Pontocerebellar hypoplasia type 4

Pontocerebellar hypoplasia type 4 (PCH4), also known as olivopontocerebellar hypoplasia or pontocerebellar hypoplasia with fatal neonatal course, is an extremely rare and severe neurodegenerative disorder characterized by profound underdevelopment (hypoplasia) of the pons and cerebellum — structures in the brainstem and hindbrain critical for motor coordination, breathing, and other vital functions. PCH4 is caused by mutations in the TSEN54 gene, which encodes a subunit of the tRNA splicing endonuclease complex essential for proper tRNA processing. The disease is inherited in an autosomal recessive manner. Clinical features are present from birth and include severe microcephaly (abnormally small head), profound intellectual disability, hypertonia (increased muscle tone) or spasticity, seizures, polyhydramnios during pregnancy, and contractures of the joints. Affected infants typically exhibit absent or minimal voluntary movements, feeding difficulties, and respiratory insufficiency. Neuroimaging reveals marked hypoplasia of the cerebellum and ventral pons, often with a characteristic "dragonfly" appearance of the cerebellum on MRI due to preferential involvement of the cerebellar vermis and hemispheres. Additional features may include excessive neuronal apoptosis and involvement of the spinal cord anterior horn cells. PCH4 represents the most severe form within the pontocerebellar hypoplasia spectrum. The prognosis is extremely poor, with most affected infants dying in the neonatal period or early infancy, often within the first months of life. There is currently no curative treatment or disease-modifying therapy available. Management is entirely supportive and palliative, focusing on seizure control, nutritional support, respiratory management, and comfort care. Genetic counseling is recommended for affected families.

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