# Bi-allelic intermediate ATXN2 repeat expansions are associated with slow progressing, leg-onset familial ALS

## TL;DR

This study identifies a rare form of familial ALS caused by ATXN2 gene repeat expansions, marked by slow progression and leg-onset symptoms.

## Contribution

The paper reports a novel autosomal recessive ALS form linked to bi-allelic ATXN2 intermediate repeat expansions.

## Key findings

- Bi-allelic ATXN2 expansions were found in five familial and five sporadic ALS cases but absent in controls.
- The condition presents with leg-onset, long survival, and no significant cerebellar atrophy.
- The study highlights the importance of ATXN2 testing for prognosis and genetic counseling in ALS.

## Abstract

The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.

ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.

In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).

Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling.