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The Molecular Basis and Clinical Management of Ataxia Telangiectasia

  • Sian D. Spacey (a1), Richard A. Gatti (a1) and Gwyn Bebb (a2)

Abstract

The unique combination of phenotypic manifestations seen in ataxia telangiectasia (AT) has intrigued neurologists, oncologists, radiation biologists and immunologists for several decades. Initially, the primary care givers of AT patients are often pediatricians but neurologists will inevitably become involved in their care. Over the last few years great strides have been made in understanding the genetic basis of this disease but useful therapeutic interventions are still not available. In this article, we review the clinical features and the current understanding of the pathophysiology of the syndrome. In addition, we address issues related to genetic counseling, prenatal diagnosis, screening and implications for AT heterozygotes.

RÉSUMÉ

La combinaison unique des manifestations phétypiques observédans l’ataxie-téngiectasie (AT) a intriguées neurologues, les oncologues, les radiobiologistes et les immunologistes depuis plusieurs dénnies. Initialement, les principaux dispensateurs de soins àes patients sont souvent les péatres, mais les neurologues sont inétablement impliqué Au cours des derniès anné, des progrèimportants ont é réisédans la comprénsion du fondement gétique de cette maladie, mais il n’existe pas encore de traitement. Nous revoyons les manifestations cliniques et les connaissances actuelles de la physiopathologie de ce syndrome. De plus, nous discutons des questions relatives au conseil gétique, au diagnostic prétal, au déstage et aux implications pour les hérozygotes.

