Metachromatic Leukodystrophy: A Narrative Review of Pathophysiology, Diagnosis, and Therapeutic Advances

Abstract

Leukodystrophies are a heterogeneous group of rare genetic disorders characterized by progressive myelin dysfunction, of which metachromatic leukodystrophy (MLD) — caused by biallelic pathogenic variants in ARSA leading to arylsulfatase A deficiency and lysosomal sulfatide accumulation — is among the most severe and best characterized. This review synthesizes current understanding of MLD's pathophysiology, including sulfatide-driven demyelination, neuroinflammation, astrogliosis, and emerging evidence of direct neuronal vulnerability from iPSC-derived models. We outline the four clinical subtypes (late-infantile, early-juvenile, late-juvenile, and adult), their genotype-phenotype correlations, and the diagnostic value of nerve conduction studies, brainstem auditory evoked responses, conventional and quantitative MRI biomarkers, and the differential diagnosis with multiple sulfatase deficiency. A substantial and often prolonged diagnostic delay — compounded by healthcare access inequities and frequent misattribution of adult-onset disease to primary psychiatric illness — remains a major barrier to timely treatment. The therapeutic landscape has been transformed by regulatory approval of autologous hematopoietic stem cell lentiviral gene therapy (atidarsagene autotemcel; arsa-cel), which produces durable preservation of motor and cognitive function when administered pre-symptomatically, while allogeneic hematopoietic cell transplantation remains standard of care for late-onset subtypes. These advances have made newborn screening (NBS) a central priority; we review validated three-tier NBS algorithms, their pilot implementation in Germany, Italy, the United Kingdom, and the United States, and associated cost-effectiveness data. Finally, we discuss the substantial caregiver burden associated with MLD and priorities for future research, including expanding global NBS coverage, improving CNS-directed gene delivery, and developing adjunct neuroprotective therapies. Early, pre-symptomatic identification and intervention remain the single greatest determinant of clinical outcome in MLD.