Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0268596 (EMA)
 2,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied metabolic, polypeptide and genetic variation in eight glutaric acidemia type II (GA II) patients with electron transfer flavoprotein (ETF) deficiency. As measured by 3H-fatty acid oxidations in fibroblasts, beta-oxidation pathway flux correlated well with clinical phenotypes. In six patients with severe neonatal onset GA II, oxidation of [9,10(n)-3H]-palmitate ranged from 2% to 22% of control and of [9,10(n)-3H]myristate, from 2% to 26% of control. Of two patients with late onset GA II, one had intermediate residual activities with these substrates and the other normal activities. Radiolabeling and immunoprecipitation studies revealed that three of the six neonatal onset GA II patients had greatly diminished or absent alpha- and beta-ETF subunits, consistent with a failure to assemble a stable heterodimer. Another neonatal onset patient showed normal synthesis of beta-ETF but decreased synthesis of alpha-ETF. Two neonatal onset and two late onset GA II patients showed normal synthesis of both subunits. Analysis of the pre-alpha-ETF coding sequence revealed seven different mutations in the six patients with neonatal onset GA II. The most common mutation was a methionine for threonine substitution at codon 266 found in four unrelated patients, while all the other mutations were seen in single patients. No mutations were detected in the two patients with late onset GA II.
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PMID:Glutaric acidemia type II. Heterogeneity in beta-oxidation flux, polypeptide synthesis, and complementary DNA mutations in the alpha subunit of electron transfer flavoprotein in eight patients. 143 Jan 99

Newly identified forms of electron transfer flavoprotein (ETF) deficiency in two patients with glutaric aciduria type II (GA II) were described. GA II has been attributed to a defect of either ETF or ETF dehydrogenase, resulting in multiple acyl-CoA dehydrogenation deficiency. ETF is a mitochondrial flavoprotein consisting of an alpha-subunit, alpha-ETF, and a beta-subunit, beta-ETF. We used pulse-chase experiments to examine the biosynthesis of ETF in fibroblasts from two patients with GA II. Patient 1 was a boy with the neonatal onset form, but without congenital anomalies, who is living at age 2 y. A defect of beta-ETF biosynthesis was noted in this patient. Patient 2 was a boy with the neonatal onset form with congenital anomalies who died on the 3rd postnatal day. He presented with a peculiar face and polycystic kidneys. In patient 2, both alpha- and beta-ETF were synthesized, but both the subunits were rapidly degraded. The lability of ETF was considered to be the cause of GA II in this patient. These two cases appear to be new forms of ETF deficiency in GA II.
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PMID:Newly identified forms of electron transfer flavoprotein deficiency in two patients with glutaric aciduria type II. 200 Feb 60

Glutaric acidemia type II (GA II) is a human genetic disorder. It has been suggested that the primary defect in this disorder is a deficiency of a protein involved in electron transport between the acyl-CoA dehydrogenases and the bc1 complex of the mitochondrial respiratory chain. Antisera were raised to purified porcine electron transfer flavoprotein (ETF) and electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO). The antisera were used to detect the two electron transferases in control and GA II fibroblasts by immunoblotting. Fibroblasts from three unrelated GA II patients were deficient in immunologically detectable ETF:QO and extracts from these three fibroblast lines contained no detectable ETF:QO catalytic activity. Fibroblasts from parents of two of these patients had ETF:QO activity intermediate between activities in control fibroblasts and fibroblasts from the patients. These data indicate that the primary defect in these patients is a deficiency of ETF:QO and that the mode of transmission of the gene is autosomal recessive. Fibroblasts from two other patients with severe GA II had normal levels of ETF-QO activity and antigen but were deficient in immunoreactive ETF. These findings show that GA II results from a deficiency of ETF in some patients and ETF:QO in others. In addition, these investigations provide strong evidence for the specificity and physiological function of the iron-sulfur flavoprotein ETF:QO.
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PMID:Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts. 298 28

