What is the pathophysiology of ataxia-telangiectasia (A-T)?

Updated: Apr 06, 2020
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
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Answer

The ATM gene encodes the protein kinase ATM, which is the key regulator of cellular response to double-strand breaks (DSB) in DNA. Therefore, ataxia-telangiectasia symptoms include all the possible consequences of the perturbations in DNA damage response (DDR). [8, 9, 10]

One basic defect associated with the malady is the abnormal sensitivity of ataxia-telangiectasia cells to x-rays and certain radiomimetic chemicals but not to ultraviolet irradiation, which leads to chromosome and chromatid breaks. Breakpoints are randomly distributed, but nonrandom chromosome rearrangements selectively affect chromosomes 7 and 14 at sites that are concerned with T-cell receptors and heavy-chain immunoglobulin coding and with the development of hematologic malignancies. Such disturbances could account for the frequency of infections and neoplasias.

As has been shown by Guerra-Maranhao et al, ataxia-telangiectasia patients are at high risk of having impaired responses to infection with pneumococci, which may be one of the causes of recurrent sinopulmonary infections in these patients. [11] The authors analyzed the production of antibodies to polysaccharide antigens in patients with ataxia-telangiectasia and found that the levels of immunoglobulin G (IgG) antibodies to serotypes 1, 3, 5, 6B, 9V, and 14 of Streptococcus pneumoniae before and after immunization with 23-valent polysaccharide vaccine were significantly lower than in a healthy population.

ATM gene targets include well-known tumor suppressor genes such as TP53 and BRCA1, both of which play an important role in the predisposition to breast cancer. Studies of ataxia-telangiectasia families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene, [12] but, to date, an increased frequency of ATM mutations has not been found in women with breast cancer. [13]

ATM mutations are poor prognostic factor in patients with lung cancer. [14]

The mechanisms responsible for neurologic disease, thymus aplasia, telangiectasias, growth retardation, and impaired organ mutation have not been elucidated, but most likely, they are linked to accelerated telomere loss. [15, 16] ATM has been shown to be pivotal for neurodevelopment, especially for stem cell differentiation, as well as for elimination of damaged postmitotic cells. [17] Frappart and McKinnon showed that the ATM protein has a proapoptotic function in the developing mouse CNS, acting in cooperation with another key proapoptotic factor—Bax protein. [18] ATM-dependent apoptosis occurred only in postmitotic populations of neurons after irradiation.

These results suggest that ATM may serve to eliminate neurons with excessive DNA damage during CNS development. A general disturbance in tissue differentiation accounts for the almost constant elevation of alpha-fetoprotein (AFP), a fetal serum protein of hepatic origin that indicates dedifferentiation of liver cells.

Research suggests that ataxia-telangiectasia may be associated with dysregulation of the immunoglobulin gene superfamily, which includes genes for T-cell receptors. The normal switch from the production of immunoglobulin M (IgM) to IgG, immunoglobulin A (IgA), and immunoglobulin E (IgE) is defective, and the same may apply to the switch from immature T cells that express the gamma/delta rather than the alpha/beta receptors. Conceivably, an absence or a mutation of a single protein coded for by chromosome 11 could explain the immunologic and perhaps even the neurologic features of the disease. The ATM protein apparently controls the cell cycle and plays a major role in the protection of the genome.

The ATM gene product has been shown to be required for cell survival and genomic stability maintenance following exposure to low labile iron concentrations. Because iron chelation agents increase ataxia-telangiectasia cell genomic stability and viability and activate ATM-dependent cellular events in normal cells, Edwin Shackelford et al suggested that pharmacological manipulation of ATM activity via iron chelation might have clinical efficacy in Parkinson disease treatment. [19]  Targeted next-generation sequencing is a rapid cost-effective method that identified five disease-causing variants in three Chinese probands in one study. [20]


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