ATXN2 intermediate expansions in amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Intermediate CAG (polyQ) expansions in the ataxin-2 (ATXN2) gene are linked to amyotrophic lateral sclerosis (ALS) risk.
• The precise repeat threshold for increased risk remains debated, with previous studies suggesting a range from 27 to 31 repeats.

Purpose of the Study:

• To investigate the association between ATXN2 polyQ expansions and neurodegenerative diseases.
• To establish the specific repeat threshold for increased risk in ALS and related disorders.
• To examine the clinical impact of ATXN2 expansions on ALS onset and survival.

Main Methods:

• Analysis of 9268 DNA samples from patients with ALS, ALS with frontotemporal dementia (FTD), FTD alone, Lewy body dementia, and controls.
• Genotyping for ATXN2 polyQ repeat lengths.
• Statistical analysis including odds ratios to determine risk.
• Clinical data review for a subset of 1362 ALS patients.

Main Results:

• Confirmed ATXN2 intermediate polyQ expansions (≥31 repeats) as a risk factor for ALS (OR=6.31).
• Identified a significantly greater risk for ALS with FTD (OR=27.59) and a lesser risk for FTD alone (OR=3.14).
• No increased risk was observed for Lewy body dementia. Earlier onset or shorter survival in ALS patients with expansions was not confirmed.

Conclusions:

• ≥31 polyQ repeats in ATXN2 are confirmed to increase ALS risk.
• A substantially higher risk for ALS with FTD is associated with these expansions.
• The absence of a more aggressive phenotype in ALS patients with expansions has implications for gene-silencing therapeutic strategies.