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SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype–phenotype correlations
  1. Stéphanie Millecamps1,
  2. François Salachas2,
  3. Cécile Cazeneuve3,
  4. Paul Gordon2,
  5. Bernard Bricka3,
  6. Agnès Camuzat1,
  7. Léna Guillot-Noël1,
  8. Odile Russaouen3,
  9. Gaëlle Bruneteau2,
  10. Pierre-François Pradat2,
  11. Nadine Le Forestier2,
  12. Nadia Vandenberghe4,
  13. Véronique Danel-Brunaud5,
  14. Nathalie Guy6,
  15. Christel Thauvin-Robinet7,
  16. Lucette Lacomblez2,8,
  17. Philippe Couratier9,
  18. Didier Hannequin10,
  19. Danielle Seilhean1,11,
  20. Isabelle Le Ber1,
  21. Philippe Corcia12,
  22. William Camu13,
  23. Alexis Brice1,3,
  24. Guy Rouleau14,
  25. Eric LeGuern1,3,
  26. Vincent Meininger2
  1. 1Centre de Recherche de l'Institut du Cerveau et de la Moelle èpinière INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France
  2. 2Assistance Publique Hôpitaux de Paris (AP-HP), Fédération des Maladies du Système Nerveux, Centre de référence maladies rares SLA, Hôpital Pitié-Salpêtrière, Paris, France
  3. 3AP-HP, Département de Génétique et Cytogénétique, Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, Hôpital Pitié-Salpêtrière, Paris, France
  4. 4Hospices Civils de Lyon, Centre SLA de Lyon, Hôpital Neurologique Pierre Wertheimer, Lyon, France
  5. 5Centre SLA-MMN, Service de Neurologie et Pathologie du Mouvement, Hôpital Roger Salengro, CHRU, Lille, France
  6. 6Service de neurologie du CHU Montpied, INSERM U929, Université Clermont 1, Clermont-Ferrand, France
  7. 7Centre de Génétique, Hôpital d'Enfants, Dijon, France
  8. 8INSERM UMRS 678, Université Pierre et Marie Curie-Paris 6, Paris, France
  9. 9Universite de Limoges, IFR 145 GEIST, Institut d'Epidemiologie Neurologique et de Neurologie Tropicale, Limoges, France
  10. 10Service de Neurologie et CMRR, INSERM U614, Centre Hospitalier Universitaire, Rouen, France
  11. 11Département de Neuropathologie, AP-HP, Université Pierre et Marie Curie-Paris 06, Hôpital Pitié-Salpêtrière, Paris, France
  12. 12Centre SLA, CHU de Tours, Université François Rabelais, Tours, France
  13. 13Centre SLA, CHU de Montpellier, Université Montpellier 1, France
  14. 14Center of Excellence in Neuromics, Centre Hospitalier de l'Université de Montreal, and Department of Medicine, University of Montreal, Montreal, Quebec, Canada
  1. Correspondence to Dr Stéphanie Millecamps, Hôpital Pitié-Salpêtrière, CRICM UMR_S975, Bât Pharmacie - 4ème étage, 47 bd de l'Hôpital, 75651 Paris cedex 13, France; stephanie.millecamps{at}


Background Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS).

Methods The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype–genotype correlations.

Results 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration.

Conclusions This study identifies new genetic associations with ALS and provides phenotype–genotype correlations with both previously reported and novel mutations.

  • ALS
  • family study
  • genetics
  • phenotype
  • mutation
  • clinical genetics
  • molecular genetics
  • motor neuron disease
  • neuromuscular disease

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  • Funding Other Funders: Association pour la Recherche sur la sclérose latérale amyotrophique et autres maladies du motoneurone (ARS).

  • 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.