Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene (PLP1) that lead to abnormal myelination in the central nervous system. It is rare, with a prevalence of 1:200 000 to 1:500 000 in the United States.

There are 3 main forms of PMD: classic, connatal, and transitional. In classic PMD, symptom onset typically occurs in infancy. Initial symptoms include pendular nystagmus, head tremor, and hypotonia. As the disease progresses, children develop spastic quadriparesis, ataxia, abnormal movements (such as dystonia, chorea, and athetosis), and cognitive impairment. Most children learn to walk with assistive devices but often lose this skill as the disease progresses. Language may develop or may be limited depending on the severity of disease. Individuals with classic PMD typically survive until late adolescence or young adulthood.

Connatal PMD is the most severe form, presenting with nystagmus at birth, respiratory distress, stridor, and significant neonatal hypotonia. Seizures may be present as well. These children never learn to walk or talk. Death occurs between infancy and the third decade of life.

Transitional PMD combines features of both classic and connatal PMD.

In addition to different forms of PMD, PLP1 mutations can lead to other neurologic disorders, including a spastic paraplegia (SPG2). SPG2 is characterized by spastic gait and autonomic dysfunction. These individuals have preserved cognition.