ataxia telangiectasia

Summary

Summary: An autosomal recessive inherited disorder characterized by choreoathetosis beginning in childhood, progressive CEREBELLAR ATAXIA; TELANGIECTASIS of CONJUNCTIVA and SKIN; DYSARTHRIA; B- and T-cell immunodeficiency, and RADIOSENSITIVITY to IONIZING RADIATION. Affected individuals are prone to recurrent sinobronchopulmonary infections, lymphoreticular neoplasms, and other malignancies. Serum ALPHA-FETOPROTEINS are usually elevated. (Menkes, Textbook of Child Neurology, 5th ed, p688) The gene for this disorder (ATM) encodes a cell cycle checkpoint protein kinase and has been mapped to chromosome 11 (11q22-q23).

Top Publications

  1. Staples E, McDermott E, Reiman A, Byrd P, Ritchie S, Taylor A, et al. Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene. Clin Exp Immunol. 2008;153:214-20 pubmed publisher
    Immunodeficiency affects over half of all patients with ataxia telangiectasia (A-T) and when present can contribute significantly to morbidity and mortality...
  2. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38:873-5 pubmed
    ..37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer...
  3. Gorodetsky E, Calkins S, Ahn J, Brooks P. ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain. DNA Repair (Amst). 2007;6:1698-707 pubmed
    The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons...
  4. Jacquemin V, Rieunier G, Jacob S, Bellanger D, d Enghien C, Lauge A, et al. Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet. 2012;20:305-12 pubmed publisher
    b>Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies...
  5. Yang Y, Herrup K. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci. 2005;25:2522-9 pubmed
    ..These results suggest that loss of cell cycle control represents a common disease mechanism that underlies the defects in the affected tissues in both human and mouse diseases...
  6. Al Tassan N, Khalil D, Shinwari J, Al Sharif L, Bavi P, Abduljaleel Z, et al. A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia. Hum Mutat. 2012;33:351-4 pubmed publisher
    ..Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis...
  7. Masci A, Mastronicola D, Arese M, Piane M, De Amicis A, Blanck T, et al. Control of cell respiration by nitric oxide in Ataxia Telangiectasia lymphoblastoid cells. Biochim Biophys Acta. 2008;1777:66-73 pubmed
    b>Ataxia Telangiectasia (AT) patients are particularly sensitive to oxidative-nitrosative stress. Nitric oxide (NO) controls mitochondrial respiration via the reversible inhibition of complex IV...
  8. Hall J. The Ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants. Cancer Lett. 2005;227:105-14 pubmed
    ..The potential role of such variants needs to be further assessed, together with functional studies to model their impact on ATM function...
  9. Verhagen M, Abdo W, Willemsen M, Hogervorst F, Smeets D, Hiel J, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology. 2009;73:430-7 pubmed publisher

