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Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, and an increased malignancy risk. Cells derived from individuals with AT show multiple defects, including high oxidant and ionizing radiation sensitivities, poor DNA repair, low iron–sulfur cluster levels, and low reduced glutathione. The clinical course of AT is progressive and unrelenting, with most individuals having a survival time of approximately twenty-five years. Presently, AT has no effective treatments, and most patients receive supportive care only. Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT. Here, I will discuss the possible molecular mechanisms of pioglitazone's favorable effects on the AT phenotype and why it may have utility in treating some aspects of AT. [ABSTRACT FROM AUTHOR]

Background Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus, dose and schedule optimization requires extended follow-up to assess prolonged treatment effects. Methods Long-term safety, tolerability, and antitumor efficacy of 3 camonsertib monotherapy dosing regimens were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on, 4 days off (160 3/4; the preliminary recommended Phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on, 1 week off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating tumor DNA (ctDNA)-based molecular response rate. Results The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (hazard ratio = 0.23, 2-sided P  = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. Conclusion The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering a substantial reduction in the incidence of anemia without any compromise to efficacy. Clinical Trial ID NCT04497116. [ABSTRACT FROM AUTHOR]

The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches. [ABSTRACT FROM AUTHOR]

• The study presents the first report of ATM :c.1564_1565del variant segregating with breast cancer and Ataxia-Telangiectasia (A-T) and in the same family. • This study highlights the importance of a comprehensive genomic investigation and appropriate cancer risk management of heterozygote carriers of ATM in families with A-T. • Given the age-related or moderate penetrance of ATM in breast cancer, ATM -positive family members of an affected individual with A-T are likely asymptomatic for breast or any other epithelial cancer. ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma. Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family. Here, using joint analysis and whole genome sequencing, we investigated ATM c.1564_1565del in a family with one homozygous member presenting with A-T (OMIM # 208900) and three heterozygous members, of whom one had breast cancer (OMIM # 114480). To our knowledge, this is the first study of ATM c.1564_1565del segregation with both A-T and breast cancer phenotypes within the same kindred. This study highlights the need for a comprehensive genomic approach in the appropriate cancer risk management of heterozygote carriers of ATM in families with A-T. [ABSTRACT FROM AUTHOR]

Background/Objectives: Ataxia telangiectasia (A‐T) is an inherited multisystem disorder with increased sensitivity to ionising radiation and elevated cancer risk. Although other cancer predisposition syndromes have established cancer screening protocols, evidence‐based guidelines for cancer screening in A‐T are lacking. This study sought to assess feasibility of a cancer screening protocol based on whole‐body MRI (WB‐MRI) in children and young people with A‐T. Design/Methods: Children and young people with A‐T were invited to undergo a one‐off non‐sedated 3‐Tesla WB‐MRI. Completion rate of WB‐MRI was recorded and diagnostic image quality assessed by two experienced radiologists, with pre‐specified success thresholds for scan completion of >50% participants and image quality between acceptable to excellent in 65% participants. Positive imaging findings were classified according to the ONCO‐RADS system. Post‐participation interviews were performed with recruited families to assess the experience of participating and feelings about waiting for, and communication of, the findings of the scan. Results: Forty‐six children and young people with A‐T were identified, of which 36 were eligible to participate, 18 were recruited and 16 underwent WB‐MRI. Nineteen parents participated in interviews. Fifteen participants (83%) completed the full WB‐MRI scan protocol. The pre‐specified image quality criterion was achieved with diagnostic images obtained in at least 93% of each MRI sequence. Non‐malignant scan findings were present in 4 (25%) participants. Six themes were identified from the interviews: (1) anxiety is a familiar feeling, (2) the process of MRI scanning is challenging for some children and families, (3) preparation is essential to reduce stress, (4) WB‐MRI provides the reassurance about the physical health that families need, (5) WB‐MRI experience turned out to be a positive experience and (6) WB‐MRI allows families to be proactive. Conclusion: This study shows that WB‐MRI for cancer screening is feasible and well‐accepted by children and young people with A‐T and their families. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency disorder (PID) caused by biallelic mutations occurring in the serine/threonine protein kinase (ATM) gene. The major role of nuclear ATM is the coordination of cell signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoints. Defects in ATM functions lead to A-T syndrome with phenotypic heterogeneity. Our study reports the case of a Tunisian girl with A-T syndrome carrying a compound heterozygous mutation c.[3894dupT]; p.(Ala1299Cysfs3;rs587781823), with a splice acceptor variant: c.[5763-2A>C;rs876659489] in the ATM gene that was identified by nextgeneration sequencing (NGS). Further genetic analysis of the family showed that the mother carried the c.[5763-2A>C] splice acceptor variant, while the father harbored the c.[3894dupT] variant in the heterozygous state. Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the identification of compound heterozygous ATM pathogenic variants by NGS in a Tunisian A-T patient. Our study outlines the importance of molecular genetic testing for A-T patients, which is required for earlier detection and reducing the burden of disease in the future, using the patients’ families [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background/Objectives Ataxia telangiectasia (A‐T) is an inherited multisystem disorder with increased sensitivity to ionising radiation and elevated cancer risk. Although other cancer predisposition syndromes have established cancer screening protocols, evidence‐based guidelines for cancer screening in A‐T are lacking. This study sought to assess feasibility of a cancer screening protocol based on whole‐body MRI (WB‐MRI) in children and young people with A‐T. Design/Methods Children and young people with A‐T were invited to undergo a one‐off non‐sedated 3‐Tesla WB‐MRI. Completion rate of WB‐MRI was recorded and diagnostic image quality assessed by two experienced radiologists, with pre‐specified success thresholds for scan completion of >50% participants and image quality between acceptable to excellent in 65% participants. Positive imaging findings were classified according to the ONCO‐RADS system. Post‐participation interviews were performed with recruited families to assess the experience of participating and feelings about waiting for, and communication of, the findings of the scan. Results Forty‐six children and young people with A‐T were identified, of which 36 were eligible to participate, 18 were recruited and 16 underwent WB‐MRI. Nineteen parents participated in interviews. Fifteen participants (83%) completed the full WB‐MRI scan protocol. The pre‐specified image quality criterion was achieved with diagnostic images obtained in at least 93% of each MRI sequence. Non‐malignant scan findings were present in 4 (25%) participants. Six themes were identified from the interviews: (1) anxiety is a familiar feeling, (2) the process of MRI scanning is challenging for some children and families, (3) preparation is essential to reduce stress, (4) WB‐MRI provides the reassurance about the physical health that families need, (5) WB‐MRI experience turned out to be a positive experience and (6) WB‐MRI allows families to be proactive. Conclusion This study shows that WB‐MRI for cancer screening is feasible and well‐accepted by children and young people with A‐T and their families.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, and an increased malignancy risk. Cells derived from individuals with AT show multiple defects, including high oxidant and ionizing radiation sensitivities, poor DNA repair, low iron–sulfur cluster levels, and low reduced glutathione. The clinical course of AT is progressive and unrelenting, with most individuals having a survival time of approximately twenty-five years. Presently, AT has no effective treatments, and most patients receive supportive care only. Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT. Here, I will discuss the possible molecular mechanisms of pioglitazone’s favorable effects on the AT phenotype and why it may have utility in treating some aspects of AT.

