Ataxia-Telangiectasia (A-T)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU


Combined Immunodeficiencies (click to enlarge the image).

AT is associated with neurologic abnormalities resulting in progressive ataxia. There are telangiectasias of the eyes and skin. There is a variable humoral and cellular immunity. In A-T, there is a predisposition to certain malignancies, especially lymphomas and leukemias.

The ATM gene is on 11q22.3. The ATM gene product has one region similar phosphatidylinositol (PI)-3 kinases and another similar to DNA repair/cell checkpoint genes. ATM is expressed in all tissues in the body.

ATM stands for AT Mutated. The ATM kinase is a part of a surveillance mechanism that finds DNA damage and stalls the progression of the cell cycle.

ATM phosphorylates:

- tumor suppressor BRCA1

- c-abl tyrosine kinase and the Nbs1 (Nijmegen breakage syndrome) protein involved in DNA repair in response to ionizing radiation

- eIF-4E-binding protein 1 – insulin resistance

A-T occurs in 1 in 20,000 to 100,000 live births, 1.4-2.0% of Caucasians in the U.S. carry one defective AT gene. Heterozygotes have none of AT sx but higher incidence of malignancy at a younger age and CAD.

A-T is AR, oculocutaneous telangiectasias are charecteristic. There is a progressive cerebellar ataxia with Purkinje cell degeneration. In AT, there is DNA fragility with abnormal chromosome translocation in lymphocytes. There are low IgA, IgE, and IgG2 with moderately reduced T cell production and functionality.

Sinopulmonary infections are the most common infections in A-T. Opportunistic infections are uncommon . Radiation hypersensitivity results in an extremely high rate of cancer. Ataxia manifests when the child learns to walk, telangiectasias develop by age 3-6. Age at death is 25 years.

Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954 (http://goo.gl/VMR27).

References

4 Examples of Ataxia - NEJM video, 2012.

Published: 08/29/2009
Updated: 05/29/2011