| Title: |
An observational study of pleiotropy and penetrance of amyotrophic lateral sclerosis associated with CAG-repeat expansion of ATXN2 |
| Authors: |
Cooper-Knock, Johnathan; Demaegd, Koen; Kernan, Aoife; Vugt, Joke van; Harvey, Calum; Moll, Tobias; O'Brien, David; Gornall, Sarah; Drury, Luke; Farhan, Sali; Dion, Patrick; Rouleau, Guy; Western, Andrea; Parsons, Paul; Mclean, Benjamin; Benatar, Michael; Berg, Leonard van den; Damme, Philip Van; Dankbaar, Jan Willem; Hendrikse, Jeroen; Koole, Wouter; de Bie, Charlotte; Hobson, Esther; Veldink, Jan; de Warenburg, Bart van; Pasterkamp, R Jeroen; Rheenen, Wouter van; Kirby, Janine; Shaw, Pamela; Es, Michael van |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2024 |
| Description: |
Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are both associated with a CAG-repeat expansion in ATXN2 and with TDP-43-positive neuronal cytoplasmic inclusions. The two disorders have been viewed as distinct entities, where an intermediate length expansion of 31–33 CAG-repeats is associated with sporadic ALS and a full length expansion of ≧ 34 CAG-repeats is associated with SCA2. We report the clinical phenotype of ATXN2 -positive patients and their relatives, identified in three specialist ALS clinics, which force a reconsideration of this dichotomy. We also report the frequency of ATXN2 expansions in two large cohorts of ALS patients and in a population-matched cohort of controls. We report ten cases of familial ALS in which disease is associated with either an intermediate or a full-length ATXN2 CAG-repeat expansion. Pedigrees and patients feature additional phenotypes including parkinsonism, dementia and essential tremor (ET). We conclude that CAG-repeat expansions in ATXN2 exhibit pleiotropy and are associated with a disease spectrum that includes ALS, SCA2, and parkinsonism; to recognise this complexity we propose the new term ‘ ATXN2 spectrum disorder’. We also observed sporadic ALS associated with full-length expansions. We conclude that ATXN2 CAG-repeat expansions, irrespective of length, should be considered a risk factor for both familial and sporadic ALS. Interrupted CAG-repeats were not perfectly aligned with an ALS phenotype in our data. Our findings have relevance for researchers, patients and families linked to CAG-repeat expansions in ATXN2 . |
| Document Type: |
other/unknown material |
| Language: |
unknown |
| DOI: |
10.21203/rs.3.rs-5419198/v1 |
| Availability: |
https://doi.org/10.21203/rs.3.rs-5419198/v1; https://www.researchsquare.com/article/rs-5419198/v1; https://www.researchsquare.com/article/rs-5419198/v1.html |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.7C27ED2A |
| Database: |
BASE |