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References

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1. Syllaba, L, Henner, K. Contribution a l’independence de l’athetose double idiopathique et congenitale. Rev Neurol 1926;1:541562.
2. Louis Barr, D. Sur un syndrome progressif comprenent des telangiectasies capillaires cutanees et conjonctivales symetriques, a disposition naevoide et des troubles cerebelleux. Confin Neurol 1941; Vol 4(Fasc 1/2): 3242.
3. Boder, E, Sedgwick, RP. Ataxia Telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasis and frequent pulmonary infection. Pediatrics 1958; 21: 526554.
4. Paterson, MC, Smith, PJ. Ataxia telangiectasia; an inherited human disorder involving hypersensitivity to ionizing radiation and related DNA-damaging chemicals. Ann Rev Genet 1979; 13:291318.
5. Swift, M, Morrell, D, Cromartie, E, et al. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 1986; 39(5): 573583.
6. Boder, E. Ataxia telangiectasia; an overview. In: Gatti, RA, Swift, M eds. Ataxia Telangiectasia; Genetics, Neuropathology and Immunology of a Degenerative Disease of Childhood. New York: Alan R Liss, 1985: 163.
7. Aicardi, J, Barbosa, C, Andermann, E, et al. Ataxia-ocular motor apraxia; a syndrome mimicking ataxia-telangiectasia. Ann Neurol 1988; 24(4): 497502.
8. Gatti, RA, Boder, E, Vinters, HV, et al. Ataxia Telangiectasis; an interdisciplinary approach to pathogenesis. Medicine 1991; 70 (No2): 99117.
9. Wong, V, Yu, YL, Chan-Lui, WY, Woo, E, Yeung, CY. Ataxia telangiectasia in Chinese children. A clinical and electrophysio-logical study. Clin Neurol Neurosurg 1987; 89(3):137144.
10. Barbieri, F, Santoro, L, Crisci, C, et al. Is the sensory neuropathy in ataxia telangiectasia distinguishable from that in Friedreich’s ataxia? Morphometric and ultrastructural study of the sural nerve in a case of Louis Bar syndrome. Acta Neuropathol 1986; 69(3–4): 213219.
11. Harding, AE. The inherited ataxias. Adv Neurol 1988; 48:3746.
12. Cabana, MD, Crawford, TO, Winkelstein, JA, Christensen, JR, Lederman, HM. Consequences of the delayed diagnosis of ataxia telangiectasia. Pediatrics 1998; 102(1):98100.
13. Chung, EO, Bodensteiner, JB, Noorani, PA, Schochet, SS. Cerebral white-matter changes suggesting leukodystrophy in ataxia telangiectasia. J Chil Neurol 1994; 9:3135.
14. Waldman, TA Broder, S, Goldman, CK, et al. Disorders of B cells and helper T cells in the pathogenesis of the immunoglobulin deficiency of patients with ataxia telangiectasia. J Clin Invest 1983;71: 282295.
15. Peterson, RD, Cooper, MD, Good, RA. Lymphoid tissue abnormalities associated with ataxia telangiectasia. Am J Med 1966; 41(3): 342359.
16. Epstein, WL, Fudenberg, HH, Reed, WB, Boder, E, Sedgwick, RP. Immunologic studies in ataxia telangiectasia. I. Delayed hypersensitivity and serum immune globulin levels in probands and first-degree relatives. Int Arch Allergy Appl Immunol 1966; 30(1): 1529.
17. Ito, M, Nakagawa, A, Hirabayashi, N, Asai, J. Bronchiolitis obliterans in ataxia telangiectasia. Virchows Arch 1997; 430(2);131137.
18. Woods, SC, Taylor, AMR. Ataxia telangiectasia in the British Isles; the clinical and laboratory features of 70 affected individuals. Quart J Med, 1992; 82: 169179.
19. Spector, BD, Filipovich, AH, Perry, GS, Kersey, KS. Epidemiology of cancer in ataxia telangiectasia. In: Bridges, BA, Hardnen, DG, eds. Ataxia Telangiectasia – A Cellular and Molecular Link Between Cancer, Neuropathology and Immune Deficiency. Chichester: Wiley, 1982: 103.
20. Morrell, D, Chase, CL, Swift, M. Cancers in 44 families with ataxia telangiectasia. Cancer Genet Cytogenet 1990; 50: 119123.
21. Taylor, AM. Leukemia and lymphoma in ataxia telangiectasia. Blood 1996; 87(2): 423–38.
22. Morgan, JL, Holcomb, TM, Morrisey, RW. Radiation reaction in ataxia telangiectasia. Am J Dis Child 1968; 116: 557558.
