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Abstract Early detection of congenital disorders by newborn screening (NBS) programs is essential to prevent or limit disease manifestation in affected neonates. These programs balance between the detection of the highest number of true cases and the lowest number of false‐positives. In this case report, we describe four unrelated cases with a false‐positive NBS result for very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD). Three neonates presented with decreased but not deficient VLCAD enzyme activity and two of them carried a single heterozygous ACADVL c.1844G>A mutation. Initial biochemical investigations after positive NBS referral in these infants revealed acylcarnitine and organic acid profiles resembling those seen in multiple acyl‐CoA dehydrogenase deficiency (MADD). Genetic analysis did not reveal any pathogenic mutations in the genes encoding the electron transfer flavoprotein (ETF alpha and beta subunits) nor in ETF dehydrogenase. Subsequent further diagnostics revealed decreased levels of riboflavin in the newborns and oral riboflavin administration normalized the MADD‐like biochemical profiles. During pregnancy, the mothers followed a vegan, vegetarian or lactose‐free diet which probably caused alimentary riboflavin deficiency in the neonates. This report demonstrates that a secondary (alimentary) maternal riboflavin deficiency in combination with reduced VLCAD activity in the newborns can result in an abnormal VLCADD/MADD acylcarnitine profile and can cause false‐positive NBS. We hypothesize that maternal riboflavin deficiency contributed to the false‐positive VLCADD neonatal screening results.

The clinical as well as biochemical and genetic spectrum of peroxisomal diseases has markedly increased over the last few years, thanks to the revolutionary advances in the field of genome analysis and several -omics technologies. This has led to the recognition of novel disease phenotypes linked to mutations in previously identified peroxisomal genes as well as several hitherto unidentified peroxisomal disorders. Correct interpretation of the wealth of data especially coming from genome analysis requires functional studies at the level of metabolites (peroxisomal metabolite biomarkers), enzymes, and the metabolic pathway(s) involved. This strategy is not only required to identify the true defect in each individual patient but also to determine the extent of the deficiency as described in detail in this article.