Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency, Mutation Screen
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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.
Preferred molecular analysis to confirm a diagnosis of short-chain acyl-CoA dehydrogenase deficiency (as a follow-up to the biochemical analyses only)
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of short-chain acyl-CoA dehydrogenase (SCAD) deficiency may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of SCAD deficiency. For carrier testing, it is important to first document the presence of an ACADS gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical and biochemical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Nagan N, Kruckeberg KE, Tauscher AL, et al: The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C4-acylcarnitine concentration in newborn blood spots. Mol Genet Metab 2003 April;78:239-246
2. Corydon MJ, Vockley J, Rinaldo P, et al: Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 2001 January;49(1):18-23
3. van Maldegem BT, Duran M, Wanders RJ, et al: Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA 2006 August;296(8):943-952