Morbidity and mortality from ataxia-telangiectasia are associated withATMgenotype

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 theATMgenotype. Methods We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzedATMmutations 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 inATMthat 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. Conclusion Morbidity and mortality among patients with A-T are associated withATMgenotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.