Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity

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.

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples

“…The screening parameters comprise acylcarnitines accumulating from lysine and tryptophan degradation as well as β‐oxidation of short‐, medium‐ and long‐chain fatty acids. Of note, genetic defects of riboflavin transport as well as maternal vitamin B 12 ‐ and riboflavin deficiency mimicking biochemical features of MADD have been described and might also be identified by NBS 45–47 …”

“…Of note, genetic defects of riboflavin transport as well as maternal vitamin B 12 -and riboflavin deficiency mimicking biochemical features of MADD have been described and might also be identified by NBS. [45][46][47] MADD is a rare disorder with only a few patients identified by NBS so far. The benefit of early detection by NBS remains to be elucidated and can be expected to be low for patients with severe, early-onset phenotypes, except for a clear early diagnosis.…”