Clinical Information

Short-chain acyl-CoA dehydrogenase (SCAD) catalyzes the first step in the mitochondrial beta-oxidation of fatty acids with a chain length of 6 to 4 carbons. SCAD deficiency is a rare autosomal recessive condition. The clinical phenotype of SCAD shows considerable variability and is incompletely defined. Of those reported cases, hypoglycemia, developmental delay, and muscle hypotonia are the most common indicated features. The diagnosis of SCAD deficiency is challenging and should be based on the clinical presentation, 2 or more findings of ethylmalonic aciduria, and determination of fatty acid flux in fibroblasts indicating deficient SCAD activity. Molecular genetic analysis of the gene associated with SCAD (ACADS) may confirm the biochemical phenotype of SCAD deficiency.

The first step in evaluation for SCAD deficiency is identification of 2 or more findings of ethylmalonic aciduria, as determined by either OAU / Organic Acids Screen, Urine or ACYLG / Acylglycines, Quantitative, Urine. Ethylmalonic aciduria is a common, although not specific, laboratory finding in patients with SCAD deficiency. Determination of fatty acid flux in fibroblasts (FAO / Fatty Acid Oxidation Probe Assay, Fibroblast Culture) is warranted for an individual with 2 or more findings of ethylmalonic aciduria.

DNA sequencing of the ACADS gene is typically utilized only when SCAD deficiency is identified through biochemical analysis. The ACADS gene, associated with SCAD deficiency, is located on chromosome 12q22 and consists of 10 exons. Molecular genetic studies revealed that some patients carry ACADS gene mutations that cause complete absence of SCAD activity, while others carry ACADS gene variants (511C->T;625G->A) that may confer disease susceptibility only in association with other factors. The allele frequencies in the general population of the 511C->T and 625G->A gene variants are 3% and 22%, respectively. The presence of 2 of these gene variants is not considered an independent diagnostic marker for SCAD deficiency. Although further investigation is needed, it is most likely that these variants are not clinically significant.

Identification of 2 ACADS gene mutations that cause complete absence of SCAD activity alone is not sufficient to explain or determine possible clinical phenotype or prognosis. The clinical significance of carrying 2 mutations is often uncertain. Therefore, the results of ACADS gene sequencing for SCAD deficiency should be interpreted in light of the clinical presentation and biochemical findings in each case.