23. Cunliffe, PN, Mann, JR, Cameron, AH, Roberts, KD, Ward, HWC. Radiosensitivity in ataxia telangiectasia. Br J Radiol 1975; 48: 374376.
24. Sardanelli, F, Parodi, RC, Ottonello, C, et al. Cranial MRI in ataxia telangiectasia. Neuroradiology 1995; 37(1): 7782.
25. Paula-Barbosa, MM, Ruela, C, Tavares, MA, et al. Cerebellar cortex ultrastructure in ataxia telangiectasia. Ann Neurol 1983; 13(3):297302.
26. Aguilar, MJ, Kamoshita, S, Landing, BH, Boder, E, Sedgwick, RP. Pathological observations in ataxia telangiectasia. A report of five cases. J Neuropathol Exp Neurol 1968; 27(4); 659676.
27. Perry, TL, Kish, SJ, Hinton, D, et al. Neurochemical abnormalities in a patient with ataxia telangiectasia. Neurology 1984; 34: 187191.
28. Dunn, HG, Meuwissen, H, Livingstone, CS, Pump, KK. Ataxia Telangiectasia. Can Med Assoc J 1964; 91: 11061118.
29. Vinters, HV, Gatti, RA, Rakic, P. Sequence of cellular events in cerebellar ontogeny relevant to expression of neuronal abnormalities in ataxia telangiectasia. In: Gatti, RA, Swift, M, eds. Ataxia Telangiectasia; Genetics, Neuropathology and Immunology of a Degenerative Disease of Childhood. New York: Alan R Liss, 1985: 233255.
30. Blocher, D, Sigut, D, Hannan, MA. Fibroblasts from ataxia telangiectasia(AT) and AT heterozygotes show an enhanced level of residual DNAdouble strand breaks after low dose-rate gamma radiation as assayed by pulsed field gel electrophoresis. Int J Radiat Biol 1991; 60(5): 791802.
31. Coquerelle, TM, Weibezahn, KF, Lucke-Huhle, C. Rejoining of double strand breaks in normal human and ataxia telangiectasia fibroblasts after exposure to 60Co gamma rays, 241 Am alpha particles or bleomycin. Int J Radiat Biol Relat Stud Phys Chem Med 1987; 51(2): 209218.
32. Murnane, JP, Painter, RB. Complementation of the defects of DNA synthesis in irradiated and unirradiated ataxia telangiectasia cells. Proc Natl Acad Sci USA 1982;79: 19601963.
33. Jaspers, NG, Painter, RB, Paterson, MC, Kidson, C, Inoue, T. Complementation analysis of ataxia telangiectasia. Kroc Found Ser 1985;19:147262.
34. Gatti, RA, Berkel, I, Boder, E, et al. Localization of an ataxia telangiectasia gene to chromosome 11q22-23. Nature 1988; 336: 577580.
35. Lange, E, Borresen, AL, Chen, X, et al. Localization of an ataxiatelangiectasia gene to an approximately 500-kb interval on chromosome 11q23.1: linkage analysis of 176 families by an international consortium. Am J Hum Genet. 1995;57(1):112–9.
36. Savitsky, K, Bar-Shira, A, Gilad, S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 268: 17491753.
37. Gilad, S, Khosravi, R, Shkedy, D, et al. Predominance of null mutations in ataxia telangiectasia. Hum Mol Genet 1996; 5(4): 433439.
38. Concannon, P, Gatti, RA. Diversity of ATM gene mutations detected in patients with ataxia telangiectasia. Hum Mutat 1997; 10(2):100107.
39. Castellvi-Bel, S, Sheikhavandi, S, Telatar, M, et al. New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCPstrategy. Hum Mutat 1999; 14: 156162.
40. Telatar, M, Teraoka, S, Wang, Z, et al. Ataxia telangiectasia; identification and detection of founder mutations in the ATM gene in ethnic populations. Am J Hum Genet 1998; 62: 8697.
41. Teraoka, S, Telatar, M, Becker-Catania, S, et al. Splicing defects in the ataxia telangiectasia gene, ATM; underlyinig mutations and phenotypic consequences. Am J Hum Genet 1999; 64:16171631.
42. Yao, R, Cooper, GM. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 1995; 267: 20032006.
43. Lavin, MF, Khanna, KK, Beamish, H, et al. Relationship of the ataxia telangiectasia protein ATM to phosphoinositide 3-kinase. Trends Biochem Sci 1995; 20(10):382383.
44. Greenwell, PW, Kronmal, SL, Porter, SE, et al. TEL1, a gene involved in controlling telomere length in S cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell 1995;82:823829.
