Spinocerebellar Ataxia 38

A number sign (#) is used with this entry because spinocerebellar ataxia-38 (SCA38) is caused by heterozygous mutation in the ELOVL5 gene (611805) on chromosome 6p12.

Description

Spinocerebellar ataxia-38 is an autosomal dominant neurologic disorder characterized by adult-onset of slowly progressive gait ataxia accompanied by nystagmus. Brain MRI shows cerebellar atrophy (summary by Di Gregorio et al., 2014).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

Di Gregorio et al. (2014) reported 4 unrelated families, 3 Italian and 1 French, with a relatively pure form of autosomal dominant spinocerebellar ataxia. Patients presented with walking difficulties due to gait ataxia between 34 and 51 years of age. Additional features included nystagmus, slow saccades, dysarthria, and limb ataxia. The disorder was slowly progressive. Several patients had distal sensory impairment consistent with axonal neuropathy. Cognition was preserved.

Inheritance

The transmission pattern of SCA38 in the families reported by Di Gregorio et al. (2014) was consistent with autosomal dominant inheritance.

Mapping

By genomewide linkage analysis of a large Italian family with autosomal dominant SCA, Di Gregorio et al. (2014) found linkage to a 56.2-Mb interval on chromosome 6p22.2-q14.1 between markers D6S276 and D6S460 (Zmax of 3.08).

Molecular Genetics

In affected members of a large Italian family with autosomal dominant SCA38, Di Gregorio et al. (2014) identified a heterozygous missense mutation in the ELOVL5 gene (G230V; 611805.0001). The mutation was found by linkage analysis and candidate gene sequencing. Screening of the ELOVL5 gene in 456 European probands with SCA identified heterozygous mutations in 3 additional families (611805.0001 and 611805.0002). Arachidonic acid and docosahexaenoic acid, 2 final products of the enzyme, were reduced in the serum of affected individuals. Transfection of the mutations into several cell lines showed that the mutant proteins had a less diffuse ER signal compared to wildtype, and tended to accumulate in the Golgi apparatus. Transfected cells showed increased levels of CHOP (DDIT3; 126337), suggesting activation of the unfolded protein response that could lead to apoptosis.

In a French man with SCA38, Di Gregorio et al. (2014) identified a heterozygous missense mutation (L72V; 611805.0002) in the ELOVL5 gene.

Population Genetics

Di Gregorio et al. (2014) identified the same ELOVL5 mutation (G230V; 611805.0001) in affected members of 3 unrelated Italian families with SCA38. Haplotype analysis indicated a founder effect.