Very Long Chain Acyl-CoA Dehydrogenase Deficiency via the ACADVL Gene

Very long chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM #201475) is a defect in the breakdown of very long chain (C14-C20) fatty acids within the mitochondria. The severity of VLCADD varies over a wide range and can be divided into three clinical groups:

(1) severe, early-onset, cardiac and multiorgan failure - within the first few months of life, affected individuals present with cardiomyopathy, arrhythmias, pericardial effusion, hepatomegaly, hypotonia, and episodes of hypoketotic hypoglycemia;

(2) hepatic or hypoketotic hypoglycemia - individuals present in early childhood with hepatomegaly and hypoketotic hypoglycemia but without the cardiac issues;

(3) later-onset episodic myopathic form - individuals are diagnosed in adolescence or adult life with muscle weakness and pain, which can be induced by exercise.

VLCADD may be detected through tandem mass spectrometry in routine neonatal screening, though affected individuals with milder phenotypes may not be identified during times of physiologic health. Incidence of VLCADD in the United States is estimated to be 1/30,000.

Very long chain acyl-CoA dehydrogenase (VLCAD), encoded by the ACADVL gene, catalyzes the first step in the catabolism of fatty acids with 14-20 carbon atoms. VLCAD deficiency exhibits autosomal recessive inheritance. Hundreds of causative ACADVL variants have been reported to date. Variants are located throughout the gene and are roughly 60% missense and 40% frameshift, splicing, or nonsense. One variant, p.Val283Ala, accounts for 20% of the pathologic alleles among those identified by newborn screening. Variants which completely eliminate enzyme activity usually cause the most severe disease, while missense variants resulting in some residual enzyme activity lead to milder childhood and adult onset forms (Andresen et al. Am J Hum Genet 64:479-494, 1999; Gregersen et al. Hum Mutat 18:169-189, 2001).

Andresen et al. (Am J Hum Genet 64:479-494, 1999) performed ACADVL gene sequencing on 55 VLCADD patients with demonstrated enzyme deficiency and found two likely causative variants in 47 patients (85%) and one likely causative variant in the remaining 8 patients. Boneh et al. (Mol Genet Metab 88:166-170, 2006) found two causative variants in 6 of 6 patients identified through neonatal screening. Analytical sensitivity should be high because nearly all variants reported to date are expected to be detected by sequence analysis of genomic DNA.

This test provides full coverage of all coding exons of the ACADVL gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).