ACADVL – Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency

Very-long-chain acyl-CoA dehydrogenase deficiency is an autosomal recessive disorder caused by biallelic loss-of-function variants in the ACADVL gene, resulting in impaired mitochondrial β-oxidation of long-chain fatty acids. Affected individuals present across a clinical spectrum from neonatal hypoketotic hypoglycemia to infantile cardiomyopathy and later-onset myopathy with exercise-induced rhabdomyolysis. Newborn screening by tandem mass spectrometry reliably identifies elevated C14:1-carnitine levels, which must be confirmed by enzymatic and molecular assays to guide management.

Genetic evidence includes autosomal recessive inheritance in over 30 unrelated probands from 27 families with concordant enzyme deficiencies and private or recurrent variants (PMID:9498103, PMID:35281659). Segregation in consanguineous and non-consanguineous pedigrees supports pathogenicity. The variant c.848T>C (p.Val283Ala) is recurrent in multiple cohorts and correlates with residual enzyme activity and milder myopathic phenotypes.

Functional studies demonstrate markedly reduced VLCAD protein and activity in patient fibroblasts, with restoration of fatty acid oxidation upon PPAR agonist treatment (bezafibrate) and in vitro correction of mutant enzyme function (PMID:16115821, PMID:8554073). Mitochondrial morphology is disrupted in patient cells, linking enzyme deficiency to organelle dysfunction.

Phenotypic spectrum includes hypoketotic hypoglycemia (HP:0001985), hypertrophic cardiomyopathy (HP:0001638), and rhabdomyolysis (HP:0003201), with variable age of onset and severity. Early diagnosis and intervention—dietary fat restriction, medium-chain triglyceride supplementation, avoidance of fasting, and emergency protocols—improve outcomes.

Key take-home: Definitive evidence supports ACADVL as the causal gene for Very-long-chain acyl-CoA dehydrogenase deficiency, enabling precise diagnosis and targeted management.

References

• Clinica chimica acta • 1998 • Mitochondrial very‐long‐chain acyl‐coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. PMID:9498103
• American journal of human genetics • 1996 • Mutation analysis of very‐long‐chain acyl‐coenzyme A dehydrogenase (VLCAD) deficiency: identification and characterization of mutant VLCAD cDNAs from four patients. PMID:8554073
• Human molecular genetics • 2005 • Bezafibrate increases very‐long‐chain acyl‐CoA dehydrogenase protein and mRNA expression in deficient fibroblasts and is a potential therapy for fatty acid oxidation disorders. PMID:16115821
• JIMD reports • 2022 • Very long‐chain acyl‐CoA dehydrogenase deficiency in a Swedish cohort: Clinical symptoms, newborn screening, enzyme activity, and genetics. PMID:35281659

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