Pontocerebellar hypoplasia type 2

Pontocerebellar hypoplasia type 2 (PCH2), also known as pontocerebellar hypoplasia with progressive microcephaly, is a severe autosomal recessive neurodegenerative disorder characterized by underdevelopment (hypoplasia) of the pons and cerebellum — structures in the brainstem and hindbrain critical for motor coordination and many other neurological functions. PCH2 is the most common subtype of the pontocerebellar hypoplasias. The majority of cases are caused by pathogenic variants in the TSEN54 gene, with less frequent involvement of TSEN2, TSEN34, and SEPSECS genes. These genes encode components of the tRNA splicing endonuclease complex, which is essential for tRNA processing. Clinical features typically manifest in the neonatal or early infantile period and include progressive microcephaly (abnormally small head circumference that worsens over time), severe intellectual disability, lack of voluntary motor development, jitteriness, dystonia, and chorea. Affected children often develop seizures and have feeding difficulties requiring supportive interventions such as gastrostomy tube placement. Extrapyramidal dyskinesias (involuntary movements) are a hallmark feature that distinguishes PCH2 from other pontocerebellar hypoplasia subtypes. Brain MRI characteristically shows a small, flattened cerebellum with a dragonfly or butterfly appearance, along with a reduced pontine prominence. There is currently no curative treatment for PCH2. Management is entirely supportive and symptomatic, focusing on seizure control with antiepileptic medications, nutritional support, physical therapy, and management of respiratory complications. The prognosis is poor, with many affected individuals surviving into childhood but with profound neurological impairment. Some patients may survive into their teens or beyond, though quality of life is significantly impacted. Genetic counseling is recommended for affected families, and prenatal or preimplantation genetic testing is available for families with known pathogenic variants.

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