Gene Therapy and Newborn Screening Transform Metachromatic Leukodystrophy Care

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by biallelic variants in the ARSA gene, resulting in deficient arylsulfatase A (ASA) enzyme activity and toxic accumulation of sulfatides in the central and peripheral nervous systems. The disease causes progressive demyelination and neurodegeneration, manifesting as deteriorating motor and cognitive function. Less common forms arise from PSAP gene variants (saposin B-dependent MLD) or SUMF1 variants (multiple sulfatase deficiency), which have important implications for treatment eligibility.

This narrative review, authored by an international consortium of neurologists, metabolic disease specialists, and stem cell transplant experts, synthesizes a decade of research progress. A key conceptual advance is recognizing that the type of presenting symptoms—not just age at onset—predicts disease trajectory. Among 97 patients across all subtypes, those with a predominantly cognitive presentation experienced significantly slower or absent motor decline compared with patients presenting with combined motor-cognitive symptoms. This distinction has direct implications for treatment timing and eligibility decisions.

On the therapeutic front, hematopoietic stem cell transplantation (HSCT) has been better characterized, with outcomes strongest in presymptomatic or minimally symptomatic patients. More transformatively, HSC gene therapy (HSC-GT), in which autologous stem cells are transduced with a functional ARSA gene ex vivo before reinfusion, has received regulatory approval in the EU, UK, and US for early-onset MLD. Long-term follow-up data demonstrate that HSC-GT can stabilize or even preserve neurological function when administered before significant disease burden accumulates. Both HSCT and HSC-GT lose efficacy once substantial demyelination has occurred, creating an urgent window for presymptomatic intervention.

Newborn screening (NBS) for MLD is expanding across multiple countries, but introduces new challenges. ASA pseudodeficiency—present in 1–2% of Caucasians and up to 25% of some populations—can confound enzyme-based screening, necessitating tiered confirmatory testing including urine sulfatide measurement and genetic analysis. Defining which NBS-identified infants will progress to symptomatic disease and when to initiate treatment remain unresolved, particularly for late-juvenile and adult-onset genotypes where disease course is highly variable.

Biomarkers for disease staging and progression prediction are an active area of development, with sulfatide levels, MRI-based metrics, and neurophysiological measures all under investigation. The review also highlights significant disparities in therapy access globally—HSC-GT carries substantial cost and infrastructure requirements, limiting availability in lower-resource settings. The authors call for continued international data sharing, harmonized NBS protocols, and research into treatments for late-onset MLD, for which no approved disease-modifying therapy currently exists.