VLCADD, the three phenotypes

Very long-chain acyl-CoA dehydrogenase deficiency presents in three clinically distinct ways. A severe early-onset form produces neonatal cardiomyopathy and historically had high infant mortality. An intermediate childhood-onset form produces hypoglycemic and hepatic crises during fasting or illness. A mild adult-onset form presents with rhabdomyolysis precipitated by exercise. The same gene, the same enzyme, the same screening assay. The clinical question at diagnosis is which of the three phenotypes the variant combination predicts, and the prediction is imperfect.

What VLCADD is

VLCADD is an autosomal recessive fatty acid oxidation disorder caused by variants in ACADVL on chromosome 17p13. ACADVL encodes very-long-chain acyl-CoA dehydrogenase, the mitochondrial enzyme that initiates beta-oxidation of long-chain fatty acids of 14 to 20 carbons. When VLCAD activity is reduced or absent, long-chain fatty acids cannot be efficiently oxidized for energy. The clinical consequences depend on residual enzyme activity.

The severe early-onset form presents in the first weeks to months of life with hypertrophic cardiomyopathy, cardiogenic shock, hypoglycemia, hepatic dysfunction, and high mortality without prompt recognition and treatment. The intermediate form presents in infancy or early childhood with episodes of hypoketotic hypoglycemia, hepatomegaly, and elevated transaminases triggered by fasting or illness. The mild adult-onset form presents in late adolescence or adulthood with episodic rhabdomyolysis, often precipitated by prolonged exercise, illness, or fasting, with elevated creatine kinase and myoglobinuria.

The genotype-phenotype correlation in VLCADD is partial but useful. Variants that produce no functional protein (null variants) tend to associate with the severe phenotype. Variants that produce reduced but functional protein, particularly missense variants near the active site, tend to associate with the intermediate or mild phenotypes. Same-variant heterogeneity exists.

Reported live-birth incidence in newborn screening programs runs roughly 1 in 30,000 to 1 in 100,000.

Detection

Newborn screening uses tandem mass spectrometry on the dried blood spot to flag elevated tetradecenoylcarnitine, C14:1, with elevated C14 and C14:2 in supportive measure. The C14:1 marker is specific for VLCADD among the FAO disorders. Confirmation uses plasma acylcarnitines, plasma amino acids, urine organic acids, and ACADVL sequencing. Functional assay of VLCAD activity in cultured fibroblasts is performed in cases with ambiguous biochemical or genetic findings.

What management looks like

Standard of care depends on the phenotype but shares a core framework. Avoidance of prolonged fasting, frequent feeds appropriate to age, long-chain-fat-restricted diet using medium-chain triglyceride supplementation, prompt intravenous dextrose during illness, and L-carnitine supplementation in selected cases are common across phenotypes. The intensity of dietary restriction is calibrated to severity: severe early-onset disease warrants strict long-chain restriction with the majority of fat as MCT, while mild adult-onset disease may require only fasting avoidance and exercise modification.

Triheptanoin (Dojolvi) was approved by the FDA in June 2020 for long-chain fatty acid oxidation disorders including VLCADD. Triheptanoin is a synthetic odd-chain triglyceride that, after oxidation, provides anaplerotic substrate to the citric acid cycle and bypasses the long-chain block. Clinical experience in VLCADD includes reductions in major metabolic events and rhabdomyolysis frequency in some recipients.

Cardiac surveillance is more intensive in severe early-onset VLCADD because of the hypertrophic cardiomyopathy risk. Echocardiography at intervals through the first decade is standard. Skeletal muscle and exercise tolerance assessment is more relevant in the mild adult-onset phenotype.

Sick-day protocols, emergency cards, and the multidisciplinary clinic relationship are part of management across the phenotypes.

What this looks like for a family

A baby is born and the heel-prick is sent. On day 4, the state lab reports elevated C14:1. On day 7, ACADVL sequencing returns biallelic pathogenic variants. The variant combination, on prior cohort data, is associated with a severe early-onset phenotype. An echocardiogram in the first week shows mild left ventricular hypertrophy. The metabolic team starts MCT-supplemented formula. Cardiology adds the baby to the surveillance schedule.

Over the first year, the cardiac findings stabilize on the dietary regimen. The first acute illness comes in the second year and is managed at the emergency department with intravenous dextrose. The child grows up on the dietary protocol with a metabolic clinic relationship that continues into adulthood.

A different baby with a milder ACADVL variant combination is identified by the same screening pattern. The neonatal echocardiogram is normal. The dietary intervention is less restrictive, focused on fasting avoidance rather than strict long-chain restriction. The first symptomatic event, in the form of exercise-induced rhabdomyolysis, may not occur until adolescence or adulthood, or may not occur at all.

That is what VLCADD care looks like in practice. The screen identifies the deficiency. The variant combination informs the phenotype prediction. The management framework is calibrated to that prediction, with adjustment as the clinical course unfolds.