrial respiratory chain, and, more specifically, a deficiency of succinic dehydrogenase, although both subunits of this enzyme proved to be present by immunologic analysis. Therapy with vitamin cofactors did not result in short-term improvement. This appears to be the first report of complex II deficiency in a patient with KSS.
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PMID:Kearns-Sayre syndrome and complex II deficiency. 271 Mar 60

The organophosphorus compound, triphenyl phosphite (TPP), caused ataxia in chickens 8-14 days after single po or iv administration. The po and iv ED50 values were 1414 and 35.4 mg/kg, respectively. Chickens which developed ataxia lost 14.4 +/- 2.5% (mean +/- SEM, n = 14) of their initial weight at 28 days and the paralyzed birds showed a severe reduction of 29.3 +/- 2.9% (n = 13) of their initial weight at death or at 28 days after dosing. For the first 4-hr interval after iv injection of 50 mg/kg, the elimination of TPP from plasma consisted of at least two exponential phases; the half-lives of the first and second phases were approximately 30 and 60 min, respectively. When the birds received 100 mg/kg (iv) fatty tissue showed the highest TPP concentration, e.g., 215 micrograms/g fresh wt at 6 hr postdosing. The half-life was approximately 24 hr. Among neural tissues, the sciatic nerve had the highest concentration, followed by the spinal cord, the cerebellum, and the cerebrum. The red muscles, such as adductor magnus, contained about 4-30 times as much TPP as did the white muscles, such as biceps brachii, 6 hr after treatment. Time course effects of TPP treatment on mitochondrial enzymes in leg skeletal muscles were examined by treating hens with 50 mg/kg (iv) and euthanizing the birds at 6 hr to 8 days postdosing. The creatine kinase (CK) activities of the adductor and the soleus were significantly decreased at 2 (48 hr), 4, and 8 days, and at 4 and 8 days postdosing, respectively. Adductor magnus and soleus succinate dehydrogenase (SDH) activities were decreased markedly at 24 and 48 hr, and at 2 (48 hr), 4, and 8 days, respectively. Cytochrome oxidase (COD) activity in adductor magnus and soleus did not decrease during the time course. Biceps femoris CK, SDH, and COD activities were not affected by TPP treatment at this dosage. These results suggest that TPP administration affects the mitochondrial metabolism in skeletal muscle, especially red muscle of chickens.
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PMID:Delayed neurotoxicity of triphenyl phosphite in hens: pharmacokinetic and biochemical studies. 278 68

Muscle biopsies from six horses with clinical histories of muscle atrophy, muscle tremors, myopathic symptoms, unsteadiness of pelvic limbs and progressive ataxia were examined. Muscle biopsies were studied with enzyme histochemical techniques to evaluate the diagnostic values of these methods in cases suspected of suffering from neuromuscular disorders. Hypertrophy, atrophy, fibre splitting, waxy degeneration, phagocytosis and necrosis were seen in haematoxylin eosin stained sections of the different cases. Fibre type predominance and fibre type grouping were seen in the calcium ion stimulated myosine ATP-ase (Ca-ATP-ase) stained sections of some cases. 'Moth-eaten fibres' were demonstrated in three cases by staining with NADH: nitro blue tetrazolium oxidoreductase (NADH-TR), succinate dehydrogenase (SDH), NADH dependent malate dehydrogenase, cytochrome c oxidase and by lactate dehydrogenase. The catabolic enzymes, acid phosphatase (ACP) and 5'-nucleotidase were active in cases with fibre phagocytosis. The oxidative part of the pentose phosphate pathway in myopathic tissue seemed to be important in three cases, demonstrated by the increased activity of glucose-6-phosphate dehydrogenase (GPDH) and 6-phosphogluconate dehydrogenase (PGDH). The important feature of diseased horse muscle was that the pathohistochemical changes were exactly the same as in diseased skeletal muscles of humans. The application of tissue saving enzyme histochemical techniques can be recommended in the study of muscle tissue from horses suffering from suspected neuromuscular disorders.
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PMID:Enzyme histochemistry on muscle biopsies as an aid in the diagnosis of diseases of the equine neuromuscular system: a study of six cases. 336 6

The results of laboratory investigations in concerning 15 patients suspected of mitochondrial disease (MD) are presented. Our purpose is to provide an outline of the investigative modalities that support the clinical suspicion and have been found to be useful in the diagnosis. Five clinical groups were studied including 5 exercise intolerances (2 with inflammatory myopathy), 3 with myopathies (1 with dilated cardiomyopathy), 2 with progressive external oftalmoplegia (1 associated with cerebellar ataxia+epilepsy+hypertrophic cardiomyopathy+pes cavus), 4 with encephalopathies (3 with myoclonic encephalopathies with ataxia and dementia and 1 with epilepsy and tremor), and 1 with metabolic acidosis and cardiomyopathy. We used the following categories of investigative procedures: clinical phenotype analysis including pedigree study, neurophysiological tests, bicycle ergometric evaluation, neuroimaging, microscopic study of skeletal muscle biopsy, post-mortem examination, biochemical assays and molecular genetic studies. EMG showed myopathic changes in 5 cases, features of neuropathy in 2, mixed myopathic and neuropathic pattern in 1 and nonspecific changes in 3. EMG was normal in 3 patients. The most common skeletal muscle abnormalities were variation in fiber size (60%), lipid inclusions (33.3%), oxidative subsarcolemmal aggregates (26.7%) and ragged-red fibers (26.7%). Electron microscopy revealed mitochondrial abnormalities in 8 out of 14 patients' muscle biopsies, and in myocardiac and hepatic tissues of another. Site of biochemical defect was located in 12 patients. Complex I defect in 6, complexes I+IV deficiencies in 3, complex II defect in 1, complex IV deficiency in 1, complexes II+IV deficiencies in 1, and complex III defect in 1. In 2 patients the biochemical defect was not located. Mitochondrial DNA alterations were not found in 7 investigated patients. The clinical spectrum of MD has become increasingly wider. After the clinica suspicion, the diagnosis depends up on the appropriate use of skeletal muscle biopsy, biochemical investigations and molecular genetic techniques. Conventional EMG and automatic measurement of the electromyogram are particularly helpful in confirming the clinical suspicion in patients with predominantly central nervous system disease or in cases in which clinical signs are few.
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PMID:[Clinical and investigative approaches in mitochondrial diseases. A review of 15 cases]. 780 49

