Pontocerebellar Hypoplasia, Type 2d

A number sign (#) is used with this entry because pontocerebellar hypoplasia type 2D (PCH2D), also known as progressive cerebellocerebral atrophy (PCCA), is caused by homozygous or compound heterozygous mutation in the SEPSECS gene (613009) on chromosome 4p15.

Description

PCH2D is an autosomal recessive disorder characterized by progressive microcephaly, postnatal onset of progressive atrophy of the cerebrum and cerebellum, profound mental retardation, spasticity, and variable seizures (summary by Ben-Zeev et al., 2003).

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

Clinical Features

Ben-Zeev et al. (2003) reported 4 unrelated patients with profound mental retardation, postnatal progressive microcephaly, spasticity, and progressive cerebellocerebral atrophy (PCCA). All patients were from nonconsanguineous Sephardic Jewish families: 2 were of Iraqi origin, and 2 were of combined Iraqi and Moroccan origin. All had normal head circumference at birth, but progressive microcephaly became apparent during the first year of life. All showed severe developmental delay, with 2 patients achieving smiling only. Progressive spasticity resulting in painful contractures and clonus developed during the first year of life. Two patients showed mild and intermittent choreiform movements, but none had dyskinesias. Two patients had seizures, including generalized tonic-clonic and myoclonic. Other features included sleep disorders and severe irritability. Brain imaging showed atrophy of both the cerebrum and cerebellum, with progression in an anterior to posterior direction, and atrophy of the vermis before atrophy of the cerebellar hemispheres. There was a gradual decrease in white matter volume with thinning of the corpus callosum, and 3 patients showed delayed myelination. None had dysmorphic features, and metabolic studies were all normal. Ben-Zeev et al. (2003) noted that there was some phenotypic overlap with pontocerebellar hypoplasia type 2 (see 277470) but considered the phenotype in the Sephardic Jewish families to be distinct, mainly due to the lack of ataxia and dystonia, lack of pontine involvement, and subtle differences in neuroimaging findings.

Makrythanasis et al. (2014) reported 3 sibs (family 26), born of consanguineous Jordanian parents, with PCH2D. The patients were 7, 4, and 2 years of age. They had global developmental delay, microcephaly, seizures, tonic upgaze, and spasticity in the upper and lower limbs. Brain MRI showed mild atrophy of the cerebellar vermis.

Inheritance

The transmission pattern of PCH2D in the families reported by Agamy et al. (2010) was consistent with autosomal recessive inheritance.

Molecular Genetics

By genomewide linkage analysis followed by candidate gene sequencing, Agamy et al. (2010) identified homozygous or compound heterozygous mutations in the SEPSECS gene (613009.0001 and 613009.0002) on chromosome 4p15 in 4 unrelated patients of Iraqi or Iraqi/Moroccan descent with progressive cerebellocerebral atrophy previously reported by Ben-Zeev et al. (2003). Both mutations were demonstrated to abolish enzyme activity, resulting in the disruption of the sole route to selenocysteine biosynthesis and the generation of essential selenoenzymes. The findings indicated that selenium and selenoproteins are critical to brain development and function. Agamy et al. (2010) noted the phenotypic similarity to other forms of PCH2 (see, e.g., PCH2A; 277400), which are also caused by mutation in genes involved in tRNA processing. SEPSECS mutations were not found in 3 additional patients from 2 families of purely Moroccan origin, also previously reported by Ben-Zeev et al. (2003), suggesting genetic heterogeneity.

In 3 sibs, born of consanguineous Jordanian parents, with PCH2D, Makrythanasis et al. (2014) identified a homozygous missense mutation in the SEPSECS gene (D489V; 613009.0003). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant (rs145703544) was present in the dbSNP database at a frequency of 0.022%. Functional studies were not performed.