Stimulator of interferon genes (STING) is an innate immune signaling protein critical to infections, autoimmunity, and cancer. STING signaling is also emerging as an exciting and integral part of many neurological diseases. Here, we discuss recent advances in STING signaling in the brain. We summarize how molecular threats activate STING signaling in the diseased brain and how STING signaling activities in glial and neuronal cells cause neuropathology. We also review human studies of STING neurobiology and consider therapeutic challenges in targeting STING to treat neurological diseases. Yang et al. review the current state of knowledge about innate immune system STING signaling in neurological diseases and discuss mechanisms of STING signaling activation, activities in different brain cell types, human relevance, and development of STING antagonists. [ABSTRACT FROM AUTHOR]

Purpose: Ataxia-telangiectasia (A-T) is a rare genetic condition with malfunctioning DNA repair processes resulting in significant clinical findings, including progressive neurologic decline, elevated malignancy risk, immunodeficiency, oculocutaneous telangiectasias, and severe pulmonary disease. Research has been limited into the quality of life of such patients and yet to be completed are studies quantitatively analyzing psychosocial, physical, and cognitive patient-reported outcomes (PROs) within the A-T population. Methods: PRO evaluations of 90 international adult and pediatric A-T patients and their caregivers were completed via secure online administration of Patient-Reported Outcomes Measurement Information System (PROMIS) short forms evaluating anger, cognition, mood, social health, fatigue, pain, anxiety, and upper extremity function. The impact of age, gender, race/ethnicity, prior malignancy diagnosis, and current supportive treatment interventions on such PROs was additionally assessed. Finally, given the importance of medical providers in the care of A-T patients and the impact of patient satisfaction on healthcare outcomes, we further analyzed, via a novel survey, how patients and caregivers perceived their primary A-T healthcare provider's A-T expertise, trustworthiness, accessibility, and level of compassion. Results/Conclusion: It was found that a diagnosis of A-T complexly impacts patient PROs, but such data offers the potential for preventative and therapeutic interventions to improve the care of such patients. While most A-T patients and their caregivers feel their primary A-T medical provider has expertise and compassion in addition to being accessible and trustworthy, a significant percentage of study subjects did not agree that their provider was an expert in A-T or overall trustworthy. [ABSTRACT FROM AUTHOR]

