Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative multisystem disorder. A minority of AT patients can present late-onset atypical presentations due to unknown mechanisms. The demographic, clinical, immunological and genetic data were collected by direct interview and examining the Iranian AT patients with late-onset manifestations. We also conducted a systematic literature review for reported atypical AT patients. We identified three Iranian AT patients (3/249, 1.2% of total registry) with later age at ataxia onset and slower neurologic progression despite elevated alpha-fetoprotein levels, history of respiratory infections, and immunological features of the syndrome. Of note, all patients developed autoimmunity in which a decrease of naïve T cells and regulatory T cells were observed. The literature searches also summarized data from 73 variant AT patients with atypical presentation indicating biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer. Variant AT patients present with milder phenotype or atypical form of classical symptoms causing under- or mis- diagnosis. Although missense mutations are more frequent, an atypical presentation can be associated with deleterious mutations due to unknown modifying factors.

Background: Specific Antibody Deficiency (SAD) is a primary immunodeficiency disease (PID) characterized by the occurrence of recurrent infections and inadequate antibody response to polysaccharide new antigens.

Objective: This study aims to determine the titer of specific antibodies against unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV-23), the presence of SAD, and its association with clinical and laboratory findings in Ataxia-telangiectasia (A-T) and selective immunoglobulin A deficiency (SIgAD) patients.

Methods: 32 A-T patients and 43 SIgAD patients were included in the study. Samples of the patients were obtained before and three weeks after vaccination with PPSV-23. Specific immunoglobulin G (IgG) directed towards pneumococcal capsular antigen and specific antibodies against whole pneumococcal antigens was measured.

Results: Comparison of the response to vaccination revealed that 81.3% of A-T patients and 18.6% of the SIgAD patients had an inadequate response to PPSV-23 (p<0.001). The prevalence of recurrent infection (p=0.034) and pneumonia (p=0.003) in SIgAD patients was significantly higher in non-responders than responders. Likewise, the number of marginal zone B cells (p=0.037), transitional B cells (p=0.019), plasmablasts (p=0.019), CD8+ naïve T cells (p=0.036), and percentage of CD8+ T cells (p=0.047), switched memory B cells (SMB) (p=0.026) and immunoglobulin M (IgM) memory B cells (p=0.022) in SIgAD patients were significantly lower in non-responder group than responder group. In contrast, the percentage of CD4 T+ cells in A-T patients was lower in the non-responder group than responders (p=0.035).

Conclusion: SAD is more frequent in A-T patients than SIgAD patients. The role of SMB and T cells should not be underestimated in SAD.

Ataxia-telangiectasia (AT) is a complex neurodegenerative disease with an increased risk for bone marrow failure and malignancy. AT is caused by biallelic loss of function variants in ATM, which encodes a phosphatidylinositol 3-kinase that responds to DNA damage. Herein, we report a child with progressive ataxia, chorea, and genome instability, highly suggestive of AT. The clinical ataxia gene panel identified a maternal heterozygous synonymous variant (NM_000051.3: c.2250G > A), previously described to result in exon 14 skipping. Subsequently, trio genome sequencing led to the identification of a novel deep intronic variant [NG_009830.1(NM_000051.3): c.1803-270T > G] inherited from the father. Transcript analyses revealed that c.1803-270T > G results in aberrant inclusion of 56 base pairs of intron 11. In silico tests predicted a premature stop codon as a consequence, suggesting non-functional ATM; and DNA repair analyses confirmed functional loss of ATM. Our findings highlight the power of genome sequencing, considering deep intronic variants in undiagnosed rare disease patients.

Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classical ataxia-telangiectasia (classical A-T) phenotype, a variant phenotype (variant A-T) exists with partly overlapping but some distinctive disease characteristics. Here we present a case series of 6 patients with classical A-T and variant A-T, which illustrates the phenotypic variability of A-T that can present in childhood with prominent extrapyramidal features, with or without cerebellar ataxia. We report the clinical data, together with a detailed genotype description, immunological analyses, and related expression of the ATM protein. We show that the presence of some residual ATM kinase activity leads to the clinical phenotype variant A-T that differs from the classical A-T. Our data illustrate that the diagnosis of the variant form of A-T can be delayed and difficult, while early recognition of the variant form as well as the classical A-T is a prerequisite for providing a correct prognosis and appropriate rehabilitation and support, including the avoidance of diagnostic X-ray procedures, given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment.

