PelizaeusMerzbach

Pelizaeus–Merzbacher disease (PMD) is a rare X-linked congenital hypomyelinating leukodystrophy caused by alterations in the PLP1 gene on Xq22. It is named after the physicians Friedrich Pelizaeus and Hans Merzbacher, who described the condition in the early 20th century. PMD primarily affects males; female carriers may be asymptomatic or mildly affected due to X-chromosome inactivation.

Genetics and presentation: PMD can arise from duplications of PLP1 or from various missense or other mutations in PLP1. Duplications often produce more severe phenotypes, while certain missense mutations can yield a spectrum from severe to relatively mild. Clinically, infants typically present with nystagmus and hypotonia, followed by delayed or arrested development, poor motor coordination, and evolving spasticity and ataxia. Dysarthria, sensory disturbances, and, in some cases, seizures may occur. Vision is usually affected due to involvement of optic pathways.

Diagnosis: Diagnosis relies on clinical features supported by neuroimaging and genetic testing. Magnetic resonance imaging shows diffuse hypomyelination of the central nervous system white matter, with persistent T2 hyperintensity and abnormal myelination patterns. Genetic testing confirms PLP1 duplications or pathogenic variants, using sequencing and copy-number analysis.

Management and prognosis: There is no cure for PMD. Management is supportive and multidisciplinary, including physical and occupational therapy, management of spasticity and seizures, nutritional support, and regular monitoring of development. The prognosis varies with severity: connatal and severe classic forms often result in significant, early disability and reduced life expectancy, while milder forms may allow longer survival with substantial motor impairment. Genetic counseling is important due to the X-linked inheritance pattern.