Open access peer-reviewed chapter
Clinical and laboratory features of rare genetic disorders that can be discriminate with A-T.
Abstract
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, telangiectasias, immunodeficiency, recurrent sinopulmonary infections, cancer susceptibility, and radiation sensitivity. AT is a complex disorder, whose neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities: immunoglobulin and antibody deficiencies and lymphopenia. AT patients have an increased predisposition for cancers, particularly of lymphoid origin. AT is caused by mutations in the ataxia telangiectasia mutated (ATM) gene, and the role of the ATM protein is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and other genotoxic stresses. The diagnosis of AT is usually supported by the combination of neurological clinical features and specific laboratory abnormalities (immunoglobulin A (IgA) deficiency, lymphopenia, and increased alpha-fetoprotein (AFP) levels). There are several other neurological and rare disorders that physicians must consider when diagnosing AT. Treatment of neurological symptoms in patients with AT is only symptomatic and supportive, as there are no known treatments that can slow or stop neurodegeneration. However, other symptoms of AT, such as antibody deficiency, lung disease, developmental disorders, diabetes, or cancer, can be effectively treated. Some hope is associated with the treatment of dexamethasone in the patient’s own blood cells, which relieves neurological symptoms.
Keywords
- ataxia telangiectasia
- immunodeficiency
- radiation sensitivity
- DNA double-strand breaks
- ATM protein
1. Introduction
The first description of patients with ataxia telangiectasia (AT) was published in 1926 [1], but it was not until 1958 that the term “ataxia telangiectasia” was first coined. AT was given its commonly used name by Elena Boder and Robert P. Sedgwick, who described a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia, and frequent pulmonary infection [2]. Ataxia telangiectasia, or AT, is also referred to as the Louis-Bar syndrome (OMIM #208900). Orphanet Orpha Number: ORPHA100.
Ataxia telangiectasia is an autosomal recessive cerebellar ataxia [3]. It is also included in inborn errors of immunity (IEI) with chromosomal instability, DNA repair disorders, and less commonly known as neurocutaneous syndrome [4]. The disease is caused by a mutation in the
Ataxia telangiectasia is characterized by progressive cerebellar degeneration, oculocutaneous telangiectasias, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging, and susceptibility to cancer development, especially of lymphoid origin. Other abnormalities, such as growth failure, poor pubertal development, gonadal atrophy, insulin-resistant diabetes, lung diseases, cutaneous abnormality, and cardiovascular disease, have also been reported in AT patients [12, 13, 14].
The prevalence of AT is estimated to be <1–9/100,000. However, the incidence of AT may be higher 1/40,000 in consanguineous population or those populations with founder effect [15]. AT patients have poor prognosis; the median survival is 25 years with a wide range. The two most common causes of death in these patients are chronic pulmonary diseases and malignancy [14, 16]. AT patients show remarkable clinical and laboratory differences that reflect the presence of genotype/phenotype correlations in these patients or other genetic/environmental disease-modifying factors. The majority of ATM mutations lead to a truncated protein, while some missense and splicing site variations cause milder phenotype [17].
Ataxia telangiectasia patients have much milder clinical progress as a result of retained expression of either normal [18, 19] or mutant ATM protein with residual activity [20, 21, 22]. These patients often retain the ability to walk into adulthood and consequently might be diagnosed when adults [19, 23]. The terms “classic” and “mild” are used to distinguish two different but widely recognized clinical presentations of AT. People with mild AT have less severe, later onset of symptoms associated with longer survival. Ataxia telangiectasia-like disorder (ATLD) [24, 25, 26], ataxia oculomotor apraxia type 1 (AOA1) [27, 28], and ataxia oculomotor apraxia type 2 (AOA2) [29, 30, 31, 32] have neurological features similar to those of AT.
Advertisement
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, 48, 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, 57, 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, 69, 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, 74, 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, 81, 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,
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, 90, 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, 93, 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, 101, 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, 103, 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, 106, 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, 130, 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].
Advertisement
3. AT diagnosis
A clinical diagnosis of AT can usually be made on the basis of the presence of characteristic neurological and non-neurological clinical signs and specific laboratory findings. Laboratory studies may be helpful in diagnosing AT by finding elevated alpha-fetoprotein (AFP) levels after age 1, spontaneous and X-ray-induced chromosomal breaks and/or rearrangements in cultured lymphoblastoid cell lines, and reduced cell survival after irradiation [133]. Imaging studies show cerebellar atrophy, not always apparent on MRI in young children, which does not necessarily correlate with the clinical picture [127].
The most common immunological abnormalities found in AT are deficiency of serum IgA, IgE, and selective IgG subscales, elevated IgM levels, lymphopenia (affecting mainly T lymphocytes), and reduced diversity of the T-cell receptor (TCR) immune repertoire [51, 71]. It is important to combine the symptoms present with the results of laboratory tests. A definitive diagnosis can be confirmed by the absence or deficiency of ATM kinase activity, measured in a lymphoblastoid cell line derived from the patient’s blood or in fibroblasts from a skin biopsy, and finally the detection of pathological mutations in the
As the whole exome sequencing becomes increasingly standard clinical practice for individuals with unusual and/or unexplained symptoms, it is likely that more people with mild forms of AT will be diagnosed [136]. This will necessarily change our views on the phenotypic expression of AT. Prenatal genetic diagnosis is possible when prospective parents each have confirmed pathogenetic mutations in ATM. Preimplantation genetic diagnosis (PGD) can avoid the birth of an affected child in parents who have an affected child (or children) with AT. At least two such cases have been described in the literature so far [137, 138].
Additionally, the newborn screening (NBS) test for severe combined immunodeficiency (SCID), introduced in recent years, can identify children born with other immunodeficiencies, including AT, which involve a deficiency or absence of T and B lymphocytes [139, 140]. Despite the lack of effective treatments for AT, early diagnosis allows for genetic counseling and family education, as well as intensive supportive care. Genetic counseling can provide AT genetic testing for siblings and other family members and help interpret test results.
