Pontocerebellar Hypoplasia, Type 2b

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2B (PCH2B) is caused by homozygous or compound heterozygous mutation in the TSEN2 gene (608753) on chromosome 3p25.

Additional forms of type 2 PCH, PCH2A (277470) and PCH2C (612390), are caused by mutations in the TSEN54 (608755) and TSEN34 (608754) genes, respectively.

Description

Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesia and chorea, epilepsy, and normal spinal cord findings (Barth, 1993).

For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

Clinical Features

Namavar et al. (2011) reported 2 sibs with PCH2B. The patients presented in early infancy with jitteriness, clonus, and impaired swallowing. One patient had dystonia, dyskinesia, central visual impairment, and seizures. Both had progressive microcephaly, and brain imaging of 1 patient showed pontocerebellar hypoplasia and dilated ventricles. Both sibs were alive at ages 1 month and 4 years, but had no hand control and no postural antigravity control. Additional clinical details were not provided.

Bierhals et al. (2013) reported a 4-year-old German boy with PCH2B. At birth, he showed microcephaly (-3.54 SD) and a receding forehead with overlapping cranial sutures. He had poor sucking and intermittent opisthotonus. At age 3.5 months, his microcephaly had progressed (-6.8 SD), and brain imaging showed simplified gyration with a thin corpus callosum, cerebral atrophy, enlarged ventricles, and hypoplasia of the brainstem, cerebellum, and cerebellar vermis, creating a 'dragonfly-like' pattern. At age 8 months, he developed an epileptic encephalopathy with refractory myoclonic and tonic seizures. He was unable to fix or follow visually and had axial hypotonia, limb hypertonia, and extensor plantar responses. At age 3 years, his head circumference was -11.4 SD and he showed severe spasticity with hyperkinetic involuntary movements. He died at age 4 years, 6 months.

Inheritance

The transmission pattern of PCH2B in the families reported by Namavar et al. (2011) and Bierhals et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Pakistani individual with PCH2 in whom no mutation in TSEN54 was found, Budde et al. (2008) found homozygosity for a missense mutation in the TSEN2 gene (608753.0001). This mutation was not found in 188 Pakistani, 92 Dutch, 54 Chinese, or 28 Palestinian controls.

In 2 sibs with PCH2B, Namavar et al. (2011) identified compound heterozygous mutations in the TSEN2 gene (608753.0001 and 608753.0002). Functional studies of the variants were not performed.

In a German male infant with PCH2B, Bierhals et al. (2013) identified compound heterozygous mutations in the TSEN2 gene (608753.0003 and 608753.0004).