Background and purpose: Ataxia–telangiectasia (A‐T) is a rare, autosomal recessive, multisystem disorder that leads to progressive neurodegeneration with cerebellar ataxia and peripheral polyneuropathy. Cerebellar neurodegeneration is well described in A‐T. However, peripheral nervous system involvement is an underdiagnosed but important additional target for supportive and systemic therapies. The aim of this study was to conduct neurophysiological measurements to assess peripheral neurodegeneration and the development of age‐dependent neuropathy in A‐T. Methods: In this prospective study, 42 classical A‐T patients were assessed. The motor and sensory nerve conduction of the median and tibial nerves was evaluated. Data were compared to published standard values and a healthy age‐ and gender‐matched control group of 23 participants. Ataxia scores (Klockgether, Scale for the Assessment and Rating of Ataxia) were also assessed. Results: In A‐T, neurophysiological assessment revealed neuropathic changes as early as the first year of life. Subjective symptomatology of neuropathy is rarely described. In the upper extremities, motor neuropathy was predominantly that of a demyelinating type and sensory neuropathy was predominantly that of a mixed type. In the lower extremities, motor and sensory neuropathy was predominantly that of a mixed type. We found significant correlations between age and the development of motor and sensory polyneuropathy in A‐T compared with healthy controls (p < 0.001). Conclusions: In A‐T, polyneuropathy occurs mostly subclinically as early as the first year of life. The current study of a large national A‐T cohort demonstrates that development of neuropathy in A‐T differs in the upper and lower extremities. [ABSTRACT FROM AUTHOR]

Louis-Bar Syndrome is a synonym for a very rare complex neurodegenerative disorder ataxia-telangiectasia (A-T). This is an autosomal recessive inherited disease that encompasses abnormalities in the cerebellum, multisystem degeneration, immunodeficiency, increased risk for malignancy and consecutive respiratory insufficiency. Most of the patients are radiosensitive and any exposing to ionization may lead to progression of the disease. Potential risks from anesthesia, mechanical ventilation, and postoperative complications in these patients have been insufficiently discussed in the literature. We present a successful anesthetic and respiratory management with one-lung ventilation in a patient with Louis-Bar Syndrome who underwent video assisted thoracoscopy (VATS) for recurrent pleural effusion. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency disorder (PID) caused by biallelic mutations occurring in the serine/threonine protein kinase (ATM) gene. The major role of nuclear ATM is the coordination of cell signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoints. Defects in ATM functions lead to A-T syndrome with phenotypic heterogeneity. Our study reports the case of a Tunisian girl with A-T syndrome carrying a compound heterozygous mutation c.[3894dupT]; p.(Ala1299Cysfs3;rs587781823), with a splice acceptor variant: c.[5763-2A>C;rs876659489] in the ATM gene that was identified by next-generation sequencing (NGS). Further genetic analysis of the family showed that the mother carried the c.[5763-2A>C] splice acceptor variant, while the father harbored the c.[3894dupT] variant in the heterozygous state. Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the identification of compound heterozygous ATM pathogenic variants by NGS in a Tunisian A-T patient. Our study outlines the importance of molecular genetic testing for A-T patients, which is required for earlier detection and reducing the burden of disease in the future, using the patients’ families.

Abstract Background Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare. Case presentation We herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (

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 (A‐T) is a very rare autosomal recessive multisystemic disorder which to date is still uncurable. The use of glucocorticoid analogs, such as dexamethasone (dex), can improve neurological symptoms in patients, but the molecular mechanism of action of these analogs remains unclear. Here, we report the effects of dex in regulating the interaction between Lamin A/C and HDAC2 in WT and A‐T cells. Upon administration of dex to A‐T cells, we first observed that the accumulation of HDAC2 on the CDKN1A promoter did not exert a repressive role on p21cip1/waf1 expression, and second, we established that HDAC2 accumulation was not dependent on Lamin A/C. Both of these results are contrary to previous reported outcomes in other cellular models. Furthermore, large amounts of LAP2α and FoxO3a were found to occupy the CDKN1A promoter with matched p21cip1/waf1 overexpression. Hence, in A‐T cells p21 could be activated as a result of a dex‐induced rearrangement of a multicomponent complex, composed of Lamin A/C, HDAC2, LAP2α, pRb, E2F1, and FoxO3a, at the CDKN1A gene promoter.

Background: Ataxia-telangiectasia is a multi-organ disease. It is due to a mutation of the Exon No. 5 ataxia telangiectasia mutated gene (c.381delA: p.v128fls). Complications including recurrent infections, progressive cerebellar ataxia, and varying degrees of humoral and cellular immunodeficiency arise. Case Presentation: We report a 7-year-old girl patient with A-T who developed acute rheumatic fever. Conclusion: Rheumatoid disorders and or infectious diseases such as acute rheumatic fever could be observed in A-T patient.

