title: Exclusion/confirmation of ataxia-telangiectasia via cell-cycle testing.
abstract: Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder with increased radiosensitivity and cancer susceptibility. The responsible gene (ATM) consists of 66 exons and a coding region of 9171 bp which precludes direct sequencing as a screening assay for confirmation or exclusion of the clinical suspicion of AT. Peripheral blood mononuclear cells of 330 patients referred for the exclusion of AT were exposed to ionizing radiation (IR) and incubated for 72 h in the presence of phytohemagglutinin. Using bivariate BrdU-Hoechst/ethidium bromide flowcytometry, the following cell cycle parameters were ascertained: (1) proportion of non-proliferating (G0,G1) cells as a measure of mitogen response, (2) proportion of first-cycle G2-phase cells relative to the growth fraction (G2/GF) as a measure of radiosensitivity. Of the cases tested, 94.2% could be unequivocally assigned either to the AT-negative or the AT-positive group of patients. Of the AT-positive cases, 11 were confirmed by ATM mutation analysis. Nineteen cases presented with non-conclusive results, mostly due to poor mitogen response; however, a combination of cell-cycle data with serum AFP concentrations led to the exclusion of AT in all but two of the uncertain cases. Substitution of ionizing radiation by the radiomimetic bleomycin was additionally tested in a small series of patients. We conclude that cell-cycle testing complemented by serum AFP measurements fulfills the criteria as a rapid and economical screening procedure for the differential diagnosis of juvenile ataxias.
authors.affiliation: Department of Human Genetics, University of Würzburg, Biozentrum am Hubland, 97074, Würzburg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Heinrich
authors.forename: Carolin
authors.initials: C
authors.lastname: Prowald
authors.forename: Richard
authors.initials: R
authors.lastname: Friedl
authors.forename: Benni
authors.initials: B
authors.lastname: Gottwald
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kalb
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Sabine
authors.initials: S
authors.lastname: Herterich
authors.forename: Holger
authors.initials: H
authors.lastname: Hoehn
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
mesh_terms: D000293:Adolescent; D001260:Ataxia Telangiectasia / Q000175:diagnosis* / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000528:radiation effects; D008297:Male; D010835:Phytohemagglutinins; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010835:Phytohemagglutinins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases