A Systematic Review of Metachromatic Leukodystrophy Newborn Screening: Transitioning from Pilot Studies to the Real...

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder causing progressive neurodegeneration through central and peripheral demyelination, leading to premature death. Recent advances in ex vivo lentiviral gene therapy have developed a potentially curative treatment approach for pre-symptomatic infants with early-onset MLD. This systematic review evaluates the current evidence regarding newborn screening (NBS) for MLD, including screening methodologies, diagnostic pathways, and implementation challenges, using the Swiss healthcare system as an illustrative example. A literature search using keywords MLD and NBS was conducted across five databases on 29 September 2025 and updated on 21 September 2026, along with contacting leading experts of the field up to 1 July 2026, resulting in the inclusion of 27 publications and six conference papers. Multi-tiered screening algorithms combining sulfatide species quantification, second-tier enzyme activity measurement, and genetic confirmation testing can reliably identify MLD-affected infants while reducing false-positive results. Pilot studies and early national implementation programs have confirmed the feasibility of population-based MLD NBS. We consider Switzerland well positioned to integrate MLD into its centralized national NBS program. Several factors, including achieving cost-effectiveness, subtype prediction, and management of uncertain cases, require thorough consideration and represent potentially universal barriers to widespread adoption of MLD NBS beyond pilot programs around the world.