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.
Neurology. 2015 Jan 20;84(3):251-8. doi: 10.1212/WNL.0000000000001159. Epub 2014 Dec 19.
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).
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.
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).
ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.
在意大利肌萎缩侧索硬化症（ALS）患者的基于人群的队列（发现队列）中，分析 ATXN2 基因中具有中等长度（CAG）扩增（编码 27-33 个谷氨酰胺，多聚 Q）的 ALS 患者的频率和临床特征，并在 ALS 三级中心的连续患者的独立队列中复制这些发现（验证队列）。
在 2007-2012 年期间，对意大利皮埃蒙特和瓦莱达奥斯塔地区的 672 名新发 ALS 患者（发现队列）进行了多聚 Q 重复评估；对照组为 509 名居住在研究地区的年龄和性别匹配的神经科健康受试者。验证队列包括 2001 年至 2013 年期间在意大利天主教大学 ALS 诊所中心连续就诊的 661 名 ALS 患者。
在发现队列中，具有≥31 个多聚 Q ATNX2 重复的 ALS 患者的频率明显更高（19 名患者与 1 名对照，p=0.0001；优势比 14.8，95%置信区间 1.9-110.8）。具有较高数量多聚 Q 重复的患者的生存时间短于具有<31 个重复的患者（中位生存时间，多聚 Q≥31，1.8 年，四分位距 [IQR] 1.3-2.2；多聚 Q<31，2.7 年，IQR 1.6-5.1；p=0.001）。在多变量分析中，多聚 Q 重复的数量增加仍然具有显著意义。在验证队列中，具有≥31 个多聚 Q 重复的患者的生存时间短于具有<31 个重复的患者（中位生存时间，多聚 Q≥31，2.0 年，IQR 1.5-3.4；多聚 Q<31，3.2 年，IQR 2.0-6.4；p=0.007）。
ATXN2 多聚 Q 中等长度重复是 ALS 生存的修饰因子。针对 ATXN2 的疾病修饰治疗代表了 ALS 的一种有前途的治疗方法。
