**2. Clinical picture and management**

In the classic presentation of AT, ataxia is often the first diagnostic sign that appears during the toddler years, usually manifest between 6 and 18 months of age. Children also have difficulty standing or sitting still and may sway slowly side-to-side or backwards. Because most of the children with classic AT have stable neurological symptoms for the first 4–5 years of life, they can initially be diagnosed as having "ataxic cerebral palsy" [33]. Beyond the age of 10, the movement problems typically cause a child to be confined to a wheelchair [34]. Eye movement abnormalities emerge in early school years. Dysarthria, which is the consequence of impaired coordination of respiratory, phonatory, and bulbar functions, can occur at any time and may or may not progress [35, 36]. Drooling may persist beyond expected ages. Swallowing

difficulties typically worsen in early teen years. Most of these neurological problems stop progressing after the age of about 12–15 years. AT patients manifest hallmarks of cerebellar dysfunction such as truncal swaying, gait ataxia, dyssynergia, muscle hypotonia, and sudden falls [33], and may have abnormal involuntary movements, including chorea, dystonia, dysphagia, athetosis, myoclonic jerks, or various tremors [37, 38]. Other extrapyramidal symptoms may include body hypokinesia or bradykinesia and facial hypomimia [34, 35]. Distal-to-proximal advancing loss of tendon reflexes is also characteristic of AT [39], reflecting a progressive sensory and motor neuropathy [35, 40].

Cerebellar degeneration in AT originates from atrophy of cerebellar vermis and hemispheres involving the dendrites and axons of Purkinje cells (PCs) and granule neurons [2]. However, microcephaly does not usually occur in AT patients because it is caused by the progressive accelerated aging process. For the majority of AT patients, neuroimaging studies in the toddler years and early childhood years are normal. As the disease progresses, MRI studies support the pathological finding of progressive and diffuse cerebellar atrophy [34, 41]. Due to the radiation exposure inherent in computed tomography (CT), MRI is the preferred method of visualizing the central nervous system (CNS) in patients with AT. Intellectual disability is not a common sign in AT; however, it occasionally occurs [8]. The correlation of neurodegenerative phenotype and ATM deficiency remains unclear, but the hypothesis suggested that ATM is the main player in maintaining cellular homeostasis and preventing disease in the nervous system. The prevailing dogma in the field is that specific neuronal cells within the cerebellum (primarily Purkinje and granule cells) are particularly sensitive to the loss of ATM. Normal ATM protein may allow neurons to repair damage DNA or initiate apoptotic pathway [42, 43]. On the other hand, neurodegeneration may be attributable to deficient-reactive oxygen species (ROS) homeostasis following dysfunction of ATM in neurons [34].

The second major symptom of AT ocular telangiectasias often occurs after the onset of neurological symptoms, usually by the age of 5–8 years, sometimes later or never. The absence of telangiectasias does not exclude the diagnosis, but is a common cause of delayed diagnosis [44, 45]. Telangiectasias may also appear on sun-exposed areas of skin in some patients and in other locations such as the pharyngeal wall, and have been seen deep inside the brain of older people with AT. The ocular telangiectasia do not bleed or itch, though they are sometimes misdiagnosed due to chronic conjunctivitis or allergy [20, 46].

Other ocular symptoms include: abnormal eye movement and visual disturbances caused by degeneration of the cerebellar cortex manifesting in AT including oculomotor apraxia, periodic alternating nystagmus (PAN), gaze-evoked nystagmus, strabismus, and vestibulo-ocular (VOR) abnormalities [47–49]. Patients with AT have prominent defects in the eye movement systems that stabilize images on the retina and in the systems that shift direction of gaze.

