Abstract
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)
Highlights
Ataxia-telangiectasia (A-T) is a devastating human autosomal recessive disorder characterized by cerebellar degeneration, conjunctival telangiectasia, immunodeficiency, genetic instability, and cancer predisposition [1, 2]
Comparison of patients with and without IgA showed that beside IgA levels, none of the other immunoglobulins were different between the groups
The major interest of the present study is to investigate the clinical and immunological consequences of IgA deficiency in A-T and whether IgA is a possible marker to assess the prognosis of A-T patients
Summary
Ataxia-telangiectasia (A-T) is a devastating human autosomal recessive disorder characterized by cerebellar degeneration, conjunctival telangiectasia, immunodeficiency, genetic instability, and cancer predisposition [1, 2]. Recurrent infections and aspiration contribute to lung disease leading. A-T patients show endocrine abnormalities, such as insulin resistance, liver disease, and growth retardation [4,5,6,7,8]. The prevalence of patients with A-T in Europe is estimated to be 1 in 150,000. The life expectancy of patients with “classical” A-T is only between 15 and 25 years of age [9]. The major cause of death is progressive lung disease and malignancies such as lymphoma or acute leukemia [3, 9]. No curative therapy is available for A-T
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