rs113994167 — ACADVL p.Val283Ala (V283A)

ACADVL V283A — The Most Common VLCAD Deficiency Variant in the US

Very long-chain acyl-CoA dehydrogenase (VLCAD) is a mitochondrial enzyme that breaks down long-chain fatty acids (14 to 20 carbons in length) for energy — a process called β-oxidation¹¹ β-oxidation
Mitochondrial β-oxidation is the main pathway for releasing energy from fats. Each cycle shortens a fatty acid chain by two carbons, generating acetyl-CoA and reducing equivalents (NADH, FADH2) that feed the electron transport chain. When VLCAD is impaired, long-chain fats accumulate, cells cannot generate ATP from fat, and toxic intermediates build up in muscle and other tissues.

The p.Val283Ala variant (c.848T>C, NM_000018.4) is the single most common VLCAD deficiency-causing variant identified in the United States. In a large cohort of 693 individuals who tested positive on newborn screening, at least one copy of p.V283A was present in approximately 10% of all affected individuals²² at least one copy of p.V283A was present in approximately 10% of all affected individuals
Miller et al., Mol Genet Metab, 2015. Because the variant permits residual enzyme activity (estimated at 10–25% of normal), it is associated with a milder, late-onset phenotype rather than the severe infantile cardiomyopathy seen with null mutations.

The Mechanism

Valine at position 283 sits within the active-site binding channel of VLCAD, a region critical for anchoring long-chain acyl-CoA substrates during dehydrogenation. The substitution of alanine — a smaller, less hydrophobic amino acid — alters the geometry of the substrate-binding pocket, reducing catalytic efficiency while preserving enough protein folding and assembly for partial function.

This partial loss of function³³ partial loss of function
As opposed to null mutations (frameshifts, nonsense, splice-site) that eliminate VLCAD protein entirely, the V283A substitution maintains a catalytically active enzyme with reduced turnover rate. This residual activity is sufficient to prevent infantile cardiomyopathy but insufficient under metabolic stress explains the phenotypic pattern: under resting, well-fed conditions, alternative energy pathways (glucose oxidation, medium-chain fatty acid metabolism via MCAD) compensate adequately. Under metabolic stress — prolonged exercise, fasting, febrile illness, or anesthesia — the impaired VLCAD pathway becomes the bottleneck, causing energy failure in skeletal muscle (rhabdomyolysis) or liver (hypoglycemia).

The Evidence

Genotype-phenotype correlation: A landmark study by Andresen et al.⁴⁴ Andresen et al.
Andresen et al., Am J Hum Genet, 1999 — 73 patients with VLCAD deficiency genotype-phenotype analysis established that mutations permitting residual enzyme activity consistently associate with the milder myopathic (adult-onset) phenotype, while null mutations (no residual activity) cause severe infantile disease with cardiomyopathy, hypoketotic hypoglycemia, and high mortality. This is a notably clear genotype-phenotype relationship compared to other fatty acid oxidation disorders.

US newborn screening cohort: Miller et al. 2015⁵⁵ Miller et al. 2015
Miller et al., Mol Genet Metab, 2015 — 693 individuals with positive newborn screens, 94 distinct ACADVL variants identified confirmed p.V283A as the most frequent single pathogenic variant, present in roughly 1 in 10 positive screens. Seven patients homozygous for V283A showed a mild phenotype responding well to standard treatment, though hypoglycemic episodes remained a clinical concern.

Long-term outcomes under treatment: A Utah-based longitudinal cohort of 26 VLCAD-deficient patients⁶⁶ 26 VLCAD-deficient patients
Rovelli et al., Mol Genet Metab, 2019 — median follow-up not specified; all ages from newborn to young adult found that treatment-compliant patients normalized biochemical parameters (C14:1-acylcarnitine, creatine kinase) and experienced no major clinical events, including no cardiac involvement beyond infancy. C14:1-carnitine levels — the primary biomarker for VLCAD enzyme function — correlated significantly with creatine kinase levels, making both useful for monitoring muscle involvement.

Practical Actions

For homozygous V283A individuals, management centers on three principles:

1. Avoid prolonged fasting: The impaired long-chain fatty acid pathway becomes critical when glycogen stores deplete (typically after 4–6 hours without carbohydrates in adults, sooner in children). Emergency protocols for illness and surgical procedures must include IV dextrose to bridge periods when oral intake is impossible.

2. Dietary modification: A low long-chain fat / high-MCT diet provides fat-based energy through a route that bypasses VLCAD. Medium-chain fatty acids (8–12 carbons) are processed by MCAD and other shorter-chain dehydrogenases, not VLCAD. MCT oil or triheptanoin (a 7-carbon triglyceride) can substitute for long-chain dietary fats.

3. Exercise management: High-intensity and prolonged aerobic exercise preferentially mobilizes long-chain fatty acids; pre-exercise carbohydrate loading and MCT supplementation reduce reliance on the impaired VLCAD pathway during activity.

Heterozygous carriers (TC genotype) have one functional ACADVL copy and are generally asymptomatic; carrier status is worth documenting for family screening purposes given the recessive inheritance pattern.

Interactions

VLCAD deficiency interacts with other fatty acid oxidation pathway enzymes. Compound heterozygosity — one V283A allele plus a different pathogenic ACADVL allele on the other chromosome — produces variable phenotypes depending on the second allele's functional impact. Individuals compound heterozygous for V283A and a null allele may have intermediate enzyme activity and unpredictable phenotype severity.

The ACADM gene (rs121434280, rs121434281)⁷⁷ ACADM gene (rs121434280, rs121434281)
ACADM encodes medium-chain acyl-CoA dehydrogenase (MCAD), which processes 6–12 carbon fatty acids. MCAD deficiency is the most common fatty acid oxidation disorder. In VLCAD deficiency, the MCT supplement strategy relies on intact MCAD activity — concurrent MCAD deficiency would eliminate this compensatory pathway and the CPT2 gene (rs201065226) — which gates long-chain fatty acid entry into mitochondria upstream of VLCAD — are relevant pathway partners.

VLCAD deficiency also interacts significantly with metabolic state: concurrent hypothyroidism, pregnancy (third trimester), or high-intensity athletic training substantially increases long-chain fatty acid demand and the risk of decompensation events.