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.

A Late Onset Ataxia With Telangiectasia

“…2,3 Examples of survival past the fifth decade exist in rare case studies. 4 Recent studies demonstrate the strong correlation between ATM kinase activity and phenotypic severity across the AT disease spectrum. 3 Patients with classical AT, possessing biallelic null ATM mutations, present in early infancy with a progressive and debilitating cerebellar ataxia.…”

“…1 Life expectancy is reduced to the mid-20s due to respiratory failure and malignancy (primarily hematologic). 4 …”

Exclusion/confirmation of Ataxia-telangiectasia via cell-cycle testing

“…Given the advanced age of the patient, the increased baseline G2/ GF ratio could indicate the accumulation of cells with agerelated DNA damage [37]. On the other hand, slow progression of the disease has been reported in older ATpatients with mild clinical course due to double missense or in frame splicing mutations of the ATM gene [10,39]. Another potential candidate for such "mild" ATM mutations in our series presented with G2/GF cell fractions that consistently were at the upper limit of non-AT controls regardless of whether his PBLs were tested after a radiation dose of 1.5, 4, 6 or 8 Gy (see Fig.…”

“…Patients with a less severe phenotype and (mostly) later onset of symptoms carry (less severe) mutations that preserve residual ATM protein function [10,22,39].…”

Wolframin mutations and hospitalization for psychiatric illness

“…27 Later, it was shown that missense mutations predominate in breast cancer populations, 28 and that some missense mutations lead to mild, almost clinically undetectable, A-T in compound heterozygotes. 29,30 Thus, the crucial next step is determining which wolframin missense mutations predispose heterozygous carriers to psychiatric disorders. The population-based application of the index-test method 11 can do this with high statistical power and unassailable rigor.…”