Abstract
Ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are rare autosomal recessive conditions caused by mutations in respectively ATM and NBS1. The encoding proteins ATM and nibrin are involved in the processing of DNA damage and maintenance of genomic stability. Ataxia telangiectasia is described. Hallmarks are cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, radiation sensitivity and predispostion to cancer. A new double missense mutation in the ATM gene in a Dutch family is reported. Two young adult brothers with AT are described with only minor cerebellar ataxia. Their most striking symptom was a resting tremor. Four adult onset AT patients are described lacking pronounced cerebellar atrophy but displaying severe spinal muscular atrophy. In the patients the ATM function, as measured by the p53 response, was close to normal. Nijmegen breakage syndrome is described extensively. Characteristics are microcephaly, typical facial appearance, immunodeficiency, chromosomal instability, X-ray hypersensitivity, and predisposition to cancer. The immunological findings in a large series of NBS patients are reported. IgA, IgG and IgG2 levels were decreased in most patients, while IgM levels were normal or even slightly increased. The data suggest a defective class switching in NBS. A neuropathological study in NBS is described. Severe microcephaly with a simplified gyral was found. The number of cortical neurons was clearly diminished. A role of NBS1 in corticogenesis is suggested. A patient with the NBS phenotype is described without a mutation in NBS1. The distinct neurological features of AT and NBS are likely to be due to different roles of ATM and nibrin in the nervous system. Nibrin seems to be particularly important for the development of the nervous system, while ATM seems to play a more maintaining role. The similarities on the laboratory level between the two disorders seem to be the result of functional links between the two proteins.
