Pontocerebellar hypoplasia type 6

Pontocerebellar hypoplasia type 6 (PCH6) is an extremely rare, severe neurodegenerative disorder characterized by underdevelopment (hypoplasia) of the pons and cerebellum — structures in the brainstem and hindbrain critical for motor coordination, balance, and other vital functions. PCH6 is caused by biallelic mutations in the RARS2 gene, which encodes mitochondrial arginyl-tRNA synthetase, an enzyme essential for mitochondrial protein synthesis. Disruption of this enzyme leads to impaired mitochondrial function, particularly affecting the central nervous system. Clinical features typically present at birth or in early infancy and include progressive microcephaly, severe intellectual disability, seizures (often intractable epilepsy with onset in the neonatal period), hypotonia, and feeding difficulties. Affected infants frequently exhibit lactic acidosis due to mitochondrial dysfunction. Brain MRI reveals characteristic pontocerebellar hypoplasia with progressive cerebellar atrophy. Many patients also demonstrate absent or minimal psychomotor development, and respiratory difficulties may occur. The prognosis for PCH6 is generally poor, with many affected individuals dying in infancy or early childhood, although some patients survive longer with supportive care. There is currently no curative treatment for PCH6. Management is entirely supportive and symptomatic, including antiepileptic medications for seizure control, nutritional support (often via gastrostomy tube), physical therapy, and management of respiratory complications. Genetic counseling is recommended for affected families.

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