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

Objectives 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.Methods ATXN2 repeat size was assessed in a large international cohort...

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Detalles Bibliográficos
Autores: Cedric Demaegd, Koen, Koole, Wouter, Van Vugt, Joke J. F. A., Dankbaar, Jan Willem, Hendrikse, Jeroen, Başak, A. Nazlı, Carvalho, Mamede de, Corcia, Philippe, Codron, Philippe, Bernard, Emilien, Guissart, Claire, Couratier, Philippe, Povedano Panades, Mónica, Van Doorn, Pieter A., Warrenburg, Bart P., Cooper-Knock, Johnathan, Jeroen Pasterkamp, R., Van Rheenen, Wouter, Van Damme, Philip, Van Den Berg, Leonard H., Herman Veldink, Jan, Van Es, Michael A., ALS Sequencing Consortium, Project MinE
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2026
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:dnet:recercat____::6530e44b1c8e2907d9334dad84e4edfd
Acceso en línea:https://hdl.handle.net/2445/229276
Access Level:acceso abierto
Palabra clave:Esclerosi lateral amiotròfica
Històries clíniques
Amyotrophic lateral sclerosis
Medical records
Descripción
Sumario:Objectives 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.Methods 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.Results 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).Discussion 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.

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