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive ataxia, choreoathetosis and immunodeficiency beginning in early childhood. An 8-year-old girl was referred with a diagnosis of AT. She had gait disturbance and dysarthria for 3years. Multiple cutaneous telangiectases were observed on her face, trunk and limbs. Sequence analysis of the ATM gene revealed a homozygous c.7308-15A>G mutation in IVS49. Human Splicing Finder predicted that the mutation could activate an intronic cryptic acceptor site. We designed primers for amplification of related exons (48-50) from cDNA for evaluating splicing pattern. Sequencing of ATM exons 48-50 revealed a 14-nucleotide insertion from intron 49, between exons 49 and 50, resulting in premature termination of translation at codon 2439. To conclude, we report a novel mutation in a classical AT case, which resulted in an alternatively spliced transcript and was predicted to form a truncated protein or null protein due to nonsense-mediated decay.

Ataxia telangiectasia (AT) is a rare neurodegenerative genetic disorder due to bi-allelic mutations in the Ataxia Telangiectasia Mutated (ATM) gene. The aim of this paper is to better define the immunological profile over time, the clinical immune-related manifestations at diagnosis and during follow-up, and to attempt a genotype-phenotype correlation of an Italian cohort of AT patients. Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network. Patients were classified at diagnosis as lymphopenic (Group A) or non-lymphopenic (Group B). Fifty eight out of 69 AT patients (84%) were genetically characterized and distinguished according to the type of mutations in truncating/truncating (TT; 27 patients), non-truncating (NT)/T (28 patients), and NT/NT (5 patients). In 3 patients, only one mutation was detected. Data on age at onset and at diagnosis, cellular and humoral compartment at diagnosis and follow-up, infectious diseases, signs of immune dysregulation, cancer, and survival were analyzed and compared to the genotype. Lymphopenia at diagnosis was related per se to earlier age at onset. Progressive reduction of cellular compartment occurred during the follow-up with a gradual reduction of T and B cell number. Most patients of Group A carried bi-allelic truncating mutations, had a more severe B cell lymphopenia, and a reduced life expectancy. A trend to higher frequency of interstitial lung disease, immune dysregulation, and malignancy was noted in Group B patients. Lymphopenia at the onset and the T/T genotype are associated with a worst clinical course. Several mechanisms may underlie the premature and progressive immune decline in AT subjects.

Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic, and immunological data of 26 cases with A-T. Clinical manifestations included oculocutaneous telangiectasia (100%), ataxia (100%), fever, loose stools or infection (67%), cerebellar atrophy (50%), nystagmus (8%), dysarthria (15.38%), and visual impairment (8%). Genetic analysis confirmed ATM gene variations in 16 unrelated cases. The most common type of variation was stopgain variants (56%). Immunoglobulin profile indicated reduced IgA, IgG, and IgM in 94%, 50%, and 20% cases, respectively. T cell lymphopenia was observed in 80% of cases among those investigated. Unusual presentations included an EBV-associated smooth muscle tumour located in the liver in one case and Hyper IgM syndrome-like presentation in two cases. Increased immunosenescence was observed in T-cell subsets (CD4+CD57+ and CD8+CD57+). T-cell receptor excision circles (TRECs) were reduced in 3/8 (37.50%) cases.

Background: Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition.

Objectives: Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature.

Search methods: 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library.

Selection criteria: All human studies that report any aspect of A-T.

Data collection and analysis: Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest.

Main results: 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months).

Conclusions: This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

Sensitive motor outcome measures are needed to efficiently evaluate novel therapies for neurodegenerative diseases. Devices that can passively collect movement data in the home setting can provide continuous and ecologically valid measures of motor function. We tested the hypothesis that movement patterns extracted from continuous wrist accelerometer data capture motor impairment and disease progression in ataxia-telangiectasia. One week of continuous wrist accelerometer data were collected from 31 individuals with ataxia-telangiectasia and 27 controls aged 2-20 years old. Longitudinal wrist sensor data were collected in 14 ataxia-telangiectasia participants and 13 controls. A novel algorithm was developed to extract wrist submovements from the velocity time series. Wrist sensor features were compared with caregiver-reported motor function on the Caregiver Priorities and Child Health Index of Life with Disabilities survey and ataxia severity on the neurologist-performed Brief Ataxia Rating Scale. Submovements became smaller, slower, and less variable in ataxia-telangiectasia compared to controls. High-frequency oscillations in submovements were increased, and more variable and low-frequency oscillations were decreased and less variable in ataxia-telangiectasia. Wrist movement features correlated strongly with ataxia severity and caregiver-reported function, demonstrated high reliability, and showed significant progression over a 1-year interval. These results show that passive wrist sensor data produces interpretable and reliable measures that are sensitive to disease change, supporting their potential as ecologically valid motor biomarkers. The ability to obtain these measures from a low-cost sensor that is ubiquitous in smartwatches could help facilitate neurological care and participation in research regardless of geography and socioeconomic status.

A strong association between rubella virus (RuV) and chronic granulomas, in individuals with inborn errors of immunity, has been recently established. Both the RA27/3 vaccine and wild-type RuV strains were highly sensitive to a broad-spectrum antiviral drug, nitazoxanide (NTZ), in vitro. However, NTZ treatment, used as a salvage therapy, resulted in little or no improvements of RuV-associated cutaneous granulomas in patients. Here, we report investigations of possible causes of treatment failures in two ataxia-telangiectasia patients. Although a reduction in RuV RNA in skin lesions was detected by real-time RT-PCR, live immunodeficiency-related vaccine-derived rubella viruses (iVDRV) were recovered from granulomas, before and after the treatments. Tizoxanide, an active NTZ metabolite, inhibited replications of all iVDRVs in cultured A549 cells, but the 50% and 90% inhibitory concentrations were 10-40 times higher than those for the RA27/3 strain. There were no substantial differences in iVDRV sensitivities, neither before nor after treatments. Analysis of quasispecies in the E1 gene, a suspected NTZ target, showed no effect of NTZ treatments on quasispecies' complexity in lesions. Thus, failures of NTZ therapies were likely due to low sensitivities of iVDRVs to the drug, and not related to the emergence of resistance, following long-term NTZ treatments.

Ataxia-telangiectasia is an autosomal recessive, rare, neurodegenerative multisystem disorder characterized by ataxia-telangiectasia, cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure associated with increased malignancy risk. Clinical diagnosis is made with ataxia-telangiectasia mutated (ATM) gene. Our case, who was diagnosed as ataxia-telangiectasia while investigating the etiology of chylous pleural effusion, is presented because of its rare occurrence.

Ataxia-telangiectasia is a rare neurodegenerative disorder characterized by progressive cerebellar ataxia, oculomotor apraxia, and choreoathetosis. Ataxia-telangiectasia is a devastating disease that negatively affects the participation of patients in daily occupations and consequently has adverse impacts on the quality of life of them and their families. This study aimed to investigate the effects of an occupational therapy intervention based on the Person-Environment-Occupation Model (PEO) on a 9-year old boy with ataxia-telangiectasia. Following a ten-session intervention, the client experienced significant improvement in occupational performance as well as participation in daily occupations as measured by Canadian Occupational Performance Measure (COPM) and the Pediatric Evaluation of Disability Inventory (PEDI), respectively.

Oculomotor assessment is an essential element of the neurological clinical examination and is particularly important when evaluating patients with movements disorders. Most of the brain is involved in oculomotor control, and thus many neurological conditions present with oculomotor abnormalities. Each of the different classes of eye movements and their features can provide important information that can facilitate differential diagnosis. This educational review presents a clinical approach to eye movement abnormalities that are commonly seen in parkinsonism, ataxia, dystonia, myoclonus, tremor, and chorea. In parkinsonism, subtle signs such as prominent square wave jerks, impaired vertical optokinetic nystagmus, and/or the "round the houses" sign suggest early progressive supranuclear gaze palsy before vertical gaze is restricted. In ataxia, nystagmus is common, but other findings such as oculomotor apraxia, supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to diagnoses such as ataxia with oculomotor apraxia, Niemann-Pick type C, or ataxia telangiectasia. Opsoclonus myoclonus and oculopalatal myoclonus present with characteristic phenomenology and are usually easy to identify. The oculomotor exam is usually unremarkable in isolated dystonia, but oculogyric crisis is a medical emergency and should be recognized and treated in a timely manner. Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a patient with dystonia or tremor, Wilson's disease is more likely. Finally, functional eye movements can reinforce the clinical impression of a functional movement disorder.

