The Natural History of Ataxia Telangiectasia

Ataxia Telangiectasia (A-T), a life shortening autosomal recessive multisystem disease, is caused by mutations in the ATM gene, and affects 1/300,000 live births. The pathophysiological basis of the disease relates to mutations in the ATM kinase gene that result in a faulty repair of breakages in double-stranded DNA. A-T causes a progressive ataxia, dystonia, and movement disorder, and is complicated by immunodeficiency, lung disease, faltering growth, limb and spinal deformities, and increased susceptibility to cancers. The disease first manifests in early childhood with balance problems and is slowly progressive, with loss of control of limb and eye movements, and speech, through the school years, resulting in severe disability by adulthood. Patients with classical A-T rarely live beyond their 20s, and there is no effective treatment. Because it is so rare, little has been published on the natural history of the condition.

The Department of Health funds the national multidisciplinary clinic for children with A-T in Nottingham, with follow-up of adults at the Royal Papworth Hospital, Cambridgeshire. Clinical and laboratory data have been collected systematically from over 170 patients, most on more than one occasion, from 2001 to date. This unique clinical collection will allow us to elucidate the natural history of A-T using a mixture of cross-sectional and longitudinal analyses, from presentation in the pre-school years to adulthood.

We will discover more about the presentation and diagnosis of A-T, and the detailed evolution of the disease as children grow to adulthood. Preliminary analyses of the neurological phenotype in 134 patients has shown important genotype-phenotype relationships and a more variable deterioration over time than anticipated, which will be investigated further. In parallel, investigation of the morbidity and mortality due to deterioration in lung function, the immune system, infections, cancers, malnutrition, and skeletal deformity will be undertaken. We will learn about the interactions between the various disease manifestations, e.g. lung disease and nutritional status, immunological impairment and neurology and risk of cancers. These discoveries will inform patient care, and help to generate hypotheses for further research projects. From the analysis of the cross-sectional data we will establish an initial Core Outcome Set, which will be further developed at Patient and Public Involvement (PPI) meetings with young people with A-T and their parents/carers.

This study is needed to accurately map the course of A-T from childhood to adulthood, to help us recognise different patterns of disease in individual patients, improve early diagnosis by understanding the reasons for diagnostic delay, anticipate complications more accurately and elucidate the best ages to intervene before rapid deterioration.

The expected clinical course involves deterioration in gross and fine motor skills, oculomotorpraxia, choreoform movements, and difficulty with chewing and swallowing. By the end of their first decade children are usually wheelchair dependent as cerebellar destruction progresses and further neurodisability ensues with development of incapacitating movement disorder and peripheral neuropathy. Sinopulmonary infections and recurrent lower respiratory tract infections with bronchiectasis are common in A-T, and current management aims to avoid and treat lung infection. The treatment for malignancy must take into consideration the fact that many oncological therapies have adverse-effects that will impact on individual function in other domains for example drugs that cause muscle weakness will exacerbate motor impairments. Also the DNA of patients with A-T is particularly susceptible to double strand breakage, which can itself cause secondary malignancies.