Spinocerebellar Ataxia, Autosomal Recessive 18

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-18 (SCAR18) is caused by homozygous mutation in the GRID2 gene (602368) on chromosome 4q22.

Description

Autosomal recessive spinocerebellar ataxia-18 is a neurologic disorder characterized by delayed psychomotor development, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and intellectual disability. Brain imaging shows progressive cerebellar atrophy (summary by Hills et al., 2013).

Clinical Features

Utine et al. (2013) reported 3 boys from a consanguineous Turkish kindred with cerebellar ataxia. The 8-year-old proband was described in detail. He presented at age 4 months with nystagmus, hypotonia, and delayed psychomotor development, and later showed unsteady gait, incoordination of gross motor movements, and dysarthria. Physical examination showed poor overall growth, rotatory nystagmus, truncal ataxia, oculomotor apraxia, pale optic disc, dysmetria, and dysdiadochokinesis. There was also evidence of pyramidal tract involvement, with hyperreflexia and extensor plantar responses. Serial brain imaging showed progressive cerebral and cerebellar atrophy. Two male cousins were similarly affected.

Hills et al. (2013) reported 3 children from a consanguineous Turkish family with early-onset cerebellar ataxia associated with eye movement abnormalities and intellectual disability. All patients had delayed psychomotor development with hypotonia, truncal and appendicular ataxia, and difficulty walking; 1 patient was wheelchair-bound at age 14 years. All patients also showed occasional or persistent tonic upgaze and nystagmus. Speech was severely limited. An unrelated child of Mexican descent, born of unrelated parents, had a similar phenotype. Brain imaging of 1 patient from the Turkish family and the Mexican patient showed progressive and severe cerebellar atrophy mainly affecting the flocculus. None of the patients had seizures or dysmorphic features.

Inheritance

The transmission pattern of SCAR18 in the families reported by Hills et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a consanguineous Turkish kindred with autosomal recessive spinocerebellar ataxia, Hills et al. (2013) found linkage to chromosome 4q22 (maximum multipoint lod score of 3.608).

Molecular Genetics

In 3 patients from a consanguineous Turkish family with SCAR18, Utine et al. (2013) identified a homozygous deletion of exons 3 and 4 in the GRID2 gene (602368.0002). The deletion, which was found by genomewide array analysis and confirmed by PCR, segregated with the disorder in the family. Functional studies were not performed.

In 3 patients from a consanguineous Turkish family with SCAR18, Hills et al. (2013) identified a homozygous deletion in the GRID2 gene (602368.0003), resulting in a truncated protein. The mutation was found by a combination of linkage analysis, candidate gene investigation, and custom array CGH. A Mexican child with a similar disorder was compound heterozygous for 2 deletions within the GRID2 gene (602368.0004 and 602368.0005). Both Utine et al. (2013) and Hills et al. (2013) noted phenotypic similarities to the phenotype of mutant mice with homozygous deletions in the Grid2 gene (see ANIMAL MODEL).

Animal Model

Lalouette et al. (1998) showed that mutations in the mouse Grid2 gene are responsible for at least 2 alleles of 'hotfoot' (ho), a recessive mouse mutant phenotype characterized by cerebellar ataxia associated with relatively mild abnormalities of the cerebellum. Using Northern blot and PCR analysis, they identified a 510-bp deletion in the ho(4J) allele and a 4-kb deletion in the ho(TgN371NRA) allele. Lalouette et al. (1998) hypothesized that each of the mutations results in loss of function because the hotfoot phenotype is similar to the Grid2 knockout phenotype (Kashiwabuchi et al., 1995).

Hills et al. (2013) noted that the hotfoot mutant mouse has an in-frame deletion of exon 2, as found in a Mexican patient with SCAR18 (see 602368.0004). Using an infrared camera, Hills et al. (2013) observed that hotfoot mice had significantly larger spontaneous and random eye movements, indicating oculomotor dysfunction, compared to controls.