Spinocerebellar Ataxia, Autosomal Recessive 14

A number sign (#) is used with this entry because autosomal recessive spinocerebellar ataxia-14 (SCAR14) is caused by homozygous mutation in the SPTBN2 gene (604985) on chromosome 11q13.

Heterozygous mutation in the SPTBN2 gene causes autosomal dominant spinocerebellar ataxia-5 (SCA5; 600224).

Description

Autosomal recessive spinocerebellar ataxia-14 is a neurologic disorder characterized by delayed psychomotor development, severe early-onset gait ataxia, eye movement abnormalities, cerebellar atrophy on brain imaging, and intellectual disability (summary by Lise et al., 2012).

Clinical Features

Lise et al. (2012) reported a consanguineous Pakistani family in which 3 individuals had early-onset cerebellar ataxia and cognitive impairment. The patients showed severely delayed motor development and achieved walking with support around age 7 years. Physical examination showed gait ataxia and dysmetria and dysdiadochokinesis of the limbs. Each patient also had abnormal eye movements with convergent squint, hypometric saccades, jerky pursuit movements, and nystagmus. There was no evidence of sensory impairment. The patients also had cognitive and speech delay with IQ levels in the learning disabled range, and all attended schools for persons with special needs. CT scans of the older patients showed progressive cerebellar atrophy, whereas CT of the youngest patient showed mild hypoplasia of the posterior corpus callosum. Neurologic examination of the parents was normal, with no evidence of ataxia.

Elsayed et al. (2014) reported a 9-year-old Egyptian girl, born of consanguineous parents, with global developmental delay and cerebellar ataxia. She began to walk with a broad-based gait at age 2.5 years. Other features included intention tremor, dysarthria, spasticity, dysmetria, and dysdiadochokinesis. She did not have nystagmus, extrapyramidal signs, or bulbar symptoms. Her brother and a first cousin had a similar phenotype. Brain imaging was not available, but the clinical features were consistent with cerebellar dysfunction.

Inheritance

The transmission pattern of autosomal recessive cerebellar ataxia in the family reported by Lise et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from a consanguineous Pakistani family with autosomal recessive spinocerebellar ataxia-14, Lise et al. (2012) identified a homozygous truncating mutation in the SPTBN2 gene (C627X; 604985.0004). The mutation was found by targeted capture of known ataxia genes followed by next-generation sequencing and was confirmed by Sanger sequencing. The mutation segregated with both the movement and the cognitive phenotypes in the family. The unaffected parents were heterozygous for the mutation, indicating that haploinsufficiency is not likely to cause the phenotype. Whole-genome sequencing did not identify any other possible pathogenic mutations that could contribute to the phenotype. Lise et al. (2012) suggested the designation 'spectrin-associated autosomal recessive cerebellar ataxia type 1 (SPARCA1).'

In affected members of an Egyptian family with SCAR14, Elsayed et al. (2014) identified a homozygous truncating mutation in the SPTBN2 gene (604985.0006).

Animal Model

Forman et al. (2012) identified a homozygous 8-bp deletion in the Sptbn2 gene in a 4-week-old Beagle dog that presented with progressive cerebellar ataxia. The mutation was found by genomewide mRNA sequencing, and segregated with the disorder in the canine pedigree. Histopathology of the cerebellum showed Purkinje cell loss and degeneration of dendritic processes, consistent with cerebellar cortical degeneration.