Abstract

Objective

Variant Ataxia‐Telangiectasia is caused by mutations that allow some retained ATM kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant Ataxia‐Telangiectasia and explore genotype‐phenotype correlations.

Methods

Cross‐sectional data were collected retrospectively. Patients were classified as variant Ataxia‐Telangiectasia based on retained ATM kinase activity.

Results

The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age ten (81%). There was a diagnostic delay of more than ten years in 68% and more than 20 years in a third of probands.

Disease severity was mild in a third of patients and 43% were still ambulant 20 years after disease onset. Only a third had predominant ataxia and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity but with a higher risk of malignancy, compared to leaky splice site mutations.

Interpretation

Individuals with variant Ataxia‐Telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis‐ or underdiagnosed due to atypical features, including exclusive extrapyramidal symptoms, normal eye movements and normal AFP levels in some individuals. Missense mutations are associated with milder neurological presentations but a particularly high malignancy risk and it is important for clinicians to be aware of these phenotypes.

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