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. [ABSTRACT FROM AUTHOR]

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare. Case presentation: We herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES). Conclusions: Although rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis. [ABSTRACT FROM AUTHOR]

Ataxia‐telangiectasia (A‐T) is a rare devastating hereditary condition, which affects multiple organ systems including cerebellar motor function as well as DNA repair, resulting in a higher incidence of cancer and immunodeficiency. The genetic defect in A‐T lies in ATM kinase, which is activated by DNA damage and regulates a plethora of substrates including the p53 tumor suppressor. We have organized an international meeting "The 19th Ataxia‐Telangiectasia Workshop 2023 (ATW2023)" with support from the Molecular Biology Society of Japan (MBSJ) and other funders. Here, we report that ATW2023 was successfully held in Kyoto from March 2nd to 5th, 2023 with more than 150 participants traveling from all over the world, despite the still smoldering COVID‐19 pandemic. In this meeting report, we will briefly describe the highlights of the meeting and would like to express our gratitude to the MBSJ for the financial support. [ABSTRACT FROM AUTHOR]

Abstract Background Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes. Objective To identify the frequency of significant hepatic fibrosis in A-T patients and to verify the association with metabolic alterations and degree of ataxia. Methods This is a cross-sectional study that included 25 A-T patients aged 5 to 31 years. Anthropometric data, liver, inflammatory, lipid metabolism and glucose biomarkers (oral glucose tolerance test with insulin curve—OGTT) were collected. The Cooperative Ataxia Rating Scale was applied to assess the degree of ataxia. The following were calculated: Homeostasis Model Assessment—Insulin Resistance, Homeostasis Model Assessment—Adiponectin (HOMA-AD), Matsuda index, aspartate aminotransferase (AST): platelet ratio index, nonalcoholic fatty liver disease fibrosis score and BARD score. Liver ultrasonography and transient liver elastography by FibroScan® were performed. Results Significant hepatic fibrosis was observed in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (p

Iron-sulfur clusters play a central role in cellular function and are regulated by the ATM protein. Iron-sulfur clusters are part of the cellular sulfide pool, which functions to maintain cardiovascular health, and consists of free hydrogen sulfide, iron-sulfur clusters, protein bound sulfides, which constitute the total cellular sulfide fraction. ATM protein signaling and the drug pioglitazone share some cellular effects, which led us to examine the effects of this drug on cellular iron-sulfur cluster formation. Additionally, as ATM functions in the cardiovasculature and its signaling may be diminished in cardiovascular disease, we examined pioglitazone in the same cell type, with and without ATM protein expression. We examined the effects of pioglitazone treatment on the total cellular sulfide profile, the glutathione redox state, cystathionine gamma-lyase enzymatic activity, and on double-stranded DNA break formation in cells with and without ATM protein expression. Pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions and reduced cystathionine gamma-lyase enzymatic activity in cells with and without ATM protein expression. Interestingly, pioglitazone also increased reduced glutathione and lowered DNA damage in cells without ATM protein expression, but not in ATM wild-type cells. These results are interesting as the acid-labile (iron-sulfur cluster), bound sulfur cellular fractions, and reduced glutathione are low in cardiovascular disease. Here we found that pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions, impinges on hydrogen sulfide synthesis, and exerts beneficial effect on cells with deficient ATM protein signaling. Thus, we show a novel pharmacologic action for pioglitazone. • Pioglitazone increases cellular iron-sulfur complex and protein sulfhydration. • Pioglitazone impinges are several aspects of hydrogen sulfide function and synthesis. • Pioglitazone increases reduced glutathione levels and DNA repair capacity in ATM protein expression-deficient cells. • Pioglitazone is a possible pharmacologic treatment for ataxia-telangiectasia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Ataxia-telangiectasia (A-T) is a multisystem genetic disorder involving ataxia, oculocutaneous telangiectasia, and immunodeficiency caused by biallelic pathogenic variants in the ATM gene. To date, most ATM variants have been reported in the Caucasian population, and few studies have focused on the genotype-phenotype correlation of A-T in the Chinese population. We herein present a Chinese patient with A-T who carries compound heterozygous variants in the ATM gene and conducted a literature review for A-T in China. Case presentation: A 7-year-old Chinese girl presented with growth retardation, ataxia, medium ocular telangiectasia, cerebellar atrophy, and elevated serum alpha-fetoprotein (AFP) level, which supported the suspicion of A-T. Notably, the serum levels of immunoglobulins were all normal, ruling out immunodeficiency. Exome sequencing and Sanger sequencing revealed two likely pathogenic ATM variants, namely NM_000051.4: c.4195dup (p.Thr1399Asnfs 15) and c.6006 + 1G>T (p.), which were inherited from her father and mother, respectively. From the Chinese literature review, we found that there was a marked delay in the diagnosis of A-T, and 38.9% (7/18) of A-T patients did not suffer from immunodeficiency in China. No genotype-phenotype correlation was observed in this group of A-T patients. Conclusion: These results extend the genotype spectrum of A-T in the Chinese population and imply that the diagnosis of A-T in China should be improved. [ABSTRACT FROM AUTHOR]

