Abstract Details

Title Association of Intermediate HTT CAG Repeats with Increased Risk and Disease Severity in Amyotrophic Lateral Sclerosis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 11-003

Objective This study investigates the frequency of intermediate HTT CAG expansions in ALS patients relative to healthy controls, thereby determining their contribution to ALS pathogenesis. Their effect on ALS phenotype and disease progression was also evaluated.

Background The pathological role of expanded CAG trinucleotide repeats (= 40) in the Huntingtin gene (HTT) has recently been established in amyotrophic lateral sclerosis (ALS). However, the impact of intermediate-sized HTT CAG expansions (i.e., 27–35 repeats) remains unclear.

Design/Methods We analyzed whole-genome sequencing data from a population-based case-control cohort and conducted a comprehensive meta-analysis of existing research to substantiate the association between intermediate HTT expansions and ALS susceptibility. We included 1,324 ALS patients and 757 healthy controls from the Piemonte and Valle d'Aosta Register for ALS (PARALS) in Northern Italy. The meta-analysis further integrated data from three published studies, incorporating data from 1,909 ALS cases and 4,420 control subjects. We further performed a phenotypic analysis comparing ALS patients with and without intermediate HTT expansions. Phenotypic comparisons included the age at disease onset, cognitive impairment, ALSFRS-R decline rate, and survival from symptom onset.

Results In the PARALS cohort, 6.80% of ALS cases and 4.62% of controls carried between 27 and 35 CAG repeats in the HTT gene, suggesting a modestly elevated ALS risk among carriers of intermediate-repeat expansions (OR = 1.50, 95% CI = 1.01–2.28, P = 0.0501). The meta-analysis reinforced this association (OR = 1.82, 95% CI = 1.48–2.23, P = 2.03 x 10-8). ALS patients with intermediate HTT expansions also demonstrated faster disease progression (?ALSFRS-R difference = +0.20 points per month, 95% CI = 0.02–0.41, P = 0.0316) and reduced survival (HR = 1.42, 95% CI = 1.13–1.79, P = 0.0018).

Conclusions This research presents compelling evidence implicating intermediate HTT expansions in ALS pathogenesis. These findings enhance our understanding of ALS and point toward potential therapeutic interventions.

Authors/Disclosures
Maurizio Grassano, MD (Dept. of Neuroscience, University of Turin) PRESENTER	Dr. Grassano has received research support from American Brain Foundation, ALS Association and ��ɫ��.
Antonio Canosa	Antonio Canosa has nothing to disclose.
Lucia Corrado	No disclosure on file
Sandra D'Alfonso	No disclosure on file
Umberto Manera, MD (Department of Neuroscience "Rita Levi Montalcini" - University of Torino)	Dr. Manera has nothing to disclose.
Rosario Vasta, MD (University of Turin, Department of Neurosciences)	Dr. Vasta has nothing to disclose.
Emanuele Koumantakis (Università degli Studi di Torino)	No disclosure on file
Giorgia Brodini	Ms. Brodini has nothing to disclose.
Francesca Palumbo (University of Turin Department of Neurosciences: Universita degli Studi di Torin)	Dr. Palumbo has nothing to disclose.
Cristina Moglia (University of Torino)	Cristina Moglia has nothing to disclose.
Ruth Chia (NIH)	No disclosure on file
Letizia Mazzini	No disclosure on file
Andrea Calvo, MD, PhD, FAAN (Dept. of Neuroscience, University of Turin)	Dr. Calvo has nothing to disclose.
Sonja W. Scholz, MD, FAAN (National Institute of Neurological Disorders and Stroke)	Dr. Scholz has received personal compensation for serving as an employee of National Institutes of Health. An immediate family member of Dr. Scholz has received personal compensation for serving as an employee of National Institutes of Health. The institution of Dr. Scholz has received research support from National Institutes of Health. The institution of an immediate family member of Dr. Scholz has received research support from National Institutes of Health. An immediate family member of Dr. Scholz has received intellectual property interests from a discovery or technology relating to health care. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Council Member with Lewy Body Dementia Association that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Editorial Board Member with JAMA Neurology that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Editorial Board Member with Journal of Parkinson's Disease that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Board Member with Mission MSA that is relevant to AAN interests or activities. Dr. Scholz has a non-compensated relationship as a Scientific Advisory Board Member with The GBA1 Canada Initiative (G-Can) that is relevant to AAN interests or activities.
Bryan Traynor, MD (National Institute on Aging)	The institution of Dr. Traynor has received research support from ALS Association. The institution of Dr. Traynor has received research support from Merck. The institution of Dr. Traynor has received research support from Myasthenia Gravis Foundation. The institution of Dr. Traynor has received research support from Cerevel Therapeutics. Dr. Traynor has received intellectual property interests from a discovery or technology relating to health care.
Adriano Chio, MD, FAAN (Dept. of Neuroscience, University of Turin)	Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Chio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Corcept.

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