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders with ataxia and dysarthria as early and dominant signs. In ADCA type II, retinal degeneration causes severe visual impairment. ADCA type II has recently been mapped to chromosome 3p by three independent groups. In the family with ADCA type II studied here, the disease has been mapped to chromosome 3p12-p21.1. Histochemical examination of muscle biopsies in 5 cases showed slight neurogenic atrophy and irregular lobulated appearance or focal decreases of enzyme activity when staining for NADH dehydrogenase, succinic dehydrogenase and cytochrome oxidase. Ragged-red fibres were scarce. Electron microscopic examination showed uneven distribution of mitochondria with large fibre areas devoid of mitochondria and/or large subsarcolemmal accumulations of small rounded mitochondria, and frequent autophagic vacuoles. These vacuoles contained remnants of multiple small rounded organelles, possibly mitochondria, and had a remarkably consistent ultrastructural appearance. Biochemical investigation of mitochondrial function showed reduced activity of complex IV and slightly reduced activity of complex I in the respiratory chain in a severely affected child while no abnormalities were found in his affected uncle.
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PMID:Muscle morphology and mitochondrial investigations of a family with autosomal dominant cerebellar ataxia and retinal degeneration mapped to chromosome 3p12-p21.1. 899 9

To distinguish the role of Mn superoxide dismutase (MnSOD) from that of cytoplasmic CuZn superoxide dismutase (CuZnSOD), the mouse MnSOD gene (Sod2) was inactivated by homologous recombination. Sod2 -/- mice on a CD1 (outbred) genetic background die within the first 10 days of life (mean, 5.4 days) with a complex phenotype that includes dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, metabolic acidosis and ketosis, and a severe reduction in succinate dehydrogenase (complex II) and aconitase (a TCA cycle enzyme) activities in the heart and, to a lesser extent, in other organs. These findings indicate that MnSOD is required to maintain the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide. On the other hand, Lebovitz et al. reported an independently derived MnSod null mouse (Sod2tmlLeb) on a mixed C57BL/6 and 129Sv background with a different phenotype. Because a difference in genetic background is the most likely explanation for the phenotypic differences, the two mutant lines were crossed into different genetic backgrounds for further analyses. To study the phenotype of Sod2tmlLeb mice CD1 background, the Sod2tmlLeb mice were crossed to CD1 for two generations before the -/+ mice were intercrossed to generate -/- mice. The life span distribution of CD1 < Sod2-/- > Leb was shifted to the left, indicating a shortened life span on the CD1 background. Furthermore, the CD1 < Sod2-/- > Leb mice develop metabolic acidosis at an early stage as was observed with CD1 < Sod2-/- > Cje. When Sod2tmlCje was placed on C57BL/6J (B6) background, the -/- mice were found to die either during midgestation or within the first 4 days after birth. However, when the B6 < Sod2 -/+ > Cje were crossed with DBA/2J (D2) for the generation of B6D2F2 < Sod2-/- > Cje mice, an entirely different phenotype, similar to that described by Lebovitz et al., was observed. The F2 Sod -/- mice were able to survive up to 18 days, and the animals that lived for more than 15 days displayed neurological abnormalities including ataxia and seizures. Their hearts were not as severely affected as were those of the CD1 mice, and neurological degeneration rather than heart defect appears to be the cause of death.
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PMID:The use of transgenic and mutant mice to study oxygen free radical metabolism. 1067 32

Genetic defects affecting the mitochondrial respiratory chain are an important cause of neurological disease. Previously, we identified a family with complex II deficiency and late-onset neurodegenerative disease with progressive optic atrophy, ataxia, and myopathy. The affected family members are now shown to carry a C-to-T transition in one allele of the nuclear gene encoding the flavoprotein subunit of complex II. Mutation of the equivalent base in Escherichia coli generates an inactive enzyme unable to bind flavin adenine dinucleotide covalently. Compatible with these findings, our patients have an approximate 50% decrease in complex II and succinate dehydrogenase activity. These results suggest that genetic defects of nuclear-encoded subunits of the mitochondrial respiratory chain can result in late-onset neurodegenerative disease.
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PMID:Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. 1097 39

A 31-year-old woman had encephalopathy, growth retardation, infantilism, ataxia, deafness, lactic acidosis, and increased signals of caudate and putamen on brain magnetic resonance imaging. Muscle biochemistry showed succinate:cytochrome c oxidoreductase (complex II-III) deficiency. Both clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation. Clinically, when taking 300mg coenzyme Q10 per day, she resumed walking, gained weight, underwent puberty, and grew 20cm between 24 and 29 years of age. Coenzyme Q10 was markedly decreased in cerebrospinal fluid, muscle, lymphoblasts, and fibroblasts, suggesting the diagnosis of primary coenzyme Q10 deficiency. An older sister has similar clinical course and biochemical abnormalities. These findings suggest that coenzyme Q10 deficiency can present as adult Leigh's syndrome.
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PMID:Coenzyme Q-responsive Leigh's encephalopathy in two sisters. 1244 28


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