Abstract Details

An intermediate-length CAG expansion (encoding ≥31 glutamines, polyQ) in the ataxin 2 (ATXN2) gene, already known as the cause of spinocerebellar ataxia type 2 (SCA2), is also associated with an increased risk of developing ALS. In addition, it could be a modifier of survival.

To detect the clinical characteristics of ALS patients carrying an intermediate ATXN2 polyQ expansion.

A total of 1,048 patients (482 female [47.8%], mean age at onset 65.5 [SD 11.1] years) were enrolled. Patients were identified through the Piemonte and Valle d’Aosta Register for ALS (PARALS) in the period 2007-2015. All patients were prospectively followed up to death or censor date (June 30^th, 2021). In 672 patients. the ATXN2 polyQ repeat expansion was detected using repeat primed PCR, while whole-genome sequencing was analyzed to count the repeat number in 376 patients.

We detected 35 cases (3.3%) in which the ATXN2 polyQ repeat number was greater than 30 (ALS-ATXN2+). Compared to patients without intermediate ATXN2 polyQ expansion (ALS-ATXN2-), ALS-ATXN2+ patients had less frequent bulbar onset disease (8.6% vs 32.8%, p=0.001), had a shorter diagnostic delay (7.7 [SD 6.6] months vs 11.7 [10.4], p=0.024), and a higher mean monthly ALSFRS-R decline (1.81 [SD 2.52] vs 0.96 [1.16], p=0.0001). The rate of FVC% decline did not differ between ALS-ATXN2+ and ALS-ATXN2- patients, and cognitive impairment was similarly distributed in the two groups. Nevertheless, the median survival time among ALS-ATXN2+ patients was 1.8 years (IQR 1.3-2.5) compared to 2.8 (IQR 2.7-5.3) in ALS-ATXN2- patients (p=0.0001). ATXN2 intermediate expansion remained independently related to survival (HR 1.55, CI 1.09-2.29, p=0.015) in Cox multivariable analysis.

Our population-based study found that ALS patients carrying the ATXN2 intermediate PolyQ expansion have a distinctive phenotype characterized by a predominant spinal onset and a more rapid clinical decline measured with ALSFRS-R and survival.