title: Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.
abstract: BACKGROUND
  Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers.
  
  
  OBJECTIVE
  We studied A-T progression and investigated whether manifestations were associated with the ATM genotype.
  
  
  METHODS
  We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers.
  
  
  RESULTS
  Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations.
  
  
  CONCLUSIONS
  Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.
authors.affiliation: CEREDIH, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France. romain.micol@gmail.com
authors.forename: Romain
authors.initials: R
authors.lastname: Micol
authors.forename: Lilia
authors.initials: L
authors.lastname: Ben Slama
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Mignot
authors.forename: Julien
authors.initials: J
authors.lastname: Beauté
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubois d'Enghien
authors.forename: Anthony
authors.initials: A
authors.lastname: Laugé
authors.forename: Janet
authors.initials: J
authors.lastname: Hall
authors.forename: Jérôme
authors.initials: J
authors.lastname: Couturier
authors.forename: Louis
authors.initials: L
authors.lastname: Vallée
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.forename: François
authors.initials: F
authors.lastname: Rivier
authors.forename: Karine
authors.initials: K
authors.lastname: Nguyen
authors.forename: Thierry
authors.initials: T
authors.lastname: Billette de Villemeur
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Stephan
authors.forename: Pierre
authors.initials: P
authors.lastname: Bordigoni
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.forename: Nathalie
authors.initials: N
authors.lastname: Aladjidi
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pedespan
authors.forename: Caroline
authors.initials: C
authors.lastname: Thomas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pellier
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.forename: Fanny
authors.initials: F
authors.lastname: Lanternier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Marc
authors.initials: M
authors.lastname: Tardieu
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
mesh_terms: D000293:Adolescent; D000328:Adult; D001260:Ataxia Telangiectasia / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality* / Q000503:physiopathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia / Q000235:genetics; D008223:Lymphoma / Q000235:genetics; D008297:Male; D009017:Morbidity; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012141:Respiratory Tract Infections / Q000235:genetics; D012189:Retrospective Studies; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases