# Newborn Screening for Metachromatic Leukodystrophy: A Systematic Literature Review

## TL;DR

This paper reviews evidence for newborn screening of metachromatic leukodystrophy, showing it can improve outcomes with early treatment.

## Contribution

The study provides the first comprehensive synthesis of evidence supporting MLD inclusion in newborn screening programs.

## Key findings

- Nationwide newborn screening for MLD is currently implemented in Norway with pilots in Germany, Austria, Italy, and the US.
- Early interventions like gene therapy and HSCT significantly improve outcomes when applied before symptom onset.
- MLD meets the Wilson and Jungner criteria for screening, with reliable assays and actionable care pathways.

## Abstract

A systematic literature review was conducted to evaluate the emerging evidence on newborn screening (NBS) for metachromatic leukodystrophy (MLD; MIM #250100). The review focuses on (1) screening assay performance, (2) diagnostic confirmation methods and care pathways, (3) feasibility of population-based identification, and (4) the impact of early diagnosis and treatment on health outcomes. Electronic databases were searched in February 2025, and supplementary searches were performed up to 17 June 2025, for articles referencing NBS for MLD and treatments for MLD; 52 publications were eligible for inclusion. Nationwide NBS for MLD is currently carried out in Norway and large prospective pilots are running in Germany, Austria, Italy and the US. MLD meets established Wilson and Jungner criteria, with a reliable screening algorithm, established confirmatory diagnostics, and actionable care pathways. There is ongoing work to develop tools to predict disease severity and subtype. Early intervention—via gene therapy for early-onset MLD and hematopoietic stem cell transplantation (HSCT) for late-onset forms—significantly improves outcomes when initiated before symptom onset. This review provides the first comprehensive synthesis of the evidence supporting MLD for inclusion in NBS programs, underscoring the public health value of early identification and intervention.