The next clinical manifestation of AT are recurrent respiratory infections. Chronic lung disease develops in more than 25% of people with AT, mostly progressing with the increasing age and neurological deterioration. Respiratory complications are the leading cause of morbidity and mortality among AT patients, as 50% of patients die in adolescence from respiratory failure [13, 16, 50]. Generally, there are three major types of lung diseases in AT patients, including recurrent sinopulmonary infections and bronchiectasis, interstitial lung disease (ILD)/pulmonary fibrosis, and neuromuscular disorders affecting respiratory function [13, 51, 52]. The pathogenesis of lung disease in AT patients is multifactorial, related to immune deficiency, abnormal

DNA damage repair, signs of premature aging, chronic inflammation, and oxidative stress [53]. Patients with respiratory infections are most often found to have reduced or absent serum immunoglobulin G2 (IgG2) and a defect in class switch recombination (CSR) [54, 55]. These mechanisms are associated with disease progression due to recurrent infections, emphysema, ineffective cough and airway clearance disorders, and oropharyngeal dysphagia [51, 52, 56].

People with AT have a decrease in their measured forced vital capacity (FVC). This may result in a functionally restrictive lung phenotype, similar to that with neuromuscular weakness associated with reduced lung reserve. A weak or ineffective cough leading to impaired mucociliary clearance (MCC) can also contribute to reduced respiratory capacity. Reduced FVC and MCC can cause recurrent respiratory infections. In addition, the situation is exacerbated by the presence of immunodeficiencies, aspiration, increased chromosomal breakage, cell senescence, inflammation, and impaired DNA damage repair due to ATM deficiency [56–58]. Shortened telomeres and sensitivity to ionizing radiation are also characteristic of AT and can increase the risk of complications such as pulmonary fibrosis when treating malignancies [59, 60].

Interstitial lung disease has been described in individuals with AT, although the exact incidence is unknown. In patients with AT who died from chronic respiratory disease, ILD was present in about 25% [61]. Symptoms of ILD include a nonproductive cough lasting >1 month, shortness of breath, and fever. There are abnormal auscultatory changes over the lungs, and interstitial changes on chest radiography. ILD can occur even in the absence of immunodeficiency. Antibiotic therapy does not result in improvement [62]. Diagnosis of ILD on the basis of clinical examination is often difficult because symptoms are nonspecific. Restrictive lung disease on pulmonary function testing may suggest the presence of an interstitial process. In AT patients with pulmonary symptoms that do not completely resolve after intensive treatment of the infection, chest radiography is helpful, but due to increased radiosensitivity, MRI may become the technique of choice. A lung biopsy is required to confirm the diagnosis of ILD. However, the diagnostic benefits of a procedure such as a lung biopsy should always be weighed against the risks associated with anesthesia and surgery [62]. It should be considered that in patients with AT, secondary pulmonary lymphoma may clinically and radiographically mimic ILD [63]. The increased risk of developing pulmonary fibrosis in patients with AT may be a result of chemotherapy for malignancies [60]. In patients with AT, progressive neuromuscular decline can worsen pulmonary function, e.g., bulbar muscle dysfunction can result in swallowing dysfunction and chronic aspiration [13, 57].

Chronic lung disease is the leading cause of death in AT (about 30%), and early intervention is key to preventing or slowing its progression. Pulmonary function tests should be performed in all children with AT starting at the age of 6 and continued annually [56, 64], and performed prior to any surgical procedure requiring anesthesia.

Chest computed tomography (CT), considered to be the "gold standard," is the best tool for assessing changes in chronic lung disease (CLD) [65]. Due to hypersensitivity to radiation, exposure to ionizing radiation should be avoided in patients with AT [66, 67]. MRI of the chest becomes such a method, which is a useful nonradiation tool in several lung diseases, because it is highly compatible with computed tomography of the chest [68–70].

The manifestation of immunodeficiency in AT is usually sinopulmonary infections that are often manifested early in life [13, 51]. Abnormalities of the immune system are observed in approximately two-thirds of patients with AT due to impaired antigen receptor recombination and class switch recombination (CSR). Generally, selective

