Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Motor Neuron Disorders

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with limited survival.
• Intermediate CAG repeat expansions in the ATXN2 gene are associated with spinocerebellar ataxia type 2 (SCA2).
• Previous studies suggested a potential link between ATXN2 intermediate repeat expansions and sporadic ALS.

Purpose of the Study:

• To investigate the role of ATXN2 CAG repeat size in a large cohort of patients with sporadic and familial ALS.
• To determine if intermediate ATXN2 repeat expansions are a risk factor for ALS.
• To explore the genetic overlap between ALS and SCA2.

Main Methods:

• Determined ATXN2 CAG repeat size in 1,948 ALS cases (sporadic and familial) and 2,002 controls.
• Utilized receiver operating characteristic analysis to identify optimal repeat size cutoffs.
• Performed a meta-analysis with previously published US-based results.

Main Results:

• Maximal ATXN2 repeat size in controls was 31.
• Longer repeat sizes (≥32) were significantly more frequent in sporadic ALS cases (0.5%) compared to controls (p=0.0006).
• A repeat length of ≥29 was optimal for discriminating ALS from controls (OR 1.92), with a stronger association found in meta-analysis (OR 2.93).
• Intermediate repeat expansions (31 or 33) were found in 1.1% of familial ALS cases.
• Phenotypes ranged from rapidly progressive ALS to slowly progressive ALS with sensory nerve involvement.

Conclusions:

• The study reveals a novel genetic overlap between ALS and SCA2.
• Intermediate ATXN2 repeat expansions represent a risk factor for both sporadic and familial ALS.
• These findings contribute to understanding the genetic heterogeneity of ALS.