Author information
- 1
- Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
- 2
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
- 3
- Department of Clinical and Molecular Medicine, Sapienza Università di Roma, Rome, Italy.
- 4
- Department of Pediatrics, Pediatric Infectious Disease and Immunology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
- 5
- Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
- 6
- INSERM UMR 830, Institut de recherche, Institut Curie, PSL Research University, Paris, France.
- 7
- Service de Génétique, Institut Curie Hôpital, Paris, France.
- 8
- French National Reference Center for Primary Immune Deficiencies (CEREDIH), Pediatric Immuno-Haematology and Rheumatology Unit, Biostatistics Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
- 9
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, Paris, France.
- 10
- INSERM UMR 1163, Sorbonne Paris Cité, Imagine Institute, Paris Descartes University, Paris, France.
- 11
- Department of Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
- 12
- Department of Neurology, Hannover Medical School, Hannover, Germany.
- 13
- Institute of Human Genetics, University of Wurzburg, Wurzburg, Germany.
- 14
- School for Cancer Studies, University of Birmingham, Birmingham, UK.
- 15
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Abstract
BACKGROUND:
Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring ATM mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations.
METHODS:
Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts. To supplement these data, we searched the literature for patients with identical genotypes.
RESULTS:
This study included 35 patients who were homozygous or compound heterozygous for the ATM c.3576G>A; p.(Ser1135_Lys1192del58) mutation and 24 patients who were compound heterozygous for the ATM c.8147T>C; p.(Val2716Ala) mutation. Compared with 51 patients with classic A-T from the Dutch cohort, patients with ATM c.3576G>A had a longer survival and were less likely to develop cancer, respiratory disease or immunodeficiency. This was also true for patients with ATM c.8147T>C, who additionally became wheelchair users later in life and had fewer telangiectasias. The oldest patient with A-T reported so far was a 78-year-old patient who was compound heterozygous for ATM c.8147T>C. ATM kinase activity was demonstrated in cells from all patients tested with the ATM c.8147T>C mutant protein and only at a low level in some patients with ATM c.3576G>A.
CONCLUSION:
Compared with classic A-T, the presence of ATM c.3576G>A results in a milder classic phenotype. Patients with ATMc.8147T>C have a variant phenotype with prolonged survival, which in exceptional cases may approach a near-normal lifespan.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS:
ataxia telangiectasia; atm gene; clinical genetics; genotype-phenotype; mutations
- PMID:
- 30819809
- DOI:
- 10.1136/jmedgenet-2018-105635