immunoglobulin A (IgA) deficiency, hypogammaglobulinemia, immunoglobulin G (IgG) subclasses' deficiency, gammopathy, and failure to make specific antibodies in responses to vaccines or infections are frequent findings in AT patients [71, 72]. A small percentage of patients with AT may also have hyper-immunoglobulin M (hyper-IgM). Since some existing symptoms of AT, such as atactic gait and dysarthria, might not be present in infancy, the diagnosis of these patients may be confused with the diagnosis of hyper-IgM syndrome [73–75]. The most common deficiencies of cellular immunity are lymphopenia with decreased B- and T cells, reduced number and faulty functioning of CD4+ T lymphocytes [71, 76]. The progressive reduction of the cellular compartment during life may reduce life expectancy of people with AT [77]. Another problem in AT patients is an increased risk of developing autoimmune and/or chronic inflammatory diseases that are associated with immune dysregulation [78, 79]. About a quarter of patients with AT may have autoimmune disorder, the most frequent organ involved being the skin with vitiligo and psoriasis. Diseases, such as Hashimoto's thyroiditis (HT), juvenile idiopathic arthritis (JIA), immune thrombocytopenic purpura (ITP), and autoimmune hemolytic anemia (AIHA), have also been reported [80–82].

All patients with AT should have at least one comprehensive immunological evaluation to assess the number and type of B- and T cells, the levels of serum immunoglobulins (IgG, IgM, and IgA) and antibody responses to T cell-dependent (e.g., tetanus, *Hemophilus influenzae* b) and T cell-independent (pneumococcal polysaccharide) vaccines [51, 83].

There are no general recommendations as to how often immunological tests should be repeated, certainly they should be performed when problems with infections occur or worsen [56, 84, 85].

Immunization of people with AT may be less effective, and these individuals often have a suboptimal response to pneumococcal vaccine, as well as to other vaccines [86]. If antibody function is normal, all routine childhood immunizations should be given, except the measles, mumps and rubella (MMR) vaccine [56]. Among other reasons, because chronic cutaneous granulomas can be associated with AT [87, 88] and they have been linked to replication of the incompetent rubella virus vaccine strain detected by PCR [89–91].

There are also skin lesions. Common skin abnormalities associated with AT include oculocutaneous telangiectasias, skin atrophy, café-au-lait spots, vitiligo, seborrheic dermatitis, and premature graying [92–94]. These patients may also have an increased incidence of vitiligo and warts, which may be due to immunodeficiency, making treatment of these complications difficult [51]. Other skin changes are cutaneous granulomas with unknown pathogenesis that occur uncommonly in various inborn errors of immunity (IEI) and manifest in almost 10% of AT patients [95]. These lesions have not been associated with an identifiable pathogen, but sometimes can be associated with painful ulceration, bleeding, or might erode down to muscle or bone [87, 96].

It has been proposed that cutaneous granulomas can be considered as a manifestation of dysregulation in innate immunity, wound healing, and tissue repair explained by the immune defects in these primary immunodeficiency disorders (PIDs) [87]. Recent data suggest that more than 40% of AT patients with cutaneous granulomas present a hyper-IgM phenotype. AT patients with granulomas had an equal distribution of all lymphocyte subsets, except for a significant reduction in B cells, naive CD4+ cells and naive CD8+ T cells, in the presence of normal total natural killer (NK) and T cells [11, 87]. B cells, CD19+, appear to play a fundamental role in wound healing; it was observed that mouse CD19 deficiency stopped skin wound healing [97].

Recently, an association has been found between the administration of live rubella vaccines and the formation of cutaneous and visceral rubella-positive granulomatous in people with AT, as well as in other immunodeficiencies with impaired DNA repair [98, 99].

Poor growth is a common feature in classic AT [100–102]. Various factors may influence growth failure in AT. They include chronic infections, insulin-like growth factor 1 (IGF-1) hormone deficiency, and reduced nutrient intake due to fatigue and swallowing problems [84, 102–104]. On the other hand, growth retardation is common in patients with AT and may be a primary feature of the disease, directly related to the ATM mutation. The study, in an Israeli cohort of patients with AT, demonstrated that impaired growth was more prominent in females than males, and that this difference is apparent at an age before gonadotropins begin to affect growth rates. Delayed pubertal development is often described as an aspect of AT. Gonadal atrophy or dysgenesis resulting in delayed pubertal development and early menopause has been reported [105–107]. We know of pregnancies in people with mild AT, but not in anyone with the classic form of the disease [108 and own observations].

