J Med Genet 49:258-263 doi:10.1136/jmedgenet-2011-100699
  • Complex traits
  • Original article

Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes

  1. François Salachas6
  1. 1Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France
  2. 2Département de Neuropathologie, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
  3. 3Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Bron, France
  4. 4Service de Neurologie et Pathologie du Mouvement, Hôpital Roger Salengro, CHRU Lille, France
  5. 5Centre SLA, CHU de Tours, Université François Rabelais, Tours, France
  6. 6Fédération des Maladies du Système Nerveux, APHP, Centre de référence maladies rares SLA, Hôpital Pitié-Salpêtrière, Paris, France
  7. 7Département de Pharmacologie, INSERM UMR S678, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France
  8. 8Service de Neurologie, Hôpital Guy de Chauliac, Université de Montpellier I, Montpellier France
  9. 9Assistance Publique Hôpitaux de Paris (AP-HP), Département de Génétique et Cytogénétique, Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, Hôpital Pitié-Salpêtrière, Paris, France
  1. Correspondence to Dr Stéphanie Millecamps, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Groupe hospitalier Pitié-Salpêtrière, 83, Bd de l'Hôpital, 75013 Paris, France; stephanie.millecamps{at}
  1. Contributors Dr Millecamps designed the study, interpreted the data and wrote the paper. Drs Millecamps and Meininger performed statistical analyses. Drs Boillee, LeGuern, Meininger and Salachas revised the manuscript for important intellectual content. Mrs Teyssou, Giraudeau and Moigneu and Dr Cazeneuve analyzed the genetic data. Drs Le Ber, Seilhean, Vandenberghe, Danel-Brunaud, Corcia, Le Forestier, Lacomblez, Bruneteau Camu, Brice, Meininger and Salachas acquired and analyzed the clinical data. All authors of this paper have read and approved the final version of the manuscript. Dr Millecamps takes full responsibility for the data, the analyses and interpretation, and the conduct of the research.

  • Received 16 December 2011
  • Revised 15 February 2012
  • Accepted 5 March 2012


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.


  • Funding Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla, France) and Association française contre les myopathies (AFM, France).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the “Comité d'Ethique de la Pitié-Salpêtrière” and the Medical Research Ethics Committee of “Assistance Publique-Hôpitaux de Paris”.

  • Provenance and peer review Not commissioned; externally peer reviewed.