More Information

Publications62

  1. Grattarola M, Borghi C, Emionite L, Lulli P, Chessa L, Vergani L. Modifications of nuclear architecture and chromatin organization in ataxia telangiectasia cells are coupled to changes of gene transcription. J Cell Biochem. 2006;99:1148-64 pubmed
    b>Ataxia telangiectasia (AT) is a rare genetic disorder caused by mutations of ATM gene. ATM kinase is a "master controller" of DNA-damage response and signal transducer of external stimuli...
  2. Terzoudi G, Manola K, Pantelias G, Iliakis G. Checkpoint abrogation in G2 compromises repair of chromosomal breaks in ataxia telangiectasia cells. Cancer Res. 2005;65:11292-6 pubmed
    ..repair of DNA double-strand breaks (DSB) and confers enhanced G(2) chromosomal radiosensitivity in ataxia telangiectasia (AT) cells...
  3. McGrath Morrow S, Lefton Greif M, Rosquist K, Crawford T, Kelly A, Zeitlin P, et al. Pulmonary function in adolescents with ataxia telangiectasia. Pediatr Pulmonol. 2008;43:59-66 pubmed
    Pulmonary complications are common in adolescents with ataxia telangiectasia (A-T), however objective measurements of lung function may be difficult to obtain because of underlying bulbar weakness, tremors, and difficulty coordinating ..
  4. Li J, Chen J, Ricupero C, Hart R, Schwartz M, Kusnecov A, et al. Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nat Med. 2012;18:783-90 pubmed publisher
    b>Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene...
  5. Desai S, Reed R, Babu S, Lorio E. ISG15 deregulates autophagy in genotoxin-treated ataxia telangiectasia cells. J Biol Chem. 2013;288:2388-402 pubmed publisher
    ..Supporting the model, we show that autophagy is activated in the brain tissues of human A-T patients. This highlights a plausible causal contribution of a novel "ISG15 proteinopathy" in A-T neuronal cell death...
  6. Barzilai A, Biton S, Shiloh Y. The role of the DNA damage response in neuronal development, organization and maintenance. DNA Repair (Amst). 2008;7:1010-27 pubmed publisher
    ..This review focuses on the DNA damage response in neuronal cells and points to the importance of this elaborate network to the integrity of the nervous system from its early development and throughout the lifetime of the organism...
  7. Ambrose M, Goldstine J, Gatti R. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet. 2007;16:2154-64 pubmed
    One of the characteristic features of cells from patients with ataxia telangiectasia (A-T) is that they are in a state of continuous oxidative stress and exhibit constitutive activation of pathways that normally respond to oxidative ..
  8. Delia D, Piane M, Buscemi G, Savio C, Palmeri S, Lulli P, et al. MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. Hum Mol Genet. 2004;13:2155-63 pubmed
    ..These findings further underscore the interconnection between ATM activity and MRN function, which rationalizes the clinical similarity between ataxia-telangiectasia (A-T) and ATLD...
  9. Shull E, Lee Y, Nakane H, Stracker T, Zhao J, Russell H, et al. Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes Dev. 2009;23:171-80 pubmed publisher
    The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage...
  10. Jeong I, Patel A, Zhang Z, Patil P, Nadella S, Nair S, et al. Role of ataxia telangiectasia mutated in insulin signalling of muscle-derived cell lines and mouse soleus. Acta Physiol (Oxf). 2010;198:465-75 pubmed publisher
    b>Ataxia telangiectasia mutated (ATM) reportedly plays a role in insulin-stimulated activation of Akt in some cell types but not in others...
  11. Barzilai A. The neuro-glial-vascular interrelations in genomic instability symptoms. Mech Ageing Dev. 2011;132:395-404 pubmed publisher
    ..Here I describe various aspects of neural and glial cell fate and the vascular system in genomic instability disorders including ataxia telangiectasia (A-T) and Nijmegen breakage syndrome.
  12. Nakamura K, Du L, Tunuguntla R, Fike F, Cavalieri S, Morio T, et al. Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia. Hum Mutat. 2012;33:198-208 pubmed publisher
  13. Kuang X, Yan M, Ajmo J, Scofield V, Stoica G, Wong P. Activation of AMP-activated protein kinase in cerebella of Atm-/- mice is attributable to accumulation of reactive oxygen species. Biochem Biophys Res Commun. 2012;418:267-72 pubmed publisher
    b>Ataxia telangiectasia (A-T) is an inherited disease, the most prominent feature of which is ataxia caused by degeneration of cerebellar neurons and synapses...
  14. Balmus G, Zhu M, Mukherjee S, Lyndaker A, Hume K, Lee J, et al. Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1. Hum Mol Genet. 2012;21:3408-20 pubmed publisher
    The human genomic instability syndrome ataxia telangiectasia (A-T), caused by mutations in the gene encoding the DNA damage checkpoint kinase ATM, is characterized by multisystem defects including neurodegeneration, immunodeficiency and ..
  15. Byrd P, Srinivasan V, Last J, Smith A, Biggs P, Carney E, et al. Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia. Br J Cancer. 2012;106:262-8 pubmed publisher
    ..Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213)...
  16. Vinck A, Verhagen M, Gerven M, de Groot I, Weemaes C, Maassen B, et al. Cognitive and speech-language performance in children with ataxia telangiectasia. Dev Neurorehabil. 2011;14:315-22 pubmed publisher
