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.