In a Dutch family, van Belzen et al. (1998) demonstrated that affected members with ataxia-telangiectasia (AT; 208900) were homozygous for 2 consecutive base substitutions in exon 55 of the ATM gene: a T-to-G transversion at position 7875 of the ATM cDNA and a G-to-C transversion at position 7876. The double base substitution resulted in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 (D2625E) and of an alanine to a proline at codon 2626 (A2626P) of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. The change in secondary structure of the ATM protein carrying the D2625E/A2626P mutation, as predicted by the method of Chou and Fasman (1978) and of Garnier et al. (1978), suggested that the double base substitution is a disease-causing mutation.
Dork et al. (2004) described a patient with an attenuated form of AT in whom the disorder was diagnosed at the age of 52 years and who died at 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; 607585.0031) of the ATM gene. Cytogenetic studies of the patient's lymphoblastoid cells revealed modest levels of bleomycin-induced chromosomal instability. Residual ATM protein was 10 to 20% of wildtype. Low residual ATM kinase activity could be demonstrated towards p53 (191170), whereas it was poorly detectable towards nibrin (602667). The results corroborated the view that the clinical variability of AT is partly determined by the mutation type and indicated that AT can present as a late adulthood disease. Although ataxia-telangiectasia was diagnosed at the age of 52 years, the patient had developed the first symptoms of ataxia at the age of 7 years. Ataxia had become prominent by the age of 14 years, and he had lost the ability to walk alone by the age of 22 years. He became permanently wheelchair-bound by the age of 45 years. Clinical diagnosis was made at the age of 52 years and confirmed by cytogenetic analysis 3 years later. His clinical phenotype thereafter was progressively dominated by chronic obstipation associated with megacolon and gastroenteritis.
