ATXN2 PolyQ Intermediate Repeat Modifies ALS Phenotype and Survival (P2.005)

Objective. To analyze the frequency and clinical characteristics of ALS patients with intermediate-length (CAG) expansion (encoding 27-33 glutamines, polyQ) in ATXN2 gene in a population-based cohort of Italian patients (discovery cohort, DC), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort, VC).Background. ATXN2 polyQ intermediate repeats have been reported to represent a risk factor for ALS. No studies on their effect on phenotype have been performed so far.Design/Methods. The DC included in 672 patients incident in 2007-2012 in Piemonte and Valle d’Aosta regions, Italy; controls were 509 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The VC included 661 ALS patients consecutively seen between 2001 and 2013 in the ALS Clinic Centre of the Catholic University in Rome, Italy.Results. In the DC the frequency of 蠅31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs. 1 control, p=0.0001; odds ratio 14.8, 95[percnt] c.i., 1.9-110.8). Patients with an increased number of polyQ repeats have a shorter survival than those with u003c31 repeats (median survival 1.8 years, interquartile range [IQR] 1.3-2.2 vs. 2.7 years, IQR 1.6-5.1) (p=0.001), and an increase frequency of spinal onset. 蠅31 polyQ ATNX2 repeats remained independently significant in multivariable analysis. In the VC, patients with 蠅31polyQ repeats have a shorter survival than those with u003c31 repeats (median survival, polyQ 蠅31, 2.0 years, IQR 1.5-3.4; polyQ u003c31, 3.2 years, IQR 2.0-6.4; p=0.007).Conclusions. ATXN2 polyQ intermediate repeat is a modifier of ALS survival and phenotype. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.Study supported by Ministero della Salute (grant RF-2010-2309849), European Community’s Health Seventh Framework Programme (grant agreement 259867), ARISLA (RepeatALS project). Disclosure: No Dr. Calvo has nothing to disclose. Dr. Moglia has nothing to disclose. Dr. Canosa has nothing to disclose. Dr. Restagno has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Barberis has nothing to disclose. Dr. Conte has nothing to disclose. Dr. Marangi has nothing to disclose. Dr. Lattante has nothing to disclose. Dr. Zollino has nothing to disclose. Dr. Sabatelli has nothing to disclose. Dr. Corrado has nothing to disclose. Dr. Mora has nothing to disclose. Dr. Mazzini has nothing to disclose. Dr. D9Alfonso has nothing to disclose.