Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes

Sophie Tezenas Du Montcel, Alexandra Durr, Peter Bauer, Karla P. Figueroa, Yaeko Ichikawa, Alessandro Brussino, Sylvie Forlani, Maria Rakowicz, Ludger Schöls, Caterina Mariotti, Bart P C Van De Warrenburg, Laura Orsi, Paola Giunti, Alessandro Filla, Sandra Szymanski, Thomas Klockgether, José Berciano, Massimo Pandolfo, Sylvia Boesch, Bela MeleghDagmar Timmann, Paola Mandich, Agnès Camuzat, Jun Goto, Tetsuo Ashizawa, Cécile Cazeneuve, Shoji Tsuji, Stefan M. Pulst, Alfredo Brusco, Olaf Riess, Alexis Brice, Giovanni Stevanin

Research output: Contribution to journalArticlepeer-review

133 Scopus citations


Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.

Original languageEnglish (US)
Pages (from-to)2444-2455
Number of pages12
Issue number9
StatePublished - Sep 2014


  • Age at onset
  • Modifier
  • Spinocerebellar ataxia
  • Trinucleotide repeat

ASJC Scopus subject areas

  • Clinical Neurology


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