Serena Lattante1, Stéphanie Millecamps1, Giovanni Stevanin1, Sophie Rivaud-Péchoux1, Carine Moigneu1, Agnès Camuzat1, Sandra Da Barroca1, Emeline Mundwiller1, Philippe Couarch1, François Salachas1, Didier Hannequin1, Vincent Meininger1, Florence Pasquier1, Danielle Seilhean1, Philippe Couratier1, Véronique Danel-Brunaud1, Anne-Marie Bonnet1, Christine Tranchant1, Eric LeGuern1, Alexis Brice1, Isabelle Le Ber1, Edor Kabashi2. 1. From the Institut du Cerveau et de la Moelle épinière (ICM) (S.L., S.M., G.S., S.R.-P., C.M., A.C., S.D., E.M., P.C., A.B., I.L., E.K.), Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, F-75013, Paris; Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, ICM (G.S.), HéSam Université, GHU Pitié-Salpêtrière, F-75013, Paris; Fédération des Maladies du Système Nerveux, Centre de référence maladies rares SLA (F.S., V.M.), Département de Neuropathologie (D.S.), Department of Neurology (A.-M.B.), Unité Fonctionnelle de neurogénétique moléculaire et cellulaire (E.L.), Département de Génétique et Cytogénétique (A.B.), and Centre de référence Démences Rares (I.L.), AP-HP, Hôpital Pitié-Salpêtrière, F-75013, Paris; Inserm U1079 (D.H.), Rouen; Centre mémoire (F.P.), Université Lille Nord de France, EA1046, CHU, Lille; Neuroépidémiologie Tropicale (P.C.), Université de Limoges INSERM UMR1094, Limoges; Service de Neurologie et Pathologie du Mouvement (V.D.-B.), Hôpital Roger Salengro, CHRU Lille; and Service de neurologie (C.T.), Hôpital de Hautepierre, CHU de Strasbourg, 1 Avenue Molière, Strasbourg, France. 2. From the Institut du Cerveau et de la Moelle épinière (ICM) (S.L., S.M., G.S., S.R.-P., C.M., A.C., S.D., E.M., P.C., A.B., I.L., E.K.), Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, F-75013, Paris; Ecole Pratique des Hautes Etudes, Laboratoire de Neurogénétique, ICM (G.S.), HéSam Université, GHU Pitié-Salpêtrière, F-75013, Paris; Fédération des Maladies du Système Nerveux, Centre de référence maladies rares SLA (F.S., V.M.), Département de Neuropathologie (D.S.), Department of Neurology (A.-M.B.), Unité Fonctionnelle de neurogénétique moléculaire et cellulaire (E.L.), Département de Génétique et Cytogénétique (A.B.), and Centre de référence Démences Rares (I.L.), AP-HP, Hôpital Pitié-Salpêtrière, F-75013, Paris; Inserm U1079 (D.H.), Rouen; Centre mémoire (F.P.), Université Lille Nord de France, EA1046, CHU, Lille; Neuroépidémiologie Tropicale (P.C.), Université de Limoges INSERM UMR1094, Limoges; Service de Neurologie et Pathologie du Mouvement (V.D.-B.), Hôpital Roger Salengro, CHRU Lille; and Service de neurologie (C.T.), Hôpital de Hautepierre, CHU de Strasbourg, 1 Avenue Molière, Strasbourg, France. edor.kabashi@icm-institute.org.
Abstract
OBJECTIVE: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. METHODS: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). RESULTS: We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. CONCLUSIONS: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS.
OBJECTIVE: The aim of this study was to establish the frequency of ATXN2polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. METHODS: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). RESULTS: We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. CONCLUSIONS:ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS.
Authors: S M Pulst; A Nechiporuk; T Nechiporuk; S Gispert; X N Chen; I Lopes-Cendes; S Pearlman; S Starkman; G Orozco-Diaz; A Lunkes; P DeJong; G A Rouleau; G Auburger; J R Korenberg; C Figueroa; S Sahba Journal: Nat Genet Date: 1996-11 Impact factor: 38.330
Authors: I Litvan; Y Agid; D Calne; G Campbell; B Dubois; R C Duvoisin; C G Goetz; L I Golbe; J Grafman; J H Growdon; M Hallett; J Jankovic; N P Quinn; E Tolosa; D S Zee Journal: Neurology Date: 1996-07 Impact factor: 9.910
Authors: G Cancel; A Dürr; O Didierjean; G Imbert; K Bürk; A Lezin; S Belal; A Benomar; M Abada-Bendib; C Vial; J Guimarães; H Chneiweiss; G Stevanin; G Yvert; N Abbas; F Saudou; A S Lebre; M Yahyaoui; F Hentati; J C Vernant; T Klockgether; J L Mandel; Y Agid; A Brice Journal: Hum Mol Genet Date: 1997-05 Impact factor: 6.150
Authors: Isabelle Le Ber; Julie van der Zee; Didier Hannequin; Ilse Gijselinck; Dominique Campion; Michèle Puel; Annie Laquerrière; Tim De Pooter; Agnès Camuzat; Marleen Van den Broeck; Bruno Dubois; François Sellal; Lucette Lacomblez; Martine Vercelletto; Catherine Thomas-Antérion; Bernard-François Michel; Véronique Golfier; Mira Didic; François Salachas; Charles Duyckaerts; Marc Cruts; Patrice Verpillat; Christine Van Broeckhoven; Alexis Brice Journal: Hum Mutat Date: 2007-09 Impact factor: 4.878
Authors: P Charles; A Camuzat; N Benammar; F Sellal; A Destée; A-M Bonnet; S Lesage; I Le Ber; G Stevanin; A Dürr; A Brice Journal: Neurology Date: 2007-06-13 Impact factor: 9.910
Authors: Andrew C Elden; Hyung-Jun Kim; Michael P Hart; Alice S Chen-Plotkin; Brian S Johnson; Xiaodong Fang; Maria Armakola; Felix Geser; Robert Greene; Min Min Lu; Arun Padmanabhan; Dana Clay-Falcone; Leo McCluskey; Lauren Elman; Denise Juhr; Peter J Gruber; Udo Rüb; Georg Auburger; John Q Trojanowski; Virginia M-Y Lee; Vivianna M Van Deerlin; Nancy M Bonini; Aaron D Gitler Journal: Nature Date: 2010-08-26 Impact factor: 49.962