Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia

Research output: Contribution to journalArticlepeer-review


  • Katherine Schon
  • Nienke J H van Os
  • Nicholas Oscroft
  • Helen Baxendale
  • Daniel Scoffings
  • Julian Ray
  • Mohnish Suri
  • William P Whitehouse
  • Puja R Mehta
  • Natasha Everett
  • Leonardo Bottolo
  • Bart P van de Warrenburg
  • Corry Weemaes
  • Michel A Willemsen
  • Marc Tischkowitz
  • Anke E Hensiek

Colleges, School and Institutes


OBJECTIVE: Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (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 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one 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 because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha-fetoprotein 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. ANN NEUROL 2019;85:170-180.

Bibliographic note

© 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.


Original languageEnglish
Pages (from-to)170-180
Number of pages11
JournalAnnals of Neurology
Issue number2
Early online date14 Dec 2018
Publication statusPublished - 29 Jan 2019