Differential diagnosis. There are some rare disorders that can be misdiagnosis with AT based on similar clinical and laboratory features. The most common disorders that are sometimes confused with AT are: cerebral palsy (CP) and Friedreich’s ataxia (FA or FRDA). Each of these diseases can be distinguished from AT based on neurological examination and clinical history. CP, unlike AT, is a nonprogressive motor dysfunction resulting from early brain injury [141]. In addition, most children with CP manifest regional or diffuse spasticity in a pattern not seen in AT. Children with ataxia due to CP will not manifest laboratory abnormalities associated with AT. In FRDA, symptoms usually tend to present later between the ages of 10 and 16 and differ from AT in the absence of telangiectasias and oculomotor apraxia, the early absence of tendon reflexes, a normal AFP, the frequent presence of scoliosis, cardiomyopathy, and abnormal ECG features [84, 142].
Other disorders with childhood-onset ataxia include ataxia telangiectasia like disorder 2 (ATLD2), ataxia oculomotor apraxia type 1 (AOA1), ataxia oculomotor apraxia type 2 (AOA2), radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome (RNF168 deficiency), and spinocerebellar ataxia with axonal neuropathy (SCAN1).
Immunodeficiency is one of the common symptoms of Nijmegen breakage syndrome (NBS, with birds like face and microcephaly), ataxia telangiectasia like disorder 1 (ATLD1, due to meiotic recombination 11 homolog A (MRE11) deficiency), and RIDDLE syndrome that can be confused with AT. As in AT, elevated serum AFP levels are also present in AOA2 and RIDDLE syndrome. Therefore, knowledge of the gene mutation in a child with ataxia, immunodeficiency, telangiectasias, radiosensitivity, and elevated AFP can distinguish AT from other disorders with ataxia of childhood onset [11, 143]. A comparison of the clinical and laboratory features of these disorders is shown in Table 1.
| Disorder | Gene | Ataxia | Telangiectasia | Immunodeficiency | Radiosensitivity | Malignancy | AFP |
|---|---|---|---|---|---|---|---|
| A-T | + | + | + | + | + | ↑ | |
| ATLD1 | + | — | — | + | NK | N | |
| ATLD2 | + | + | — | NK | + | N | |
| AOA1 | + | — | — | + | — | N | |
| AOA2 | + | — | — | — | — | ↑ | |
| NBS | — | — | + | + | ++ | N | |
| RIDDLE | +/− | + | + | + | NK | ↑ |
Table 1.
ataxia-telangiectasia (A-T), ATLD 1 – ataxia telangiectasia-like disorder 1 (ATLD1), ataxia telangiectasia-like disorder 2 (ATLD2), ataxia oculomotor apraxia type 1 (AOA1), ataxia oculomotor apraxia type 2 (AOA2), Nijmegen breakage syndrome (NBS), radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE), alpha-fetoprotein (AFP).
Advertisement
4. AT treatment
Treatment of AT is symptomatic and supportive. As regards the neurological symptoms, no therapy can slow degeneration, but physical, occupational, and speech therapies as well as exercise may help maintain function. In some patients, certain anti-Parkinson and antiepileptic drugs may partially ameliorate symptoms. Commonly prescribed drugs include trihexyphenidyl (an antimuscarinic), amantadine (an antiparkinsonian) [144], baclofen (an antispastic), and botulinum toxin injections (a paralytic). Less commonly used drugs that may also be beneficial include gabapentin and pregabalin (an anticonvulsant), and clonazepam (a tranquilizer and antiseizure medication) [34, 145]. Also, glucocorticoids (especially betamethasone) have been reported to improve neurological symptoms in AT but corticosteroid side effects were quickly observed [146]. To avoid the characteristic side effects of long-term steroid administration, a method of monthly infusions of autologous erythrocytes loaded with dexamethasone has been developed (EryDex; EryDel, Urbino, Italy). Preliminary results are promising, with demonstrated efficacy in improving neurological status, especially in young patients with AT [147, 148].
Regular screening to assess lung function can detect early deterioration of lung function and allow earlier intervention. These interventions may include chest physiotherapy, a cough support device, and assistance to improve MCC. These interventions can be used daily as maintenance therapies. In some children with AT, with bronchial hyperresponsiveness, bronchodilators may benefit [57]. Children with chronic or recurrent sinopulmonary disease should be treated with antibiotics when appropriate, chest physiotherapy and airway clearance techniques to reduce the risk of developing bronchiectasis and chronic lung disease [57].
To maintain respiratory muscle strength and minimize the progression of lung disease, it is important to have adequate nutrition and maintain a normal body mass index. All people with AT should avoid secondhand smoke exposure and have minimal exposure to other environmental pollution. If lung disease develops, appropriate management should be considered: liberal use of antibiotics, antibiotic prophylaxis, corticosteroids, and immunoglobulin supplementation in those patients with AT who are immunocompromised [57, 62].
Recurrent lung infections may involve dysfunctional swallow (dysphagia) with aspiration, but some people with AT can be taught to drink, chew, and swallow more safely reducing the risk of aspiration [56]. Because the nutritional deficit in some people with AT may be more severe than previously appreciated, early nutritional intervention and ongoing nutritional support and education for patients, families, and caregivers are crucial [101, 149].
High-calorie foods are then recommended, and a gastrostomy tube (G-tube or feeding tube) is rarely used. A gastrostomy tube is recommended when a child cannot eat enough to grow, is not gaining weight and when dysphagia with aspiration causes breathing problems and/or when meals take too long or stressful [150].
People with IgG deficiency or impaired antibody function should receive standard immunoglobulin replacement therapy. Despite the low T-lymphocyte count found, prophylactic antibiotic use to prevent opportunistic infections is not necessary, unless individuals are treated chronically with corticosteroids, other immunosuppressive drugs, or chemotherapy [56, 84, 85]. Individuals with normal ability to produce antibody should receive an annual influenza vaccine, and additional pneumococcal vaccines at intervals to maintain high levels of antipneumococcal antibodies [85].
Cutaneous granulomas can be persistent, progressive, and very difficult to treat. To date, treatment has been attempted with topical and systemic corticosteroids, intravenous immunoglobulin, antitumor necrosis factor therapy, and antiviral therapy, with either mediocre or transient results [96, 151]. Only in immunodeficient patients with DNA repair disorders who underwent hematopoietic stem cell transplantation due to cancer observed granuloma healing [152, 153, and own observation].
