Pontocerebellar Hypoplasia, Type 4

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 4 (PCH4) is caused by homozygous or compound heterozygous mutation in the TSEN54 gene (608755) on chromosome 17q25.

Description

Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. Pontocerebellar hypoplasia type 4 (PCH4) is characterized by severe course and early lethality (Budde et al., 2008).

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

Clinical Features

Albrecht et al. (1993) reported what they considered to be a 'new' syndrome in 3 sibs (2 females and 1 male) with severe neonatal encephalopathy manifested clinically by microcephaly, myoclonus, and muscular hypertonia. All 3 died in infancy. Autopsy of the brain in the proposita revealed severe neuronal loss in the inferior olives and the pontine nuclei; severe hypoplasia of the cerebellum and micrencephaly; and diffuse gliosis of the white matter in all areas of the brain. No teratogenic exposure was identified. The Hispanic parents denied consanguinity, but their families originated from the same geographic area. The authors favored autosomal recessive inheritance but could not exclude autosomal dominant transmission with variable or reduced penetrance or maternal transmission.

Patel et al. (2006) referred to this form of pontocerebellar hypoplasia as type 4 (PCH4).

Cassandrini et al. (2010) reported an Italian infant girl with lethal PCH4. She presented at birth with hypertonia, congenital contractures, and seizures, and died at age 1 month. Brain MRI showed marked cerebellar atrophy with a peculiar cavitation in the hemispheres and vermis, and severe hypoplasia of the brainstem. Neuropathologic examination showed reduced volume of the cerebellar cortex with loss of Purkinje cells and loss of the ventral pontine nuclei. However, there was a regular pattern of the 4-layered cortex. There was a fetal pattern to the shrunken inferior olivary nuclei.

Namavar et al. (2011) reported 9 patients with PCH4, some of whom had previously been reported by Budde et al. (2008). All had severe congenital symptoms, variably including polyhydramnios, contractures, severe myoclonus, and prolonged dependence on mechanical ventilation. Brain imaging showed pontocerebellar hypoplasia and an immature cerebral cortex. All but 1 patient died in the first year of life.

Inheritance

The transmission pattern of PCH4 in the families reported by Namavar et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 individuals with PCH4, Budde et al. (2008) found mutations in the TSEN54 gene (608755), encoding the noncatalytic subunit of the tRNA splicing endonuclease. One patient carried an ala307-to-ser substitution (A307S) in isolation on one allele and as part of a complex mutation on the other (608755.0001, 608755.0002). The other 2 individuals carried the A307S substitution in compound heterozygosity with different missense mutations (608755.0003, 608755.0004).

In an Italian infant girl with lethal PCH4, Cassandrini et al. (2010) identified compound heterozygosity for 2 mutations in the TSEN54 gene: the A307S mutation and a 14-bp deletion (608755.0005).