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Genotype, extrapyramidal features and severity of variant Ataxia‐Telangiectasia

Schon, Katherine; Os, Nienke; Oscroft, Nicholas; Baxendale, Helen; Scoffings, Daniel; Ray, Julian; Suri, Mohnish; Whitehouse, William P.; Mehta, Puja R.; Everett, Natasha; Bottolo, Leonardo; Warrenburg, Bart P.; Byrd, Philip J.; Weemaes, Corry; Willemsen, Michel A.; Tischkowitz, Marc; Taylor, A. Malcolm; Hensiek, Anke E.

Genotype, extrapyramidal features and severity of variant Ataxia‐Telangiectasia Thumbnail


Authors

Katherine Schon

Nienke Os

Nicholas Oscroft

Helen Baxendale

Daniel Scoffings

Julian Ray

Mohnish Suri

William P. Whitehouse

Puja R. Mehta

Natasha Everett

Leonardo Bottolo

Bart P. Warrenburg

Philip J. Byrd

Corry Weemaes

Michel A. Willemsen

Marc Tischkowitz

A. Malcolm Taylor

Anke E. Hensiek



Abstract

Objective: Variant Ataxia‐Telangiectasia is caused by mutations that allow some retained ATM kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant Ataxia‐Telangiectasia and explore genotype‐phenotype correlations.
Methods: Cross‐sectional data were collected retrospectively. Patients were classified as variant Ataxia‐Telangiectasia based on retained ATM kinase activity.
Results: The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age ten (81%). There was a diagnostic delay of more than ten years in 68% and more than 20 years in a third of probands.
Disease severity was mild in a third of patients and 43% were still ambulant 20 years after disease onset. Only a third had predominant ataxia and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity but with a higher risk of malignancy, compared to leaky splice site mutations.
Interpretation: Individuals with variant Ataxia‐Telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis‐ or underdiagnosed due to atypical features, including exclusive extrapyramidal symptoms, normal eye movements and normal AFP levels in some individuals. Missense mutations are associated with milder neurological presentations but a particularly high malignancy risk and it is important for clinicians to be aware of these phenotypes.

Citation

Schon, K., Os, N., Oscroft, N., Baxendale, H., Scoffings, D., Ray, J., …Hensiek, A. E. (2018). Genotype, extrapyramidal features and severity of variant Ataxia‐Telangiectasia. Annals of Neurology, 85(2), 170-180. https://doi.org/10.1002/ana.25394

Journal Article Type Article
Acceptance Date Dec 12, 2018
Online Publication Date Dec 14, 2018
Publication Date Dec 14, 2018
Deposit Date Jan 25, 2019
Publicly Available Date Mar 29, 2024
Journal Annals of Neurology
Print ISSN 0364-5134
Electronic ISSN 1531-8249
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 85
Issue 2
Pages 170-180
DOI https://doi.org/10.1002/ana.25394
Keywords Neurology; Clinical Neurology
Public URL https://nottingham-repository.worktribe.com/output/1497215
Publisher URL https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25394

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