- Human pathology

Home > D. General pathology > Genetic and developmental anomalies > ataxia telangiectasia

ataxia telangiectasia

Monday 27 October 2003

Definition: Ataxia telangiectasia (AT) is another autosomal recessive disorder characterized by cerebellar ataxia, progressive mental retardation, immune defects, severe muscular incoordination, and a strong predisposition to malignancy, particularly in the lymphoreticular system. The term telangiectasia describes the dilatation of blood vessels, particularly in the eyes and skin.

Patients with this disease have several defects, including hypersensitivity to ionising radiation. Death is mostly due to infection, with increased predisposition to lymphoid malignant diseases.

Clinical synopsis

The disease relentlessly progresses to death early in the second decade. Patients first come to medical attention because of recurrent sinopulmonary infections and unsteadiness in walking.

Later on, speech is noted to become dysarthric, and eye movement abnormalities develop. Many affected individuals develop lymphoid malignant disease (T-cell leukemia, T-cell lymphoma); gliomas and carcinomas have been reported in some.


The abnormalities are predominantly in the cerebellum, with loss of Purkinje and granule cells; there is also degeneration of the dorsal columns, spinocerebellar tracts, and anterior horn cells and a peripheral neuropathy. Telangiectatic lesions have been reported in the CNS as well as in the conjunctiva and skin of the face, neck, and arms.

The nuclei of cells in many organs (e.g., Schwann cells in dorsal root ganglia and peripheral nerves, endothelial cells, pituicytes) show a bizarre enlargement of the cell nucleus to two to five times normal size and are referred to as amphicytes. The lymph nodes, thymus, and gonads are hypoplastic.


The ataxia-telangiectasia locus on chromosome 11q22-23 has been identified as a large gene, ATM, that encodes a protein with a kinase domain; the protein orchestrates the cellular response to double-stranded DNA breaks.

The carrier frequency of ataxia-telangiectasia has been estimated at 1%; in these individuals, the mutated ataxia-telangiectasia allele may underlie an increased risk of cancer, specifically breast cancer.


- Chromosomal breakage is also a common feature. AT cells are abnormally sensitive to killing by ionizing radiation and for long it has been considered an ’X-ray analogue’ of XP, since XP patients are sensitive to UV light and not X-ray.

- However, unlike the observations with XP, no clearly defect on DNA repair was identified in AT cells. Curiously, the AT cells are abnormally resistant to the inhibition of DNA synthesis by ionizing radiation, suggesting a defect in the processing of DNA damage.

- The latter trait has been used to identify 4 complementation groups for the classical form of the disease (Jaspers et al., 1988), which, however, are all associated with mutations on the same recently cloned gene, named ATM (for AT mutated, Savitsky et al., 1995).

- The ATM gene encoded a putative protein that is homolog to several yeast and mammalian phosphatidylinositol 3-prime (PI-3) kinases, that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control.

- This is consistent with cell cycle defects observed in AT cells, including the absence of G1-S checkpoint after ionizing radiation (Kastan et al., 1992).

- Although, as for the other genetic disorders described above, AT is a very rare disease, affecting about 1:40,000 live births, the cloning of the ATM gene has a great impact.

- The disease is found only in individuals with mutations in both alleles, that is, in homozygosis. Heterozygous relatives of AT patients are apparently normal, but there are indications that they are more likely to develop tumors than individuals unrelated to these patients.

- Since the heterozygous individuals are very frequent in the population, about 1%, it has been estimated that heterozygosis of the AT disease may be associated with an important fraction of persons that die of cancer before the age of 45 (Swift et al., 1987).

- This is particularly clear in association with breast cancer: approximately 8.8% of the patients with breast cancer in the US white population might be heterozygous for the ATM gene (Swift et al., 1987).

- The identification of the most frequent mutations that inactivate this gene will provide an important tool for the screening and diagnosis of cancer-prone individuals.


The ataxia telangiectasia gene locus encodes ATM, a protein kinase involved in DNA damage-triggered signal transduction to p53 activation and checkpoint arrest.

T cells from patients with ataxia telangiectasia have shorter telomeres than age-matched controls, consistent with a greater rate of cell turnover due to unrepaired genome damage.

The product of the gene (ATM) mutated in the human genetic disorder ataxia-telangiectasia (A-T) plays a central role in the recognition and signaling of DNA damage.

ATM is one of an ever growing number of proteins which when mutated compromise the stability of the genome and predispose to tumour development. Mechanisms for recognising double strand breaks in DNA, maintaining genome stability and minimizing risk of cancer are discussed.

Constitutive expression of hTERT in patients’ cells increases telomere length and prevents proliferative senescence, but does not fully rescue telomere dysfunction; these findings suggest that ATM may have a direct role at the telomere as well.


- mutations in the ATM gene


- Shiloh Y, Andegeko Y, Tsarfaty I. In search of drug treatment for genetic defects in the DNA damage response: the example of ataxia-telangiectasia. Semin Cancer Biol. 2004 Aug;14(4):295-305. PMID: 15219622

- Jeggo PA, Carr AM, Lehmann AR. Splitting the ATM : distinct repair and checkpoint defects in ataxia-telangiectasia. Trends Genet. 1998 Aug ;14(8):312-6. PMID : 9724963

- Rotman G, Shiloh Y. ATM: from gene to function. Hum Mol Genet. 1998;7(10):1555-63. PMID: 9735376