title: Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes.
abstract: BACKGROUND
  Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS.
  
  
  METHODS
  We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations.
  
  
  RESULTS
  The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene (SOD1, TARDBP, FUS) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p<0.0001 vs SOD1, p=0.002 vs TARDBP, p=0.011 vs FUS, p=0.0153 vs other FALS) and SALS (p=0.047). FALS patients with C9ORF72 expansions had more frequent association with FTD than the other FALS patients (p<0.0001 vs SOD1, p=0.04 vs TARDBP, p=0.004 vs FUS, p=0.03 vs other FALS). C9ORF72-linked FALS patients presented an older age of onset than SOD1 (p=0.0139) or FUS mutation (p<0.0001) carriers. Disease duration was shorter for C9ORF72 expansion carriers than for SOD1 (p<0.0001) and TARDBP (p=0.0242) carriers, other FALS (p<0.0001) and C9ORF72-negative SALS (p=0.0006).
  
  
  CONCLUSIONS
  Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes.
authors.affiliation: Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, INSERMUMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France. stephanie.millecamps@upmc.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Millecamps
authors.forename: Séverine
authors.initials: S
authors.lastname: Boillée
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.forename: Danielle
authors.initials: D
authors.lastname: Seilhean
authors.forename: Elisa
authors.initials: E
authors.lastname: Teyssou
authors.forename: Marine
authors.initials: M
authors.lastname: Giraudeau
authors.forename: Carine
authors.initials: C
authors.lastname: Moigneu
authors.forename: Nadia
authors.initials: N
authors.lastname: Vandenberghe
authors.forename: Véronique
authors.initials: V
authors.lastname: Danel-Brunaud
authors.forename: Philippe
authors.initials: P
authors.lastname: Corcia
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Pradat
authors.forename: Nadine
authors.initials: N
authors.lastname: Le Forestier
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Gaelle
authors.initials: G
authors.lastname: Bruneteau
authors.forename: William
authors.initials: W
authors.lastname: Camu
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: François
authors.initials: F
authors.lastname: Salachas
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D055815:Young Adult
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1