R5.4f: DNA Damage/Repair Syndromes


Ataxia telangiectasia is an autosomal recessive syndrome caused by mutation of the ataxia telangiectasia mutated (ATM) gene. The mutated gene is present in about 0.5 - 1% of the population, and the disease has a prevalence of 1/100,000.

Clinical Features

Homozygotes show the following features:

  • Progressive cerebellar ataxia (all cases) and other neurological features
    • Ataxia is usually truncal (onset ~ 3 years) before progressing to limbs
    • Most patients wheelchair bound by age 12
    • Ocular motor apraxia in most
    • Dysarthria in most
    • Normal cognitive function in most cases
  • Cutaneous and conjunctival telangiectasia
    • Helps to distinguish AT from other causes of cerebellar ataxia
  • Immunodeficiency
    • Levels of IgA and IgG are frequently low in these patients
    • The most common site of infections are the sinuses and respiratory tract
  • Increased risk of malignancies
    • Usually haematological (95%)
  • Increased sensitivity to ionising radiation


AT patients lack function of the ATM gene. This is an important sensor of damage due to ionising radiation, particularly double strand breaks. In the absence of the ATM gene, there is reduced capacity of the cell to respond to this damage. Cell cycle arrest is less inducible and repair of damage is reduced. This can lead to increased cell death during physiological development, explaining the changes seen in the syndrome.
Increased radiation sensitivity is due to the lack of sensing of radiation damage, causing normal cells to become more radiosensitive.

Li Fraumeni Syndrome

Li Fraumeni Syndrome is a very rare disease caused by a germline mutation of the TP53 gene. It is most common is Ashkanazi Jews. TP53 has a broad range of activities that are tumour suppressing, including:

  • DNA damage response, in which it is activated by DNA damage detection by ATM or MRN. It promotes cell cycle arrest to allow repair to take place, or if damage is too severe also promotes apoptosis. Loss of TP53 allows cells to acquire mutations more rapidly (see Hallmarks of Cancer). This also prevents malignant cells from repairing fatal damage prior to entering mitosis and may contribute to the increased radiosensitivity of many cancer cell lines relative to normal cells.
  • Cell Cycle Arrest, where rapidly dividing cells usually upregulate expression of TP53. Loss of TP53 prevents this arrest and cells may keep progressing through the cell cycle
  • Apoptosis, where TP53 is an important signal for apoptosis. Malignant cells typically suppress apoptosis and this is one method of doing so.

Patients with Li Fraumeni are at particular risk of [1]:

Tumours typically occur at a younger age than expected.

The clinical diagnosis of Li Fraumeni syndrome requires a sarcoma in a patient under 45, with a first degree relative with any cancer before age 45 and an additional first or second degree relative with a cancer before age 45 or another sarcoma.


1. Li, F. P., Fraumeni, J. F., Mulvihill, J. J., Blattner, W. A., Dreyfus, M. G., Tucker, M. A., & Miller, R. W. (1988). A cancer family syndrome in twenty-four kindreds. Cancer Research, 48(18), 5358–5362.