In adolescent females, sex hormone replacement therapy may need to be considered to support optimal linear growth, development of secondary sex symptoms, and prevention of osteoporosis. Vitamin D levels should be monitored and treated with an appropriate dose [12].
Despite the poor prognosis of many AT cancers, they manage to be successfully treated. Cancer treatment should only take place in specialized oncology centers and only after consultation with a clinician who has specific experience in AT. Standard cancer treatment regimens should be modified to minimize or prevent cytotoxicity from radiomimetic drugs [73, 85]. Radiotherapy can only be used exceptionally and at reduced doses. The use of cyclophosphamide needs to be monitored as late onset of severe hemorrhage from bladder telangiectasia has been observed [154]. Even with modified therapy, late complications of chemotherapy are observed in some people with AT [155]. Although routine bone marrow transplantation is not currently recommended [156], it has however been performed successfully in several cases of hematopoietic malignancies in AT [157, 158].
Advertisement
5. Quality of life
Children with AT experience varying degrees of difficulty in functioning at school due to progressive neurodegeneration. There is an impairment of fine and gross motor coordination, resulting in reduced writing and computer skills. Dysarthria and delayed speech initiation, poor facial expressions, and delayed reaction time to visual and verbal cues, which limit the ability to communicate, are observed. Eye movement disorders with oculomotor apraxia limit reading ability. Mental and physical fatigue is commonly observed. People with AT, through the prism of motor disability, may additionally be perceived as intellectually impaired without actually having any impairment. Social awareness is usually normal. Although this disparity can lead to social isolation and depression, many people with AT do well to overcome these difficulties, especially in the presence of a supportive environment at school. As survival and quality of life improve, some people with AT manage to complete higher education and lead independent lives with support [85].
Advertisement
6. Final remarks
That’s why a number of voluntary patient organizations and support groups have sprung up in various countries around the world, working closely with scientific and medical experts to find effective therapies to improve quality of life and provide education and support for families affected by AT. The most active internationally are the AT Children’s Project from the USA and the AT Society from the UK. In October 2014, a clinical guidance document on the diagnosis and treatment of ataxia telangiectasia in children was published by the UK AT Society [128]. To quickly make data on people with AT available to researchers and doctors for analysis, the Global AT Family Data Platform was launched in July 2016 [159]. In parallel with the Platform and voluntary patient organizations, work is underway on an international registry of patients with AT. The registry will include baseline and longitudinal data provided by clinicians and clinical centers that treat people with AT. Analysis of data from growing patient registries [128, 159] will inform natural history, improve disease management, and aid therapy development.
Advertisement
7. Conclusion
There are still many unresolved questions regarding the complexity and severity of AT, such as the influence of environmental factors, disease-modifying genes, epigenetics, telomere length, and the gut microbiome on the presentation, severity, and progression of various AT manifestations, which remain unknown.
Researchers are investigating ways to apply recent breakthroughs in the fields of gene and mutation-targeted therapies to AT [160, 161].
References
- 1.
Henner K. Apropos of the description of "ataxia teleangiectasis" by Mme Louis-Bar. Priority of the description, by lad. Syllaba and K. Henner in 1926, of the conjunctival vascular network. Revue Neurologique (Paris). 1968; 118 (1):60-63 - 2.
Boder E, Sedgwik RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics. 1958; 21 (4):526-554 - 3.
Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. The New England Journal of Medicine. 2012; 366 (7):636-646 - 4.
Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. Journal of Clinical Immunology. 2022; 42 (7):1473-1507 - 5.
Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 1988; 336 (6199):577-580 - 6.
Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995; 268 (5218):1749-1753 - 7.
Lavin MF, Gueven N, Grattan-Smith P. Defective responses to DNA single- and double-strand breaks in spinocerebellar ataxia. DNA Repair (Amst). 2008; 7 (7):1061-1076 - 8.
Chun HH, Gatti RA. Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst). 2004; 3 (8-9):1187-1196 - 9.
Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Human Molecular Genetics. 2007; 16 (18):2154-2164 - 10.
Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012; 119 (6):1490-1500 - 11.
Amirifar P, Ranjouri MR, Yazdani R, Abolhassani H, Aghamohammadi A. Ataxia-telangiectasia: A review of clinical features and molecular pathology. Pediatric Allergy and Immunology. 2019; 30 (3):277-288 - 12.
Nissenkorn A, Levy-Shraga Y, Banet-Levi Y, Lahad A, Sarouk I, Modan-Moses D. Endocrine abnormalities in ataxia telangiectasia: Findings from a national cohort. Pediatric Research. 2016; 79 (6):889-894 - 13.
Bott L, Lebreton J, Thumerelle C, Cuvellier J, Deschildre A, Sardet A. Lung disease in ataxia-telangiectasia. Acta Paediatrica. 2007; 96 (7):1021-1024 - 14.
Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Annals of Internal Medicine. 2000; 133 (10):770-778 - 15.
Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia-telangiectasia in the United States. American Journal of Human Genetics. 1986; 39 (5):573-583 - 16.
Crawford TO, Skolasky RL, Fernandez R, Rosquist KJ, Lederman HM. Survival probability in ataxia telangiectasia. Archives of Disease in Childhood. 2006; 91 (7):610-611 - 17.
Gilad S, Chessa L, Khosravi R, Russell P, Galanty Y, Piane M, et al. Genotype-phenotype relationships in ataxia-telangiectasia and variants. American Journal of Human Genetics. 1998; 62 (3):551-561 - 18.
McConville CM, Stankovic T, Byrd PJ, McGuire GM, Yao QY, Lennox GG, et al. Mutations associated with variant phenotypes in ataxia-telangiectasia. American Journal of Human Genetics. 1996; 59 (2):320-330 - 19.
Sutton IJ, Last JI, Ritchie SJ, Harrington HJ, Byrd PJ, Taylor AM. Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity. Annals of Neurology. 2004; 55 (6):891-895 - 20.
Carrillo F, Schneider SA, Taylor AM, Srinivasan V, Kapoor R, Bhatia KP. Prominent oromandibular dystonia and pharyngeal telangiectasia in atypical ataxia telangiectasia. Cerebellum. 2009; 8 (1):22-27 - 21.