    ..To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function...
  17. Olsen J, Hahnemann J, Børresen Dale A, Tretli S, Kleinerman R, Sankila R, et al. Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer. 2005;93:260-5 pubmed
    ..have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia (AT), a rare autosomal recessive disease...
  18. Li J, Han Y, Plummer M, Herrup K. Cytoplasmic ATM in neurons modulates synaptic function. Curr Biol. 2009;19:2091-6 pubmed publisher
    ..Also, cytoplasmic ATM physically associates with the homologous PI 3-kinase, ATR. The neurological symptoms of ataxia-telangiectasia may thus result from defective nonnuclear functions of ATM not associated with DNA repair...
  19. Austen B, Barone G, Reiman A, Byrd P, Baker C, Starczynski J, et al. Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients. Br J Haematol. 2008;142:925-33 pubmed publisher
    b>Ataxia Telangiectasia (A-T) patients have biallelic inactivation of the ATM gene and exhibit a 200-fold-increased frequency of lymphoid tumours...
  20. Cavaciuti E, Lauge A, Janin N, Ossian K, Hall J, Stoppa Lyonnet D, et al. Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer. 2005;42:1-9 pubmed
    ..The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein...
  21. Rimkus S, Katzenberger R, Trinh A, Dodson G, Tibbetts R, Wassarman D. Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia. Genes Dev. 2008;22:1205-20 pubmed publisher
    Mutations in ATM (Ataxia telangiectasia mutated) result in Ataxia telangiectasia (A-T), a disorder characterized by progressive neurodegeneration...
  22. Miles P, Treuner K, Latronica M, Olefsky J, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am J Physiol Endocrinol Metab. 2007;293:E70-4 pubmed
    b>Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene...
  23. Sharma N, Lebedeva M, Thomas T, Kovalenko O, Stumpf J, Shadel G, et al. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. DNA Repair (Amst). 2014;13:22-31 pubmed publisher
    b>Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer...
  24. Thompson D, Easton D. The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia. 2004;9:221-36 pubmed
    ..The identification of such genes can provide a basis for targeted prevention of breast cancer...
  25. Gueven N, Luff J, Peng C, Hosokawa K, Bottle S, Lavin M. Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant. Free Radic Biol Med. 2006;41:992-1000 pubmed
    Mutations in the ATM gene (mutated in ataxia telangiectasia) in both humans and mice predispose to lymphoid tumors. A defect in this gene also causes neurodegeneration in humans and a less severe neurological phenotype in mice...
  26. Khan A, Oystreck D, Koenig M, Salih M. Ophthalmic features of ataxia telangiectasia-like disorder. J AAPOS. 2008;12:186-9 pubmed
    b>Ataxia telangiectasia (AT) is a recessive neurodegenerative disease due to a faulty repair mechanism for breaks in double-stranded DNA (ATM mutation)...
  27. Kitagawa R, Kastan M. The ATM-dependent DNA damage signaling pathway. Cold Spring Harb Symp Quant Biol. 2005;70:99-109 pubmed
    ..Focusing on ATM and SMC1, the molecular controls of these pathways is discussed...
  28. Uchisaka N, Takahashi N, Sato M, Kikuchi A, Mochizuki S, Imai K, et al. Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. J Pediatr. 2009;155:435-8 pubmed publisher
    ..They both had ataxia with cerebellar atrophy and mental retardation. They had the same mutation of the MRE11 gene, which has not been reported previously (c.727T>C and g.24994G>A)...
  29. Isaian A, Bogdanova N, Houshmand M, Movahadi M, Aghamohammadi A, Agamohammadi A, et al. BAK, BAX, and NBK/BIK proapoptotic gene alterations in Iranian patients with ataxia telangiectasia. J Clin Immunol. 2010;30:132-7 pubmed publisher
    b>Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder characterized by variable immunodeficiency, progressive neurodegeneration, occulocutaneous telangiectasia, and an increased susceptibility to malignancies...
  30. Kulinski J, Leonardo S, Mounce B, Malherbe L, Gauld S, Tarakanova V. Ataxia telangiectasia mutated kinase controls chronic gammaherpesvirus infection. J Virol. 2012;86:12826-37 pubmed publisher
  31. Guo Z, Kozlov S, Lavin M, Person M, Paull T. ATM activation by oxidative stress. Science. 2010;330:517-21 pubmed publisher
    ..Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells...
  32. Tumbale P, Appel C, Kraehenbuehl R, Robertson P, Williams J, Krahn J, et al. Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease. Nat Struct Mol Biol. 2011;18:1189-95 pubmed publisher
  33. Chun H, Gatti R. Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst). 2004;3:1187-96 pubmed
    ..The term "A-T variant" has a diminishing usefulness...
  34. Degan P, d Ischia M, Pallardo F, Zatterale A, Brusco A, Calzone R, et al. Glutathione levels in blood from ataxia telangiectasia patients suggest in vivo adaptive mechanisms to oxidative stress. Clin Biochem. 2007;40:666-70 pubmed
    To evaluate an in vivo pro-oxidant state in patients with ataxia telangiectasia (AT).
  35. Lavin M, Birrell G, Chen P, Kozlov S, Scott S, Gueven N. ATM signaling and genomic stability in response to DNA damage. Mutat Res. 2005;569:123-32 pubmed
