Newborn screening · Fatty acid oxidation disorder
Very Long-Chain Acyl-CoA Dehydrogenase Deficiency · VLCADD
Long-chain fatty acid oxidation defect. Severity ranges from neonatal cardiac to adult-onset rhabdomyolysis.
Description
Very long-chain acyl-CoA dehydrogenase deficiency, VLCADD, is an autosomal recessive long-chain fatty acid oxidation disorder. Pathogenic variants in ACADVL reduce the activity of very long-chain acyl-CoA dehydrogenase, the inner mitochondrial membrane enzyme that catalyzes the first step of beta-oxidation for fatty acids of fourteen to twenty carbons. With reduced activity, long-chain fatty acids cannot be efficiently oxidized for energy during fasting or illness, and long-chain acylcarnitine intermediates accumulate. The causative gene is ACADVL on chromosome 17p13.1.
Clinical presentation falls along a wide spectrum that correlates loosely with residual enzyme activity. Severe neonatal disease presents in the first weeks of life with hypoketotic hypoglycemia, hypertrophic or dilated cardiomyopathy, pericardial effusion, hepatic dysfunction, and arrhythmia. Intermediate disease presents in infancy and childhood with episodic hypoglycemia and hepatic crisis triggered by fasting illness. Milder later-onset disease presents in adolescence or adulthood with exercise intolerance, myalgia, and rhabdomyolysis after sustained activity, prolonged fasting, cold exposure, or febrile illness. Some adults identified through cascade testing remain effectively asymptomatic.
Detection is by newborn screening on the dried blood spot using tandem mass spectrometry. The primary marker is elevated tetradecenoylcarnitine, C14:1, often reported with the C14:1 to C16 ratio. Confirmation uses plasma acylcarnitine, fibroblast acyl-CoA dehydrogenase assay or fatty acid oxidation flux studies, and ACADVL sequencing. Reported live-birth incidence in newborn screening programs is roughly 1 in 30,000 to 1 in 100,000. VLCADD is on the US RUSP core panel.
Treatments to date
Standard of care is restriction of long-chain fat, replacement of long-chain fat calories with medium-chain triglyceride oil, frequent feeding, and avoidance of fasting. Cornstarch supports overnight glucose stability in older children. Pre-exercise medium-chain triglyceride dosing is used in older children and adults with the milder myopathic phenotype to reduce exercise-induced rhabdomyolysis. Carnitine use is selective and debated. Cardiac surveillance with echocardiogram is part of routine follow-up given the risk of cardiomyopathy in severe forms.
Triheptanoin, marketed as Dojolvi by Ultragenyx, was approved by the FDA in June 2020 as a source of medium and odd-chain fatty acids for long-chain fatty acid oxidation disorders in adults and children at least six months of age. The label includes VLCADD. The seven-carbon fatty acid in triheptanoin enters both beta-oxidation and the citric acid cycle through anaplerosis, restoring intermediates that long-chain fatty acid oxidation cannot supply.
During acute illness, standard metabolic emergency protocols apply, with intravenous dextrose to suppress lipolysis. No gene therapy is approved. Outcomes have improved substantially since universal newborn screening, since infants who would once have died of unexplained sudden cardiac collapse are now treated before the first metabolic crisis.