Polyglutamine (CAG) Intermediate Repeat Expansions in ATXN2 is Associated with a More Aggressive Form of ALS Across Multiple Independent Cohorts

Objective: To investigate the association of intermediate length poly CAG expansions in ATXN2 with functional disease progression in amyotrophic lateral sclerosis measured using the ALSFRS-R and respiratory vital capacity (SVC/FVC). Background: ALS is a heterogeneous neurodegenerative condition for which effective treatments are lacking. Multiple human genetic studies have identified intermediate repeat CAG expansions in ATXN2, as a significant risk factor for developing ALS [Elden 2010; Neuenschwander 2014; Sproviero 2017]. With the emergence of candidate disease-modifying ATXN2 therapies, including antisense oligonucleotides, it is critical to understand the association of intermediate CAG repeats with ALS disease progression. Design/Methods: We performed a retrospective multi-cohort analysis of 20 intermediate CAG (30–33) ATXN2 expansion cases and 640 non-expanded matched controls without a CAG expansion ( Results: Sex, baseline age, disease duration, site of onset (bulbar vs. limb) and baseline ALSFRS-R and vital capacity did not differ between intermediate and non-expanded cases within each cohort. Meta-analyses revealed that across cohorts, ALS patients with intermediate CAG repeats exhibited a faster slope of decline on ALSFRS-R (z=2.92; p=0.0035) and vital capacity (z=2.77; p=0.0056) relative to non-expanded disease controls. Conclusions: Our results build on the mounting evidence of the pathologic role of ATXN2 intermediate repeat mutations in ALS further supporting the therapeutic potential of targeting ATXN2 for the treatment of ALS. Disclosure: Dr. McMillan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Axon Advisors. Dr. McMillan has received research support from Biogen, Inc and Avanir Pharmaceuticals. Dr. Tsai has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Inc. Dr. Tsai holds stock and/or stock options in Biogen Inc. which sponsored research in which Dr. Tsai was involved as an investigator. Dr. Tsai holds stock and/or stock options in Biogen Inc.. Dr. Hurt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Inc. Dr. Hurt holds stock and/or stock options in Biogen Inc which sponsored research in which Dr. Hurt was involved as an investigator. Dr. Wuu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Inc.. Dr. Wuu holds stock and/or stock options in Biogen Inc. which sponsored research in which Dr. Wuu was involved as an investigator. Dr. Ford has nothing to disclose. Dr. Van Deerlin has received research support from Asuragen. Dr. Elman has nothing to disclose. Yes - Amicus – Advisory Board; Amylyx – Advisory Board; Acceleron – Advisory BoardDr. McCluskey has nothing to disclose. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Inc.. Dr. Chang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Chang holds stock and/or stock options in Biogen, stock greater than 10K which sponsored research in which Dr. Chang was involved as an investigator. Dr. Rademakers has nothing to disclose. Dr. Van Blitterswijk has nothing to disclose. Dr. Sun has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Inc.. Dr. Consortium has nothing to disclose. Dr. Consortium has nothing to disclose. Dr. Benatar has served on the AveXis Scientific Advisory Board ($2,151), Genentech Honorarium as visiting speaker ($1,000) The University of Miami has received funding from Biogen ($50K) and Orphazyme ($40K) in support of my ALS research program.Dr. Harms has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Sanofi, and Maze Therapeutics. Dr. Harms has received research support from Biogen. Dr. Currier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Currier holds stock and/or stock options in Biogen Inc. which sponsored research in which Dr. Currier was involved as an investigator.