Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype-phenotype study

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia

“…The patients with classical A-T generally have two truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes have at least one missense or splice site mutation resulting in the expression of ATM with some kinase activity (see the section on phenotype/genotype correlation). Patients with variant A-T have a later onset of disease and less severe antibody deficiency [5,10,11].…”

Late-onset ataxia telangiectasia

“…A median onset of ataxia at 27 years, with age at death of 37 years, in patients possessing residual ATM kinase activity have previously been reported. 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.…”

“…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. Wheelchair use is near invariable by late childhood.…”

“…Extrapyramidal movement disorders rather than cerebellar signs dominate the presentation and often predate ataxia, which may or may not emerge in a slowly progressive form in adulthood. 3 Oculocutaneous telangiectasia and other characteristic features are typically mild or absent.…”

“…1 Recently it has become apparent that a spectrum of milder adult-onset phenotypes exist (variant AT), associated with residual expression of functional ATM protein. 2,3 These patients demonstrate a predominance of extrapyramidal features, later age at ataxia onset, slower progression, and an extended lifespan. We report the case of a woman first diagnosed with AT at the unusually late age of 60.…”