Glutaric acidemia type II (GA II) is a metabolic disorder caused by deficiency of electron transport flavoprotein or its oxyreductase. It is characterized by acidosis, hypoglycemia, hyperammonemia, organic aciduria, and "sweat-sock" odor. Neonatal GA II differs from most inborn metabolic errors in that there are prominent congenital malformations. We recently observed two infants at autopsy with GA II whose malformations included: subcortical renal glomerular cysts, renal medullary dysplasia, cerebral pachygyria, pulmonary hypoplasia, and facial dysmorphism. In addition, there was lipid accumulation in liver, heart, and renal tubular epithelium, tissues that use fatty acids as a primary source of energy. Review of previous reports of 12 patients showed that these lesions are typical of neonatal GA II. The pattern of lesions, in particular the striking localization of renal dysplasia to the medulla, suggests that the malformations may be the consequence of an accumulation of toxic metabolites that is not corrected by placental transfer.
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PMID:Glutaric acidemia type II. Comparison of pathologic features in two infants. 317 28

Incubation of intact fibroblasts from a patients with glutaric aciduria type II with [2-14C]riboflavin showed normal synthesis of flavin mononucleotide and flavin adenine dinucleotide. This is taken as evidence for normal transport of riboflavin into the cells and normal activity of riboflavin kinase (EC 2.7.1.26) and flavin mononucleotide adenylyltransferase (EC 2.7.7.2). The ability of intact fibroblasts to oxidize 1-14C-fatty acids and [6-14C]lysine is impaired in the patient which together with the urinary excretion pattern of organic acids indicates a defective dehydrogenation of fatty acid acyl-CoAs and glutaryl-CoA. However, dehydrogenation of (C6-C10) fatty acid acyl-CoA derivatives and glutaryl-CoA was normal when the dehydrogenases were measured in fibroblast homogenate with artificial electron acceptors. In vivo, these dehydrogenases transfer their electrons to CoQ10 in the main electron transport chain via electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. Glutaric aciduria type II fibroblasts showed very diminished activity when the glutaryl-CoA dehydrogenase activity was measured without artificial electron acceptor but with intact endogenous electron transport system. As the NADH and succinate oxidation seems normal in glutaric aciduria type II patients, this is strong evidence for a defect in either the electron transfer flavoprotein or the electron transfer flavoprotein dehydrogenase.
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PMID:Glutaric aciduria type II: evidence for a defect related to the electron transfer flavoprotein or its dehydrogenase. 643 13

The previous biochemical evidence had suggested that glutaric aciduria type II (GA II) is due to deficient dehydrogenation of multiple short-chain acyl coenzyme A's (CoA's), bu the precise biochemical mechanism underlying this disease was unknown. We investigated substrate oxidation and in vitro activities of isovaleryl CoA- and butyryl CoA dehydrogenases as well as that of electron-transferring flavoprotein (ETF) in cultured skin fibroblasts from a patient with GA II. GA II cells have a markedly decreased ability to oxidize [1-14C]butyrate, [2-14C]lysine, and [2,14C]leucine (3, 9, and 9% of control values, respectively). Mitochondrial isovaleryl CoA- and butyryl CoA dehydrogenase activities in GA II cells were determined using a tritium release assay with [2,3-3H] acyl-CoA's as substrate. When an artificial electron acceptor, phenazine methosulfate (PMS) was not added in the assay media, these activities were 108 and 113% of controls, respectively. This represents the normal abilities of the dehydrogenases in GA II cells to bind the substrate and to catalyze tritium exchange between the bound substrate and solvent. When PMS was added to the assay mixture, these activities were 88 and 70% of control values, respectively, indicating that these enzymes can both dehydrogenate their substrates normally and then transfer electrons to an acceptor (PMS). ETF activity in mitochondrial sonic supernatants from GA II cells, as assessed by a newly devised method, was 159% of control values. These observations suggest that the acyl CoA dehydrogenases themselves and ETF are not defective in GA II. Therefore, the deficiency of another common gene product necessary for the function of all the affected acyl CoA dehydrogenases must be sought to explain the etiology of GA II.
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PMID:Glutaric aciduria type II: in vitro studies on substrate oxidation, acyl-CoA dehydrogenases, and electron-transferring flavoprotein in cultured skin fibroblasts. 720 50

