Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations

• Published in: American journal of medical genetics 2004-04, Vol.126A (3), p.272-277
• Main Authors: Dörk, Thilo, Bendix-Waltes, Regina, Wegner, Rolf-Dieter, Stumm, Markus
• Format: Article
• Language: English
• Subjects: A-T variant; Age of Onset; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia Mutated Proteins; ataxia-telangiectasia; ATM function; Cell Cycle Proteins - metabolism; Child; Disease Progression; DNA Mutational Analysis; DNA-Binding Proteins; Frameshift Mutation - genetics; Heterozygote; Humans; Male; Middle Aged; Mutation, Missense - genetics; Nuclear Proteins - metabolism; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; RNA Splicing; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins
• ISSN: 1552-4825; 0148-7299; 1552-4833
• DOI: 10.1002/ajmg.a.20601

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. © 2003 Wiley‐Liss, Inc.