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.

Ataxia telangiectasia (A-T) is a rare, multisystem progressive condition that typically presents in early childhood. In the absence of cure, people with A-T require coordinated multidisciplinary care to manage their complex array of needs and to minimize the disease burden. Although symptom management has proven benefits for this population, including improved quality of life and reduced complications, there is a need for guidance specific to the nursing and allied healthcare teams who provide care within the community. A scoping review, adopting the Joanna Briggs Institute methodology, was undertaken. It aimed to identify and map the available expertise from nursing and allied healthcare and management of children and young people with A-T ≤ 18 years of age. A rigorous search strategy was employed which generated a total of 21,118 sources of evidence, of which 50 were selected for review following screening by experts. A range of interventions were identified that reported a positive impact on A-T-related impairments, together with quality of life, indicating that outcomes can be improved for this population. Most notable interventions specific to A-T include therapeutic exercise, inspiratory muscle training, and early nutritional assessment and intervention. Further research will be required to determine the full potential of the identified interventions, including translatability to the A-T setting for evidence related to other forms of ataxia. Large gaps exist in the nursing and allied health evidence-base, highlighting a need for robust research that includes children and young people with A-T and their families to better inform and optimize management strategies.

Loss of the ATM protein kinase in humans results in Ataxia-telangiectasia, a disorder characterized by childhood-onset neurodegeneration of the cerebellum as well as cancer predisposition and immunodeficiency. Although many aspects of ATM function are well-understood, the mechanistic basis of the progressive cerebellar ataxia that occurs in patients is not. Here we review recent progress related to the role of ATM in neurons and the cerebellum that comes from many sources: animal models, post-mortem brain tissue samples, and human neurons in culture. These observations have revealed new insights into the consequences of ATM loss on DNA damage, gene expression, and immune signaling in the brain. Many results point to the importance of reactive oxygen species as well as single-strand DNA breaks in the progression of molecular events leading to neuronal dysfunction. In addition, innate immunity signaling pathways appear to play a critical role in ATM functions in microglia, responding to various forms of nucleic acid sensors and regulating survival of neurons and other cell types. Overall, the results lead to an updated view of transcriptional stress and DNA damage resulting from ATM loss that results in changes in gene expression as well as neuroinflammation that contribute to the cerebellar neurodegeneration observed in patients.

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder caused by the pathological variants of the ATM gene. Owing to i ts r arity a nd n ature, complications of AT, such a s malignant tumors, a re often difficult to manage with standard imaging studies and treatments, and there are no established management strategies. We report the case of a woman who had AT in childhood and developed breast cancer in her 20s; the disease was successfully managed by the decision-making of multidisciplinary physicians professionals with ethics support. She was immunocompromised, ataxic, and mentally impaired. The patient's mother noticed a tumor in her right breast and subsequently brought her to our department. Although preoperative testing and surgical procedures were limited as AT is extremely radiosensitive, the patient was diagnosed with cT2N0M0 breast cancer and underwent right mastectomy and axillary lymph node sampling. The final diagnosis was pT2N0M0 pStage IIA mucinous carcinoma, and immunohistochemistry of the tumor specimen was estrogen receptor-positive, progesterone receptor-positive, and HER2-negative. Tamoxifen was administered as postoperative adjuvant therapy, and the patient has survived to date without recurrence. Here, we report our experience with breast cancer treatment for AT, along with a review of the literature.

Cerebellar ataxia is often the first and irreversible outcome in the disease of ataxia-telangiectasia (A-T), as a consequence of selective cerebellar Purkinje neuronal degeneration. A-T is an autosomal recessive disorder resulting from the loss-of-function mutations of the ataxia-telangiectasia-mutated ATM gene. Over years of research, it now becomes clear that functional ATM-a serine/threonine kinase protein product of the ATM gene-plays critical roles in regulating both cellular DNA damage response and central carbon metabolic network in multiple subcellular locations. The key question arises is how cerebellar Purkinje neurons become selectively vulnerable when all other cell types in the brain are suffering from the very same defects in ATM function. This review intended to comprehensively elaborate the unexpected linkages between these two seemingly independent cellular functions and the regulatory roles of ATM involved, their integrated impacts on both physical and functional properties, hence the introduction of selective vulnerability to Purkinje neurons in the disease will be addressed.

Introduction: Ataxia telangiectasia (A-T) is a life-limiting autosomal recessive disease characterized by cerebellar degeneration, ocular telangiectasias, and sinopulmonary disease. Since there is no cure for A-T, the standard of care is primarily supportive.

Areas covered: We review clinical trials available in PubMed from 1990 to 2023 focused on lessening A-T disease burden. These approaches include genetic interventions, such as antisense oligonucleotides, designed to ameliorate disease progression in patients with select mutations. These approaches also include pharmacologic treatments that target oxidative stress, inflammation, and mitochondrial exhaustion, to attenuate neurological progression in A-T. Finally, we discuss the use of biological immunotherapies for the treatment of malignancies and granulomatous disease, along with other supportive therapies being used for the treatment of pulmonary disease and metabolic syndrome.

Expert opinion: Barriers to successful genetic and pharmacologic interventions in A-T include the need for personalized treatment approaches based on patient-specific ATM mutations and phenotypes, lack of an animal model for the neurologic phenotype, and extreme rarity of disease making large-scale randomized trials difficult to perform. Ongoing efforts are needed to diagnose patients earlier, discover more effective therapies, and include more individuals in clinical trials, with the goal to lessen disease burden and to find a cure for patients with A-T.

Ataxia-telangiectasia (A-T) is caused by absence of the catalytic activity of ATM, a protein kinase that plays a central role in the DNA damage response, many branches of cellular metabolism, redox and mitochondrial homeostasis, and cell cycle regulation. A-T is a complex disorder characterized mainly by progressive cerebellar degeneration, immunodeficiency, radiation sensitivity, genome instability, and predisposition to cancer. It is increasingly recognized that the premature aging component of A-T is an important driver of this disease, and A-T is therefore an attractive model to study the aging process. This review outlines the current state of knowledge pertaining to the molecular and cellular signatures of aging in A-T and proposes how these new insights can guide novel therapeutic approaches for A-T.

Background: Ataxia telangiectasia (AT) is a genetic multisystemic disorder affecting the nervous system. Data on neurocognitive functioning in AT are limited and focused on patients at various stages of disease. Because of the genetic nature of the disorder, parents of patients may also display subtle neurological problems. This study aimed to evaluate neurocognitive functioning in patients with AT and their unaffected parents.

Methods: The study included 26 patients with AT and 41 parents among which 13 patients and 18 parents were evaluated with neurocognitive tests. Clinical and radiological data were reviewed retrospectively. Data were analyzed with descriptive statistics.

Results: The median ages of patients and parents were 12.5 years (interquartile range [IQR] = 9.5) and 38.0 years (IQR = 12.0), respectively. Median intelligence quotients were 62.0 (IQR = 21.3) and 82.5 (IQR = 16.8), respectively, for patients and parents. Rates of intellectual disability for patients and parents were 100.0% and 83.3%, respectively. Areas of impairment in patients in decreasing order of frequency were motor skills, visual perception/memory, visual-manual coordination, spontaneous/focused and sustained attention (100.0% for each), social judgment, as well as vocabulary and arithmetic skills (75.0% for each). Areas of impairment in unaffected parents in decreasing order of frequency were visual-manual coordination (77.8%), working memory (76.5%), and visual perception and motor skills (66.7% for each).

Conclusion: Intellectual disabilities, visual-spatial disabilities, and reduced visual-motor coordination seem to be similar in patients with AT and their parents. These results should be replicated with larger samples from multiple centers and may form putative cognitive endophenotypes for the disorder.

Background: Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The immunodeficiency comprises predominantly immunoglobulin deficiency, mainly IgA and IgG₂, with a variable severity. So far, the exact mechanisms underlying the immunoglobulin deficiency, especially the variable severity, remain unelucidated.

