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Short-chain acyl-coenzyme A dehydrogenase deficiency

https://doi.org/10.1016/j.ymgme.2008.09.007Get rights and content

Abstract

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.

Section snippets

Clinical presentation

The first published case of what was initially considered to be SCADD was a 53-year-old woman with progressive myopathy whose symptoms began in her forties [13]. She was later felt to have a multiple acyl-CoA dehydrogenation defect [14]. True SCADD was first reported in two neonates who were found to have increased urinary ethylmalonate excretion; the diagnosis was confirmed enzymatically in skin fibroblasts [15]. One of these infants died of overwhelming neonatal acidosis as would be typical

Molecular genetics and functional implications of SCAD mutations

Understanding the molecular basis of SCADD is key to deciphering its variable clinical picture. The SCAD gene is located on chromosome 12q22 and is approximately 13 kb long with 10 exons and 1236 nucleotides of coding sequence [26], [27]. SCAD, like all of the ACADs, is a flavoprotein that is synthesized in the cytosol as a precursor and transported to the mitochondria for further processing by proteolytic cleaving of an N-terminal mitochondrial targeting sequence into a mature form [27], [28].

Pathophysiology of SCADD

Most individuals have not presented with the classic picture of hypoketotic hypoglycemia, recurrent rhabdomyolysis, or cardiomyopathy that characterize many other fatty acid oxidation disorders. A 14 month old with SCADD was reported to have hypoglycemia, but ketonuria was also present, suggesting that ketone body formation is not significantly impacted in SCADD [37]. One explanation for the lack of classical biochemical findings is that since SCAD is only needed at the end of the β-oxidation

Diagnosis of SCADD

Biochemical markers of SCADD include increased urinary EMA and butyrylglycine, increased plasma butyrylcarnitine, and decreased SCAD activity in skin fibroblasts or muscle, though some enzymatic assays are not sufficiently sensitive for reliable measurements [11]. During times of metabolic stress, methylsuccinate (the hydrolyzed product of isomerization of ethylmalonyl-CoA by methylmalonyl-CoA isomerase) may also be excreted in the urine [14], [15]. Some patients have been reported to have low

Management

Little firm data exists on the appropriate therapy for SCADD and there is not a consensus on the need to treat it. Chronic management of SCADD, if institutued, should be similar to other fatty acid oxidation disorders, focusing on decreasing catabolic drive as well as providing alternative sources of energy. During acute crises, intravenous fluids with high dextrose concentrations (usually at least 10% to give 8–10 mg/kg/min of glucose intake) with or without intralipids can be used to reverse

Discussion

SCADD demonstrates several of the clinical and public policy issues currently facing many inborn errors of metabolism identified by expanded newborn screening with tandem mass spectrometry, including deficiency of short/branched chain- and isobutyryl-CoA dehydrogenases as well as 3-methylcrotonyl-CoA carboxylase. Issues surrounding these disorders echo similar problems faced in earlier decades of newborn screening with diseases such as histidinemia and the Duarte variant galactosemia.

Acknowledgments

JV was funded in part by NIH grant R01-DK54936 and the Mathew Fisch Fund of the Children’s Hospital of Pittsburgh Foundation.

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