Abstract
Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype–phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.
Highlights
Ataxia telangiectasia (AT) is a rare genetic multisystem disorder of childhood due to mutations in the Ataxia Telangiectasia Mutated (ATM) gene
When we evaluated the incidence of cancer according to both genotype and the immunological status at diagnosis we found that cancer occurred in 7% of patients who belonged to T and B cell compartment (T/T)-Group A (1/13) and in 45.4% (5/11) of patients who belonged to T/TGroup B (P = 0.06)
The prognosis is very poor since the majority of patients require wheelchair by 8–10 years of age and most patients usually die in their mid-20 s from malignancy or chronic pulmonary disease [19]
Summary
Ataxia telangiectasia (AT) (http://omim.org/entry/208900) is a rare genetic multisystem disorder of childhood due to mutations in the Ataxia Telangiectasia Mutated (ATM) gene. Different types of ATM gene mutations are associated to different forms of the disease. Truncating mutations are related to the classic form of AT and are associated to the complete absence of the protein function. Missense mutations allow for some residual ATM kinase activity, and this causes milder forms of AT [3–5]. ATM protein exerts a central role in the signal-transduction pathway activated by DNA double-strand breaks (DSBs); AT is considered the prototype of the DNA-repair defect syndromes [6, 7]. Gene rearrangements and DSBs repair by ATM are required for a proper maturation of either T or B cells [2]. In B cells the absence of a functional ATM protein leads to a defect in class switch recombination (CSR), supporting a role of ATM in this process [5, 8]
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