The ataxia-telangiectasia mutated (ATM) protein kinase is, as the name implies, mutated in the human genetic disorder ataxia-telangiectasia (A-T). This protein has its "finger in many pies", being responsible for the phosphorylation of many thousands of proteins in different signaling pathways in its role in protecting the cell against a variety of different forms of stress that threaten to perturb cellular homeostasis. The classical role of ATM is the protection against DNA damage, but it is evident that it also plays a key role in maintaining cell homeostasis in the face of oxidative and other forms of non-DNA damaging stress. The presence of ATM is not only in the nucleus to cope with damage to DNA, but also in association with other organelles in the cytoplasm, which suggests a greater protective role. This review attempts to address this greater role of ATM in protecting the cell against both external and endogenous damage.

Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case-control study to determine the prevalence of 32 known ATM mutations causing A-T in Spanish population in 323 BRCA1/BRCA2 negative hereditary breast cancer (HBC) cases and 625 matched Spanish controls. For the detection of the 32 ATM mutations we used the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. We identified one patient carrier of the c.8264_8268delATAAG ATM mutation. This mutation was not found in the 625 controls. These results suggest a low frequency of these 32 A-T causing mutations in the HBC cases in our population. Further case-control studies analyzing the entire coding and flanking sequences of the ATM gene are warranted in Spanish BC patients to know its implication in BC predisposition.

Background: Ataxia-telangiectasia (A-T) is a progressive multisystemic neurodegenerative disease. The phenotypic spectrum includes conditions (variant A-T) with mild, late-onset, and atypical clinical presentations characterized by the prevalence of dyskinetic rather than ataxic features.

Cases: We describe the clinical presentations of 3 siblings with early-onset truncal ataxia without obvious neurological deterioration or biological markers of classic A-T phenotype. We performed functional and genetic evaluation of 3 siblings with very mild neurological phenotype. Genetic evaluation with a next-generation sequencing panel for genes causative of cerebellar ataxia detected 2 known ATM gene variants, missense c.9023G>A p.(Arg3008His), and leaky splicing c.1066-6T>G variants. Functional studies showed mildly reduced ATM expression and residual kinase activity in the probands compared with healthy controls.

Conclusions: These results suggest the importance of investigating ATM variants even in the presence of clinical and biological atypical cases to ensure specific therapeutic regimens and oncological surveillance in these patients.

Background: Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder. Most patients have progressive cerebellar ataxia, oculocutaneous telangiectasia, frequent pulmonary infection, and an increased risk of malignancies. Although N-acetyl-dl-leucine (ADLL) has shown some efficacy in patients with AT, its more pharmacologically active enantiomer, N-acetyl-l-leucine (NALL), has just recently been investigated in ataxic individuals. The current study assessed the efficacy of NALL in patients with AT.

Methods: This 2 × 2 crossover, double-blind, randomized clinical trial was conducted on 20 patients with AT. After excluding four patients, 16 subjects (eight females, eight males; mean age 9.8 ± 3.5 years) with a definitive genetic diagnosis of AT were randomly assigned to one of two study groups, with one group receiving 1-4 g/day NALL or a placebo for six weeks. Subjects then had a 4-week washout before crossing over to the other treatment for an additional six weeks. The Spinocerebellar Ataxia Functional Index (SCAFI) and the Scale for Assessment and Rating of Ataxia (SARA) score assessed patients' motor function. Quality of life (QOL) was evaluated by a specialist using the PedsQL questionnaire. Fasting blood samples were taken from all subjects before and after each intervention to determine potential side effects.

Results: Although patients' nausea and constipation were improved, the results failed to reveal any significant benefits of NALL treatment on ataxia symptoms. NALL treatment had no significant effects on SARA, SCAFI-9HPT (9-hole peg test) nondominant, SCAFI-9HPT dominant, or SCAFI-8WMT (8 m walking time) (p > 0.05). Our patient's Physical Health score in Child self-report and Parent proxy-report did not significantly change in the treatment group compared to the placebo (p > 0.05). Furthermore, there were no significant changes in energy and macronutrient intake after NALL treatment. None of the volunteers reported serious or moderate side effects.

Conclusions: To the best of our knowledge, this was the first placebo-controlled, randomized clinical trial exploring NALL's potential effects for treating AT. Despite improvements in some symptomss, NALL intervention failed to improve motor function significantly. However, patients' nausea and constipation were improved by NALL, which can be a relevant benefit clinically.