A near-miss: very long chain acyl-CoA dehydrogenase deficiency with normal primary markers in the initial well-timed newborn screening specimen

To the Editor: Ficicioglu et al reported the first infant with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) not detected by newborn screening performed within the ideal time frame. The experience of the New England Newborn Screening Program (NENSP) extends the number of VLCADD cases with a false-negative result and suggests that common interventions used in neonatal units might contribute to such errors. The initial specimen, collected from the infant on day of life (DOL)-2 (weight, 2420 g; gestational age, 34 weeks), screened normal. The values of VLCADD-specific markers C14:1 (0.34 mM) and C14:2 (0.12 mM) were below the NENSP cutoffs (0.70 mM and 0.17 mM, respectively), as well as the cutoffs of most other programs worldwide. A second specimen obtained on discharge from the special care nursery on DOL-9 was suggestive of VLCADD (C14:1, 0.82 mM; C14:2, 0.27 mM). A review of data for the initial specimen revealed that althoughmarkers were normal, the discriminator indices used by the NENSP to reflect a VLCADD profile when primary markers are abnormal were above their cutoffs. VLCADD was subsequently confirmed by diagnostic plasma acylcarnitine profiles and the detection of two pathogenic mutations on the VLCADD gene, 684G>A (A232T) and 848T>C (V283A). This neonate’s clinical history was notable for prematurity and initial poor oral intake, necessitating a hospital stay, but was otherwise unremarkable. The neonate received 10% dextrose intravenously from DOL-1 to DOL-5 and was then transitioned to oral feeds. We feel that dextrose, by suppressing fatty acid oxidation, might have masked the characteristic acylcarnitine accumulation. Our case underscores the fact that screening may fail to identify VLCADD and other disorders, especially in neonates receiving therapeutic interventions. Routine rescreening of such neonates at discharge in addition to the initial screen, even when the initial screen is normal, and analysis of biomarker profiles regardless of primary marker concentrations might reduce the risk of missing infants with these disorders.