Newborn Screening for X-Linked Adrenoleukodystrophy: A Systematic Literature Review.
4 affiliations
- 1Laboratorio de Metabolopatías y Cribado Neonatal, Hospital Regional Universitario de Málaga, 29011 Malaga, Spain.
- 2Instituto de Investigación Biomédica de Málaga IBIMA Plataforma BIONAND, 29590 Malaga, Spain.
- 3Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, 29071 Malaga, Spain.
- 4Departamento de Biomedicina y Odontología, Facultad de Ciencias Biomédicas y Deporte, Universidad Europea de Andalucía, 29010 Malaga, Spain.
Abstract
X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy and peroxisomal disorder. It was added to newborn screening (NBS) programs following its first implementation in New York in 2013. Since then, X-ALD screening has expanded rapidly, although important differences exist among programs. This systematic review aimed to evaluate the global implementation of NBS for X-ALD, including screening methodologies, screening performance, prevalence estimates, genetic findings, and clinical follow-up outcomes. A systematic search of PubMed and EMBASE identified 13 publications describing NBS programs conducted between 2013 and June 2026. All programs used C26:0-lysophosphatidylcholine (C26:0-LPC) as the primary biomarker, although substantial heterogeneity was observed in analytical methodologies, cut-off values, screening algorithms, and follow-up strategies. Positive predictive values ranged from 9.1% to 100%, while screening detection rates varied from 1:3118 to 1:51,081, reflecting differences in study design, screening population, sample size, and screening approaches. Variants of uncertain significance (VUS) accounted for 52.6% of individuals detected with classified ABCD1 variant findings, representing a major challenge for genetic counseling and clinical management. Most identified newborns were asymptomatic at diagnosis, supporting the role of NBS in enabling early surveillance for adrenal insufficiency and cerebral disease before irreversible manifestations occur. In addition, differences between universal and sex-specific screening strategies highlight ongoing clinical and ethical debates regarding the scope of X-ALD NBS. Overall, current evidence supports the feasibility of NBS for X-ALD and its ability to enable presymptomatic ascertainment and early clinical surveillance; however, greater harmonization of screening protocols, improved variant interpretation, and long-term outcome studies are needed to optimize program performance and clinical benefit.
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BibTeX
@article{cabreragonzalez2026newborn,
title = {{Newborn Screening for X-Linked Adrenoleukodystrophy: A Systematic Literature Review.}},
author = {María Isabel Cabrera-González and Yolanda De Diego-Otero and Raquel Yahyaoui},
journal = {International journal of neonatal screening},
year = {2026},
month = sep,
doi = {10.3390/ijns12040080},
url = {https://europepmc.org/article/MED/42924757},
note = {CC BY},
}
RIS
TY - JOUR
TI - Newborn Screening for X-Linked Adrenoleukodystrophy: A Systematic Literature Review.
AU - María Isabel Cabrera-González
AU - Yolanda De Diego-Otero
AU - Raquel Yahyaoui
PY - 2026
DA - 2026/09/30
JO - International journal of neonatal screening
DO - 10.3390/ijns12040080
UR - https://europepmc.org/article/MED/42924757
AB - X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy and peroxisomal disorder. It was added to newborn screening (NBS) programs following its first implementation in New York in 2013. Since then, X-ALD screening has expanded rapidly, although important differences exist among programs. This systematic review aimed to evaluate the global implementation of NBS for X-ALD, including screening methodologies, screening performance, prevalence estimates, genetic findings, and clinical follow-up outcomes. A systematic search of PubMed and EMBASE identified 13 publications describing NBS programs conducted between 2013 and June 2026. All programs used C26:0-lysophosphatidylcholine (C26:0-LPC) as the primary biomarker, although substantial heterogeneity was observed in analytical methodologies, cut-off values, screening algorithms, and follow-up strategies. Positive predictive values ranged from 9.1% to 100%, while screening detection rates varied from 1:3118 to 1:51,081, reflecting differences in study design, screening population, sample size, and screening approaches. Variants of uncertain significance (VUS) accounted for 52.6% of individuals detected with classified ABCD1 variant findings, representing a major challenge for genetic counseling and clinical management. Most identified newborns were asymptomatic at diagnosis, supporting the role of NBS in enabling early surveillance for adrenal insufficiency and cerebral disease before irreversible manifestations occur. In addition, differences between universal and sex-specific screening strategies highlight ongoing clinical and ethical debates regarding the scope of X-ALD NBS. Overall, current evidence supports the feasibility of NBS for X-ALD and its ability to enable presymptomatic ascertainment and early clinical surveillance; however, greater harmonization of screening protocols, improved variant interpretation, and long-term outcome studies are needed to optimize program performance and clinical benefit.
SN - 2409-515X
ER -