Pelizaeus-Merzbacher disease, connatal form

Pelizaeus-Merzbacher disease, connatal form, is the most severe subtype of Pelizaeus-Merzbacher disease (PMD), a rare X-linked hypomyelinating leukodystrophy caused by mutations in the PLP1 gene located on chromosome Xq22. This gene encodes proteolipid protein 1, a major structural component of central nervous system myelin. In the connatal form, the disease manifests at birth or within the first weeks of life, distinguishing it from the classic form which typically presents in early infancy with milder initial symptoms. The connatal form is sometimes referred to as PMD type II or connatal PMD. The connatal form primarily affects the central nervous system due to a severe deficiency in myelin formation. Key clinical features include profound nystagmus (involuntary eye movements) present from birth, severe hypotonia progressing to spasticity, stridor and breathing difficulties in the neonatal period, seizures, feeding difficulties, and profound psychomotor developmental delay. Affected individuals typically fail to achieve significant developmental milestones such as sitting, walking, or speaking. Progressive spasticity, dystonia, and ataxia develop over time. Brain MRI characteristically shows a near-complete absence of myelination. There is currently no cure or disease-modifying treatment for the connatal form of Pelizaeus-Merzbacher disease. Management is supportive and multidisciplinary, focusing on nutritional support (often requiring gastrostomy tube placement), respiratory management, seizure control with antiepileptic medications, physical therapy to manage spasticity, and orthopedic interventions as needed. The prognosis is poor, with significantly reduced life expectancy, often with survival into childhood or early adolescence, though some individuals may survive longer with intensive supportive care. Research into gene therapy and stem cell transplantation is ongoing but remains experimental.

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