Direct Prediction of VLCADD Severity Using Newborn Screening Analyte Data

A critical concern of newborn screening (NBS) for very‐long chain acyl‐CoA dehydrogenase deficiency (VLCADD) is the difficulty of predicting clinical outcomes. To address this, we investigated neonatal C18:2‐carnitine concentrations as a possible predictor of VLCADD phenotype. To investigate the impact of sex, gestational age (GA) at birth, sampling day and birth weight on C18:2‐carnitine, we analyzed NBS‐dried blood spots (DBS) from Dutch newborns born between 2018 and 2020 ( n = 209.785). After normalization for resulting confounders, C18:2‐carnitine concentrations were investigated in NBS‐DBS ( n = 15) and neonatal plasma ( n = 35) of Dutch VLCADD‐patients, and in German NBS‐DBS ( n = 6) and correlated with clinical severity and diagnostic assays. Results showed that C18:2‐carnitine concentrations were affected by GA, sampling day, birth weight and, to a lesser extent, by sex. High C18:2‐carnitine, normalized for GA, sampling day and birth weight, reliably identified all VLCADD‐patients with (expected) severe phenotypes. The differentiating C18:2‐carnitine was identified as linoleylcarnitine. In conclusion, this study shows that neonatal C18:2‐carnitine concentrations can serve to predict disease severity directly after positive NBS for VLCADD. Patients with high C18:2‐carnitine concentrations can be considered “severe” and require strict dietary treatment and close monitoring. Patients with low C18:2‐carnitine concentrations can be identified as “mild” and only need preventive dietary measures.