title: Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations.
abstract: Ataxia-telangiectasia (A-T) is caused by mutations of the ATM gene, the product of which is involved in the regulation of cellular responses to radiation damage. Ataxia usually starts in early childhood but a delayed age at onset and slower rate of neurological deterioration has been found for some patients with variant A-T. Only few patients have been documented to survive into the 4th decade. We report on a patient with an attenuated form of A-T who was diagnosed as having A-T by the age of 52 years and died by the age of 60 years. He was found to be a compound heterozygote for a double missense mutation (D2625E and A2626P) and a novel splicing mutation (496 + 5G --> A) of the ATM gene. Cytogenetic studies of the patient's lymphoblastoid cells revealed modest levels of bleomycin-induced chromosomal instability. Residual ATM protein was found at a level of 10-20% of wildtype. Low residual ATM kinase activity could be demonstrated towards p53, whereas it was poorly detectable towards nibrin. Our results corroborate the view that the clinical variability of A-T is partly determined by the mutation type and indicate that A-T can extend to late adulthood disease.
authors.affiliation: Clinics of Obstetrics and Gynecology, Medical School Hannover, Hannover, Germany. doerk.thilo@mh-hannover.de
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Regina
authors.initials: R
authors.lastname: Bendix-Waltes
authors.forename: Rolf-Dieter
authors.initials: RD
authors.lastname: Wegner
authors.forename: Markus
authors.initials: M
authors.lastname: Stumm
mesh_terms: D017668:Age of Onset; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D018450:Disease Progression; D016368:Frameshift Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D012326:RNA Splicing; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases