Located on chromosome 17, the ACADVL gene encodes the very long-chain acyl-CoA dehydrogenase protein (VLCAD), an enzyme required to break down (metabolize) a group of fats called very long-chain fatty acids.GHR
Over 100 mutations in the ACADVL gene may lead to VLCAD deficiency, a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting) or in some cases by illness or exercise. The three clinical types of VLCAD deficiency are described (according to OMIM) as:
- Severe, early-onset, usually within the first days of life, with cardiomyopathy and early death
- Milder, childhood form, with onset by age 4 years, lesser cardiac involvement, and hypoketotic hypoglycemia
- Mild adult form, with onset after age 13 years, no cardiac involvement, and restricted to muscle involvement with rhabdomyolysis
Generally, null mutations (resulting in no protein) lead to more severe disease, while missense mutations leading to proteins with residual activity are associated with the milder childhood and adult forms. A more in-depth discussion may be found in this GeneReview.
The most common pathogenic allele, rs113994167 (c.848T>C or p.Val283Ala), is observed in symptomatic compound heterozygotes and in homozygotes; it is typically associated with the non-cardiac phenotypes and is not considered among the most severe mutations. It accounts for approximately 10-30% of all pathogenic alleles detected by newborn screening.GeneReviews