Adriano Chiò1, Andrea Calvo2, Cristina Moglia2, Antonio Canosa2, Maura Brunetti2, Marco Barberis2, Gabriella Restagno2, Amelia Conte2, Giulia Bisogni2, Giuseppe Marangi2, Alice Moncada2, Serena Lattante2, Marcella Zollino2, Mario Sabatelli2, Alessandra Bagarotti2, Lucia Corrado2, Gabriele Mora2, Enrica Bersano2, Letizia Mazzini2, Sandra D'Alfonso2. 1. From the ALS Center (A. Chiò, A. Calvo, C.M., A. Canosa, M. Brunetti, M. Barberis), "Rita Levi Montalcini" Department of Neuroscience, University of Torino; the Laboratory of Molecular Genetics (M. Brunetti, M. Barberis, G.R.), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (A. Chiò, A. Calvo); the Neuroscience Institute of Torino (NIT) (A. Chiò, A. Calvo); the Departments of Neurosciences, Ophthalmology, Genetics, Rehabilitation, and Child Health (A. Canosa), University of Genoa; the Neurological Institute (A. Conte, G.B., M.S.) and the Institute of Medical Genetics (G. Marangi, A.M., S.L., M.Z.), Catholic University of the Sacred Heart, Rome; the Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) (M. Bagarotti, L.C., S.D.), and the Department of Neurology (E.B., L.M.), "Amedeo Avogadro" University of Eastern Piedmont, Novara; the Salvatore Maugeri Foundation (A.B.), IRCSS, Pavia; the Scientific Institute of Milan (G. Mora); and Azienda Ospedaliera Universitaria Maggiore della Carità (E.B., L.M.), Novara, Italy. achio@usa.net. 2. From the ALS Center (A. Chiò, A. Calvo, C.M., A. Canosa, M. Brunetti, M. Barberis), "Rita Levi Montalcini" Department of Neuroscience, University of Torino; the Laboratory of Molecular Genetics (M. Brunetti, M. Barberis, G.R.), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino (A. Chiò, A. Calvo); the Neuroscience Institute of Torino (NIT) (A. Chiò, A. Calvo); the Departments of Neurosciences, Ophthalmology, Genetics, Rehabilitation, and Child Health (A. Canosa), University of Genoa; the Neurological Institute (A. Conte, G.B., M.S.) and the Institute of Medical Genetics (G. Marangi, A.M., S.L., M.Z.), Catholic University of the Sacred Heart, Rome; the Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) (M. Bagarotti, L.C., S.D.), and the Department of Neurology (E.B., L.M.), "Amedeo Avogadro" University of Eastern Piedmont, Novara; the Salvatore Maugeri Foundation (A.B.), IRCSS, Pavia; the Scientific Institute of Milan (G. Mora); and Azienda Ospedaliera Universitaria Maggiore della Carità (E.B., L.M.), Novara, Italy.
Abstract
OBJECTIVE: To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27-33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort). METHODS: PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle d'Aosta regions, Italy, in the 2007-2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy. RESULTS: In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9-110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3-2.2; polyQ <31, 2.7 years, IQR 1.6-5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5-3.4; polyQ <31, 3.2 years, IQR 2.0-6.4; p = 0.007). CONCLUSIONS: ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.
OBJECTIVE: To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27-33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort). METHODS:PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle d'Aosta regions, Italy, in the 2007-2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy. RESULTS: In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9-110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3-2.2; polyQ <31, 2.7 years, IQR 1.6-5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5-3.4; polyQ <31, 3.2 years, IQR 2.0-6.4; p = 0.007). CONCLUSIONS:ATXN2polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.
Authors: Adriano Chiò; Gabriele Mora; Mario Sabatelli; Claudia Caponnetto; Christian Lunetta; Bryan J Traynor; Janel O Johnson; Mike A Nalls; Andrea Calvo; Cristina Moglia; Giuseppe Borghero; Maria Rosaria Monsurrò; Vincenzo La Bella; Paolo Volanti; Isabella Simone; Fabrizio Salvi; Francesco O Logullo; Riva Nilo; Fabio Giannini; Jessica Mandrioli; Raffaella Tanel; Maria Rita Murru; Paola Mandich; Marcella Zollino; Francesca L Conforti; Silvana Penco; Maura Brunetti; Marco Barberis; Gabriella Restagno Journal: Neurobiol Aging Date: 2015-06-18 Impact factor: 4.673
Authors: Stephen A Goutman; Jonathan Boss; Adam Patterson; Bhramar Mukherjee; Stuart Batterman; Eva L Feldman Journal: J Neurol Neurosurg Psychiatry Date: 2019-02-13 Impact factor: 10.154
Authors: Giuseppe Borghero; Maura Pugliatti; Francesco Marrosu; Maria Giovanna Marrosu; Maria Rita Murru; Gianluca Floris; Antonino Cannas; Leslie D Parish; Tea B Cau; Daniela Loi; Anna Ticca; Sebastiano Traccis; Umberto Manera; Antonio Canosa; Cristina Moglia; Andrea Calvo; Marco Barberis; Maura Brunetti; Alan E Renton; Mike A Nalls; Bryan J Traynor; Gabriella Restagno; Adriano Chiò Journal: Neurobiol Aging Date: 2015-06-25 Impact factor: 4.673
Authors: Antonella Antenora; Carlo Rinaldi; Alessandro Roca; Chiara Pane; Maria Lieto; Francesco Saccà; Silvio Peluso; Giuseppe De Michele; Alessandro Filla Journal: Ann Clin Transl Neurol Date: 2017-08-10 Impact factor: 4.511