Objective: We characterized the clinical impact of immunoglobulin deficiencies in AT and elucidated their mechanisms in AT.

Methods: We analyzed long-term immunoglobulin levels, immunophenotyping, and survival time in our cohort (n = 87, median age 16 years; maximum 64 years). Somatic hypermutation and class-switch junctions in B cells were analyzed by next-generation sequencing. Furthermore, an in vitro class-switching induction assay was performed, followed by RNA sequencing, to assess the effect of ATM inhibition.

Results: Only the hyper-IgM AT phenotype significantly worsened survival time, while IgA or IgG₂ deficiencies did not. The immunoglobulin levels showed predominantly decreased IgG₂ and IgA. Moreover, flow cytometric analysis demonstrated reduced naive B and T lymphocytes and a deficiency of class-switched IgG₂ and IgA memory B cells. Somatic hypermutation frequencies were lowered in IgA- and IgG₂-deficient patients, indicating hampered germinal center reaction. In addition, the microhomology of switch junctions was elongated, suggesting alternative end joining during class-switch DNA repair. The in vitro class switching and proliferation were negatively affected by ATM inhibition. RNA sequencing analysis showed that ATM inhibitor influenced expression of germinal center reaction genes.

Conclusion: Immunoglobulin deficiency in AT is caused by disturbed development of class-switched memory B cells. ATM deficiency affects both germinal center reaction and choice of DNA-repair pathway in class switching.

Background: Ataxia Telangiectasia (AT) is a genetic disorder characterized by compromised DNA repair, cerebellar degeneration, and immune dysfunction. Understanding the molecular mechanisms driving AT pathology is crucial for developing targeted therapies.

Methods: In this study, we conducted a comprehensive analysis to elucidate the molecular mechanisms underlying AT pathology. Using publicly available RNA-seq datasets comparing control and AT samples, we employed in silico transcriptomics to identify potential genes and pathways. We performed differential gene expression analysis with DESeq2 to reveal dysregulated genes associated with AT. Additionally, we constructed a Protein-Protein Interaction (PPI) network to explore the interactions between proteins implicated in AT.

Results: The network analysis identified hub genes, including TYROBP and PCP2, crucial in immune regulation and cerebellar function, respectively. Furthermore, pathway enrichment analysis unveiled dysregulated pathways linked to AT pathology, providing insights into disease progression.

Conclusion: Our integrated approach offers a holistic understanding of the complex molecular landscape of AT and identifies potential targets for therapeutic intervention. By combining transcriptomic analysis with network-based methods, we provide valuable insights into the underlying mechanisms of AT pathogenesis.

Purpose: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurological deficits, including prominent oculomotor dysfunction. We report 5 cases of eye movement assessment in children 9-15 years old with A-T.

Methods: Three different oculomotor tasks (gaze holding, visually guided saccades and visual search) were used, and video-oculography was performed. Additionally, the scale for the assessment and rating of ataxia (SARA) score was used to assess severity of the cerebellar ataxia.

Results: Unstable gaze holding, nystagmus and saccadic intrusions were found. In addition to psychophysiological assessment results, we provide quantitative analysis of oculomotor activity, revealing a specific abnormal oculomotor pattern, consisting of (i) marked saccade hypermetria, (ii) unstable gaze holding, and (iii) gaze-evoked nystagmus.

Conclusion: Our study opens the prospect to evaluate efficacy and safety of alternative methods for supporting the patient and improving his/her life quality.

