Very long-chain acyl-CoA dehydrogenase deficiency nomenclature: compound heterozygosity

As recently reviewed [1], very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) is an inherited metabolic disease and one of several mitochondrial fatty acid oxidation disorders. In agreement with the previous literature [2], Yamada and Taketani [1] state that VLCAD is inherited in an autosomal recessive pattern; however, we have a clinical case of a male with compound heterozygous pathogenic mutations in the ACADVL gene that has ubiquitously abnormal phenotype tests consistent with VLCAD diagnosis. We posit that VLCAD is not inherited in an autosomal recessive pattern and/or there are patients with a compound heterozygote genotype and a mild phenotype that should be formally recognized in research and clinical practice.

VLCAD is one of many inherited genotypes that present phenotypic responses in newborn patients and has been included in newborn screening worldwide since the 1990s. Although not diagnostic, newborn screening flags patients to undergo further diagnostic testing for VLCAD including: (1) acylcarnitine analysis using tandem mass spectrometry, (2) residual β-oxidation enzyme activity, and/or (3) genetic analysis. As demonstrated in Table 1, VLCAD has a clear and distinct phenotype and despite being a heterogeneous disorder, VLCAD can be clearly identified with an appropriate ensemble of diagnostic testing. The patient we observed clearly and ubiquitously has a phenotype consistent with VLCAD diagnosis (Table 1) based on robust and standard diagnostic clinical testing procedures. Tandem mass spectrometry was used to analyze acylcarnitine profiles at 31 h, 4, and 356 days of life, and each acylcarnitine profile demonstrated a phenotype consistent with VLCAD diagnosis. Using intact fibroblasts extracted from a skin biopsy at 4 days of life, triplicate radio-high-performance liquid chromatography of the β-oxidation acyl-³H-carnitine intermediates derived from palmitate, branched-chain amino acids and ³H-carnitine revealed marked elevations in concentrations of myristyl-(C₁₄)- and palmityl-(C₁₆)-carnitines and low concentrations of acetyl-(C₂)-carnitine, consistent with a VLCAD phenotype (Table 1).

Table 1 Phenotype characteristics of VLCAD on screening and diagnostic clinical analyses

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