Author information
- 1
- East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.
- 2
- Departments of Neurology & Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
- 3
- Ataxia Telangiectasia Service, Respiratory Support and Sleep Centre, Papworth Hospital. Papworth Everard, Cambridge, CB23 3RE, UK.
- 4
- Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.
- 5
- Department of Neurophysiology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.
- 6
- Nottingham Clinical Genetics Service, National Paediatric Ataxia-Telangiectasia Clinic, Nottingham, UK.
- 7
- School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
- 8
- Department of Paediatric Neurology, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, NG7 2UH, UK.
- 9
- Department of Medical Genetics, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
- 10
- The Alan Turing Institute, British Library, 96 Euston Road, London NW1, DB, UK.
- 11
- MRC Biostatistics Unit, University of Cambridge, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
- 12
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
- 13
- Department of Pediatrics, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands.
- 14
- Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.
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. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS:
ATM; Ataxia-Telangiectasia; genotype-phenotype correlation; prognosis
- PMID:
- 30549301
- DOI:
- 10.1002/ana.25394