The genetic disorder, ataxia‐telangiectasia (A‐T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A‐T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A‐T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA‐seq analysis of A‐T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A‐T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A‐T cells. We observed in them a robust activation of interferon‐stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non‐canonical cGAS‐STING‐mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A‐T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence‐associated secretory phenotype (SASP) factors known for their paracrine pro‐fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A‐T patients and its associated symptoms, which develop as the patients advance in age. [ABSTRACT FROM AUTHOR]

Ataxia‐Telangiectasia (A‐T) is a very rare autosomal recessive multisystemic disorder which to date is still uncurable. The use of glucocorticoid analogs, such as dexamethasone (dex), can improve neurological symptoms in patients, but the molecular mechanism of action of these analogs remains unclear. Here, we report the effects of dex in regulating the interaction between Lamin A/C and HDAC2 in WT and A‐T cells. Upon administration of dex to A‐T cells, we first observed that the accumulation of HDAC2 on the CDKN1A promoter did not exert a repressive role on p21cip1/waf1 expression, and second, we established that HDAC2 accumulation was not dependent on Lamin A/C. Both of these results are contrary to previous reported outcomes in other cellular models. Furthermore, large amounts of LAP2α and FoxO3a were found to occupy the CDKN1A promoter with matched p21cip1/waf1 overexpression. Hence, in A‐T cells p21 could be activated as a result of a dex‐induced rearrangement of a multicomponent complex, composed of Lamin A/C, HDAC2, LAP2α, pRb, E2F1, and FoxO3a, at the CDKN1A gene promoter. [ABSTRACT FROM AUTHOR]

ATM depletion is associated with the multisystemic neurodegenerative syndrome ataxia–telangiectasia (A–T). The exact linkage between neurodegeneration and ATM deficiency has not been established yet, and no treatment is currently available. In this study, we aimed to identify synthetic viable genes in ATM deficiency to highlight potential targets for the treatment of neurodegeneration in A–T. We inhibited ATM kinase activity using the background of a genome-wide haploid pluripotent CRISPR/Cas9 loss-of-function library and examined which mutations confer a growth advantage on ATM-deficient cells specifically. Pathway enrichment analysis of the results revealed the Hippo signaling pathway as a major negative regulator of cellular growth upon ATM inhibition. Indeed, genetic perturbation of the Hippo pathway genes SAV1 and NF2, as well as chemical inhibition of this pathway, specifically promoted the growth of ATM-knockout cells. This effect was demonstrated in both human embryonic stem cells and neural progenitor cells. Therefore, we suggest the Hippo pathway as a candidate target for the treatment of the devastating cerebellar atrophy associated with A–T. In addition to the Hippo pathway, our work points out additional genes, such as the apoptotic regulator BAG6, as synthetic viable with ATM-deficiency. These genes may help to develop drugs for the treatment of A–T patients as well as to define biomarkers for resistance to ATM inhibition-based chemotherapies and to gain new insights into the ATM genetic network. [ABSTRACT FROM AUTHOR]