Ataxia-telangiectasia (A-T) is a rare, childhood-onset, multi-systemic, progressive condition. Parents of children with rare diseases like A-T are emotionally, socially, and psychologically impacted by the diagnosis. To examine the parental perspective of having a child with A-T, and to better understand how parents cope with an A-T diagnosis, we conducted 10 semistructured interviews. Thematic analysis using a phenomenological approach resulted in five themes: (1) Parental responsibilities change as the result of an A-T diagnosis, (2) An A-T diagnosis brings about shifts in identity for all family members, (3) Parental coping changes over time, (4) A-T parents experience continuous uncertainty and a lack of stability, and (5) A-T parents receive support from various people, places, and resources. Many parents fostered resilience by adopting a present-centered and positive mindset about the impacts of the diagnosis. Parents also became A-T experts and used their knowledge to advocate for their children and help mentor other parents. Responses from parents indicated a need for providers to incorporate parental mental well-being check-ins to pediatric rare disease appointments and welcome parents as respected members of their children's care team. Genetic counselors are in a unique position to help coordinate complex care for children with A-T (and other rare diseases) and provide support to family members using the framework of family-centered care. This paper offers suggestions for expanding support and learning to cope with a difficult diagnosis for parents of children with rare diseases, specifically A-T, based on stories from parents of children with A-T.

Ataxia-Telangiectasia (A-T) is an autosomal recessive neurodegenerative disease associated with cerebellar ataxia and extrapyramidal features. A-T has a complex and diverse phenotype with varying rates of disease progression. The development of robust natural history studies and therapeutic trials relies on the accurate recording of phenotype using relevant and validated severity of illness indexes. We compared the commonly used Scale for the Assessment and Rating of Ataxia (SARA) and the disease-specific A-T Neurological Examination Scale Toolkit (A-T NEST), in our adult A-T cohort. We found a strong correlation between A-T NEST and the established SARA score, validating the use of A-T NEST and SARA in capturing the natural history of A-T patients.

Ataxia telangiectasia (A-T) (OMIM 208900) is an autosomal recessive multisystem disorder characterised by progressive cerebellar ataxia, telangiectasias, immunodeficiency and a predisposition to malignancy. 'Variant' A-T has later onset of neurological symptoms and slower progression compared with the 'classic' form. A woman presented with short stature in late childhood. Karyotype revealed rearrangements involving chromosomes 7 and 14. A chromosomal breakage disorder gene panel demonstrated compound heterozygote mutations in her ATM gene including one mutation c.7271T>G with residual ATM function, confirming the diagnosis of variant A-T. Since diagnosis, she has developed progressive cerebellar ataxia and telangiectasias. Long-standing restrictive and aversive feeding behaviours presented challenges for her management and necessitated gastrostomy.

Ataxia-telangiectasia (A-T) is a disease caused by mutations in the ATM gene (11q22.3-23.1) that induce neurodegeneration Sasihuseyinoglu AS et al. Pediatr Allergy Immunol Pulmonol 31(1):9-14, 2018, Teive HAG et al. Parkinsonism Relat Disord 46:3-8, 2018. Clinically, A-T is characterized by ataxia, mucocutaneous telangiectasia, immunodeficiency, and malignancy. Movement disorders have been the most described and well-studied symptoms of A-T. Other studies have reported visuospatial processing disorders, executive function disorders and emotional regulation disorders, which are clinical manifestations that characterize cerebellar cognitive affective syndrome (CCAS) Choy KR et al. Dev Dyn 247(1):33-46, 2018. To describe the neurocognitive and emotional state of pediatric patients with ataxia-telangiectasia and to discuss whether they have cerebellar cognitive affective syndrome. This observational, cross-sectional, and descriptive study included 9 patients with A-T from May 2019 to May 2021. A complete medical history was retrieved, and tests were applied to assess executive functions, visual-motor integration and abilities, language, psychological disorders, and ataxia. Six girls and 3 boys agreed to participate. The age range was 6 to 14 years. The participants included five schoolchildren and four teenagers. Eight patients presented impaired executive functioning. All patients showed some type of error in copying and tracing (distortion) in the performance of visual perceptual abilities. Emotional disorders such as anxiety and depression were observed in six patients. Eight patients presented with dyslalia and impairments in word articulation, all patients presented with ataxia, and seven patients used a wheelchair. All patients presented symptoms consistent with CCAS and had variable cognitive performance.