45. Hari, KL, Santerre, A, Sekelsky, JJ, et al. The mei-41 gene of D melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 1995; 82: 815821.
46. Keegan, KS, Holtzman, DA, Plug, AW et al. The Atr and Atm protein kinases associate with different sites along meiotically pairing chromosomes. Genes Dev 1996; 10(19):24232437.
47. Jung, M, Lee, S, Zhang, Y, Dritschilo, A. Regulation of p53 in response to ionizing radiation in ataxia telangiectasia fibroblasts. Int J Radiat Oncol Biol Phys 1997; 37(2):417422.
48. Canman, CE, Lim, DS, Cimprich, KA, et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science. 1998; 281:16771679.
49. Baskaran, R, Wood, LD, Whitaker, LL, et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to radiation. Nature 1997; 387: 516519.
50. Shafman, T, Khanna, KK, Kedar, P, et al. Interaction between ATM protein and c-Abl in response to DNAdamage. Nature 1997; 387: 520523.
51. Kim, ST, Lim, DS, Canman, CE, Kastan, MB. Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem 1999;274(53):37538–43.
52. Dasika, GK, Lin, SC, Zhao, S, et al. DNAdamage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. Oncogene 1999;18(55):78837899.
53. Khosravi, R, Maya, R, Gottlieb, T, et al. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNAdamage. Proc Natl Acad Sci USA 1999; 96(26): 1497314977.
54. Piret, B, Schoonbroodt, S, Piette, J. The ATM protein is required for sustained activation of NF-kappaB following DNA damage. Oncogene 1999; 18(13): 22612271.
55. Gatei, M, Young, D, Cerosaletti, KM, et al. ATM – dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet. 2000;25(1):115–9.
56. Watters, D. Molecular mechanisms of ionizing radiation-induced apoptosis. Immunol Cell Biol 1999; 77(3): 263271.
57. Herzog, KH, Chong, MJ, Kapsetaki, M, Morgan, JI, McKinnon, PJ. Requirement for ATM in ionizing radiation-induced cell death in the developing central nervous system. Science 1998; 280: 10891091.
58. Xia, Y, Welch, CL, Warden, CH, et al. Assignment of the mouse ataxia telangiectasia gene (ATM) to mouse chromosome 9. Mamm Genome 1996; 7(7): 554555.
59. Barlow, C, Hirotsun, S, Paylor, R, et al. ATM-deficient mice; a paradigm of ataxia telangiectasia. Cell 1996; 86: 159171.
60. Elson, A, Wang, Y, Daugherty, CJ, et al. Pleiotropic defects in ataxia telangiectasia protein-deficient mice. Proc Natl Acad Sci USA 1996; 93(23): 1308413089.
61. Eilam, R, Peter, Y, Elson, A, et al. Selective loss of dopaminergic nigro-striatal neurons in brains of ATM-deficient mice. Proc Natl Acad Sci USA 1998; 95(21):1265312656.
62. Soares, HD, Morgan, JI, McKinnon PJ ATM expression patterns suggest a contribution from the peripheral nervous system to the phenotype of ataxia telangiectasia. Neuroscience 1998; 86(4): 10451054.
63. Oka, A, Takashima, S. Expression of the ataxia telangiectasia gene (ATM) product in human cerebellar neurons during development. Neurosci Lett 1998; 252(3): 195198.
64. Huo, YK, Wang, Z, Hong, J-H, et al. Radiosensitivity of ataxia telangiectasia, X-linked agammaglobulinemia and related syndromes. Cancer Res 1994; 54: 25442547.
65. Weemaes, CMR, Hustinx, TWJ, Scheres, JMJC, et al. A new chromosomal instability disorder; the Nijmegen breakage syndrome. Acta Paediatr Scand 1981; 70: 557562.
66. Curry, CJR, O’Lague, P, Tsai, J, et al. AT Fresno: a phenotype linking ataxia telangiectasia with the Nijmegen breakage syndrome. Am J Hum Genet 1989; 45: 270275.
67. Wegner, RD, Metzger, M, Hanefeld, NG, et al. A new chromosomal instability disorder confirmed by complementation studies. Clin Genet 1988; 33: 2032.
68. Jaspers, NGJ, Gatti, RA, Baan, C, Linssen, PCML, Bootsma, D. Genetic complementation analysis of ataxia telangiectasia and Nijmegan breakage syndrome; a survey of 50 patients. Cytogenet Cell Genet 1988; 49: 259263.
69. Gilad, S, Chessa, L, Khosravi, R, et al. Genotype-phenotype relationships in ataxia telangiectasia and variants. Am J Hum Genet 1998; 62: 551561.
