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49 - Ataxia telangiectasia

from Part VIII - Cerebellar degenerations

Published online by Cambridge University Press:  04 August 2010

M. Flint Beal ,
Anthony E. Lang  and
Albert C. Ludolph
By
Richard A. Gatti ,
Tom O. Crawford ,
Alan S. Mandir ,
Susan Perlman  and
Howard T. J. Mount
M. Flint Beal
Affiliation:
Cornell University, New York
Anthony E. Lang
Affiliation:
University of Toronto
Albert C. Ludolph
Affiliation:
Universität Ulm, Germany
Richard A. Gatti
Affiliation:
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Tom O. Crawford
Affiliation:
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Alan S. Mandir
Affiliation:
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Susan Perlman
Affiliation:
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Howard T. J. Mount
Affiliation:
CRND, Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada
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Summary

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder associated with abnormal function of the nervous, immune and endocrine systems. It was initially described by Syllaba and Henner (1926) and was more completely characterized by Boder and Sedgwick (1958), who also coined the name. The disorder is characterized by a progressive gait and truncal ataxia, immunodeficiency, thymic degeneration, chromosomal instability, predisposition to lymphoreticular malignancies and hypersensitivity to ionizing radiation (for review see Boder, 1985; Gatti et al., 1991; Sedgwick & Boder, 1991; Woods & Taylor, 1992; Gatti, 2002).

Early research into the genetic cause of A-T suggested the presence of as many as four different responsible genes since fusion of fibroblasts from various A-T patients were able to complement one another in radiation sensitivity assays (Jaspers et al., 1988). However, all four groups were subsequently found to have loss-of-function mutations in a single gene, named ATM (ataxia-telangiectasia mutated), located on chromosome 11q22.3 (Gatti et al., 1988; Savitsky et al., 1995).

The ATM protein is a serine/threonine kinase responsible for maintaining genomic integrity by triggering arrest of the cell cycle, increasing transcription of stress response genes, and repair of double strand breaks in DNA (Shiloh, 2003). Among the many identified substrates are p53, p53BP, MDM2, Chk2, nibrin, Mre11, H2AX, SMC1, Pin2/TRF1, FANCD2, MDC1, and BRCA1. A-T patients express a functionally deficient ATM message, with diminished or absent levels of ATM protein (Chun et al., 2003). How mutations in ATM result in radiation hypersensitivity or neuronal integrity remains unclear.

Type
Chapter
Information
Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
 , pp. 738 - 748
Publisher: Cambridge University Press
Print publication year: 2005

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References

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  • Ataxia telangiectasia
    • By Richard A. Gatti, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Tom O. Crawford, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Alan S. Mandir, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Susan Perlman, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Howard T. J. Mount, CRND, Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada
  • M. Flint Beal, Cornell University, New York, Anthony E. Lang, University of Toronto, Albert C. Ludolph, Universität Ulm, Germany
  • Book: Neurodegenerative Diseases
  • Online publication: 04 August 2010
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544873.050
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  • Ataxia telangiectasia
    • By Richard A. Gatti, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Tom O. Crawford, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Alan S. Mandir, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Susan Perlman, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Howard T. J. Mount, CRND, Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada
  • M. Flint Beal, Cornell University, New York, Anthony E. Lang, University of Toronto, Albert C. Ludolph, Universität Ulm, Germany
  • Book: Neurodegenerative Diseases
  • Online publication: 04 August 2010
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544873.050
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  • Ataxia telangiectasia
    • By Richard A. Gatti, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Tom O. Crawford, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Alan S. Mandir, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Susan Perlman, Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA, Howard T. J. Mount, CRND, Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada
  • M. Flint Beal, Cornell University, New York, Anthony E. Lang, University of Toronto, Albert C. Ludolph, Universität Ulm, Germany
  • Book: Neurodegenerative Diseases
  • Online publication: 04 August 2010
  • Chapter DOI: https://doi.org/10.1017/CBO9780511544873.050
Available formats
×