ABSTRACT
Ataxia telangiectasia (AT) is a remarkable disorder, the basis of which is a deficiency in the cellular response to DNA strand breaks. It was the first human disorder to be described in which patients were shown to be unusually sensitive to ionizing radiation, a response synonymous with a deficiency in the repair of DNA double strand breaks. The reason for this was mutation of ATM, a large gene that encodes a 370 kDa protein kinase with important functions in the cellular response to DNA damage. The relationship of all the clinical features of AT to this basic cellular defect are still incompletely resolved and this is particularly true of the cardinal clinical feature of AX the progressive neurodegeneration caused by cerebellar atrophy and possibly other brain lesions. Alongside AT must be considered ataxia telangiectasia like disorder (ATLD), where again patients show an unusual sensitivity to ionizing radiation and indeed as the name suggests, share many of the neurological and cellular features of AT. However, this disorder is caused by mutation of another gene, hM REl 1. There are several other autosomal recessive cerebellar ataxias (ARCAs) that also include Friedreich’s ataxia, ataxia oculomotor apraxia Type l 13 and ataxia oculomotor apraxia Type 2 as well as AT and ATLD and it can be difficult to distinguish them at the neurological level. A ll these disorders, therefore, have cerebellar ataxia as an important feature, but related to AT and ATLD is another disorder, Nijmegen Breakage Syndrome, where there is no cerebellar ataxia. Curiously, the mutated gene here is NBS1. The Nbsl protein exists in a complex with Mre 11 and another protein hRad50 and so the question immediately arises why the clinical features of NBS and ATLD are not more similar. Finally, in this introduction, since ATLD has been identified as a disorder quite recently one can ask whether other similar disorders remain to be identified. I believe that the answer must be an unqualified “yes”.
