title: Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases.
abstract: OBJECTIVE
  To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).
  
  
  METHODS
  Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion.
  
  
  RESULTS
  The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 × 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 × 10(-4)).
  
  
  CONCLUSIONS
  The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.
authors: Department of Neurology, Rudolph Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht.
authors: Wouter
authors: W
authors: van Rheenen
authors: Marka
authors: M
authors: van Blitterswijk
authors: Mark H B
authors: MH
authors: Huisman
authors: Lotte
authors: L
authors: Vlam
authors: Perry T C
authors: PT
authors: van Doormaal
authors: Meinie
authors: M
authors: Seelen
authors: Jelena
authors: J
authors: Medic
authors: Dennis
authors: D
authors: Dooijes
authors: Marianne
authors: M
authors: de Visser
authors: Anneke J
authors: AJ
authors: van der Kooi
authors: Joost
authors: J
authors: Raaphorst
authors: Helenius J
authors: HJ
authors: Schelhaas
authors: W Ludo
authors: WL
authors: van der Pol
authors: Jan H
authors: JH
authors: Veldink
authors: Leonard H
authors: LH
authors: van den Berg
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000073885:C9orf72 Protein; D015331:Cohort Studies; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics; D042622:DNA Repeat Expansion; D003704:Dementia / Q000150:complications / Q000235:genetics; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000150:complications / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics*; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009154:Mutation / Q000502:physiology; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D011506:Proteins / Q000235:genetics*; D013534:Survival; D055815:Young Adult
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D004247:DNA