Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inherited disorder of mitochondrial fatty acid oxidation that is characterized by the presence of increased butyrylcarnitine and ethylmalonic acid (EMA) concentrations in plasma and urine. Individuals with symptomatic SCADD may show relatively severe phenotype, while the majority of those who are diagnosed through newborn screening by tandem mass spectrometry may remain asymptomatic. As such, the associated clinical symptoms are very diverse, ranging from severe metabolic or neuromuscular disabilities to asymptomatic. Molecular analysis of affected individuals has identified rare gene variants along with two common gene variants, c.511C > T and c.625G > A. In vitro studies have demonstrated that the common variants as well as the great majority of rare variants, which are missense variants, impair folding, that may lead to toxic accumulation of the encoded protein, and/or metabolites, and initiate excessive production of ROS and chronic oxidative stress. It has been suggested that this cell toxicity in combination with yet unknown factors can trigger disease development. This association and the full implications of SCADD are not commonly appreciated. Accordingly, there is a worldwide discussion of the relationship of clinical manifestation to SCADD, and whether SCAD gene variants are disease associated at all. Therefore, SCADD is not part of the newborn screening programs in most countries, and consequently many patients with SCAD gene variants do not get a diagnosis and the possibilities to be followed up during development.