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About 115 patients with pontocerebellar hypoplasia type 1 (PCH1) have been reported.

The clinical course is severe. Neonates with PCH1 present with hypotonia, impaired swallowing with subsequent feeding difficulties, and progressive, postnatal microcephaly. A severe psychomotor deficit subsequently becomes apparent. If patients survive past infancy, patients have oculomotor manifestations including strabismus, nystagmus and oculomotor apraxia. The most severe cases of PCH1 manifest prenatally with polyhydramnios and arthrogryposis multiplex congenital.

PCH1 is genetically heterogeneous. Recessive mutations in the EXOSC3 gene (9p13.2) are found in 40-50% of patients and are the most prevalent cause of PCH1. Mutations in EXOSC8 (13q13.3) and EXOSC9 (4q27) are recently described as a rare cause of PCH1. Mutations in 3 families have been identified in SLC25A46 (5q22.1) and VRK1 (14q32.2) in 2 families. In single cases, recessive mutations have been found in TSEN54 (17q25.1) and RARS2 (6q15). From the small groups reported, severity is suggested to depend on genotype.

MRI shows pontocerebellar hypoplasia with cerebellar hemispheres variably affected. Variable findings include spinal anterior horn degeneration and absence of pontine hypoplasia. Lack of awareness often results in a delay in diagnosis or a diagnosis is never made.

PCH type 2 and 4 (TSEN54-related PCH) can be considered. PCH2 is the most common type of PCH, characterized by dyskinesia and seizures. Brain MRI typically shows pontocerebellar hypoplasia with relative sparing of the vermis compared to the hemispheres, similar to PCH1. In PCH1 however, the pons may be unaffected while in PCH2 the ventral pons is flattened. PCH4 is a more severe than PCH2 and often associated with congenital contractures and polyhydramnios. Spinal Muscular Atrophy (SMA) type 1, caused by biallelic pathogenic variants in SMN1, is characterized by anterior horn cell degeneration, similar to that observed in PCH1. Cognitive function is normal in SMA.

Prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation. In families in which the causal mutation is detected, prenatal testing or pre-implantation genetic diagnosis (PGD) should be offered.

PCH1 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH1. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.

Treatment is symptomatic in PCH.

Prognosis is poor; the majority of patients will only live into infancy. Patients with EXOSC3 mutation have a less severe prognosis.