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 age 30 months; 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 age 30 months and 16 years. Initial symptoms can involve worsening school performance, personality changes, and behavioral issues. Progression of neurologic symptoms is variable. The majority of patients die before age 20 years.
Adult MLD has onset after age 16 years 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.
The gross motor function classification in MLD (GMFC-MLD) scale is globally used for measurement of gross motor function in patients with MLD and ranges from level 0 (normal function) to level 6 (the loss of all gross motor function).
