PelizaeusMerzbachers

Pelizaeus–Merzbacher disease (PMD) is a rare X-linked recessive hypomyelinating leukodystrophy caused by mutations in the PLP1 gene on the X chromosome. It disrupts the production or maintenance of myelin, the insulating sheath around nerve fibers, leading to a spectrum of lifelong neurological impairments.

Genetics and presentation vary by mutation. PLP1 gene duplications commonly produce classic to severe forms, sometimes called connatal PMD, with symptoms present at or soon after birth. Point mutations and other rearrangements can yield milder, transitional, or more variable phenotypes. Because the condition is X-linked, affected males are typically more severely affected, while carrier females may be asymptomatic or have mild features.

Clinical features evolve over time. Infants often show nystagmus and hypotonia, with delayed motor development. As the disease progresses, spasticity, ataxia, dystonia, poor coordination, and difficulties with speech and swallowing may appear. Seizures occur less frequently but can occur in some cases. The disease course is usually chronic and associated with stationary or slowly progressive disability.

Diagnosis relies on neuroimaging and genetic testing. MRI typically reveals diffuse hypomyelination of the central white matter, with reduced myelin development and distinctive patterns such as a tigroid appearance in some patients. Genetic testing confirms PLP1 mutations or duplications.

There is no cure. Management is supportive and multidisciplinary, emphasizing physical and occupational therapy, management of spasticity, nutritional support, respiratory care, and educational planning. Prognosis is variable and largely depends on the specific genetic etiology and severity of the presentation. PMD was first described in the early 20th century and is named for Pelizaeus and Merzbacher, who identified the condition.