Very Long-Chain Acyl-Coa Dehydrogenase (ACADVL) Deficiency Indications for Ordering Disease Overview

Very Long-Chain Acyl-CoA Dehydrogenase (ACADVL) Deficiency Indications for Ordering Disease Overview

• Abnormal newborn screen suggestive of very long-chain Incidence: ~1/40,000 newborns in U.S. acyl-CoA dehydrogenase (VLCAD) deficiency Clinical Presentation • Diagnostic testing for individual with clinical and/or • Varies in severity and age of onset biochemical evidence of VLCAD deficiency o Hypoketotic hypoglycemia, hepatomegaly, hepatic • Carrier testing for reproductive partner of an individual failure, and fasting-induced coma affected with, or a carrier of, VLCAD deficiency • Newborn acute disease Test Description o Hypoglycemia, arrhythmia, Reye-like symptoms, hypertrophic cardiomyopathy, and sudden infant death • Bidirectional sequencing of the entire coding region and o Morbidity and mortality: high for acute presentation in intron-exon boundaries of the ACADVL gene newborn • Multiplex ligation-dependent probe amplification (MLPA) • Infancy or early childhood: milder to detect large ACADVL coding region o Resembles medium-chain acyl-CoA dehydrogenase deletions/duplications (MCAD) deficiency o Fasting intolerance and Reye-like syndrome triggered by Tests to Consider prolonged fasting or illness Diagnostic Issues o Increased liver function tests and elevated creatine phosphokinase (CPK) Biochemical studies can be completely normal if obtained • Adolescent or adult onset while the patient is metabolically stable; molecular testing or o Resembles carnitine palmitoyl transferase 2 (CPT2) functional studies are needed for definitive diagnosis. deficiency Biochemical Tests o Myopathy, exercise-induced rhabdomyolysis, and • Acylcarnitine Quantitative Profile, Plasma 0040033 myoglobinuria • Carnitine Panel 0081110 Pathophysiology • Organic Acids, Urine 0098389 • VLCAD enzyme Molecular Tests o Involved in mitochondrial beta-oxidation of long-chain fatty acids Very Long-Chain Acyl-CoA Dehydrogenase Deficiency o Fuels hepatic ketogenesis during periods of high energy (ACADVL) Sequencing and Deletion/Duplication 2004212 demand (depleted hepatic glycogen stores) • Preferred molecular test to diagnose or rule out VLCAD • VLCAD deficiency leads to the accumulation of very long- deficiency following clinical and/or biochemical chain fatty acids presentation. Familial Mutation, Targeted Sequencing 2001961 Genetics • Use to assess for a sequence variant previously identified in a family member; a copy of a relative’s lab result is Gene: ACADVL REQUIRED. Inheritance: autosomal recessive Deletion/Duplication Analysis by MLPA 3003144 Variants • Use to assess for large deletion/duplication previously • Variants throughout the ACADVL gene identified in a family member; a copy of a relative’s lab o Some genotype-phenotype correlation may exist report is REQUIRED.

Test Interpretation References

Sensitivity/Specificity • Andresen BS, Olpin S, Poorthuis BJ, et al. Clear correlation • Clinical sensitivity of genotype with disease phenotype in very-long-chain o Sequencing and deletion/duplication: >90% acyl-CoA dehydrogenase deficiency. Am J Hum Genet. • Analytical sensitivity and specificity: 99% 1999 Feb;64(2):479-94. • Leslie ND, Valencia A, Strauss AW, et al. Very Long-Chain Results Acyl-Coenzyme A Dehydrogenase Deficiency. In: Adam • Two pathogenic ACADVL gene variants on opposite chromosomes MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, o Predicts VLCAD deficiency University of Washington, 1993-2019. Seattle, WA [Last • One pathogenic variant Revision: May 2019; Accessed: Aug 2019]

o Individual is at least a carrier for VLCAD deficiency • Pena LD, van Calcar SC, Hansen J, et al. Outcomes and genotype-phenotype correlations in 52 individuals with • Lack of gene variant reduces likelihood of VLCAD deficiency or carrier state VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. Mol Genet Metab. 2016; 118(4): 272- • Variants of unknown clinical significance may be identified 81. Limitations • Pervaiz MA, Kendal F, Hegde M, et al. MCT oil-based diet • The following are not detected reverses hypertrophic cardiomyopathy in a patient with o Regulatory region and deep intronic variants very long chain acyl-coA dehydrogenase deficiency. Indian o Deletions/duplications in exon 2 of ACADVL J Hum Genet. 2011; 17(1): 29-32. • Diagnostic errors may occur due to rare sequence variations