Short-chain acyl-coenzyme A dehydrogenase deficiency

Division of Human and Molecular Genetics, Children's Hospital of Philadelphia, Abramson Research Center, Room 1002, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 01/2009; 95(4):195-200. DOI: 10.1016/j.ymgme.2008.09.007
Source: PubMed


Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a disorder of mitochondrial fatty acid oxidation that leads to the accumulation of butyrylcarnitine and ethylmalonic acid in blood and urine. Originally described with a relatively severe phenotype, most patients are now diagnosed through newborn screening by tandem mass spectrometry and remain asymptomatic. Molecular analysis of affected individuals has identified a preponderance of private inactivating point mutations and one common one present in high frequency in individuals of Ashkenazi Jewish ancestry. In addition, two polymorphic variants have been identified that have little affect on enzyme kinetics but impair folding and stability. Individuals homozygous for one of these variants or compound heterozygous for one of each often show an increased level of ethylmalonic acid excretion that appears not to be clinically significant. The combination of asymptomatic affected newborns and the frequent variants can cause much confusion in evaluating and treating individuals with SCADD. The long-term consequences and the need for chronic therapy remain current topics of contention and investigation.

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Available from: Michael J Bennett
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    • "It was found that ethanol intervention changed the metabolism of short-chain dicarboxylic acids, TCA cycle, amino acids, and aromatic compounds. Ethanol-induced oxidative stress and mitochondrial dysfunction probably result in oxidation disorder of short chain fatty acids or branch chain amino acids, and thereby such disorders prevents the body from converting short chain fatty acids into energy (Bok et al. 2003; Jethva et al. 2008). The significantly elevated malonic acid and ethylmalonic acid in ethanol group of Wistar rats indicated that they suffered more hepatic injury than the ethanol group of SD rats. "
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    • "The urinary and serum profiles of MADD patients are found to share remarkable similarities with the ones observed in this study. It has been well established that elevated dimethylglycine and sarcosine (Burns et al., 1998; Goodman et al., 1980), ethylmalonate, butyrylcarnitine, butyrylglycine (Amendt et al., 1987; Bhala et al., 1995; Birkebaek et al., 2002; Jethva et al., 2008; Koeberl et al., 2003; Przyrembel et al., 1976; van Maldegem et al., 2006), 3-hydroxy-2-ethylpropionate, isobutyrylcarnitine , 2-methylbutyrylcarnitine, 2-methylbutyrylgly- cine, and glutarate (Andresen et al., 2000; Bennett et al., 1994; Bonafe et al., 2000; Korman, 2006; Korman et al., 2005; Tanaka et al., 1966; Vockley and Ensenauer, 2006) are hallmarks in patients with varying degrees of MADD. For the primary flavoprotein dehydrogenases, the reducing equivalents are transferred sequentially to the electron transfer flavoprotein (ETF), ETF-ubiquinone oxidoreductase (ETF:QO), FIG. 4. Leucine metabolism and the box plots of leucine catabolites altered by EGME treatment. "
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    ABSTRACT: Ethylene glycol monomethyl ether (EGME) is a widely used industrial solvent known to cause adverse effects to human and other mammals. Organs with high metabolism and rapid cell division, such as testes, are especially sensitive to its actions. In order to gain mechanistic understanding of EGME-induced toxicity, an untargeted metabolomic analysis was performed in rats. Male rats were administrated with EGME at 30 and 100 mg/kg/day. At days 1, 4, and 14, serum, urine, liver, and testes were collected for analysis. Testicular injury was observed at day 14 of the 100 mg/kg/day group only. Nearly 1900 metabolites across the four matrices were profiled using liquid chromatography-mass spectrometry/mass spectrometry and gas chromatography-mass spectrometry. Statistical analysis indicated that the most significant metabolic perturbations initiated from the early time points by EGME were the inhibition of choline oxidation, branched-chain amino acid catabolism, and fatty acid β-oxidation pathways, leading to the accumulation of sarcosine, dimethylglycine, and various carnitine- and glycine-conjugated metabolites. Pathway mapping of these altered metabolites revealed that all the disrupted steps were catalyzed by enzymes in the primary flavoprotein dehydrogenase family, suggesting that inhibition of flavoprotein dehydrogenase-catalyzed reactions may represent the mode of action for EGME-induced toxicity. Similar urinary and serum metabolite signatures are known to be the hallmarks of multiple acyl-coenzyme A dehydrogenase deficiency in humans, a genetic disorder because of defects in primary flavoprotein dehydrogenase reactions. We postulate that disruption of key biochemical pathways utilizing flavoprotein dehydrogenases in conjugation with downstream metabolic perturbations collectively result in the EGME-induced tissue damage.
    Full-text · Article · Dec 2010 · Toxicological Sciences
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    • "On the other hand, non-REM sleep abnormalities, such as abnormal cross-correlations between facial temperatures and delta and theta frequencies, are found in patients with SAD that have atypical depressive symptoms [59]. The rs1799958 SNP (G>A) in ACADS results in the conversion of glycine to serine and associates with the short chain acyl-CoA dehydrogenase deficiency [60] that is characterized by lipid storage myopathy and muscle weakness. "
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