Assessment of carnitine excretion and its ratio to plasma free carnitine as a biomarker for primary carnitine deficiency in newborns

In the Netherlands, newborns are referred by the newborn screening (NBS) Program when a low free carnitine (C0) concentration (<5 μmol/l) is detected in their NBS dried blood spot. This leads to ~85% false positive referrals who all need an invasive, expensive and lengthy evaluation. We investigated whether a ratio of urine C0 / plasma C0 (Ratio(U:P)) can improve the follow‐up protocol for primary carnitine deficiency (PCD). A retrospective study was performed in all Dutch metabolic centres, using samples from newborns and mothers referred by NBS due to low C0 concentration. Samples were included when C0 excretion and plasma C0 concentration were sampled on the same day. Ratio(U:P) was calculated as (urine C0 [μmol/mmol creatinine])/(plasma C0 [μmol/l]). Data were available for 59 patients with genetically confirmed PCD and 68 individuals without PCD. The Ratio(U:P) in PCD patients was significantly higher (p value < 0.001) than in those without PCD, median [IQR], respectively: 3.4 [1.2–9.5], 0.4 [0.3–0.8], area under the curve (AUC) 0.837. Classified for age (up to 1 month) and without carnitine suppletion (PCD; N = 12, Non‐PCD; N = 40), medians were 6.20 [4.4–8.8] and 0.37 [0.24–0.56], respectively. The AUC for Ratio(U:P) was 0.996 with a cut‐off required for 100% sensitivity at 1.7 (yielding one false positive case). Ratio(U:P) accurately discriminates between positive and false positive newborn referrals for PCD by NBS. Ratio(U:P) is less effective as a discriminative tool for PCD in adults and for individuals that receive carnitine suppletion.