Very long chain acyl-CoA dehydrogenase deficiency (VLCAD1) is an inherited autosomal recessive metabolic disorder of fatty acid oxidation. Fatty acid oxidation provides a source of energy during periods of fasting, as well as during times of increased energy demands such as illness or exercise. The VLCAD enzyme catalyzes the initial step of mitochondrial β-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons. In VLCAD, these long chain fatty acids cannot be metabolized, which can lead to metabolic crises due to lack of adequate energy supplies. In addition, very long chain fats and their potentially toxic derivatives accumulate and cause damage to tissues such as the heart, liver and muscles.
Based on clinical presentations, VLCAD is categorized into three types. The severe form typically presents between birth and the first few months of life. In addition to metabolic crises, it is characterized by hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The moderate form, also called the hepatic or hypoketotic hypoglycemic form, typically presents during late infancy or early childhood with hypoketotic hypoglycemia and hepatomegaly, with cardiomyopathy less likely than in the severe form. The mild form generally has an onset in the teen years or adulthood and is characterized by episodic myopathy that typically presents with rhabdomyolysis induced by exercise, muscle cramps and/or pain, and exercise intolerance (G.97).
Definitions of VLCAD phenotypes used in this guideline are described in (RECOMMENDATION TABLE #1, VLCAD Phenotypes). VLCAD may be suspected based on clinical presentation or based on abnormal results on newborn screening. Further information can be found at http://www.ncbi.nlm.nih.gov/books/NBK6816/.
1Condition abbreviation taken from NIH/NLM Newborn Screening Coding and Terminology Guide .
In the United States, about one in 75,000 babies is diagnosed with VLCAD via newborn screening (F.4425). Newborn screening for VLCAD is performed by tandem mass spectrometry (MS/MS). The primary marker for VLCAD is elevation of plasma C14:1 acylcarnitine or a ratio involving C14:1 and other long chain acylcarnitines. In addition to true positives for early-onset VLCAD deficiency, a positive NBS result can be due to later onset forms of VLCAD, unaffected carrier status, effect of maternal VLCAD deficiency, and false positives (L.308). About 50% of those with positive NBS screens for VLCAD deficiency are unaffected carriers with a mutation in the ACADVL gene (L.308). Further information can be found at http://www.newbornscreening.info/Pro/fattyaciddisorders/VLCADD.html
Confirmatory testing consists of a combination of tests: analysis of the plasma acylcarnitine profile, genetic testing, functional assessment of β-oxidation in cultured fibroblasts (in vitro probe study), or direct VLCAD enzyme activity assay using protein extracts from cultured fibroblasts or lymphocytes (G.97). Further information can be found at https://www.acmg.net/staticcontent/act/c14.pdf
VLCAD is the product of an alteration in the ACADVL gene. Over 100 different pathogenic variants associated with VLCAD deficiency have been identified, with no single common variant (L.308, F.4055). Most patients with VLCAD have sequence variants in the ACADVL gene, and duplication/deletion mutations in the gene are rare (L.308, F.660). Generally, sequence analysis of ACADVL is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found (G.97). Further information can be found at https://www.ncbi.nlm.nih.gov/gtr/tests/238927/