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Ataxia telangiectasia


Other namesLouis-Bar syndrome
Atlas_Id 10003
Note see also, in Deep Insight section: Ataxia-Telangiectasia and variants
Inheritance autosomal recessive; frequency is about 1 to 2.5/105 newborns; heterozygotes are estimated to be 1% of the general population; founder effect are found in some isolated population


Note ataxia telangiectasia is a chromosome instability syndrome with cerebellar degeneration, immunodeficiency, and an increased risk of cancers; A-T cells are defective in recognizing double-strand DNA damage to signal for repair
Phenotype and clinics
  • onset of the disease is often noted during the second year of life: there is progressive cerebellar ataxia (initially truncal, with further peripheral extension); ataxia is a constant feature in this disease; oculomotor apraxia, dysarthria, and dystonia; leading to muscular atrophia
  • telangiectasia: facial region exposed to sunlight, and eyes (conjunctiva)
  • combined immunodeficiency (in 70 %): thymus hypoplasia, and IgG2 and 4, IgA, IgE deficiency
  • other features: growth retardation; hypogonadism; occasionally diabetes mellitus
  • Neoplastic risk
  • risk of cancers is X 100, consisting mainly of T- cell malignancies (a 70-fold and 250-fold increased risks of leukemia and lymphoma respectively) and B-cell malignancies, but not myeloid leukemia; carcinomas of the skin, ovary, breast, and stomach have also been described
  • cancer treatment is complicated by radiation- and chemo-sensitivity
  • Evolution progressive cerebellar degeneration: patients are usually in a wheelchair by the age of ten
  • respiratory infection is the common cause of death, with cancer being the second most common.
  • survival is often into fourth decade today where optimal medical care is available
  • Cytogenetics

    Inborn conditions
  • spontaneous chromatid/chromosome breaks, triradials, quadriradials (less prominent phenomenon than in Fanconi anaemia); telomeric associations
  • the best diagnosis test is on the (pathognomonic) highly elevated level (10% of mitoses) of inv(7)(p14q35), t(14;14)(q11;q32), and other non clonal stable chromosome rearrangements involving 2p12, 7p14, 7q 35, 14q11, 14q32, and 22q11 (illegitimate recombinations between immunoglobulin superfamilly genes Ig and TCR); normal level of those rearrangements are: 1/500 (inv(14)), 1/200 (t(7;14)), 1/10 000 (inv(7))
  • clonal rearrangements further occur in 10% of patients, but without manifestation of malignancy: t(14;14), inv(14), or t(X;14)
      Sporadic (rows 1 and 2) and clonal (row 3) rearrangements in ataxia telangiectasia (R- banding). Row 1, from left to right: inv(7)(p14q35), t(7;7)(p14;q35), t(14;14)(q11;q32), inv(14)(q11q32); Row 2:, from left to right: t(7;14)(p14;q11), t(7;14)(q35;q11), t(7;14)(p14;q32), t(7;14)(q35;q32); Row 3, from left to right: inv(14)(q11;q32), t(X;14)(q28;q11) (note the late replicating X on the left ), t(14;14)(q11;q32) - Courtesy Alain Aurias (modified figure reprinted from Médecine/Sciences 1986; 2: 298-303., by permission of the publisher Masson).
    Cytogenetics of cancer clonal rearrangements in T-cell ALL and T-PLL (prolymphocytic leukaemia) in AT patients are complex, with the frequent involvement of t(14;14)(q11;q32)(q11;q32), or t(X;14)(q28;q11), implicating the genes TCL1 or MTCP1 respectively, as is found in T-PLL in non-AT patients

    Other findings

  • high sensitivity to ionizing radiations and to radiomimetic drugs (diagnostic may in part be based on the hypersensitivity of AT lymphocytes to killing by gamma irradiation); cell irradiation does not inhibit S phase (DNA synthesis): this is quite pathognomonic of AT, and shows that G1 checkpoint is deficient; there is a lack of P53, GADD45 and P21 induction, and a fall in radiation-induced apoptosis; P53 phosphorylation at ser15 is deficient
  • lenthening of the cell cycle
  • difficult to grow cells with phytohemaglutinin: karyotypes should be performed with interleukine 2 in 4 days cultures
  • other: increased level of serum alpha-fetoprotein
  • Genes involved and Proteins

    Gene NameATM (Ataxia telangiectasia mutated) is responsible for the vast majority of A -T cases.
    Location 11q22-q23.1
      ATM (11q22.3) in normal cells: PAC 891P24 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
    Description 66 exons spanning 184 kb of genomic DNA
    Description 3056 amino acids; 350 kDa; contains a Pl 3-kinase-like domain
    Localisation mostly in the nucleus in replicating cells, cytoplasm in differentiating cells
    Function mediates cell cycle arrest in response to ionizing radiation through the phophorylation of targets including p53, cAbl, BRCA1, H2AX, IkB-alpha and chk1
    Germinal various types of mutations, dispersed throughout the gene, and therefore most patients are compound heterozygotes; however, most mutations appear to inactivate the ATM protein by truncation, large deletions, or annulation of initiation or termination. Missense mutations have been described in breast cancer patients, but do not seem to contribute to ataxia-telangiectasia.

    To be noted

  • heterozygote cancer risk: the relative risk of breast cancer in A-T heterozygote women has been estimated through epidemiological studies to be 3.9 (CI 2.1-7.1), and through haplotype analysis to be 3.32 (CI 1.75-6.38); since the A-T heterozygote frequency is about 1 %, 2-4 % of breast cancer cases may be due to ATM heterozygosity; the risk of other types of cancer in A-T heterozygotes is low
  • the A-T variant Nijmegen breakage syndrome does not involve the same gene.
  • External links

    OrphanetAtaxia telangiectasia
    Other databaseAtaxia-Telangiectasia - GeneClinics
    AssociationThe A-T Children's Project
    AssociationAtaxia-Telangiectasia Mutation Database


    New data on clonal anomalies of chromosome 14 in ataxia telangiectasia: tct(14;14) and inv(14).
    Aurias A, Croquette MF, Nuyts JP, Griscelli C, Dutrillaux B
    Human genetics. 1986 ; 72 (1) : 22-24.
    PMID 3943860
    Probable involvement of immunoglobulin superfamily genes in most recurrent chromosomal rearrangements from ataxia telangiectasia.
    Aurias A, Dutrillaux B
    Human genetics. 1986 ; 72 (3) : 210-214.
    PMID 3456975
    Ataxia-telangiectasia: an inherited disorder of ionizing-radiation sensitivity in man. Progress in the elucidation of the underlying biochemical defect.
    McKinnon PJ
    Human genetics. 1987 ; 75 (3) : 197-208.
    PMID 3549535
    Molecular characterization of different ataxia telangiectasia T-cell clones. I. A common breakpoint at the 14q11.2 band splits the T-cell receptor alpha-chain gene.
    Stern MH, Zhang FR, Griscelli C, Thomas G, Aurias A
    Human genetics. 1988 ; 78 (1) : 33-36.
    PMID 3422210
    Molecular characterization of ataxia telangiectasia T cell clones. III. Mapping the 14q32.1 distal breakpoint.
    Stern MH, Zhang FR, Thomas G, Griscelli C, Aurias A
    Human genetics. 1988 ; 81 (1) : 18-22.
    PMID 3264259
    Incidence of cancer in 161 families affected by ataxia-telangiectasia.
    Swift M, Morrell D, Massey RB, Chase CL
    The New England journal of medicine. 1991 ; 325 (26) : 1831-1836.
    PMID 1961222
    The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species.
    Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G
    Human molecular genetics. 1995 ; 4 (11) : 2025-2032.
    PMID 8589678
    Atm-deficient mice: a paradigm of ataxia telangiectasia.
    Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A
    Cell. 1996 ; 86 (1) : 159-171.
    PMID 8689683
    Leukemia and lymphoma in ataxia telangiectasia.
    Taylor AM, Metcalfe JA, Thick J, Mak YF
    Blood. 1996 ; 87 (2) : 423-438.
    PMID 8555463
    Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways.
    Barlow C, Brown KD, Deng CX, Tagle DA, Wynshaw-Boris A
    Nature genetics. 1997 ; 17 (4) : 453-456.
    PMID 9398849
    Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene.
    Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A
    Genome research. 1997 ; 7 (6) : 592-605.
    PMID 9199932
    Cell-cycle signaling: Atm displays its many talents.
    Westphal CH
    Current biology : CB. 1997 ; 7 (12) : R789-R792.
    PMID 9382823
    ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.
    Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van 't Veer LJ
    American journal of human genetics. 2000 ; 66 (2) : 494-500.
    PMID 10677309
    ATM phosphorylates histone H2AX in response to DNA double-strand breaks.
    Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ
    The Journal of biological chemistry. 2001 ; 276 (45) : 42462-42467.
    PMID 11571274
    REVIEW articlesautomatic search in PubMed
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    Written04-1998Jean Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
    Updated10-1999Nancy Uhrhammer, Jacques-Olivier Bay and Richard A Gatti
    Institute of Human Genetics, Charite, Humboldt-University, 10098 Berlin, Germany
    Updated10-2002Nancy Uhrhammer, Jacques-Olivier Bay and Richard A Gatti
    UCLA School of Medicine, Department of Pathology, 675 Young Drive South, Macdonald Research Laboratories, Los Angeles, CA 90095-1732, USA


    This paper should be referenced as such :
    Uhrhammer N, Bay JO, Gatti RA
    Ataxia telangiectasia;
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version :
    History of this paper:
    Atlas Genet Cytogenet Oncol Haematol. October 2002
    Atlas Genet Cytogenet Oncol Haematol. October 2002

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Wed Jun 17 15:19:26 CEST 2015

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