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

Abstract

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.

Neurocognitive Characterization of an SCA28 Family Caused by a Novel AFG3L2 Gene Mutation

“…The identified c.2011G>C nucleotide change is a novel variant determining the p.Gly671Arg alteration, which is pathogenic [8]. Table 2 demonstrates that the clinical phenotype of our patients is similar to that of the 82 earlier published SCA28 patients [6][7][8][10][11][12][13][14][15][16][17][18]. The lack of ophthalmoparesis, ptosis and slowing of saccades in our patients are the main differences, but these symptoms usually appear later in the course of the disease.…”

“…Reviewing the available data from the scientific literature, only 9 out of 82 were described to had some kind of cognitive abnormality, without further specification [6][7][8][10][11][12][13][14][15][16][17][18]. Despite some limitations, including low case number and the fact that neuropsychological tests are poor localizers of brain pathology, the cognitive investigation performed in this study revealed slight abnormalities which may indicate the importance of integrity of cerebellar functioning in intact prefrontal activity [42].…”

“…All SCA28 cases were identified in the Caucasian population, except for one patient from Africa reported in the literature [6][7][8][10][11][12][13][14][15][16][17][18]. There is a lack of thorough cognitive characterization of SCA28 patients in the literature.…”

Early onset and slow progression of SCA28, a rare dominant ataxia in a large four-generation family with a novel AFG3L2 mutation

“…3 However, the authors do not specify the SCA28 gene name nor the exact position of this amino-acid substitution. Thus, it remains unclear whether both missense mutations are identical.…”

“…2 After 2 years, the first set of SCA28 mutations was reported. 3 At the annual meeting of the American Society of Human Genetics 2008, Cagnoli et al and Di Bella et al presented their results regarding the ATPase family gene 3-like 2 gene (AFG3L2) to be causative for SCA28. Overall, they have found at least six different missense mutations in the AFG3L2 gene in eight families.…”