Confirming a diagnosis
Confirming diagnosis of Ataxia-Telangiectasia
When a clinical diagnosis of A-T has been made or there is a strong clinical indication of A-T, genetic confirmation of this should be obtained by identifying the ATM mutations present. In the UK this is carried out by Professor Malcolm Taylor’s laboratory at the University of Birmingham, which is designated by the NSCT to do this. The laboratory will also seek to investigate the consequences of the specific mutations present in the ATM gene (see below). A blood sample in lithium heparin will allow all this to be carried out.
As a more general screen for Ataxia-Telangiectasia, as part of the diagnostic process, the following tests are carried out, based on receipt of a blood sample in lithium heparin:
A chromosomal radiosensitivity analysis is carried out on the blood lymphocytes as sensitivity to ionising radiation is a characteristic of A-T.
A lymphoblastoid cell line (LCL) is also made from the blood sample and a western blot carried out to look for loss of ATM protein.
If these two tests indicate the likelihood of A-T, the patient’s ATM gene is sequenced in order to identify both mutations.
If the western blot reveals some residual ATM protein activity, as the result of e.g. a missense or leaky splice-site mutation, an activity assay is also carried out to determine whether the ATM protein has some activity. There is a strong phenotype-genotype correlation in A-T and patients with some residual A-T kinase activity generally have a milder clinical picture.
All these tests are preferred. For example, some patients have no measurable increase in chromosomal radiosensitivity; however, the western blot shows up a greatly reduced level of ATM protein. This is because the ATM present has some activity that is effective in reducing chromosome damage. Similarly some A-T patients have normal levels of ATM protein on a western blot, but the radiosensitivity assay will indicate a lot of chromosome damage. This is because the mutant ATM protein expressed has no kinase activity.
As well as being provided to the physician requesting the confirmation, this information is made available to the doctors at the specialist A-T centres.
For more information about the process or to arrange for an analysis, please contact:
Professor of Cancer Genetics
Institute of Cancer and Genomic Sciences
University of Birmingham
Tel: 0121 414 4488
Fax: 0121 414 4486
Email: Professor Malcolm Taylor