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.

Download full-text


Available from: Michael J Bennett,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic differences of experimental animals contribute to pharmacological variations. Sprague–Dawley (SD) and Wistar rats are commonly used experimental rats with similar genetic background, and considered interchangeable in practical researches. In this study, we present the urinary metabolomics results, based on gas chromatography coupled to mass spectrometry (GC/MS), which reveal the systematic metabolic differences between SD and Wistar rats under different perturbations such as fasting, feeding, and consecutive acute ethanol interventions. The different metabotypes between the two strains of rats involve a number of metabolic pathways and symbiotic gut microflora. SD rats exhibited higher individualized metabolic variations in the fasting and feeding states, and a stronger ability to recover from an altered metabolic profile with less hepatic injury from the consecutive ethanol exposure, as compared to Wistar rats. In summary, the GC/MS-based urinary metabolomics studies demonstrated an intrinsic metabolic difference between SD and Wistar rats, which warrants consideration in experimental design using these animal strains. KeywordsMetabolomics–Systematic difference–Sprague–Dawley rats–Wistar rats–Ethanol intervention–GC/MS
    Metabolomics 09/2011; 7(3):363-374. DOI:10.1007/s11306-010-0252-5 · 3.86 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Toxicological Sciences 12/2010; 118(2):643-52. DOI:10.1093/toxsci/kfq211 · 3.85 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Depression and alcohol abuse or dependence (AUD) co-occur in the general population more frequently than expected by chance. Alcohol use influences the circadian rhythms generated by the central pacemaker in the suprachiasmatic nucleus, and circadian rhythm alterations in turn are common in depressive disorders as well as among persons addicted to alcohol. 32 SNPs in 19 circadian clockwork related genes were analyzed using DNA from 76 individuals with comorbid depression and AUD, 446 individuals with AUD and 517 healthy controls with no psychiatric diagnosis. The individuals participated in a nationwide health examination study, representative of the general population aged 30 and over in Finland. The CLOCK haplotype TTGC formed by SNPs rs3805151, rs2412648, rs11240 and rs2412646, was associated with increased risk for comorbidity (OR = 1.65, 95% CI = 1.14-2.28, P = 0.0077). The SNPs of importance for this suggestive association were rs2412646 and rs11240 indicating location of the functional variation in the block downstream rs2412648. There was no indication for association between CLOCK and AUD. Our findings suggest an association between the CLOCK gene and the comorbid condition of alcohol use and depressive disorders. Together with previous reports it indicates that the CLOCK variations we found here may be a vulnerability factor to depression given the exposure to alcohol in individuals having AUD.
    Journal of Circadian Rhythms 01/2010; 8(1):1. DOI:10.1186/1740-3391-8-1
Show more