Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis.

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. Thereafter we have screened 105 patients with autosomal dominant spinocerebellar ataxia who had resulted negative for mutations in known SCA genes. Genetic screening allowed the identification in a second Italian family of a distinct missense mutation located in the very same functional domain of the protein. The affected members of this second family exhibited a neurological phenotype similar to that of the original family. Both mutations, not found in more than 500 chromosomes, are associated with amino acid changes (Glu-->Lys and Ser-->Leu, respectively) in evolutionarily conserved residues of the alleged SCA28 gene. Our data point to a putative pathogenic role of these mutations, and indicate SCA28 as the sixth recognized SCA genotype caused by point mutations.