Immune deficiencies, infection, and systemic immune disorders
Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype

Preliminary findings were presented in part at the 12th Meeting of the European Society for Immunodeficiencies (ESID), October 16-19, 2008, ‘s-Hertogenbosch, The Netherlands.
https://doi.org/10.1016/j.jaci.2011.03.052Get rights and content

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.

Conclusion

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.

Section snippets

Diagnosis

ATM was genotyped in patients with 3 or more of the following: ataxia, oculocutaneous telangiectasia, recurrent infections, low serum levels of IgA, high serum levels of α-fetoprotein (≥10-fold the upper limit of normal), or A-T karyotype abnormalities (≥4% of metaphase lymphocytes with translocations at 7p14, 7q35, 14q11, 14q32, 2p12, or 22q11, as described in 1982).8 When no blood samples were available from pediatric patients or their parents, making analysis of ATM impossible, A-T was

Diagnosis and sociodemographic characteristics

From June 2006 to September 2007, 242 diagnoses of A-T were confirmed according to the described diagnostic criteria; 240 patients born from 1954 to 2005 were enrolled in the cohort (2 patients declined to participate). A-T was diagnosed based on clinical, laboratory, and molecular criteria for 76.7% (184/240) of the patients and based on clinical and laboratory criteria for only 23.3% (56/240) of the patients. In the latter group, in addition to ataxia, 96.4% (54/56) of the patients presented

Discussion

We have associated morbidity and mortality from A-T with the type of mutation in ATM using data from 240 patients. Analysis of this cohort indicated that time to diagnosis decreased from 1954 to 2007, possibly because of increasing knowledge about the disease and the availability of karyotype analysis in 1982 and ATM sequence analysis in 1997. Despite these advances and the fact that patients are almost always given a diagnosis of A-T at teaching hospitals because of the rarity and complexity

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      The disease AT itself has a highly variable presentation, with variant AT coined for patients with mild symptoms [67]. Age of symptom onset and presentation are known to be influenced by the genotype of AT patients and whether activity of the ATM protein is retained [68–71]. Numerous case reports exist for such patients who are either diagnosed late or otherwise do not follow the natural history of AT, including patients with mild or missing symptoms as a result of a mutation with partial function [72–76].

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    Supported by Sophie and Yves Ayache, CEREDIH (French National Reference Center for Primary Immunodeficiencies), and INCa (National Cancer Institute of France).

    Disclosure of potential conflict of interest: A. Fischer receives research support from CEREDIH. The rest of the authors have declared that they have no conflict of interest.

    Romain Micol is currently affiliated with Transgene, Centre d’Infectiologie Lyon Biopôle, Lyon, France.

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