Metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD), also known as arylsulfatase A deficiency or sulfatide lipidosis, is a rare inherited lysosomal storage disorder caused by mutations in the ARSA gene (most commonly) or, less frequently, in the PSAP gene encoding the activator protein saposin B. The disease results in deficient activity of the enzyme arylsulfatase A, leading to accumulation of sulfatides (cerebroside sulfate) in the white matter of the central and peripheral nervous systems, as well as in the kidneys and other visceral organs. This sulfatide accumulation causes progressive destruction of the myelin sheath (demyelination), which is essential for proper nerve signal transmission. MLD is classified into three clinical forms based on age of onset: late-infantile (onset before age 30 months, the most common and severe form), juvenile (onset between ages 3 and 16 years), and adult (onset after age 16 years). Key symptoms include progressive motor regression, loss of previously acquired developmental milestones, gait abnormalities (ataxia), spasticity, peripheral neuropathy, seizures, and progressive cognitive decline leading to dementia. In the late-infantile form, children typically present with difficulty walking, hypotonia that progresses to spasticity, and rapid neurological deterioration. The juvenile and adult forms tend to progress more slowly and may initially present with behavioral changes, declining school performance, or psychiatric symptoms before motor involvement becomes apparent. Historically, treatment for MLD was limited to supportive care. Hematopoietic stem cell transplantation (HSCT) has been used with some benefit, particularly in pre-symptomatic or early-symptomatic juvenile and adult forms, though outcomes are variable and the procedure carries significant risks. A major therapeutic advance occurred with the approval of atidarsagene autotemcel (Libmeldy), an ex vivo lentiviral-based gene therapy for eligible patients with late-infantile or early-juvenile forms who are pre-symptomatic or have early symptoms. This gene therapy involves autologous hematopoietic stem cells genetically modified to express functional ARSA. Enzyme replacement therapy and substrate reduction approaches are also under investigation in clinical trials.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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