title: Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2.
abstract: OBJECTIVE
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons that results in progressive muscle weakness and limits survival to 2-5 years after disease onset. Intermediate CAG repeat expansions in ataxin 2 (ATXN2), the causative gene of spinocerebellar ataxia type 2 (SCA2), have been implicated in sporadic ALS. We studied ATXN2 in a large cohort of patients with sporadic and familial ALS.
  
  
  METHODS
  We determined ATXN2 CAG repeat size in 1,948 sporadic and familial ALS cases and 2,002 controls from Belgium and the Netherlands.
  
  
  RESULTS
  In controls, the maximal ATXN2 repeat size was 31. In sporadic ALS, a significant amount of longer repeat sizes (≥ 32, range 32-39) were encountered (in 0.5% or 10/1,845 ALS cases, vs 0% in controls, p = 0.0006). Receiver operating characteristic analysis showed that a cutoff of ≥ 29 appeared optimal to discriminate ALS from control (p = 0.036, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.04-3.64). A meta-analysis with the previously published results from the United States showed that the association between a repeat length of ≥ 29 and ALS became stronger (p < 0.0001, OR 2.93, 95% CI 1.73-4.98). In unexplained familial ALS, we found an intermediate repeat expansion of 31 and a homozygous repeat expansion of 33 each in 1.1% of families. The phenotype of patients with ALS with expanded repeat sizes ranged from rapidly progressive typical ALS to slowly progressive ALS with reduced sensory nerve action potentials.
  
  
  CONCLUSIONS
  Our data reveal a novel genetic overlap between ALS and SCA2.
authors.affiliation: Department of Neurology, University Hospital Leuven, Leuven, Belgium. wim.robberecht@uzleuven.be
authors.forename: P
authors.initials: P
authors.lastname: Van Damme
authors.forename: J H
authors.initials: JH
authors.lastname: Veldink
authors.forename: M
authors.initials: M
authors.lastname: van Blitterswijk
authors.forename: A
authors.initials: A
authors.lastname: Corveleyn
authors.forename: P W J
authors.initials: PW
authors.lastname: van Vught
authors.forename: V
authors.initials: V
authors.lastname: Thijs
authors.forename: B
authors.initials: B
authors.lastname: Dubois
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
authors.forename: L H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: W
authors.initials: W
authors.lastname: Robberecht
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000067528:Ataxins; D001530:Belgium; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009426:Netherlands; D010375:Pedigree; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019680:Trinucleotide Repeat Expansion
chemical_list: D000067528:Ataxins; D009419:Nerve Tissue Proteins