Too Early to Tell? Balancing Diagnostic Accuracy of Newborn Screening for Propionic Acidemia Versus a Timely Referral.

Abstract

In the Netherlands, the newborn screening (NBS) program includes screening for propionic aciduria (PA) and methylmalonic aciduria (MMA). When initial screening reveals elevated C3 concentrations or abnormal ratios (C3/C2, C3/C16), a second-tier test measuring methylcitric acid (MCA) for PA and methylmalonic acid (MMA^mb) for MMA is performed. While this two-tier approach reduces false positives effectively, it can delay referral from the NBS program and diagnosis of propionic aciduria. We describe four early-onset PA cases in which the current Dutch screening algorithm negatively impacted clinical outcomes, highlighting the need for expedited referral. We investigated different alternative screening strategies to identify the most effective approach for improving timeliness, while maintaining the high specificity of Dutch PA NBS. This revised approach prioritizes the evaluation of the C3/C2 ratio in first-tier screening. Specifically, samples with a C3/C2 ratio ≥ 0.75 should be referred directly for medical consultation and confirmatory testing. For all other samples with less pronounced biochemical abnormalities, the existing two-tier screening algorithm remains an appropriate NBS protocol. To position our approach internationally, a survey of European NBS programs was conducted to compare screening and referral protocols for PA across the region.