Background: Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes. Objective: To identify the frequency of significant hepatic fibrosis in A-T patients and to verify the association with metabolic alterations and degree of ataxia. Methods: This is a cross-sectional study that included 25 A-T patients aged 5 to 31 years. Anthropometric data, liver, inflammatory, lipid metabolism and glucose biomarkers (oral glucose tolerance test with insulin curve—OGTT) were collected. The Cooperative Ataxia Rating Scale was applied to assess the degree of ataxia. The following were calculated: Homeostasis Model Assessment—Insulin Resistance, Homeostasis Model Assessment—Adiponectin (HOMA-AD), Matsuda index, aspartate aminotransferase (AST): platelet ratio index, nonalcoholic fatty liver disease fibrosis score and BARD score. Liver ultrasonography and transient liver elastography by FibroScan® were performed. Results: Significant hepatic fibrosis was observed in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (p < 0.001), had lower platelet count values (p = 0.027), serum albumin (p = 0.019), HDL-c (p = 0.013) and Matsuda index (p = 0.044); and high values of LDL-c (p = 0.049), AST (p = 0.001), alanine aminotransferase (p = 0.002), gamma-glutamyl transferase (p = 0.001), ferritin (p = 0.001), 120-min glycemia by OGTT (p = 0.049), HOMA-AD (p = 0.016) and degree of ataxia (p = 0.009). Conclusions: A non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Ataxia-telangiectasia is a rare genetically inherited disease with multisystem involvement. We evaluated the clinical and laboratory features of patients diagnosed in our clinic with ataxia-telangiectasia. Materials and Methods: The files of children diagnosed with ataxia-telangiectasia in our clinic between 2008 and 2021 were evaluated retrospectively. Results: Twelve children diagnosed with ataxia-telangiectasia were included in the study. Fifty percent of our patients were boys, and 50% were girls. There was a family history of ataxia-telangiectasia in seven patients and consanguineous marriage between the parents of 11 patients. The mean age at diagnosis of the patients was 5.5 years. Our cases had telangiectasia in the conjunctiva (n=8), a nevus (n=5), cafe-au-lait spots (n=5), hypopigmentation (n=4), and skin telangiectasia (n=3). Eosinophilia (n=1), lymphopenia (n=7), and neutropenia (n=1) were also found. Our patients were determined to be below -2 SD for age in terms of IgE levels in 25%, IgA levels in 58.3%, and IgG levels in 8.3%. Antibody responses were negative for anti-hepatitis B surface (HBs) IgG (n=5), anti-measles IgG (n=7), anti-mumps IgG (n=6), anti-VZV IgG (n=6), anti-tetanus IgG (n=6), and anti-hepatitis A virus IgG (n=3). Seven patients had homozygous ataxia-telangiectasia gene (ATM) mutations. We most commonly detected homozygous c.4940T>G (p.L1647R) and homozygous c.6047A>G (p.D2016) mutations. Alpha-fetoprotein (AFP) levels were elevated in all patients. We started intravenous immunoglobulin (IVIG) therapy for 10 patients. Conclusion: Ataxia and telangiectasia were the most common findings of the disease, followed by immunological findings, growth retardation, and pigmentation abnormalities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundAtaxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, including classic A-T and milder form of AT. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T such as ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifesting isolated generalized or segmental dystonia without any signs of classical A-T.MethodsAn A-T pedigree with predominant dystonia was collected. Genetic testing was performed by targeted panel of genes involved in movement disorders. The candidate variants were further confirmed by Sanger sequencing. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T.ResultsTwo novel ATM mutations, p.I2683T and p.S2860P, were identified in the family. The proband presented isolated segmental dystonia without any signs of ataxia and telangiectasias. We reviewed the literatures and found that the patients with dystonia-dominant A-T tend to have a later-onset and slower progression of the disease.ConclusionTo our knowledge, this is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. Early ATM genetic testing should be considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder with no available curative treatment. Although the positive effects of N-acetyl-DL-leucine on cerebellar ataxia have been reported previously, there is little evidence of N-acetyl-DL-leucine's effects in patients with AT. This study assessed the effect of 16 weeks N-acetyl-DL-leucine supplementation on ataxia symptoms in a 9-year-old female with AT. The subject consumed 4 g/day N-acetyl-DL-leucine (2 g in the morning and 2 g in the evening) for 16 weeks. Safety was assessed via clinical blood chemistry prior to the intervention and after 6 and 16 weeks. Additionally, The Scale for the Assessment and Rating of Ataxia (SARA) score was used to assess the drug's effects on ataxia symptoms at baseline, 6, 12, and 16 weeks. Quality of life has also been evaluated by a specialist using the PedsQL questionnaire.Despite some initial (first week only) nausea and constipation, supplementation with N-acetyl-DL-leucine was well tolerated and safe according to blood chemistry measures. The SARA score progressively improved, and by week 16 had improved by 11.0 points (48.88%). Parent and self-reported quality of life assessments indicated physical, emotional, social, and school functions all improved by 16 weeks. Supplementation with N-acetyl-DL-leucine at a dose of 4 g/day for 16 weeks was well tolerated and significantly improved ataxia symptoms and quality of life measures in a young child with AT. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (AT) is a multisystemic neurodegenerative inborn error of immunity (IEI) characterized by DNA repair defect, chromosomal instability, and hypersensitivity to ionizing radiation. Impaired DNA double-strand break repair determines a high risk of developing hematological malignancies, especially lymphoproliferative diseases. Poor response to treatment, excessive chemotherapy toxicities, and the need for avoiding exposure to ionizing radiation make the successful clinical management of patients with AT challenging for oncologists. We describe the favorable outcome of the LBCL with IRF4 rearrangement at stage III in a 7-year-old female patient diagnosed with AT. The patient was treated according to the B-HR arm of the INTER-B-NHL-COP 2010 protocol, including the administration of rituximab, cyclophosphamide, methotrexate, prednisone, etc. She presented excessive treatment toxicities despite individually reduced doses of methotrexate and cyclophosphamide. However, in the MRI there was no significant reduction in pathologic lymph nodes after three immunochemotherapy courses. Therefore, a lymph node biopsy was taken. Its subsequent histopathological examination revealed tuberculosis-like changes, though tuberculosis suspicion was excluded. After two following immunochemotherapy courses, PET-CT confirmed complete remission. From March 2022 onwards, the patient has remained in remission under the care of the outpatient children's oncology clinic. [ABSTRACT FROM AUTHOR]

BackgroundRare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT).MethodsData from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used.ResultsFifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved.ConclusionRIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

Ataxia-telangiectasia confers a significant increase in the development of several cancer types, most commonly leukemia and lymphoma. However, as the natural history for these patients is evolving and their lifespan is increasing, there is the potential for the development of additional uncommon tumors in an already rare patient population. We report the first case, to our knowledge, of an incidental retroperitoneal tumor in a 26-year-old woman undergoing evaluation for hepatic dysfunction. The mass was suspicious for retroperitoneal sarcoma, but proved to be an extramedullary hematopoietic pseudotumor after extensive pathologic evaluation. The changing landscape of neoplasms associated with ataxia-telangiectasia is discussed with emphasis on previously underreported benign and malignant tumors.