Verhagen MM, Abdo WF, Willemsen MA, Hogervorst FB, Smeets DF, Hiel JA, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology. 2009; 73 (6):430-437 - 22.
Stewart GS, Last JI, Stankovic T, Haites N, Kidd AM, Byrd PJ, et al. Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype. The Journal of Biological Chemistry. 2001; 276 (32):30133-30141 - 23.
Hiel JAP, van Engelen BGM, Weemaes CMR, Broeks A, Verrips A, ter Laak H, et al. Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia. Neurology. 2006; 67 (2):346-349 - 24.
Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell. 1999; 99 (6):577-587 - 25.
Delia D, Piane M, Buscemi G, Savio C, Palmeri S, Lulli P, et al. MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. Human Molecular Genetics. 2004; 13 (18):2155-2163 - 26.
Fernet M, Gribaa M, Salih MA, Seidahmed MZ, Hall J, Koenig M. Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. Human Molecular Genetics. 2005; 14 (2):307-318 - 27.
Aicardi J, Barbosa C, Andermann E, Andermann F, Morcos R, Ghanem Q , et al. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Annals of Neurology. 1988; 24 (4):497-502 - 28.
Le Ber I, Moreira MC, Rivaud-Péchoux S, Chamayou C, Ochsner F, Kuntzer T, et al. Cerebellar ataxia with oculomotor apraxia type 1: Clinical and genetic studies. Brain. 2003; 126 (Pt 12):2761-2772 - 29.
Le Ber I, Bouslam N, Rivaud-Péchoux S, Guimarães J, Benomar A, Chamayou C, et al. Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: A clinical and genetic study in 18 patients. Brain. 2004; 127 (Pt 4):759-767 - 30.
Németh AH, Bochukova E, Dunne E, Huson SM, Elston J, Hannan MA, et al. Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34. American Journal of Human Genetics. 2000; 67 (5):1320-1326 - 31.
Izatt L, Németh AH, Meesaq A, Mills KR, Taylor AM, Shaw CE. Autosomal recessive spinocerebellar ataxia and peripheral neuropathy with raised alpha-fetoprotein. Journal of Neurology. 2004; 251 (7):805-812 - 32.
Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nature Genetics. 2004; 36 (3):225-227 - 33.
Boder E. Ataxia-telangiectasia: An overview. Kroc Foundation Series. 1985; 19 :1-63 - 34.
Hoche F, Seidel K, Theis M, Vlaho S, Schubert R, Zielen S, et al. Neurodegeneration in ataxia telangiectasia: What is new? What is evident? Neuropediatrics. 2012; 43 (3):119-129 - 35.
Crawford TO. Ataxia telangiectasia. Seminars in Pediatric Neurology. 1998; 5 (4):287-294 - 36.
Boder E, Sedgwick RP. Ataxia-telangiectasia. (clinical and immunological aspects). Psychiatrie, Neurologie und Medizinische Psychologie. Beihefte. 1970; 13-14 :8-16 - 37.
Shaikh AG, Zee DS, Mandir AS, Lederman HM, Crawford TO. Disorders of upper limb movements in ataxia-telangiectasia. PLoS One. 2013; 8 (6):e67042 - 38.
Pearson TS. More than ataxia: Hyperkinetic movement disorders in childhood autosomal recessive ataxia syndromes. Tremor and Other Hyperkinetic Movements (N Y). 2016; 6 :368 - 39.
Sedgwick RP. Boder E. In: Vinken PJ, Bruyn GW, editors. Handbook of Clinical Neurology. Vol. 14. Amsterdam: North Holland Publishing; 1972 - 40.
Kwast O, Ignatowicz R. Progressive peripheral neuron degeneration in ataxia-telangiectasia: An electrophysiological study in children. Developmental Medicine and Child Neurology. 1990; 32 (9):800-807 - 41.
Sahama I, Sinclair K, Pannek K, Lavin M, Rose S. Radiological imaging in ataxia telangiectasia: a review. Cerebellum. 2014; 13 (4):521-530 - 42.
Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, et al. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron. 2004; 41 (4):549-561 - 43.
Lee Y, McKinnon PJ. Responding to DNA double strand breaks in the nervous system. Neuroscience. 2007; 145 (4):1365-1374 - 44.
Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, Lederman HM. Consequences of the delayed diagnosis of ataxia-telangiectasia. Pediatrics. 1998; 102 (1 Pt 1):98-100 - 45.
Devaney R, Pasalodos S, Suri M, Bush A, Bhatt JM. Ataxia telangiectasia: presentation and diagnostic delay. Archives of Disease in Childhood. 2017; 102 (4):328-330 - 46.
Lin DD, Barker PB, Lederman HM, Crawford TO. Cerebral abnormalities in adults with ataxia-telangiectasia. AJNR. American Journal of Neuroradiology. 2014; 35 (1):119-123 - 47.
Lewis RF, Lederman HM, Crawford TO. Ocular motor abnormalities in ataxia telangiectasia. Annals of Neurology. 1999; 46 (3):287-295 - 48.
Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Straumann D, et al. Gaze fixation deficits and their implication in ataxia-telangiectasia. Journal of Neurology, Neurosurgery, and Psychiatry. 2009; 80 (8):858-864 - 49.
Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Straumann D, et al. Ataxia telangiectasia: A "disease model" to understand the cerebellar control of vestibular reflexes. Journal of Neurophysiology. 2011; 105 (6):3034-3041 - 50.
Canny GJ, Roifman C, Weitzman S, Braudo M, Levison H. A pulmonary infiltrate in a child with ataxia telangiectasia. Annals of Allergy. 1988; 61 (6):422-3-466-8 - 51.
Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. The Journal of Pediatrics. 2004; 144 (4):505-511 - 52.
Lefton-Greif MA, Crawford TO, Winkelstein JA, Loughlin GM, Koerner CB, Zahurak M, et al. Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia. The Journal of Pediatrics. 2000; 136 (2):225-231 - 53.
Pagano G, Korkina LG, Brunk UT, Chessa L, Degan P, del Principe D, et al. Congenital disorders sharing oxidative stress and cancer proneness as phenotypic hallmarks: Prospects for joint research in pharmacology. Medical Hypotheses. 1998; 51 (3):253-266 - 54.