    ..Mechanisms for recognising double strand breaks in DNA, maintaining genome stability and minimizing risk of cancer are discussed...
  36. Taylor A, Byrd P. Molecular pathology of ataxia telangiectasia. J Clin Pathol. 2005;58:1009-15 pubmed
    b>Ataxia telangiectasia (A-T) is one of a group of autosomal recessive cerebellar ataxias...
  37. Bhatti S, Kozlov S, Farooqi A, Naqi A, Lavin M, Khanna K. ATM protein kinase: the linchpin of cellular defenses to stress. Cell Mol Life Sci. 2011;68:2977-3006 pubmed publisher
    ..In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients...
  38. Shaikh A, Marti S, Tarnutzer A, Palla A, Crawford T, Straumann D, et al. Ataxia telangiectasia: a "disease model" to understand the cerebellar control of vestibular reflexes. J Neurophysiol. 2011;105:3034-41 pubmed publisher
    ..In 13 subjects with ataxia telangiectasia (A-T), a disease associated with profound cerebellar cortical degeneration, we found abnormalities of ..
  39. Cavalieri S, Funaro A, Porcedda P, Turinetto V, Migone N, Gatti R, et al. ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions. Hum Mutat. 2006;27:1061 pubmed
    ..The breakpoints of these deletions were sequenced in an attempt to understand the mechanisms of mutations; both deletions involved regions rich in repeated elements...
  40. Lavin M, Gueven N, Bottle S, Gatti R. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br Med Bull. 2007;81-82:129-47 pubmed
    ..We describe the natural course of disease, some supportive therapeutic approaches already in use and those with potential based on our knowledge of molecular and cellular characteristics of this disorder...
  41. Jiang H, Tang B, Xia K, Hu Z, Shen L, Tang J, et al. Mutation analysis of the ATM gene in two Chinese patients with ataxia telangiectasia. J Neurol Sci. 2006;241:1-6 pubmed
    b>Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein level, chromosomal instability, predisposition to cancer, and radiation ..
  42. Mallott J, Kwan A, Church J, González Espinosa D, Lorey F, Tang L, et al. Newborn screening for SCID identifies patients with ataxia telangiectasia. J Clin Immunol. 2013;33:540-9 pubmed publisher
    ..Deep sequencing was employed to find causes of T lymphocytopenia in such infants...
  43. Gazulla J, Benavente I, Sarasa Barrio M. [Adult-onset ataxia-telangiectasia. A clinical and therapeutic observation]. Neurologia. 2006;21:447-51 pubmed
    ..A synergistic effect with pregabalin is proposed as the cause of the improvement obtained with the addition of tiagabine...
  44. Biton S, Barzilai A, Shiloh Y. The neurological phenotype of ataxia-telangiectasia: solving a persistent puzzle. DNA Repair (Amst). 2008;7:1028-38 pubmed publisher
    ..A-T remains a prototype disease for the study of the DDR's role in CNS development and maintenance...
  45. Lee Y, McKinnon P. Responding to DNA double strand breaks in the nervous system. Neuroscience. 2007;145:1365-74 pubmed
    ..A prime example is the neurodegenerative syndrome ataxia telangiectasia (A-T), which results from inactivation of the ATM kinase, a crucial nexus for the cellular response to DNA ..
  46. Crawford T, Skolasky R, Fernandez R, Rosquist K, Lederman H. Survival probability in ataxia telangiectasia. Arch Dis Child. 2006;91:610-1 pubmed
    b>Ataxia telangiectasia is a rare, multiorgan neurodegenerative disorder with enhanced vulnerability to cancer and infection...
  47. Chiam L, Verhagen M, Haraldsson A, Wulffraat N, Driessen G, Netea M, et al. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation?. Dermatology. 2011;223:13-9 pubmed publisher
    Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T).
  48. Verhagen M, Last J, Hogervorst F, Smeets D, Roeleveld N, Verheijen F, et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat. 2012;33:561-71 pubmed publisher
    ..Each patient is left with a tremendously increased cancer risk...
  49. Mavrou A, Tsangaris G, Roma E, Kolialexi A. The ATM gene and ataxia telangiectasia. Anticancer Res. 2008;28:401-5 pubmed
    b>Ataxia telangiectasia (AT) is a rare neurodegenerative, autosomal recessive disorder characterized by chromosome instability, radiosensitivity, immunodeficiency and a predisposition for cancer...
  50. Exley A, Buckenham S, Hodges E, Hallam R, Byrd P, Last J, et al. Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia. Clin Immunol. 2011;140:26-36 pubmed publisher
    ..pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age...
  51. Menotta M, Biagiotti S, Bianchi M, Chessa L, Magnani M. Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity. J Biol Chem. 2012;287:41352-63 pubmed publisher
    b>Ataxia telangiectasia (AT) is a rare genetic disease, still incurable, resulting from biallelic mutations in the ataxia telangiectasia-mutated (ATM) gene...
  52. Tamimi R, Hankinson S, Spiegelman D, Kraft P, Colditz G, Hunter D. Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study. Breast Cancer Res. 2004;6:R416-22 pubmed
    The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks...
  53. Castillo P, Bogliolo M, Surralles J. Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage. DNA Repair (Amst). 2011;10:518-25 pubmed publisher
    Fanconi anemia (FA) and ataxia telangiectasia (AT) share common traits such chromosomal instability and proneness to hematological cancers...