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Developmental Medicine and Child... Jul 2017Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency,... (Review)
Review
Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, 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 classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.
Topics: Ataxia Telangiectasia; Humans
PubMed: 28318010
DOI: 10.1111/dmcn.13424 -
Orphanet Journal of Rare Diseases Nov 2016Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer... (Review)
Review
DEFINITION OF THE DISEASE
Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.
EPIDEMIOLOGY
The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.
CLINICAL DESCRIPTION
A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.
ETIOLOGY
A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.
DIAGNOSIS
The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.
DIFFERENTIAL DIAGNOSIS
There are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.
ANTENATAL DIAGNOSIS
Antenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.
GENETIC COUNSELING
Genetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.
MANAGEMENT AND PROGNOSIS
Treatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.
Topics: Animals; Ataxia Telangiectasia; Cerebellum; Humans; Lung Diseases; Mutation; Purkinje Cells
PubMed: 27884168
DOI: 10.1186/s13023-016-0543-7 -
Pediatric Allergy and Immunology :... May 2019Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene... (Review)
Review
Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoint. The pathogenesis of A-T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermatologic complications.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Diagnosis, Differential; Humans; Mutation; Pathology, Molecular
PubMed: 30685876
DOI: 10.1111/pai.13020 -
Expert Review of Clinical Immunology Sep 2020Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, variable... (Review)
Review
INTRODUCTION
Ataxia-telangiectasia (A-T) is a rare autosomal recessive syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, and cancer predisposition. Mutations cause A-T in the () gene encoding a serine/threonine-protein kinase.
AREAS COVERED
The authors reviewed the literature on PubMed, Web of Science, and Scopus databases to collect comprehensive data related to A-T. This review aims to discuss various update aspects of A-T, including epidemiology, pathogenesis, clinical manifestations, diagnosis, prognosis, and management.
EXPERT OPINION
A-T as a congenital disorder has phenotypic heterogeneity, and the severity of symptoms in different patients depends on the severity of mutations. This review provides a comprehensive overview of A-T, although some relevant questions about pathogenesis remain unanswered, probably owing to the phenotypic heterogeneity of this monogenic disorder. The presence of various clinical and immunologic manifestations in A-T indicates that the identification of the role of defective ATM in phenotype can be helpful in the better management and treatment of patients in the future.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Humans; Mutation; Oxidative Stress; Phenotype; Primary Immunodeficiency Diseases; Risk
PubMed: 32791865
DOI: 10.1080/1744666X.2020.1810570 -
Pediatrics and Neonatology Sep 2022
Topics: Ataxia Telangiectasia; Humans
PubMed: 35431147
DOI: 10.1016/j.pedneo.2022.01.004 -
Handbook of Clinical Neurology 2015Ataxia telangiectasia (AT) is an autosomal recessive multisystem genetic disorder caused by a mutation in the ATM gene encoding for the ATM protein. AT systemic... (Review)
Review
Ataxia telangiectasia (AT) is an autosomal recessive multisystem genetic disorder caused by a mutation in the ATM gene encoding for the ATM protein. AT systemic manifestations include cutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent sinopulmonary infections, and a tendency to develop lymphoid malignancies. These complications are explained by the major role played by ATM in DNA repair. AT is also the second most common childhood onset neurodegenerative disorder of the cerebellum, presenting with progressive ataxia and oculomotor apraxia and often accompanied by extrapyramidal movement disorders. Ataxia typically begins around the time children start to walk at about 1 year of age and leads to wheelchair dependence by the second decade of life. Cerebellar atrophy is evident on imaging after 2 years of life and is progressive. Abnormal DNA repair mechanisms do not entirely explain the pathophysiology in nondividing neurons. The nervous system involvement is better explained by the role ATM plays in antioxidative defense, mitochondrial homeostasis, and DNA chromatin packing. A better understanding of the underlying pathophysiologic mechanisms of this devastating disease may enable disease-modifying treatments in the future. Meanwhile, treatment is mainly supportive and does not change the poor prognosis of the disease although it improves the patient's quality of life.
Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Humans; Mutation
PubMed: 26564081
DOI: 10.1016/B978-0-444-62702-5.00014-7 -
Practical Neurology Oct 2020Ataxia telangiectasia is an autosomal recessive DNA repair disorder characterised by complex neurological symptoms, with an elevated risk of malignancy, immunodeficiency... (Review)
Review
Ataxia telangiectasia is an autosomal recessive DNA repair disorder characterised by complex neurological symptoms, with an elevated risk of malignancy, immunodeficiency and other systemic complications. Patients with variant ataxia telangiectasia-with some preserved ataxia telangiectasia-mutated (ATM) kinase activity-have a milder and often atypical phenotype, which can lead to long delays in diagnosis. Clinicians need to be aware of the spectrum of clinical presentations of ataxia telangiectasia, especially given the implications for malignancy surveillance and management. Here, we review the phenotypes of ataxia telangiectasia, illustrated with case reports and videos, and discuss its pathological mechanisms, diagnosis and management.
Topics: Ataxia Telangiectasia; Brain; Humans; Mutation; Neurologists; Phenotype
PubMed: 32958592
DOI: 10.1136/practneurol-2019-002253 -
Handbook of Clinical Neurology 2012
Review
Topics: Ataxia Telangiectasia; History, 20th Century; Humans; Nervous System
PubMed: 21827897
DOI: 10.1016/B978-0-444-51892-7.00019-X -
Expert Opinion on Investigational Drugs 2023Ataxia telangiectasia (A-T) is a life-limiting autosomal recessive disease characterized by cerebellar degeneration, ocular telangiectasias, and sinopulmonary disease.... (Review)
Review
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.
Topics: Animals; Humans; Ataxia Telangiectasia; Mutation; Lung Diseases; Oxidative Stress; Phenotype
PubMed: 37622329
DOI: 10.1080/13543784.2023.2249399 -
Advances in Experimental Medicine and... 2001
Review
Topics: Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Damage; DNA-Binding Proteins; Disease Models, Animal; Humans; Immune Tolerance; Mice; Mice, Knockout; Mutation; Neoplasms; Nervous System; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 11774566
DOI: 10.1007/978-1-4615-0685-0_26