Metachromatic Leukodystrophy

Metachromatic Leukodystrophy results from mutations in the ARSA gene encoding arylsulfatase A or in the PSAP gene encoding prosaposin, a required sulfatide activator protein. ARSA deficiency prevents breakdown of sulfatides, resulting in accumulation of these myelin components in oligodendrocytes, neurons, and peripheral tissues. Sulfatide accumulation triggers demyelination, neuronal dysfunction, and neuroinflammation. The pattern of sulfatide deposits creates characteristic metachromatic staining under microscopy, which is diagnostic. Disease severity correlates with residual ARSA activity: infantile forms have minimal or absent activity, late-infantile forms have very low activity, and juvenile forms have slightly higher residual activity. The infantile form is most severe, presenting with loss of previously acquired developmental milestones, progressive loss of motor function, spasticity, and cognitive decline. Without treatment, children become severely disabled by age 3-4 years and die in early childhood. Late-infantile forms progress similarly but with a slightly later onset. Juvenile forms progress more slowly over years to decades. Adult-onset forms may present with psychiatric symptoms, cognitive decline, or progressive motor symptoms and can remain relatively stable for extended periods. MRI shows progressive white matter demyelination and atrophy. Urine analysis may show elevated sulfatides. Treatment options include hematopoietic stem cell transplantation for early-stage infantile disease, enzyme replacement therapy, and gene therapy approaches.