Spinocerebellar Ataxia 45

A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-45 (SCA45) is caused by heterozygous mutation in the FAT2 gene (604269) on chromosome 5q33.

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

Clinical Features

Nibbeling et al. (2017) reported a family (RF14) in which 6 patients spanning 2 generations had late-onset spinocerebellar ataxia after age 40. The proband was noted to have a relatively pure cerebellar syndrome with limb and gait ataxia, downbeat nystagmus, and dysarthria. No detailed clinical information was available for the remaining affected family members. An unrelated patient (case DNA056251) had onset of slowly progressive gait and limb ataxia and dysarthria at around 50 years of age. He did not have nystagmus. Brain MRI showed atrophy of the cerebellar vermis and hemosiderin deposits in the mesencephalon.

Inheritance

The transmission pattern of SCA45 in the family reported by Nibbeling et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 5 affected members of a family (RF14) with SCA45, Nibbeling et al. (2017) identified a heterozygous missense mutation in the FAT2 gene (K3586N; 604269.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family was 1 of 20 unrelated families with autosomal dominant SCA who underwent whole-exome sequencing. A second heterozygous missense mutation (R3649E; 604269.0002) was subsequently identified in a patient (case DNA056251) with apparently sporadic SCA45. This patient was 1 of 96 individuals with SCA who were screened with a gene panel. In vitro studies modeling the variants to corresponding variants in mouse cDNA showed that the mutant proteins had significantly increased colocalization with markers in the Golgi apparatus compared to wildtype, and functional studies suggested that the mutations, particularly K3587N, may change cell aggregation and adhesion properties.