Vitamin D deficiency has been commonly found in patients with AT, given the implications for bone health and possibly for susceptibility to malignancies [12].

People with AT have been found to have cholesterol profiles associated with a higher risk for cardiovascular disease [109], diabetes with insulin resistance [110], and steatohepatitis [111, 112]. These findings suggest that ATM dysregulation is associated with the development of metabolic syndrome, demonstrating a significant role of functional protein in glucose and insulin metabolism [113, 114]. People with AT should undergo screening for these conditions during adolescence and early adult life so that timely treatments can be initiated.

People with AT have an increased predisposition to malignancy, ranging from 10 to 25% [73, 115]. The most common types of malignancies in patients with AT are lymphoid tumor. Leukemias and lymphomas (T-cell acute lymphoblastic leukemias [ALLs] and T-cell lymphocytic leukemias [T-PLL]) tend to occur in younger patients under the age of 20. These two types of cancers account for 85% of all malignancies in children [116]. B-cell non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) have also been frequently described in patients with AT [117, 118]. Adult patients with AT are susceptible to both lymphoid malignancies and solid tumors, such as cancers of the breast, stomach, liver, parotid gland, and esophagus [84, 119].

Another factor that may predispose to the development of lymphomas (such as HL and B-cell NHL) is the Epstein-Barr virus (EBV). Individuals with AT present an impaired immune response to EBV infection, which is associated with cellular immune deficiencies and DNA repair defects [11, 120].

Adults with AT may benefit from annual whole-body MRIs to screen for malignancies. Patients diagnosed with malignancy should be treated in specialist centers and treatment modifications and dose reductions are usually needed to minimize side effects and optimize outcomes [121, 122].

Heterozygous carriers of the ATM mutation have an increased risk of developing breast cancer, with an estimated risk of 5.1 over that in the whole population, whereas there is no evidence for an increased risk of lymphoid malignancies [119, 123]. A 2016 meta-analysis found the cumulative risk of breast cancer in carriers to amount to approximately 6% by age 50 and 30% by age 80 [124]. While there is insufficient evidence that ATM heterozygotes may increase the risk of other cancers, there are studies suggesting an increased risk of gastric and colorectal cancers [125]. Cancer

screening guidelines are being developed for ATM mutation carriers. Standard breast cancer surveillance, including monthly breast self-exam, yearly breast MRI and mammogram and, additionally for both male and female ATM mutation carriers, colon cancer screenings with a colonoscopy (every 3–5 years compared to every 10 years for the whole of the population), should be performed [126].

Another complication observed in older people with AT pertains to orthopedic complications: these include an acquired clubfoot deformity and, less commonly, scoliosis. Sometimes finger contractures develop, most often due to inflammatory connective tissue disease, but sometimes due to neuropathy [127 and own observation].

Some people with AT suffer from bladder and/or bowel incontinence, recurrent vomiting especially in the morning, decreased sleep efficiency, and dizziness which may connect with neurological complications [84, 128].

Feeding and swallowing (chewing) can become difficult for people with AT as they get older [52]. Involuntary movements can make it difficult to eat independently and cause a mess or extend meal times excessively. Dysphagia is common in AT and usually appears in the second decade of life due to neurological changes that impair the coordination of oropharyngeal movements. Problems involving the pharynx can cause aspiration of fluids, food, and saliva. Dysphagia with silent aspiration can cause pulmonary sequelae in AT [52].

Dysphagia can also cause nutritional deficiencies, as the process of eating becomes slow and difficult. Some people with AT stop eating or reduce their food intake due to frustration or fatigue with the process. Inadequate caloric intake can contribute to stunted growth in children and weight maintenance in the elderly, causing a lower body mass index (BMI) compared to healthy, age-matched controls [104, 129–131]. Poor nutrition can exacerbate symptoms of neurological disability. Abnormal respiratory-swallowing coupling is associated with an increased risk of aspiration and can cause swallowing problems before the development of feeding and pulmonary sequelae in AT [132].
