Very long chain acyl-CoA dehydrogenase deficiency (VLCADD)

It is a disorder of mitochondrial oxidation of long-chain fatty acids whose clinical manifestations are highly variable. It produces symptoms such as cardiomyopathy, hypoglycemia and exercise intolerance.

Very long chain acyl CoA dehydrogenase deficiency (VLCADD) belongs to the group of inborn errors of metabolism diseases. It is a pathology with a highly variable clinical picture, individuals with VLCADD may have symptoms ranging from mild to severe and include: cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.

VLCADD is often included in neonatal screening programs, where acylcarnitine levels are usually determined. Its incidence is estimated to be between 1 in 30,000 and 1 in 100,000 births.

Symptoms

VLCADD is a clinically heterogeneous disease and is divided into three subtypes:

Severe infantile VLCADD manifests between 3 and 12 months of life and during the neonatal period. It is characterized by hypoketotic hypoglycemias, hepatopathies, cardiac arrhythmias and cardiomyopathies that can be life-threatening.
Moderately severe infantile VLCADD has a later onset (early neonatal period to childhood) and usually presents with hypoketotic hypoglycemia, low mortality and, rarely, cardiomyopathy.
Late-onset myopathic VLCADD occurs in older children and young adults (usually more than 10 years of age), with isolated skeletal muscle involvement, physical exercise intolerance, myalgia, rhabdomyolysis, myalgia, rhabdomyolysis, and rheumatoid arthritis.It is usually triggered by physical exercise, fasting, heat or cold, or aggression of any kind, although viral infections may also provoke or accelerate the process.

Disease management

To prevent the onset of symptoms, patients with VLCADD should avoid fasting and follow a controlled diet low in long-chain fatty acids, high in medium-chain triglycerides and rich in protein. Supplementation with oil rich in medium chain triglycerides or triheptanoin, carnitine, linoleic acid, arachidonic acid, alpha-linolenic acid and docosahexaenoic acid is sometimes recommended. Frequent meals are recommended in children and physical exercise should be performed following medical recommendations and avoiding very demanding exercises so that patients do not develop exercise intolerance. Patients who develop rhabdomyolysis usually improve with diets rich in carbohydrates.

If there is a metabolic crisis, high-energy fluids (more than 10% dextrose) are usually administered.

Genes analyzed

ACADVL

Bibliography

Leslie ND, Saenz-Ayala S. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2009 May 28 [updated 2022 Jun 16]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

Miller MJ, Burrage LC, Gibson JB, et al . Recurrent ACADVL molecular findings in individuals with a positive newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the United States. Mol Genet Metab. 2015 Nov;116(3):139-45.

Rovelli V, Manzoni F, Viau K, et al . Clinical and biochemical outcome of patients with very long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2019 May;127(1):64-73.