Umetsu DT, Ambrosino DM, Quinti I, Siber GR, Geha RS. Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency. The New England Journal of Medicine. 1985; 313 (20):1247-1251 - 55.
van Os NJH, Jansen AFM, van Deuren M, Haraldsson A, van Driel NTM, Etzioni A, et al. Ataxia-telangiectasia: Immunodeficiency and survival. Clinical Immunology. 2017; 178 :45-55 - 56.
McGrath-Morrow SA, Gower WA, Rothblum-Oviatt C, Brody AS, Langston C, Fan LL, et al. Evaluation and management of pulmonary disease in ataxia-telangiectasia. Pediatric Pulmonology. 2010; 45 (9):847-859 - 57.
McGrath-Morrow SA, Rothblum-Oviatt CC, Wright J, Schlechter H, Lefton-Greif MA, Natale VA, et al. Multidisciplinary Management of Ataxia Telangiectasia: Current perspectives. Journal of Multidisciplinary Healthcare. 2021; 14 :1637-1644 - 58.
McKinnon PJ. ATM and ataxia telangiectasia. EMBO Reports. 2004; 5 (8):772-776 - 59.
Stanley SE, Rao AD, Gable DL, McGrath-Morrow S, Armanios M. Radiation sensitivity and radiation necrosis in the short telomere syndromes. International Journal of Radiation Oncology, Biology, Physics. 2015; 93 (5):1115-1117 - 60.
Chen RL, Wang PJ, Hsu YH, Chang PY, Fang JS. Severe lung fibrosis after chemotherapy in a child with ataxia-telangiectasia. Journal of Pediatric Hematology/Oncology. 2002; 24 (1):77-79 - 61.
Schroeder SA, Swift M, Sandoval C, Langston C. Interstitial lung disease in patients with ataxia-telangiectasia. Pediatric Pulmonology. 2005; 39 (6):537-543 - 62.
Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, et al. ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia. European Respiratory Society. 2015; 24 (138):565-581 - 63.
Yalçin B, Kutluk MT, Sanal O, Akyüz C, Anadol D, Cağlar M, et al. Hodgkin's disease and ataxia telangiectasia with pulmonary cavities. Pediatric Pulmonology. 2002; 33 (5):399-403 - 64.
McGrath-Morrow SA, Lederman HM, Aherrera AD, Lefton-Greif MA, Crawford TO, Ryan T, et al. Pulmonary function in children and young adults with ataxia telangiectasia. Pediatric Pulmonology. 2014; 49 (1):84-90 - 65.
Brody AS. Thoracic CT technique in children. Journal of Thoracic Imaging. 2001; 16 (4):259-268 - 66.
Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. The New England Journal of Medicine. 2007; 357 (22):2277-2284 - 67.
Jeggo P. The role of the DNA damage response mechanisms after low-dose radiation exposure and a consideration of potentially sensitive individuals. Radiation Research. 2010; 174 (6):825-832 - 68.
Eibel R, Herzog P, Dietrich O, Rieger CT, Ostermann H, Reiser MF, et al. Pulmonary abnormalities in immunocompromised patients: Comparative detection with parallel acquisition MR imaging and thin-section helical CT. Radiology. 2006; 241 (3):880-891 - 69.
Montella S, Santamaria F, Salvatore M, Pignata C, Maglione M, Iacotucci P, et al. Assessment of chest high-field magnetic resonance imaging in children and young adults with noncystic fibrosis chronic lung disease: Comparison to high-resolution computed tomography and correlation with pulmonary function. Investigative Radiology. 2009; 44 (9):532-538 - 70.
Serra G, Milito C, Mitrevski M, Granata G, Martini H, Pesce AM, et al. Lung MRI as a possible alternative to CT scan for patients with primary immune deficiencies and increased radiosensitivity. Chest. 2011; 140 (6):1581-1589 - 71.
Driessen GJ, Ijspeert H, Weemaes CM, Haraldsson Á, Trip M, Warris A, et al. Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. The Journal of Allergy and Clinical Immunology. 2013; 131 (5):1367-1375 - 72.
Sanal O, Ersoy F, Yel L, Tezcan I, Metin A, Ozyürek H, et al. Impaired IgG antibody production to pneumococcal polysaccharides in patients with ataxia-telangiectasia. Journal of Clinical Immunology. 1999; 19 (5):326-334 - 73.
Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d'Enghien C, Brousse N, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: A report from the French national registry of primary immune deficiencies. Journal of Clinical Oncology. 2015; 33 (2):202-208 - 74.
Noordzij JG, Wulffraat NM, Haraldsson A, Meyts I, van’t Veer LJ, Hogervorst FB, et al. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Archives of Disease in Childhood. 2009; 94 (6):448-449 - 75.
Pietrucha BM, Heropolitańska-Pliszka E, Wakulińska A, Skopczyńska H, Gatti RA, Bernatowska E. Ataxia-telangiectasia with hyper-IgM and Wilms tumor: Fatal reaction to irradiation. Journal of Pediatric Hematology/Oncology. 2010; 32 (1):e28-e30 - 76.
Fiorilli M, Businco L, Pandolfi F, Paganelli R, Russo G, Aiuti F. Heterogeneity of immunological abnormalities in ataxia-telangiectasia. Journal of Clinical Immunology. 1983; 3 (2):135-141 - 77.
Cirillo E, Polizzi A, Soresina A, Prencipe R, Giardino G, Cancrini C, et al. Progressive depletion of B and T lymphocytes in patients with ataxia telangiectasia: Results of the Italian primary immunodeficiency network. Journal of Clinical Immunology. 2022; 42 (4):783-797 - 78.
McGrath-Morrow SA, Collaco JM, Detrick B, Lederman HM. Serum Interleukin-6 levels and pulmonary function in ataxia-telangiectasia. The Journal of Pediatrics. 2016; 171 :256-61.e1. DOI: 10.1016/j.jpeds.2016.01.002 Epub 2016 Feb 2 - 79.
McGrath-Morrow SA, Ndeh R, Collaco JM, Rothblum-Oviatt C, Wright J, O'Reilly MA, et al. Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia. PLoS One. 2018; 13 (12):e0209496. DOI: 10.1371/journal.pone.0209496 eCollection 2018 - 80.
