Spinocerebellar ataxia type 28

We have recently mapped the spinocerebellar ataxia type 28 (SCA28) locus on chromosome 18p11.22 in a four-generation Italian family. The clinical phenotype in affected individuals of this family was characterized by juvenile onset, slowly progressive gait and limb ataxia, dysarthria, hyperreflexia at lower limbs, nystagmus, and ophthalmoparesis. The mean age at onset was 19.5 years, and no evidence of anticipation between generations was observed. The disease locus on chromosome 18p11.22-q11.2 was found to span a region of 7.9 Mb of genomic DNA. Direct sequencing of candidate genes within the critical interval led to the identification of a heterozygous point mutation in one of them. The mutation was located in a highly conserved domain with proposed functional properties in the protein product of the SCA28 gene, and segregated with the disease phenotype in all affected members of this family. Further genetic screening in 105 patients with autosomal dominant spinocerebellar ataxia negative for mutations in known SCA genes allowed the identification of a distinct missense mutation in a second Italian family. Both mutations are associated with amino acid changes in evolutionarily conserved residues of the alleged SCA28 gene, and indicate SCA28 as the sixth recognized SCA genotype caused by point mutations.