1FC3.4 Mutation load of m.3243A>G in tRNALeu in different samples in a family affected of MELAS

Abstract

Background: Ataxia-Telangiectasia (A-T) is a rare autosomal recessive multisystem disorder, classically characterized by progressive neurodegeneration with early onset ataxia, telangiectasia, immunodeficiency, elevated a-fetoprotein (AFP), radiosensitivity, chromosome instability and cancer predisposition. Some A-T patients exhibit a milder clinical course. A-T is caused by mutations in the ATM gene, more than 400 mutations has been described. Aim of the study: to obtain a comprehensive description of the clinical spectrum as well as genotype-phenotype correlations in A-T patients. Methods: Clinical and laboratory data of 51 Dutch A-T patients were retrospectively collected. ATM protein expression and kinase activity measurements were performed for 35 patients. Results: Absence of ATM kinase activity results in a classical phenotype. ATM protein without kinase activity protects only against IgG defeciency. Residual kinase activity protects against malignancies, endocrinopathy, telangiectasia, pulmonary problems, absence of immunoglobulines and leads to extended lifespan. Residual kinase activity results in a milder neurological phenotype with predominance of extrapyramidal instead of cerebellar symptoms. In adulthood, all A-T patients had elevated AFP levels and chromosome 7/14 rearrangements. X-ray hypersensitivity in lymphocytes was significantly lower in patients with residual ATM kinase activity. All patients have an increased risk of malignancies. Conclusion: The severity of the phenotype depends on the presence of ATM protein and of residual ATM kinase activity as determined by the genotype. The presence of ATM protein results in better immunological function compared with the absence of ATM protein. ATM protein with residual kinase activity results in the mildest phenotype: the larger the amount of kinase activity the milder the phenotype.