Patiroglu T, Gungor HE, Unal E, Kurtoglu S, Yikilmaz A, Patiroglu T. Hashimoto thyroiditis associated with ataxia telangiectasia. Journal of Pediatric Endocrinology & Metabolism. 2012; 25 (3-4):349-352 - 81.
Heath J, Goldman FD. Idiopathic thrombocytopenic purpura in a boy with ataxia telangiectasia on immunoglobulin replacement therapy. Journal of Pediatric Hematology/Oncology. 2010; 32 (1):e25-e27 - 82.
Alyasin S, Khoshkhui M, Abolnezhadian F. Autoimmune hemolytic anemia in a patient with probable ataxia telangiectasia: A case report. Iranian Journal of Immunology. 2014; 11 (3):217-220 - 83.
Chopra C, Davies G, Taylor M, Anderson M, Bainbridge S, Tighe P, et al. Immune deficiency in ataxia-telangiectasia: A longitudinal study of 44 patients. Clinical and Experimental Immunology. 2014; 176 (2):275-282 - 84.
Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet Journal of Rare Diseases. 2016; 11 (1):159 - 85.
Taylor AMR, Rothblum-Oviatt C, Ellis NA, Hickson ID, Meyer S, Crawford TO, et al. Chromosome instability syndromes. Nature Reviews. Disease Primers. 2019; 5 (1):64 - 86.
Stray-Pedersen A, Aaberge IS, Früh A, Abrahamsen TG. Pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine; immunogenicity in patients with ataxia-telangiectasia. Clinical and Experimental Immunology. 2005; 140 (3):507-516 - 87.
Chiam LY, Verhagen MM, Haraldsson A, Wulffraat N, Driessen GJ, Netea MG, et al. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: Reflection of inappropriate immune regulation? Dermatology. 2011; 223 (1):13-19 - 88.
Shoimer I, Wright N, Haber RM. Noninfectious granulomas: A sign of an underlying immunodeficiency? Journal of Cutaneous Medicine and Surgery. 2016; 20 (3):259-262 - 89.
Bodemer C, Sauvage V, Mahlaoui N, Cheval J, Couderc T, Leclerc-Mercier S, et al. Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency. Clinical Microbiology and Infection. 2014; 20 (10):O656-O663 - 90.
Neven B, Pérot P, Bruneau J, Pasquet M, Ramirez M, Diana JS, et al. Cutaneous and visceral chronic granulomatous disease triggered by a rubella virus vaccine strain in children with primary Immunodeficiencies. Clinical Infectious Diseases. 2017; 64 (1):83-86 - 91.
Perelygina L, Plotkin S, Russo P, Hautala T, Bonilla F, Ochs HD, et al. Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies. The Journal of Allergy and Clinical Immunology. 2016; 138 (5):1436-1439 - 92.
Cohen LE, Tanner DJ, Schaefer HG, Levis WR. Common and uncommon cutaneous findings in patients with ataxia-telangiectasia. Journal of the American Academy of Dermatology. 1984; 10 (3):431-438 - 93.
Ivonye C, Jamched U, Anderson D, Adesunloye B. Uncommon skin lesion in a patient with ataxia-telangiectasia. International Journal of Dermatology. 2008; 47 (10):1051-1052 - 94.
Pesce K, Rothe MJ. The premature aging syndromes. Clinics in Dermatology. 1996; 14 (2):161-170 - 95.
Lehman H. Skin manifestations of primary immune deficiency. Clinical Reviews in Allergy and Immunology. 2014; 46 (2):112-119 - 96.
Privette ED, Ram G, Treat JR, Yan AC, Heimall JR. Healing of granulomatous skin changes in ataxia-telangiectasia after treatment with intravenous immunoglobulin and topical mometasone 0.1% ointment. Pediatric Dermatology. 2014; 31 (6):703-707 - 97.
Iwata Y, Yoshizaki A, Komura K, Shimizu K, Ogawa F, Hara T, et al. CD19, a response regulator of B lymphocytes, regulates wound healing through hyaluronan-induced TLR4 signaling. The American Journal of Pathology. 2009; 175 (2):649-660 - 98.
Browne R, Cliffe L, Ip W, Brown K, McDermott E. A case of wild-type rubella-associated cutaneous granuloma in ataxia telangiectasia. Pediatric Dermatology. 2022; 39 (4):619-621 - 99.
Buchbinder D, Hauck F, Albert MH, Rack A, Bakhtiar S, Shcherbina A, et al. Rubella virus-associated cutaneous granulomatous disease: A unique complication in immune-deficient patients, not limited to DNA repair disorders. Journal of Clinical Immunology. 2019; 39 (1):81-89 - 100.
Stewart E, Prayle AP, Tooke A, Pasalodos S, Suri M, Bush A, et al. Growth and nutrition in children with ataxia telangiectasia. Archives of Disease in Childhood. 2016; 101 (12):1137-1141 - 101.
Ross LJ, Capra S, Baguley B, Sinclair K, Munro K, Lewindon P, et al. Nutritional status of patients with ataxia-telangiectasia: A case for early and ongoing nutrition support and intervention. Journal of Paediatrics and Child Health. 2015; 51 (8):802-807 - 102.
Voss S, Pietzner J, Hoche F, Taylor AM, Last JI, Schubert R, et al. Growth retardation and growth hormone deficiency in patients with ataxia telangiectasia. Growth Factors. 2014; 32 (3-4):123-129 - 103.
Ersoy F, Berkel AI, Sanal O, Oktay H. Twenty-year follow-up of 160 patients with ataxia-telangiectasia. The Turkish Journal of Pediatrics. 1991; 33 (4):205-215 - 104.
Schubert R, Reichenbach J, Zielen S. Growth factor deficiency in patients with ataxia telangiectasia. Clinical and Experimental Immunology. 2005; 140 (3):517-519 - 105.
Peterson RD, Cooper MD, Good RA. Lymphoid tissue abnormalities associated with ataxia-telangiectasia. The American Journal of Medicine. 1966; 41 (3):342-359 - 106.
