Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures

• Published in: Neurogenetics Vol. 15; no. 1; pp. 59 - 64
• Main Authors: McFarland, Karen N., Liu, Jilin, Landrian, Ivette, Zeng, Desmond, Raskin, Salmo, Moscovich, Mariana, Gatto, Emilia M., Ochoa, Adriana, Teive, Hélio A. G., Rasmussen, Astrid, Ashizawa, Tetsuo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2014; Springer Nature B.V
• Subjects: Adult; Alleles; Biomedical and Life Sciences; Biomedicine; Cluster Analysis; Cohort Studies; Convulsions & seizures; DNA Repeat Expansion - genetics; Epilepsy; Epilepsy - ethnology; Epilepsy - genetics; Female; Genetic Association Studies; Genetic disorders; Genotype & phenotype; Haplotypes; Human Genetics; Humans; Male; Mexico; Microsatellite Repeats; Middle Aged; Molecular Medicine; Neurological disorders; Neurosciences; Original Article; Phenotype; Risk; Sequence Analysis, DNA; Spinocerebellar Ataxias - genetics; Mexico; Repeat interruptions; SCA10; Repeat expansion; Ataxia; Epileptic seizures; Phenotype–genotype correlation
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-013-0385-6

Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed “ATCCT interruptions,” experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confer a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling.