Katherine Schon
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.
Authors
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., Suri, M., Whitehouse, W. P., Mehta, P. R., Everett, N., Bottolo, L., Warrenburg, B. P., Byrd, P. J., Weemaes, C., Willemsen, M. A., Tischkowitz, M., Taylor, A. M., & 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 | Jan 25, 2019 |
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 |
Contract Date | Jan 25, 2019 |
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