McFarlin DE, Strober W, Waldmann TA. Ataxia-telangiectasia. Medicine (Baltimore). 1972; 51 (4):281-314 - 107.
Zadik Z, Levin S, Prager-Lewin R, Laron Z. Gonadal dysfunction in patients with ataxia telangiectasia. Acta Paediatrica Scandinavica. 1978; 67 (4):477-479 - 108.
Worth PF, Srinivasan V, Smith A, Last JI, Wootton LL, Biggs PM, et al. Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia. Movement Disorders. 2013; 28 (4):524-528 - 109.
Andrade IGA, Costa-Carvalho BT, da Silva R, Hix S, Kochi C, Suano-Souza FI, et al. Risk of atherosclerosis in patients with ataxia telangiectasia. Annals of Nutrition & Metabolism. 2015; 66 (4):196-201 - 110.
Donath H, Hess U, Kieslich M, Theis M, Ohlenschläger U, Schubert R, et al. Diabetes in patients with ataxia telangiectasia: A National Cohort Study. Frontiers in Pediatrics. 2020; 8 :317 - 111.
Viswanathan P, Sharma Y, Maisuradze L, Tchaikovskaya T, Gupta S. Ataxia telangiectasia mutated pathway disruption affects hepatic DNA and tissue damage in nonalcoholic fatty liver disease. Experimental and Molecular Pathology. 2020; 113 :104369 - 112.
Paulino TL, Rafael MN, Hix S, Shigueoka DC, Ajzen SA, Kochi C, et al. Is age a risk factor for liver disease and metabolic alterations in ataxia telangiectasia patients? Orphanet Journal of Rare Diseases. 2017; 12 (1):136 - 113.
Yang DQ , Halaby MJ, Li Y, Hibma JC, Burn P. Cytoplasmic ATM protein kinase: An emerging therapeutic target for diabetes, cancer and neuronal degeneration. Drug Discovery Today. 2011; 16 (7-8):332-338 - 114.
Ditch S, Paull TT. The ATM protein kinase and cellular redox signaling: Beyond the DNA damage response. Trends in Biochemical Sciences. 2012; 37 (1):15-22 - 115.
Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL, Davies EG, et al. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. British Journal of Cancer. 2011; 105 (4):586-591 - 116.
Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood. 1996; 87 (2):423-438 - 117.
Ben Arush MW. Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Medical and Pediatric Oncology. 1999; 32 (6):479-480 - 118.
Sandoval C, Swift M. Hodgkin disease in ataxia-telangiectasia patients with poor outcomes. Medical and Pediatric Oncology. 2003; 40 (3):162-166 - 119.
Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia. The New England Journal of Medicine. 1991; 325 (26):1831-1836 - 120.
Kulinski JM, Leonardo SM, Mounce BC, Malherbe L, Gauld SB, Tarakanova VL. Ataxia telangiectasia mutated kinase controls chronic gammaherpesvirus infection. Journal of Virology. 2012; 86 (23):12826-12837 - 121.
Seidemann K, Henze G, Beck JD, Sauerbrey A, Kühl J, Mann G, et al. Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): Experience from the BFM trials. Annals of Oncology. 2000; 11 (Suppl 1):141-145 - 122.
Machida S, Tomizawa D, Tamaichi H, Okawa T, Endo A, Imai K, et al. Successful treatment of diffuse large B-cell lymphoma in a patient with ataxia telangiectasia using rituximab. Journal of Pediatric Hematology/Oncology. 2013; 35 (6):482-485 - 123.
Olsen JH, Hahnemann JM, Børresen-Dale AL, Brøndum-Nielsen K, Hammarström L, Kleinerman R, et al. Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. Journal of the National Cancer Institute. 2001; 93 (2):121-127 - 124.
Marabelli M, Cheng SC, Parmigiani G. Penetrance of ATM gene mutations in breast cancer: A meta-analysis of different measures of risk. Genetic Epidemiology. 2016; 40 (5):425-431 - 125.
Perlman S, Becker-Catania S, Gatti RA. Ataxia-telangiectasia: Diagnosis and treatment. Seminars in Pediatric Neurology. 2003; 10 (3):173-182 - 126.
Hall MJ, Forman AD, Pilarski R, Wiesner G, Giri VN. Gene panel testing for inherited cancer risk. Journal of the National Comprehensive Cancer Network. 2014; 12 (9):1339-1346 - 127.
Gatti R, Perlman S. 1999 Mar 19 [Updated 2016 Oct 27]. Ataxia-Telangiectasia. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya a, Editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023 - 128.
Ataxia-Telangiectasia in Children: Guidance on Diagnosis and Clinical Care. http://www.atsociety.org.uk/data/files/William/A-T_Clinical_Guidance_Document_Final.pdf [Accessed: April 16, 2023]. - 129.
Boder E, Sedgwick R. Ataxia Telangiectasia: A Review of 101 Cases, in Little Club Clinics in Developmental Medicine No. 8. London: Heinemann Books; 1963. pp. 110-118 - 130.
Woods CG, Taylor AM. Ataxia telangiectasia in the British Isles: The clinical and laboratory features of 70 affected individuals. The Quarterly Journal of Medicine. 1992; 82 (298):169-179 - 131.
Kieslich M, Hoche F, Reichenbach J, Weidauer S, Porto L, Vlaho S, et al. Extracerebellar MRI-lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age. Cerebellum. 2010; 9 (2):190-197 - 132.
Lefton-Greif MA, Perlman AL, He X, Lederman HM, Crawford TO. Assessment of impaired coordination between respiration and deglutition in children and young adults with ataxia telangiectasia. Developmental Medicine and Child Neurology. 2016; 58 (10):1069-1075 - 133.
Sun X, Becker-Catania SG, Chun HH, Hwang MJ, Huo Y, Wang Z, et al. Early diagnosis of ataxia-telangiectasia using radiosensitivity testing. The Journal of Pediatrics. 2002; 140 (6):724-731 - 134.
Stray-Pedersen A, Borresen-Dale AL, Paus E, Lindman CR, Burgers T, Abrahamsen TG. Alpha fetoprotein is increasing with age in ataxia-telangiectasia. European Journal of Paediatric Neurology. 2007; 11 (6):375-380 - 135.
