Benefits and pitfalls in newborn screening for carnitine uptake deficiency: a 4-year single-center experience

TL;DR

This study examines the effectiveness of newborn screening for carnitine uptake deficiency, finding a high false positive rate and suggesting ways to improve screening accuracy.

Contribution

The study provides a 4-year single-center analysis of newborn screening for carnitine uptake deficiency, highlighting limitations and proposing strategies to reduce false positives.

Findings

Newborn screening for CUD has a high false positive rate, with 41% of cases being false positives.

Factors like gestational age, low birth weight, and breastfeeding may contribute to false positives.

Strategies like revising diagnostic cutoffs and using second-tier tests could improve screening efficiency.

Abstract

Carnitine uptake deficiency (CUD) is an inherited disorder caused by SLC22A5 gene variants resulting in low plasma and intracellular carnitine concentrations. Although newborn screening (NBS) enables a timely diagnosis of CUD, its efficiency is being debated. The aim of this work was to assess the benefits and limitations of NBS for CUD. A retrospective, observational single-center study was conducted on newborns born between 2017 and 2020 recalled for low free carnitine (C0) values. Biochemical, molecular, dietary and perinatal data were collected. Maternal acylcarnitine profiles and SLC22A5 genotype were also recorded, if available.

Among 160,015 newborns in the study period, forty-six infants were enrolled in the study: three infants were diagnosed with CUD (incidence 1:53,338 newborns), sixteen infants with a maternal disorder, five infants with one heterozygous SLC22A5 variant, and nineteen (41%) infants were false positives. Among false positives, additional factors potentially contributing to the observed low C0 values (i.e., gestational age < 37 weeks, low birth weight, C-section, exclusive breastfeeding) were identified. All enrolled infants were asymptomatic. The association of low C0 with concurrent Ctot values ≤ 19 µmol/L in dried blood spot appeared to argue against a false positive case.

Collected data showed that NBS for CUD is burdened by a high false positive rate. Besides individuals with CUD, those with maternal disorders and heterozygous individuals who do not require medical care were also identified. Increasing the efficiency of NBS is a compelling need. Possible strategies to minimize false positives include regular revision of diagnostic cutoffs assessment of fractional excretion of carnitine and implementation of new analytical strategies such as the development of second-tier tests.

The online version contains supplementary material available at 10.1186/s13023-025-04133-0.

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