Abstract Details

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

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S35 - Amyotrophic Lateral Sclerosis (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

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 (<24) who met diagnostic criteria for ALS. Independent cohorts were comprised of the Phenotype-Genotype Biomarker Cohort from the CReATe Consortium (5 cases, 122 controls), University of Pennsylvania (5 cases, 180 controls), GTAC (3 cases, 197 controls), and the EMPOWER clinical trial (7 cases, 161 controls). Cross-sectional analyses evaluated baseline demographic factors and individualized ALS functional rating scale (ALSFRS-R) and vital capacity (SVC/FVC) slopes over 12 months. Meta-analysis was used to assess standardized mean differences across groups.

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.

Authors/Disclosures
Corey McMillan, PhD (University of Pennsylvania) PRESENTER	Dr. McMillan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. McMillan has received research support from Biogen. The institution of Dr. McMillan has received research support from NIH.
Ellen Tsai, PhD	No disclosure on file
	No disclosure on file
Joanne Wuu, SCM (Univ of Miami, Dept Of Neurology)	The institution of Ms. Wuu has received research support from NIH NINDS. The institution of Ms. Wuu has received research support from NIH NCATS/NINDS. The institution of Ms. Wuu has received research support from CDC. The institution of Ms. Wuu has received research support from Target ALS. The institution of Ms. Wuu has received research support from ALS Recovery Fund. The institution of Ms. Wuu has received research support from NIH/NINDS. The institution of Ms. Wuu has received research support from NIH NINDS. The institution of an immediate family member of Ms. Wuu has received research support from NIH NINDS.
Alice Ford (University of Pennsylvania)	No disclosure on file
	No disclosure on file
Lauren B. Elman, MD	Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Dr. Elman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Edgewise Therapeutics. Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Dr. Elman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Apellis Pharamaceuticals. Dr. Elman has received publishing royalties from a publication relating to health care.
Colin Quinn, MD (University of Pennsylvania)	Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx Pharmaceuticals. Dr. Quinn has received personal compensation in the range of $0-$499 for serving as a Consultant for Amicus. Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapeutics. Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Quinn has received personal compensation in the range of $0-$499 for serving as a Consultant for Clene Nanomedicine. Dr. Quinn has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Partners Health Care. Dr. Quinn has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Robins Kaplan.
Leo McCluskey, MD (Atrium Health Neurosciences Institute)	No disclosure on file
	No disclosure on file
Ih Chang	Ih Chang has received personal compensation for serving as an employee of Cerevel. Ih Chang has received stock or an ownership interest from Cerevel Therapeutics.
Rosa Rademakers, PhD (Mayo Clinic Dept of Neuroscience)	Rosa Rademakers, PhD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mayo Clinic. Rosa Rademakers, PhD has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arkuda Therapeutics. Rosa Rademakers, PhD has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Alzheimer Fondation. Rosa Rademakers, PhD has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Kisick Family Foundation (FTD grant program). The institution of Rosa Rademakers, PhD has received research support from NIH. The institution of Rosa Rademakers, PhD has received research support from DOD. The institution of Rosa Rademakers, PhD has received research support from Flanders Institute for Biotechnology (VIB). The institution of Rosa Rademakers, PhD has received research support from Flanders Funds for Scientific Research.
Marka M. Van Blitterswijk, MD, PhD (Mayo Clinic Florida)	No disclosure on file
	No disclosure on file
Michael G. Benatar, MBChB, DPhil, FAAN (University of Miami)	Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arrowhead. Dr. Benatar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Benatar has received personal compensation in the range of $0-$499 for serving as a Consultant for Annexon. Dr. Benatar has received personal compensation in the range of $0-$499 for serving as a Consultant for UniQure. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunovant. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cartesian. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Benatar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for CorEvitas. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Canopy. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alaunos. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prilenia. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alector. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Woolsey. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Benatar has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Michael G. Benatar, MBChB, DPhil, FAAN (University of Miami)	Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arrowhead. Dr. Benatar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Benatar has received personal compensation in the range of $0-$499 for serving as a Consultant for Annexon. Dr. Benatar has received personal compensation in the range of $0-$499 for serving as a Consultant for UniQure. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunovant. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cartesian. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Benatar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for CorEvitas. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Canopy. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alaunos. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prilenia. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alector. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Benatar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Woolsey. Dr. Benatar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Benatar has received intellectual property interests from a discovery or technology relating to health care.
Matthew Harms, MD (Columbia)	Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Harms has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Muscular Dystrophy Association. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Invitae. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Variant Bio. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for uniQure. Dr. Harms has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Littlepage Booth. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for O'Connor First. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Searcy Denney. Dr. Harms has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Ford, Parshall & Baker LLC . The institution of Dr. Harms has received research support from ALS Association. The institution of Dr. Harms has received research support from Ionis. The institution of Dr. Harms has received research support from ALS Finding a Cure. The institution of Dr. Harms has received research support from Target ALS.
Nicolas Currier	No disclosure on file

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