Spinocerebellar Ataxia 40

A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-40 (SCA40) is caused by heterozygous mutation in the CCDC88C gene (611204) on chromosome 14q32. One such family has been reported.

Clinical Features

Tsoi et al. (2014) reported a family from Hong Kong, China, in which 5 individuals had adult-onset spinocerebellar ataxia. Two affected individuals were described in detail. The 65-year-old proband presented with unsteady gait and dysarthria at age 43. Features included gait ataxia, wide-based gait, ocular dysmetria, intention tremor, scanning speech, dysdiadochokinesis, and hyperreflexia. She became a 'wheelchair user' 18 years after disease onset. Her younger brother presented with ataxic gait and dysarthria at age 42 years. He also had ocular dysmetria, impaired vertical gaze, scanning speech, and spastic paraparesis, and became a 'wheelchair user' 17 years after disease onset. Brain MRI of both patients showed pontocerebellar atrophy.

Inheritance

The transmission pattern of SCA40 in the family reported by Tsoi et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a family from Hong Kong, China, with SCA40, Tsoi et al. (2014) identified a heterozygous missense mutation in the CCDC88C gene (R464H; 611204.0004). The mutation was found by a combination of linkage analysis and whole-exome sequencing. Functional studies showed that mutant CCDC88C activated JNK (601158) and triggered apoptosis, consistent with a gain of function.