This retrospective cohort described 218 patients with AT in Latin America. Cerebellar ataxia was the first manifestation (around 2 years of age), followed by a myriad of symptoms as patients grow older: ocular and cutaneous telangiectasia, postural changes, ocular apraxia, dysarthria, and excessive salivation. After 8 years of age, patients presented with dysphagia, endocrinologic and metabolic disorders, and use of wheelchair. Due to its rareness (estimated prevalence of less than 1–9/100,000 and incidence between 1 in 20,000/100,000 live births [14]) and lack of telangiectasias in initial presentation, it is not uncommon to observe a significant diagnostic delay among AT patients, usually around 4 years after onset of symptoms [15,16,17,18]. This situation has been changing as access to newborn screening (NBS) is growing worldwide. T-cell receptor excision circles and kappa-receptor excision circles measurements through Guthrie cards at birth can detect AT patients before clinical symptoms occur. Despite a curative treatment is not available, early diagnosis of AT allows to carry out timely in-depth immunological and genetic testing, may prevent the development of severe infections, and improve quality of life [19,20]. Currently, many countries among Latin America are leading efforts to implement NBS for immunodeficiencies and reduce the diagnostic and treatment delay [21].
Infections are frequent among patients with AT, mainly in the upper and lower respiratory tract (pneumonia, bronchitis, otitis, and sinusitis), varying from 40–70% among studies [15,16,17,18,22]. As also shown by our analysis, bacteria are the most frequent pathogens. Some relevant viral infections and opportunistic agents have also been reported [22,23], but much less often (< 10% and < 2% of cases, respectively). In addition, bronchiectasis is commonly described, probably due to recurrent lower respiratory tract infections and chronic inflammation [9,16].
Regarding the immunological profile, we found low IgA and high IgM levels the most frequent humoral defects among AT patients, followed by low IgG in 28% of patients. Although no severe adverse reactions, variable vaccine responses were observed, with higher seroconversion with tetanus, measles and rubella vaccines, and lower titles of specific IgG to pneumococcus and hepatitis B. In the cellular compartment, CD3+, CD4+, CD8 + and CD19 + lymphopenias were present in most cases. These abnormalities of the adaptive immune system were observed by most cohorts [9,15,16,22,24,17,25], some of them even suggesting the “hyper IgM profile” to be included in the diagnostic criteria [18].
Some studies have tried to correlate infection symptoms to immunoglobulin levels in AT patients. Moin and colleagues [17], showed a positive correlation between clinical immunologic symptoms and immunoglobulin deficiencies. On other hand, Nowak-Wegrzyn et al. [22] found no association between frequency of sinopulmonary infections and deficiency of IgG, IgA, or subclasses of IgG. In the present study, although IgG was not correlated with infections, there was a significant association between serum IgA levels ≤ 7 mg/dL and recurrent airway infections. Interestingly, despite frequent T cell lymphopenia in many cases, our patients rarely presented with opportunistic infections.
The discrepancy between the frequent laboratory expression of humoral and cellular abnormalities and the variable clinical expression with infections is still subject of debate; there is evidence of more complex immune defects in these patients. Kraus et al. [26] demonstrated abnormal TCR-Vβ repertoires, with different degrees of clonality and reduced expression; no clear clustering of expansions to specific TCR-Vβ genes and abnormal PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in 50% of the patients. Conversely, Weitering et al. [27] recently published a study that shown that AT patients have a fully developed memory T cell compartment despite strongly reduced naïve T cells, which can be explained by the presence of normal numbers of stem cell memory T cells in the naìve T cell compartment, which support the maintenance of the memory T cells. There is also evidence that milder phenotypes may be influenced not only by residual kinase activity, but abnormal activation of downstream responders to double-strand breakage in the Mre11-Rad50-Nbs1 complex [28,29].
Few studies evaluated longitudinally the immunological markers of these patients. Early evidence suggested immunodeficiency was progressive [30,31]. Despite that, more recent cross-sectional data [22,24] showed that immune abnormalities tend to not deteriorate throughout the time. In fact, Chopra et al. [24] even highlight the importance to screen for other factors besides immunodeficiency in patients presenting later with chest symptoms, such as interstitial lung disease, swallowing disorders, poor cough reflex or neurological degeneration. Indeed, in our study, lymphocyte counts did not decay as patients grow older, but there was a significant decrease in IgA and IgM levels with age. This information should be taken into consideration in clinical practice, as periodic immune evaluation is recommended in all patients, especially in those who present with a significant infectious phenotype.
Currently, the management of AT is based on supportive care and symptomatic treatment [32]. Even though some treatments aiming to slow neurodegeneration with antioxidants have risen during the last decades, evidence is still lacking [32,16]. Due to the complexity and severity of AT, patients should receive a multidisciplinary team of health care professionals [33,34,35,36]. Multidisciplinary rehabilitation therapy enables to preserve and improve activity levels, muscle strength and prevent joint contractures [35]. Occupational therapy helps patients to use devices for daily activities and maintain an adequate sitting position [36]. All patients in our cohort were being treated with at least one complementary treatment, including unusual methods like equine therapy and hydrotherapy.
Cancer is the leading cause of death among AT patients [15,22]. Like in other reports [37,38,39,40], our cohort showed hematologic cancers (lymphomas and leukemia) were the most common. It was also observed a high rate of positive familial history of cancer (around 20%). This enhanced cancer susceptibility is well stablished and can be explained by impaired DNA damage responses and radiosensitivity. Besides that, Desimio et al. [41] evidenced reduced NKG2D expression in NK cells of patients with AT, which may contribute to susceptibility to cancer and infections.
Infections are the second major cause of death in patients with AT [9]. Prophylactic antibiotics and immunoglobulin replacement therapy (IgRT) are beneficial in decreasing the severity and frequency of infections [15]. We reported relatively high rates of success with these treatments (57% and 71%, respectively). Traditionally, IgRT is considered in patients with recurrent infections and evidence of low IgG levels and/or poor antibody responses. Further studies are needed to assess the role of prophylactic antibiotics and IgRT in AT-related mortality.
In our study, we found similar mean time of survival than other studies [16,22,34,42], with most patients with AT surviving until the second or third decade of life. Our multiple regression analysis showed that both female gender and low IgG level at first immunological evaluation were significant factors in reducing lifespan of AT. This information is useful in clinical practice, as early interventions in these groups of patients may lead to improved care or a benefit in mortality.
This retrospective cohort study describes the largest cohort of patients with AT in Latin America, providing relevant information of the clinical, immunological profiles, and survival estimates. Despite that, there are some limitations in our study. First, being a retrospective, questionnaire-based study, selection and information biases must be considered. Second, the clinical spectrum of AT is not uniform; different ATM mutations, residual protein function and level of kinase activity lead to varied clinical and laboratorial phenotypes [43]. Patients with this “variant” or “atypical” AT may present symptoms at a later age of onset and longer survival rates, in contrast to the “classical” presentation [5]. Third, genotype information and functional assays are still lacking in some countries of LA; by the time of the study, they were rarely available. Due to that fact, we could not gather these data from patients.