70. Saar, K, Chrzanowska, KH, Stumm, M, et al. The gene for the ataxia telangiectasia variant, Nijmegen Breakage Syndrome, maps to a 1-cM interval on chromosome 8q21. Am J Hum Genet 1997;60: 605610.
71. Cerosaletti, KM, Lange, E, Stringham, HM, et al. Fine localization of the Nijmegen Breakage Syndrome gene to 8q21; evidence for a common founder haplotype. Am J Hum Genet 1998; 63: 125134.
72. Varon, R, Vissinga, C, Platzer, M, et al. Nibrin, a novel DNAdouble-strand break repair protein, is mutated in Nijmegen Breakage Syndrome. Cell 1998; 93: 467476.
73. Lavin, MF, Concannon, P, Gatti, RA. Eighth International Workshop on ataxia telangiectasia (ATW8). Cancer Res 1999; 59: 38453849.
74. Sandoval, C, Swift, M. Treatment of lymphoid malignancies in patients with ataxia telangiectasia. Med Pediatr Oncol 1998; 31(6): 491497.
75. Pagano, G, Korkina, LG, Brunk, UT, et al. Congenital disorders sharing oxidative stress and cancer proneness as phenotypic hallmarks; prospects for joint research in pharmacology. Med Hypotheses 1998; 51(3): 253266.
76. Perlman, SL. Treatment of ataxia telangiectasia. In: Gatti, RA, Painter, RB, eds. Ataxia Telangiectasia. Heidelberg: Springer Verlag. 1993:269278.
77. Athma, P, Rappaport, R and Swift, M. Molecular genotyping shows that Ataxia Telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996;92:130134.
78. Swift, M, Reitnauer, PJ, Morrell, D, Chase, CL. Breast and other cancers in families with Ataxia telangiectasia. New Eng J Med 1987; 316: 12891294.
79. Pippard, EC, Hall, AJ, Barker, DJ, Bridges, BA. Cancer in homozygotes and heterozygotes of ataxia telangiectasia and xeroderma pigmentosum in Britain. Cancer Res 1988; 48: 29292932.
80. Swift, M. Ionizing radiation, breast cancer, and ataxia telangiectasia. J Natl Cancer Inst 1994; 86 (21): 15711572.
81. Swift, M, Morrell, D, Massey, RB, Chase, CL. Incidence of cancer in 161 families affected by ataxia telangiectasia. New Eng J Med 1991; 325: 18311836.
82. Fitzgerald, MG, Bean, JM, Hegde, SR, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet 1997; 15: 307310.
83. Ramsay, J, Birrell, G, Lavin, M. Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients. Radiother Oncol 1998; 47(2): 125128.
84. Bebb, G, Zhe, Yu, Jian, Chen, et al. Absence of mutations in the ATM gene in forty-seven cases of sporadic breast cancer. Br J Cancer 1999; 80: 19791981.
85. Appleby, JM, Barber, JB, Levine, E, et al. Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy. Br J Cancer 1997; 76(12): 15461549.
86. Paterson, MC, Anderson, AK, Smith, BP, Smith, PJ. Enhanced radiosensitivity of cultured fibroblasts from ataxia telangiectasia heterozygotes manifested by defective colony-forming ability and reduced DNA repair replication after hypoxic gammairradiation. Cancer Res 1979; 39: 37253734.
87. Scott, D, Spreadborough, AR, Roberts, SA. Radiation-induced G2 delay and spontaneous chromosome aberrations in ataxia telangiectasia homozygotes and heterozygotes. Int J Radiat Biol 1994; 66; S157-163.
88. Bebb, DG, Steele, PP, Warrington, PJ, Moffat, JA, Glickman, BW. Caffeine does not potentiate gamma-radiation induced DNA damage in ataxia telangiectasia lymphoblastoid cells. Mutat Res 1998; 401: 2732.
89. Barlow, C, Eckhaus, MA, Schaffer, AA, Wynshaw-Boris, A. ATM haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice. Nature Genet 1999; 21(4):3593–60.
90. Kerlikowske, K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years; comparison of relative and absolute benefit. J Natl Cancer Inst Monogr 1997, 22: 7986.
91. Gatti, RA, Peterson, KL, Novak, J, et al. Prenatal genotyping of ataxia telangiectasia. Lancet 1993; 342: 376.

The Molecular Basis and Clinical Management of Ataxia Telangiectasia

  • Sian D. Spacey (a1), Richard A. Gatti (a1) and Gwyn Bebb (a2)

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