Taylor AM, Byrd PJ. Molecular pathology of ataxia telangiectasia. Journal of Clinical Pathology. 2005; 58 (10):1009-1015 - 136.
Bower M. Diagnostic yield of targeted next generation sequencing approach in a young population: High frequency of recessive ataxias and implementation of a next generation sequencing copy-number variation. In: 5th Ataxia Investigators Meeting (AIM 2014). Las Vegas, NV; 2014 - 137.
Hellani A, Laugé A, Ozand P, Jaroudi K, Coskun S. Pregnancy after preimplantation genetic diagnosis for ataxia telangiectasia. Molecular Human Reproduction. 2002; 8 (8):785-788 - 138.
Verlinsky Y, Rechitsky S, Sharapova T, Laziuk K, Barsky I, Verlinsky O, et al. Preimplantation diagnosis for immunodeficiencies. Reproductive Biomedicine Online. 2007; 14 (2):214-223 - 139.
Borte S, von Döbeln U, Fasth A, Wang N, Janzi M, Winiarski J, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012; 119 (11):2552-2555 - 140.
Mallott J, Kwan A, Church J, Gonzalez-Espinosa D, Lorey F, Tang LF, et al. Newborn screening for SCID identifies patients with ataxia telangiectasia. Journal of Clinical Immunology. 2013; 33 (3):540-549 - 141.
Herskind A, Greisen G, Nielsen JB. Early identification and intervention in cerebral palsy. Developmental Medicine and Child Neurology. 2015; 57 (1):29-36 - 142.
Cook A, Giunti P. Friedreich's ataxia: Clinical features, pathogenesis and management. British Medical Bulletin. 2017; 124 (1):19-30 - 143.
Pietrucha B, Heropolitańska-Pliszka E, Geffers R, Enßen J, Wieland B, Bogdanova NV, et al. Clinical and biological manifestation of RNF168 deficiency in two polish siblings. Frontiers in Immunology. 2017; 8 :1683 - 144.
Nissenkorn A, Hassin-Baer S, Lerman SF, Levi YB, Tzadok M, Ben-Zeev B. Movement disorder in ataxia-telangiectasia: Treatment with amantadine sulfate. Journal of Child Neurology. 2013; 28 (2):155-160 - 145.
van Egmond ME, Elting JW, Kuiper A, Zutt R, Heineman KR, Brouwer OF, et al. Myoclonus in childhood-onset neurogenetic disorders: The importance of early identification and treatment. European Journal of Paediatric Neurology. 2015; 19 (6):726-729 - 146.
Broccoletti T, Del Giudice E, Cirillo E, Vigliano I, Giardino G, Ginocchio VM, et al. Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia. European Journal of Neurology. 2011; 18 (4):564-570 - 147.
Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, D'Agnano D, et al. Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: Results of a phase 2 trial. Orphanet Journal of Rare Diseases. 2014; 9 :5 - 148.
Leuzzi V, Micheli R, D'Agnano D, Molinaro A, Venturi T, Plebani A, et al. Positive effect of erythrocyte-delivered dexamethasone in ataxia-telangiectasia. Neurology Neuroimmunology & Neuroinflammation. 2015; 2 (3):e98 - 149.
Pommerening H, van Dullemen S, Kieslich M, Schubert R, Zielen S, Voss S. Body composition, muscle strength and hormonal status in patients with ataxia telangiectasia: A cohort study. Orphanet Journal of Rare Diseases. 2015; 10 :155 - 150.
Lefton-Greif MA, Crawford TO, McGrath-Morrow S, Carson KA, Lederman HM. Safety and caregiver satisfaction with gastrostomy in patients with ataxia telangiectasia. Orphanet Journal of Rare Diseases. 2011; 6 :23 - 151.
Mitra A, Gooi J, Darling J, Newton-Bishop JA. Infliximab in the treatment of a child with cutaneous granulomas associated with ataxia telangiectasia. Journal of the American Academy of Dermatology. 2011; 65 (3):676-677 - 152.
Woelke S, Valesky E, Bakhtiar S, Pommerening H, Pfeffermann LM, Schubert R, et al. Treatment of granulomas in patients with ataxia telangiectasia. Frontiers in Immunology. 2018; 9 :2000 - 153.
Bakhtiar S, Woelke S, Huenecke S, Kieslich M, Taylor AM, Schubert R, et al. Pre-emptive allogeneic hematopoietic stem cell transplantation in ataxia telangiectasia. Frontiers in Immunology. 2018; 9 :2495 - 154.
Lavin MF, Gueven N, Bottle S, Gatti RA. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. British Medical Bulletin. 2007; 81-82 :129-147 - 155.
Sandlund JT, Hudson MM, Kennedy W, Onciu M, Kastan MB. Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies. Pediatric Blood & Cancer. 2014; 61 (2):360-362 - 156.
Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, et al. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. The Journal of Allergy and Clinical Immunology. 2018; 141 (1):322-328.e10. DOI: 10.1016/j.jaci.2017.02.036 Epub 2017 Apr 7 - 157.
Beier R, Sykora KW, Woessmann W, Maecker-Kolhoff B, Sauer M, Kreipe HH, et al. Allogeneic-matched sibling stem cell transplantation in a 13-year-old boy with ataxia telangiectasia and EBV-positive non-Hodgkin lymphoma. Bone Marrow Transplantation. 2016; 51 (9):1271-1274 - 158.
Ussowicz M, Musiał J, Duszeńko E, Haus O, Kałwak K. Long-term survival after allogeneic-matched sibling PBSC transplantation with conditioning consisting of low-dose busilvex and fludarabine in a 3-year-old boy with ataxia-telangiectasia syndrome and ALL. Bone Marrow Transplantation. 2013; 48 (5):740-741 - 159.
The Global A-T Family Data Platform. Available from: https://www.atfamilies.org/ . [Accessed: April 16, 2023]. - 160.
Du L, Pollard JM, Gatti RA. Correction of prototypic ATM splicing mutations and aberrant ATM function with antisense morpholino oligonucleotides. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104 (14):6007-6012 - 161.
Du L, Jung ME, Damoiseaux R, Completo G, Fike F, Ku JM, et al. A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Molecular Therapy. 2013; 21 (9):1653-1660