Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Clinical characteristics: Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.

Diagnosis/testing: The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in ACADVL on molecular genetic testing. If one ACADVL pathogenic variant is found and suspicion of VLCAD deficiency is high, specialized biochemical testing using cultured fibroblasts or lymphocytes may be needed for confirmation of the diagnosis.

Management: Treatment of manifestations:

1. Routine daily treatment. Low-fat formula or low long-chain fat / high medium-chain triglyceride (MCT) medical food, with 13%-39% of calories as total fat; total dietary protein above the dietary reference intake for age; MCT oil or triheptanoin supplementation; carnitine supplementation; consider supplementation with linoleic acid, arachidonic acid, alpha-linolenic acid, and docosahexaenoic acid; frequent feeding in infants and a bedtime snack high in complex carbohydrates in children and adults; nasogastric tube feeding for those with feeding issues; guided exercise and avoidance of severe exercise to address exercise intolerance in older individuals; standard treatment of cardiomyopathy; supportive developmental therapies as needed.

2. Emergency outpatient treatment. Consider a trial outpatient treatment at home for up to 12 hours, including frequent high carbohydrate feedings, reduced fasting duration time, antipyretics, and antiemetics.

3. Acute inpatient treatment. Administration of high-energy fluids (≥10% IV dextrose) with electrolytes at a rate of at least 1.5 times maintenance (minimum of 8 mg/kg/min of glucose) while avoiding the use of L-carnitine and IV lipids; standard treatment for cardiomyopathy / cardiac failure; ample hydration and alkalization of the urine for those with rhabdomyolysis.

Prevention of secondary complications: Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect kidney function and to prevent acute kidney failure secondary to myoglobinuria; if a surgery or procedure is required, notify designated metabolic center in advance of the procedure to discuss perioperative management with surgeons and anesthesiologists; some anesthetics may be contraindicated.

Surveillance: Measurement of growth parameters (including head circumference) and assessment of feeding skills (in infants/toddlers) at each visit; plasma carnitine panel, acylcarnitine profile, and creatine kinase level every three months for the first year of life, every three to six months for those between age one and seven years, and every six to 12 months for those older than age seven years; red blood cell or plasma essential fatty acids every six months for those on long-chain fat restriction; measurement of vitamins A, D, and E annually or as clinically indicated for those on long-chain fat restriction; echocardiogram at least annually or as clinically indicated; DXA scan every five years in adults; measurement of complete blood count, ferritin level, comprehensive metabolic panel, troponin, and B-type natriuretic protein as clinically indicated.

Agents/circumstances to avoid: Fasting; myocardial irritation; dehydration; high-fat diet; and volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate.

Evaluation of relatives at risk: Evaluation of all at-risk sibs of any age is warranted to identify those who would benefit from treatment and preventive measures.

Pregnancy management: Labor and postpartum periods are catabolic states and place the mother at higher risk for rhabdomyolysis and subsequent myoglobinuria. A management plan for labor and delivery is necessary for the affected pregnant woman. In addition to regular assessment by a cardiologist and maternal fetal medicine specialist, the following are recommended: visit with a nutritionist familiar with VLCAD deficiency monthly or at least in each trimester; measurement of plasma carnitine panel (total, free, esters) and creatine kinase level at each visit; plasma acylcarnitine profile weekly to monthly; red blood cell or plasma essential fatty acids (for those on long-chain fat restriction) at least once during pregnancy; echocardiogram either prior to conception or as soon as a pregnancy is recognized; measurement of vitamins A, D, and E (for those on long-chain fat restriction), complete blood count, ferritin level, and metabolic panel as a baseline or as clinically indicated.

Genetic counseling: VLCAD deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ACADVL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variants in the family are known.