Glutaric aciduria type I is an autosomal recessive disorder resulting from a deficiency of glutaryl-CoA dehydrogenase. This leads to an accumulation of glutaric and 3-hydroxyglutaric acids and secondary carnitine deficiency. The symptomatology is discussed, especially those resulting from lesions in the basal ganglia, and the encephalopathic episodes which are often precipitated by infections. The variability of the clinical presentation is stressed. The most serious complications are collections of fluid and blood in the middle fossae, the bleeding resulting from rupture of bridging veins. The prognosis does not seem to be related to the extent of the enzyme deficiency. The diagnosis is confirmed by identifying the abnormal acids in the urine and the deficiency of the enzyme in cultured fibroblasts. The differential diagnosis is reviewed: from other biochemical disorders and from other cerebral lesions. Treatment is by special diet and carnitine supplementation. The dystonia can prove difficult to treat, and surgery may be needed to remove the collections of fluid and blood. Glutaric aciduria type II is caused by a deficiency of either electron transport flavoprotein or of electron transport flavoprotein oxoreductase. The symptoms can be mild or severe. The former may only occur in times of stress, and the latter include congenital anomalies, especially of the kidneys and heart. The pathology of these are discussed. The demonstration of organic acids in the urine and the results of muscle and liver biopsies confirm the diagnosis, and treatment with a special diet and supplementation with carnitine and riboflavine is effective.
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PMID:Glutaric aciduria types I and II. 1636 16

Glutaric acidemia type 2 (GA2) is an autosomal recessive disorder resulting from a deficiency of electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) that manifests from most severe neonatal to late-onset forms. However, the genetic defect responsible for the disease and clinical severity is not well-characterized. In order to understand the relationship between the phenotype and genetic defect, we investigated the clinical and molecular features of 15 Japanese patients, including 4 previously reported cases. Three patients had the neonatal form and 8 patients had the late-onset form, 1 of whom presented an extremely mild phenotype. Immunoblot analysis showed that either ETFalpha, ETFbeta, or ETFDH was significantly reduced or absent in all patients. However, no specific enzyme deficiency predominated, and there were no associations with the clinical severity. Genetic analyses identified 15 mutations including non-sense, missense, splice site mutations, and small deletions, in ETFA, ETFB and ETFDH genes. Although almost all mutations were unique to Japanese patients and no common mutations were found, some of them appeared to be associated with a specific phenotype. Our results suggest that clinical and mutational spectrums of Japanese GA2 patients are heterogeneous and that genetic diagnoses may help to predict a prognosis and provide more accurate diagnostic information for patients and families with GA2.
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PMID:Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. 1828 5

In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.
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PMID:Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD). 2002 44

Glutaric aciduria type II, also known as multiple acyl coenzyme A dehydrogenase deficiency, is an autosomal recessive, mitochondrial organic acid disorder that impairs electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase, and causes a defect in flavin metabolism or transport. It has a heterogeneous clinical presentation, with at least three different phenotypic appearances. Magnetic resonance (MR) imaging of the brain in this disorder shows a T2-weighted prolongation in the corpus striatum, putamen, caudate nucleus, middle cerebral peduncles and splenium of the corpus callosum. We report a seven-month-old male Caucasian child who presented at the paediatrics emergency department with a sweetish breath. He was clinically diagnosed with diabetic ketoacidosis. However, on MR imaging, brain evaluation and laboratory analysis, he was found to have glutaric aciduria type II.
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PMID:MR imaging findings of glutaric aciduria type II. 2050 99


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