To explore neurological factors affecting quality of life (QoL) in children and young people with ataxia-telangiectasia (A-T), from both child and parent perspective. 24 children/young people with A-T (mean age 11.2 ± 3.5 years; 13 males) and 20 parents were recruited, and 58% were reassessed after an average interval of 3.4 years. Participants completed the PedsQL QoL assessment. Participants with A-T underwent structured neurological examination. QoL data from 20 healthy controls and their parents was used for comparison. Children/young people with A-T rated their QoL higher than parental ratings across time points, with no longitudinal change. Higher age of the child participant correlated with lower parental (r = −0.43, p =.008) but not child ratings of QoL (r = −0.16, p =.380). Child and parent QoL ratings from the A-T group were lower than respective ratings from controls (η p 2 = 0.44 and η p 2 = 0.75 respectively, both p <.0005, controlled for socioeconomic status). Parental, but not child, ratings of QoL was predicted by a regression model based on neurological scores (R 2 = 0.44, p =<.001). Neurological disability does not determine child/young person QoL ratings in A-T. While certain aspects of neurological disability predict parent-proxy ratings, there is no decline in QoL over time. These results may reflect resilience in the face of a complex life-limiting disorder. [Display omitted] • Child ratings of QoL in A-T are significantly higher than parental ratings. • Age negatively correlated with parent QoL ratings, but there was no relationship between age and child QoL self-ratings. • Neurological function significantly predicts parental, but not the child's own ratings of their QoL. • Over time, QoL ratings did not decline with increasing disability reflecting high levels of resilience in this sample. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (A-T) is a severe syndromic neurodegenerative inborn error of immunity characterized by DNA reparation defect, chromosomal instability, and hypersensitivity to ionizing radiation, thereby predisposing affected individuals to malignant transformation. While the leading disease symptomatology is associated with progressively debilitating cerebellar ataxia accompanied by central and peripheral nervous system dysfunctions, A-T is a multisystemic disorder manifesting with the heterogeneity of phenotypic features. These include airway and interstitial lung disease, chronic liver disease, endocrine abnormalities, and cutaneous and deep-organ granulomatosis. The impaired thymic T cell production, defective B cell development and antibody production, as well as bone marrow failure, contribute to a combined immunodeficiency predisposing to infectious complications, immune dysregulation, and organ-specific immunopathology, with the A-T hyper-IgM (HIGM) phenotype determining the more severe disease course. This study aimed to clarify the immunodeficiency and associated immune dysregulation as well as organ-specific immunopathology in children with A-T. We also sought to determine whether the hyper-IgM and non-hyper-IgM phenotypes play a discriminatory role and have prognostic significance in anticipating the clinical course and outcome of the disease. We retrospectively reviewed the medical records of twelve A-T patients, aged from two to eighteen years. The patients' infectious history, organ-specific symptomatology, and immunological workup including serum alpha-fetoprotein, immunoglobulin isotypes, IgG subclasses, and lymphocyte compartments were examined. For further comparative analysis, all the subjects were divided into two groups, HIGM A-T and non-HIGM A-T. The clinical evaluation of the study group showed that recurrent respiratory tract infections due to viral and bacterial pathogens and a chronic obstructive airway disease along with impaired humoral immunity, in particular complete IgA deficiency, were noted in all the A-T patients, with both HIGM and non-HIGM phenotypes. The most important features with the discriminatory role between groups, were autoimmune disorders, observable four times more frequently in HIGM than in non-HIGM A-T. Two patients with the HIGM A-T phenotype were deceased due to liver failure and chronic Epstein-Barr virus (EBV) infection. It may therefore be assumed that the HIGM form of A-T is associated with more profound T cell dysfunction, defective immunoglobulin class switching, chronic EBV expansion, and poorer prognosis.

