Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by mutations in the ARSA gene, which encodes arylsulfatase A enzyme. Arylsulfatase A deficiency leads to impaired breakdown of sulfatides. Sulfatide accumulation in the central nervous system (CNS) leads to myelin breakdown. Sulfatides can also accumulate in the peripheral nervous system, kidneys, and gallbladder.

MLD is characterized by 3 clinical subtypes with variable age of onset and progression:

• Late-infantile MLD is the most common and has onset before 30 months of age; it typically presents with progressive hypotonia, weakness, and dysarthria and regression of cognitive, language, and motor skills. Most children die within 5 years after onset of symptoms.
• Juvenile MLD has onset between 30 months and 16 years of age. Initial symptoms can involve worsening school performance, personality changes, and behavioral issues. Progression of neurologic symptoms is variable. The majority of patients die before 20 years of age.
• Adult MLD has onset after 16 years of age and has a highly variable presentation. Initial symptoms often involve declining job performance or psychiatric symptoms, often leading to initial diagnosis of mood disorders or psychosis. Neurologic symptoms include weakness, peripheral neuropathy, loss of coordination, and spasticity.