Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Review
In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
[updated ].

Excerpt

Clinical characteristics: Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial β-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: Diagnosis is established in an individual with abnormal acylcarnitine analysis on biochemical testing and/or 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: Use of intravenous (IV) glucose as an energy source, treatment of cardiac rhythm disturbance, and monitoring of rhabdomyolysis. Cardiac dysfunction may be reversible with early, intensive supportive care (occasionally including extracorporeal membrane oxygenation) and diet modification. Prevention of primary manifestations: Individuals with the more severe forms are typically placed on a low-fat formula, with supplemental calories provided through medium-chain triglycerides. Clinical trials of triheptanoin have shown some potential benefit for exercise tolerance. Prevention of secondary complications: Acute rhabdomyolysis is treated with ample hydration and alkalization of the urine to protect renal function and to prevent acute renal failure secondary to myoglobinuria. Surveillance: Suggested evaluations include annual physical exam including cardiac status, echocardiography on an annual or biannual basis, and annual assessment of nutritional status to avoid obesity, which can become a significant, difficult-to-manage problem in this disorder. Agents/circumstances to avoid: Fasting, myocardial irritation, dehydration, and high-fat diet, volatile anesthetics and those that contain high doses of long-chain fatty acids such as propofol and etomidate. Evaluation of relatives at risk: Evaluation of older and younger sibs of a proband to identify those who would benefit from institution of 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.

Genetic counseling: VLCAD deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Publication types

  • Review