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)

Patients affected by medium-chain acyl CoA dehydrogenase (MCAD) deficiency, a frequent inborn error of metabolism, suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. In the present study, we investigated the in vitro effect of the medium-chain fatty acids (MCFA), at concentrations varying from 0.01 to 3 mM, accumulating in MCAD deficiency on some parameters of energy metabolism in cerebral cortex of young rats. (14)CO(2) production from [U(14)] glucose, [1-(14)C] acetate and [1,5-(14)C] citrate was evaluated by incubating cerebral cortex homogenates from 30-day-old rats in the absence (controls) or presence of octanoic acid, decanoic acid or cis-4-decenoic acid. OA and DA significantly reduced (14)CO(2) production from acetate by around 30-40%, and from glucose by around 70%. DA significantly reduced (14)CO(2) production from citrate by around 40%, while OA did not affect this parameter. cDA inhibited (14)CO(2) production from all tested substrates by around 30-40%. The activities of the respiratory chain complexes and of creatine kinase were also tested in the presence of DA and cDA. Both metabolites significantly inhibited cytochrome c oxidase activity (by 30%) and complex II-III activity (DA, 25%; cDA, 80%). Furthermore, only cDA inhibited complex II activity (by 30%), while complex I-III and citrate synthase were not affected by these MCFA. On the other hand, only cDA reduced the activity of creatine kinase in total homogenates, as well as in mitochondrial and cytosolic fractions from cerebral cortex (by 50%). The data suggest that the major metabolites which accumulate in MCAD deficiency, with particular emphasis to cDA, compromise brain energy metabolism. We presume that these findings may contribute to the understanding of the pathophysiology of the neurological dysfunction of MCAD deficient patients.
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PMID:Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. 1556 46

A 26-year-old man with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) was admitted to our hospital for further cardiovascular examination. A muscle biopsy demonstrated strongly succinate dehydrogenase-reactive blood vessels. Pulse wave contour analysis revealed that both capacitive and oscillatory compliance were markedly reduced in this patient compared with 45 normal age-matched control subjects. Hepatocyte growth factor was remarkably elevated in this patient over that of 10 normal control subjects. These findings suggest that a MELAS patient has not only pathologic but also functional vascular involvement. If so, patients with MELAS need systemic vascular assessment.
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PMID:Vascular involvement in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. 1589 69

We studied muscle biopsies of 103 pediatric patients in whom clinical suspicion for disorder of energy metabolism was highest in 13 patients, intermediate in 8 patients, and lowest in 82 patients. Electron transport complex (ETC) enzyme activity measurements were available in 96 of 103 patients. Most children with unclassified encephalopathy before biopsy had negative or equivocal morphological and biochemical evaluation for disorder of energy metabolism (72/85). The incidence of ETC abnormality and morphological abnormality in muscle from 39 patients with clinical encephalomyopathy (groups I, II, and III) was 20% and 38%, respectively. In 21 children with high or intermediate clinical suspicion of mitochondriopathy, light microscopy was confirmative in 12, ultrastructure was confirmative in 15, and major ETC abnormality was present in only 4 (29%) of 14. In 82 children with lower clinical suspicion of mitochondriopathy, morphological criteria at both the light and electron microscopic level were absent, and major abnormality of ETC activity was uncommon, in 9 (11%) of 82. Partial reductions of ETC activity occurred in 15 (18%) of 82, but are of uncertain significance. Ragged blue fibers were more prevalent in infants with mitochondriopathy than ragged red fibers. Increase of large, but not small, subsarcolemmal mitochondrial aggregates based on succinate dehydrogenase histochemistry is a useful indicator for mitochondriopathy. Thus, a distinction should be made between small aggregates (normal) and large aggregates. Using strict criteria to define pathological mitochondria, we concluded that electron microscopy is a powerful tool in the diagnosis of mitochondriopathy mainly when clinical suspicion is high. We found no consistent difference in the frequency of mitochondrial "proliferation" as currently defined or in citrate synthase activity in any group. Better patient selection in infants and children and better methods for investigation of mitochondriopathy are needed.
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PMID:Investigation of children for mitochondriopathy confirms need for strict patient selection, improved morphological criteria, and better laboratory methods. 1642 17

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a syndrome associated with mitochondrial DNA mutations such as A3243G, the most common mutation. Ragged-red fibers and strongly succinate dehydrogenase-reactive blood vessels in the muscle are diagnostic pathologic features of MELAS. In general, the first typical attack of MELAS occurs in children at school age; it is rare for stroke-like episodes to occur in early infancy. This report describes a 4-month-old male harboring A3243G, whose phenotype at onset was consistent with that of MELAS in infancy. The patient was admitted because of disturbances of consciousness and ventilatory insufficiency. Remarkable lactic acidosis was observed. MRI revealed several bilateral lesions. Periodic lateralized epileptic discharges on the EEG suggested regional lesions. Biopsied muscle displayed scattered ragged-red fibers and succinate dehydrogenase-reactive blood vessels; over 90% of muscle mitochondrial DNA had A3243G. This case suggests that MELAS can develop in early infancy with its typical clinical presentation. The high percentage of A3243G may contribute to the early onset of the MELAS phenotype in this patient.
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PMID:An infant with a mitochondrial A3243G mutation demonstrating the MELAS phenotype. 1650 96

