Spinocerebellar Ataxia, Autosomal Recessive 15

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-15 (SCAR15) is caused by homozygous mutation in the KIAA0226 gene (RUBCN; 613516) on chromosome 3q29. One such family has been reported.

Clinical Features

Assoum et al. (2010) reported a consanguineous Saudi Arabian family in which 3 sisters had onset of cerebellar ataxia in early childhood. All showed delayed motor development with delayed walking. Two sisters had a more severe form of the disorder, with an unsteady gait apparent since learning to walk, whereas the third developed unsteady gait around age 7 years. Other features included dysarthria, upper limb involvement, abnormal eye movements, and hyporeflexia. Two patients had increased reflexes in the lower limbs. At age 7 months the 2 sisters who were more severely affected developed epilepsy, which was responsive to treatment with no relapse in either girl since age 3 years; both subsequently showed moderate mental retardation. Brain MRI was normal in the 3 girls at ages 16, 9, and 8 years, respectively, but showed mild cerebellar atrophy and prominent folia in 1 patient at age 18 years, suggesting progression of the disorder. At ages 16 to 25 years, they had limited walking without aid, but were unable to run.

Inheritance

The transmission pattern of spinocerebellar ataxia in the family reported by Assoum et al. (2010) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sisters, born of consanguineous Saudi Arabian parents, with autosomal recessive spinocerebellar ataxia, Assoum et al. (2010) identified a homozygous mutation in the KIAA0226 gene (613516.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. The mutation results in the loss of the highly conserved DAG binding-like motif. Heterozygous carriers were unaffected. No mutations in the KIAA0226 gene were found in 172 additional families with non-Friedreich (FRDA; 229300) ataxia. Assoum et al. (2013) found that transfection of mutant KIAA0226 in COS-1 and HeLa cells resulted in mislocalization of the mutant protein from the late endosome and lysosomes to diffuse cytosolic distribution. The findings suggested that the mutation results in a loss of proper protein function, and that the disorder may relate to defects in endolysosomal machinery.