Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia

Abstract

Objective: Variant ataxia-telangiectasia is caused by mutations that allow some retained ataxia telangiectasia-mutated (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 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one 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 because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha-fetoprotein 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. ANN NEUROL 2019;85:170-180.

Figure 1

Age at (A) symptom onset, (B) diagnosis with ataxia‐telangiectasia, and (C) first using a wheelchair were obtained from each individual's clinical notes.

Figure 2

(A) MRI scans showing examples of mild, moderate and severe cerebellar atrophy. The top row shows midline images to assess vermian atrophy and the bottom row shows parasagittal images for assessing hemispheric atrophy. (B) MRI scans showing examples of white matter lesions. (C) MRI scans showing microbleeds. MRI = magnetic resonance imaging.

Figure 3

(A) Graph shows number of individuals in each neurological phenotypic group in patients with retained ATM kinase activity attributed to a missense mutation or a leaky splice‐site mutation. (B) Graph shows numbers of individuals who use a wheelchair or are still ambulant in patients with retained ATM kinase activity due to a missense mutation or a leaky splice‐site mutation. (C) Graphs shows cross‐sectional clinical neurological disease severity in patients with retained ATM kinase activity attributed to a missense mutation or a leaky splice‐site mutation. (D) Graph shows number of malignancies diagnosed in patients with retained ATM kinase activity attributed to a missense mutation or a leaky splice‐site mutation. ATM = ataxia telangiectasia‐mutated.