Ethylmalonic aciduria is a common finding in patients affected by short-chain acyl-CoA dehydrogenase (SCAD) deficiency and other diseases characterized by encephalopathy, muscular symptomatology, and lactic acidemia. Considering that the pathophysiological mechanisms of these disorders are practically unknown and that lactic acidosis suggest an impairment of energy production, the objective of the present work was to investigate the in vitro effect of ethylmalonic acid (EMA), at concentrations varying from 0.25 to 5.0 mM, on important parameters of energy metabolism in human skeletal muscle, such as the activities of the respiratory chain complexes and of creatine kinase, which are responsible for most of the ATP produced and transferred inside the cell. We verified that EMA significantly inhibited the activity of complex I-III at concentrations as low as 0.25 mM, complex II-III at 1 mM and higher concentrations, and complex II at the concentration of 5 mM. In contrast, complex IV was not inhibited by the acid. Finally, we observed that the activity of creatine kinase was significantly inhibited by EMA at the concentrations of 1 and 5 mM. These results suggest that EMA compromises energy metabolism in human skeletal muscle. In case the in vitro effects detected in the present study also occur in vivo, it is tempting to speculate that they may contribute, at least in part, to explain the hypotonia/myopathy, as well as the increased concentrations of lactic acid present in the patients affected by illnesses in which EMA accumulates.
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PMID:Inhibition of the electron transport chain and creatine kinase activity by ethylmalonic acid in human skeletal muscle. 1677 66

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients.
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PMID:Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. 1686 82

Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl-CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient.
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PMID:Ethylmalonic encephalopathy: clinical and biochemical observations. 1771 31

The authors have studied changes of activity of succinate dehydrogenase (SD) of peripheral blood lymphocytes of newborn with hypoxic-ischemic encephalopathy at early neonatal period and against cerebrokurin medicine administration. Newborn children with hypoxic-ischemic encephalopathy due to severe asphyxia have significant disturbancies of cyto-energy metabolism which is proved through decrease in activity index of SD and decrease in quantity of the cells with moderate and high activity. Lymphocytes of newborns with severe asphyxia were caracterized on six days by absence of the cells with moderate and high activity. Newborns with severe asphyxia who had been prescribed cerebrokurin had on their six days considerable increase in lymphocytes with moderate and high activity.
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PMID:[Peculiarity of cell energy metabolism in newborns with hypoxic-ischemic encephalopathy caused by asphyxia]. 1871 95

We present clinical, magnetic resonance imaging and MR spectroscopic findings of a female patient, first admitted at the age of 9 months for regression of motor milestones and signs of mild spastic diplegia. Magnetic resonance imaging (MRI) demonstrated periventricular white matter abnormalities with sparing of the subcortical white matter. Subsequent MRIs, performed at the ages of 13 and 16 months, demonstrated progression of the white matter changes, progressive white matter rarefaction and cystic degeneration, and additional involvement of the corpus callosum; only the subcortical white matter remained spared. Proton MR spectroscopy revealed lactate elevation in the white matter. Blood lactate and lactate/pyruvate ratio were mildly elevated. Subsequent analysis of mitochondrial function in muscle tissue showed decreases in substrate oxidation and in ATP and CrP production rates. Complex I activity was seriously decreased, whereas mild decreases of complex II and IV activities were also noted. Analysis of the NDUFV1 gene revealed compound heterozygosity for two point mutations, each of them carried by one parent. The further clinical course of the patient was uphill; she slowly regained all previously lost motor milestones. In conclusion, diffuse white matter changes on MRI are compatible with mitochondrial encephalopathy and not necessarily associated with a severe clinical course.
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PMID:MR spectroscopy and serial magnetic resonance imaging in a patient with mitochondrial cystic leukoencephalopathy due to complex I deficiency and NDUFV1 mutations and mild clinical course. 1899 Nov 97

Isovaleric acidemia (IVAcidemia) is an inborn error of metabolism due to deficiency of isovaleryl-CoA dehydrogenase activity, leading to predominant accumulation of isovaleric acid (IVA). Patients affected by IVAcidemia suffer from acute episodes of encephalopathy, whose underlying mechanisms are poorly known. In the present study we investigated whether an intracerebroventricular injection of IVA could compromise energy metabolism in cerebral cortex of young rats. IVA administration significantly inhibited (14)CO(2) production from acetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates prepared 24 h after injection. However, no alterations of these parameters were observed 2 h after injection. In contrast, no significant differences were found in the activities of succinate dehydrogenase, isocitrate dehydrogenase, electron transfer chain complexes or creatine kinase in rats sacrificed 2 or 24 h after IVA administration. Moreover, IVA injection significantly inhibited Na(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA administration, while pre-treatment of rats with creatine completely prevented the inhibitory effects of IVA on Na(+),K(+)-ATPase. In conclusion, in vivo administration of IVA inhibits the citric acid cycle probably through the enzyme citrate synthase, as well as Na(+),K(+)-ATPase, a crucial enzyme responsible for maintaining the basal potential membrane necessary for a normal neurotransmission. It is presumed that inhibition of these activities may be involved in the pathophysiology of the neurological dysfunction of isovaleric academic patients. The present findings are of particular interest because treatment with creatine supplementation may represent a potential novel adjuvant therapeutic strategy in IVAcidemia.
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PMID:Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats. 1921 Sep 57


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