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AT-like disorder

Ataxia-telangiectasia-like disorder

Some years ago a small group of teenagers were diagnosed as probably having ataxia telangiectasia. This was because they showed the same neurological features as AT, for example the ataxia, abnormality of eye movement and difficulties with speech. Subsequently, it was shown that they did not have mutations in the ATM gene, but instead showed mutations in another gene called MRE11.

The question is why do patients with mutations in either of these two separate genes, ATM or MRE11, develop AT or an AT like disorder respectively? What is the connection between the two genes? The answer is that the Mre11 protein is required for the full activation or functioning of the ATM protein. A reduction in the level of Mre11 protein leads to a failure of ATM to function properly, in ATLD patients, just as though there was some abnormal ATM protein present. The effective reduction in the activity of ATM in these ATLD patients may well account for the similar clinical effects, although the clinical features of AT and ATLD are not identical.

ATLD individuals may have the same early age of onset with similar features to AT, like ataxic of jerky movements and difficulties with eye movements, but there may also be a slower rate of progression. Interestingly they do not show the ocular telangiectasia. At the cellular level there is also increased radiosensitivity, although the degree of radiosensitivity is not as great as for typical AT patients. Overall, therefore, the clinical and cellular features of ATLD may be a little milder than those in AT.

To make matters a little more complicated the Mre11 protein is part of a complex of three proteins, Mre11/Rad50/Nbn. All three affect the functioning of ATM. There are also individuals with mutations in either the RAD50 or NBN gene. Cells from these individuals show reduction in activity of ATM protein and there are also clinical similarities between them.  Interestingly, the clinical features of NBN and RAD50 patients are different to those of ATM and MRE11 individuals, but the reasons for this are not known.

Here is a link to the original scientific paper on ATLD.

Our thanks to Prof Malcolm Taylor for his help in producing this article.