Ataxia-telangiectasia (A-T) is a syndromic inborn error of immunity (IEI) characterized by genomic instability, defective reparation of the DNA double-strand breaks, and hypersensitivity to ionizing radiation disturbing cellular homeostasis. The role of imaging diagnostics and the conscious choice of safe and advantageous imaging technique, as well as its correct interpretation, are crucial in the diagnostic process and monitoring of children with A-T. This study aimed at defining the role of a radiologist in the early diagnosis of A-T, as well as in detecting and tracking disease complications associated with infections, inflammation, lymphoproliferation, organ-specific immunopathology, and malignancy. Based on our single-center experience, retrospective analysis of investigations using ionizing radiation-free techniques, ultrasound (US), and Magnetic Resonance Imaging (MRI), was performed on regularly followed-up 11 pediatric A-T patients, 6 girls and 5 boys, aged from 2 to 18 years, with the longest period of observation coming to over 13 years. Our attention was especially drawn to the abnormalities that were observed in the US and MRI examinations of the lungs, abdominal cavity, and lymph nodes. The abdominal US showed no abnormalities in organ dimensions or echostructure in 4 out of 11 children studied, yet in the other 7, during follow-up examinations, hepato- and/or splenomegaly, mesenteric, visceral, and paraaortic lymphadenopathy were observable. In 2 patients, focal changes in the liver and spleen were shown, and in one patient progressive abdominal lymphadenopathy corresponded with the diagnosis of non-Hodgkin lymphoma (NHL). The lung US revealed multiple subpleural consolidations and B line artifacts related to the interstitial-alveolar syndrome in 5 patients, accompanied by pleural effusion in one of them. The MRI investigation of the lung enabled the detection of lymphatic nodal masses in the mediastinum, with concomitant airway lesions characteristic of bronchiectasis and focal parenchymal consolidations in one A-T patient with chronic respiratory failure. This patient also manifested organomegaly and granulomatous liver disease in abdominal MRI examination. Our study shows that the use of modern US capabilities and MRI is safe and efficient, thereby serving as a recommended advantageous imaging diagnostic tool in monitoring children with IEI and DNA instability syndromes.

With disease-modifying approaches under evaluation in ataxia-telangiectasia and other ataxias, there is a need for objective and reliable biomarkers of free-living motor function. In this study, we test the hypothesis that metrics derived from a single wrist sensor worn at home provide accurate, reliable, and interpretable information about neurological disease severity in children with A-T. A total of 15 children with A-T and 15 age- and sex-matched controls wore a sensor with a triaxial accelerometer on their dominant wrist for 1 week at home. Activity intensity measures, derived from the sensor data, were compared with in-person neurological evaluation on the Brief Ataxia Rating Scale (BARS) and performance on a validated computer mouse task. Children with A-T were inactive the same proportion of each day as controls but produced more low intensity movements (p < 0.01; Cohen's d = 1.48) and fewer high intensity movements (p < 0.001; Cohen's d = 1.71). The range of activity intensities was markedly reduced in A-T compared to controls (p < 0.0001; Cohen's d = 2.72). The activity metrics correlated strongly with arm, gait, and total clinical severity (r: 0.71–0.87; p < 0.0001), correlated with specific computer task motor features (r: 0.67–0.92; p < 0.01), demonstrated high reliability (r: 0.86–0.93; p < 0.00001), and were not significantly influenced by age in the healthy control group. Motor activity metrics from a single, inexpensive wrist sensor during free-living behavior provide accurate and reliable information about diagnosis, neurological disease severity, and motor performance. These low-burden measurements are applicable independent of ambulatory status and are potential digital behavioral biomarkers in A-T. [ABSTRACT FROM AUTHOR]

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disease characterized by ataxia, cutaneous and ocular telangiectasia, impaired immunity with susceptibility to sino-pulmonary infections, radiation sensitivity, and cancers particularly of hemato-lymphoid origin. Liver function tests abnormalities and elevated alfa feto-protein have been reported in A-T; however, there is no reported case of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in literature. These tumors should be treated in similar fashion as in general population; however, reduction of chemotherapy dose might be helpful in decreasing chemo-toxicity.

ATM depletion is associated with the multisystemic neurodegenerative syndrome ataxia–telangiectasia (A–T). The exact linkage between neurodegeneration and ATM deficiency has not been established yet, and no treatment is currently available. In this study, we aimed to identify synthetic viable genes in ATM deficiency to highlight potential targets for the treatment of neurodegeneration in A–T. We inhibited ATM kinase activity using the background of a genome-wide haploid pluripotent CRISPR/Cas9 loss-of-function library and examined which mutations confer a growth advantage on ATM-deficient cells specifically. Pathway enrichment analysis of the results revealed the Hippo signaling pathway as a major negative regulator of cellular growth upon ATM inhibition. Indeed, genetic perturbation of the Hippo pathway genes SAV1 and NF2, as well as chemical inhibition of this pathway, specifically promoted the growth of ATM-knockout cells. This effect was demonstrated in both human embryonic stem cells and neural progenitor cells. Therefore, we suggest the Hippo pathway as a candidate target for the treatment of the devastating cerebellar atrophy associated with A–T. In addition to the Hippo pathway, our work points out additional genes, such as the apoptotic regulator BAG6, as synthetic viable with ATM-deficiency. These genes may help to develop drugs for the treatment of A–T patients as well as to define biomarkers for resistance to ATM inhibition-based chemotherapies and to gain new insights into the ATM genetic network.