Ataxia telangiectasia (AT) is an autosomal recessive disorder that affects 1/40,000 to 1/100,000 individuals. It is characterized by cerebellar ataxia, oculocutaneous telangiectasias, immune defects, endocrine abnormalities, sensitivity to ionizing radiation, chromosome rearrangements, and a predisposition to malignancy. The thymus can be embryonic or hypoplastic in appearance. Defects in both humoral and cellular immunity are present and could be responsible for severe morbidity. Although prenatal growth retardation could occur, the usual onset of symptoms occurs in early childhood. Progressive ataxia is generally the first symptom, followed by choreiform movements (in approx 90% of patients) and conjunctival telangiectasias, which usually appear between 3 and 5 yr of age. AT results in a decreased life expectancy, with few patients reaching the age of 50.
The predisposition to malignancy, primarily B-cell lymphomas and chronic T-cell leukemias, is well described (64). Approximately one-third of patients will develop a malignancy in their lifetime (64). AT patients are also more sensitive to radiotherapy used in treatment of cancer and are at risk for early and late complications (65). Interestingly, heterozygotes are also at increased risk for malignancy; increased rates of breast cancer in mothers of affected individuals have been noted (66,67).
Cytogenetic evaluation provides evidence for a high degree of chromosome breakage, translocations, and inversions involving regions other than the gene locus. The translocations often involve chromosomes 7 and 14 at the sites of T-cell receptor genes and immunoglobulin heavy-chain genes (64). Defective DNA repair mechanisms, including abnormal progression through cell cycle checkpoints, are thought to be responsible for the chromosome rearrangements (64).
6.1. GENETICS In the late 1970s, complementation studies demonstrated the existence of at least four AT complementation groups, which suggested the possible involvement of four distinct genes. Linkage analysis, which mapped AT to 11q22-23, indicated that all four complementation groups were linked to the same locus. The gene responsible for ataxia telangiectasia, ATM, has been identified and ATM mutations have been found in all four complementation groups, suggesting a single AT gene (68). ATM encodes a 12-kb transcript that has sequence homology to mammalian and yeast cell regulatory proteins (68). Although these proteins appear to play a part in the cellular response to DNA damage, the specific function of the ATM gene product has not yet been elucidated.
6.2. MOLECULAR DIAGNOSIS Historically, confirmation of a clinical diagnosis of AT has been done in the cyto-genetics laboratory. Bleomycin or radiation stress tests have been utilized to demonstrate the abnormal response of AT chromosomes. Karyotypes are analyzed for increased numbers of chromosome rearrangements, with particular attention paid to the chromosome 7; 14 translocations commonly seen in AT. Prenatal diagnosis in affected families has traditionally been done by linkage analysis using a fetal sample collected by amniocentesis or chorionic villi sampling (65). Over 400 different mutations in the ATM gene have been identified in various populations and this figure continues to grow (http://www. vmresearch.org/atm.htm). A majority of these (70%) result in a truncated protein product and are, therefore, detected efficiently by PTT (69,70). Other mutation-scanning methodologies such as SSCP and conformation-sensitive gel electrophoresis (CSGE) followed by direct sequencing have also been used with success. However, because of the heterogeneous nature of these mutations, only specific "founder" mutations in certain subpopulations such as the Amish, Moroccan Jews, Sardinians, and Mennonites are currently available for clinical testing (71). Another hurdle in the identification of mutations in the ATM gene has been the difficulty in distinguishing pathological disease-causing mutations from benign polymorphisms, because of a lack of understanding of the functional domains of this protein at the cellular level.
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