Pontocerebellar Hypoplasia, Type 2f

A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2F (PCH2F) is caused by homozygous mutation in the TSEN15 gene (608756) on chromosome 1q25.

Description

Pontocerebellar hypoplasia type 2F is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly and variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity (summary by Breuss et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470).

Clinical Features

Alazami et al. (2015) reported a boy (13DG0167), born of consanguineous parents, with primary microcephaly and global developmental delay. Breuss et al. (2016) reported follow-up on this patient, who was born to Saudi parents. He showed progressive microcephaly (-9.7 SD), developed severe epilepsy at age 8 months, and was unable to sit, roll, speak, or follow visually at age 16 months. Other features included axial hypotonia, appendicular hypertonia with spasticity, and hyperreflexia with extensor plantar responses. Brain imaging showed hypoplasia of the cerebellum and pons. He had a similarly affected older sister, and the parents previously had 3 spontaneous abortions. A 2.5-year-old unrelated girl, born of consanguineous Pakistani parents, had microcephaly (-3.4 SD) and intellectual disability at age 1.5 years. She developed seizures at age 11 months, but did not show spasticity. Other features included hypotonia, poor language skills, and lack of ambulation. Brain imaging showed pontocerebellar hypoplasia and atrophy of the frontoparietal cortex. In a third family, 2 brothers, born of consanguineous Syrian parents, had progressive microcephaly (-3.0 to -4.4 SD) and intellectual disability, but could speak a few words and showed visual fixation and following. One of the boys walked at age 13 months, but the other could not walk at age 5.5 years. Neither had seizures or abnormal motor findings, and brain imaging was not available. Breuss et al. (2016) noted that none of the patients had central visual impairment, and only 1 of the patients had severe spasticity, suggesting that the overall phenotype is slightly milder than that observed in patients with other forms of PCH2.

Inheritance

The transmission pattern of PCH2F in the families reported by Breuss et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy, born of consanguineous Saudi parents, with PCH2F, Alazami et al. (2015) identified a homozygous missense mutation in the TSEN15 gene (W76G; 608756.0001). Functional studies of the variant were not performed. The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing.

In 3 affected individuals from 2 unrelated consanguineous families with PCH2F, Breuss et al. (2016) identified 2 different homozygous missense mutations in the TSEN15 gene (Y152C, 608756.0002 and H116Y, 608756.0003). The mutations were found by either whole-exome sequencing or direct sequencing, and segregated with the disorder in the families. The mutations also matched homozygosity mapping results. In vitro functional expression studies showed that these 2 mutations and the mutation reported by Alazami et al. (2015) resulted in changes in protein expression and alterations of the stoichiometry of the interacting TSEN subunits in different ways, but all resulted in almost complete lack of in vitro tRNA cleavage activity.