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.

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

“…In particular, neurological evaluations were comprised of the Scale for the Assessment and Rating of Ataxia (SARA) (27), the Inventory of Non-Ataxia Signs (INAS) (29), Activities of Daily Living (ADL) (35), the SCA Functional Index (SCAFI) (36), the Composite Cerebellar Functional Severity Score (CCFS) (37), and a gait mobility score. Of note, the gait mobility score was determined by R.H., based on the Schon et al scale (66) to provide a classification for the current level of mobility for each participant. This scale is comprised of five levels of motor functionality: 0-asymptomatic, 1impaired gait (no assistance required), 2-impaired gait (utilizes cane when ambulating), 3requires walker, 4-wheelchair bound, 5-bedridden.…”

Evidence of pathogenicity for the leaky splice variant c.1066‐6T>G in ATM

“…A milder type of A-T designated "variant A-T" is caused by biallelic variants with at least one missense or splice site mutation resulting in expression of ATM with some residual kinase activity (Dörk, Bendix-Waltes, Wegner, & Stumm, 2004;Schon et al, 2019;Sutton et al, 2004;Taylor, Lam, Last, & Byrd, 2015;Verhagen et al, 2012). Previous reports described a wide range of ATM missense and leaky splice site mutations, associated with relatively mild phenotypes (Schon et al, 2019). Due to the atypical presentation, these phenotypes often go undiagnosed for years, and many subjects with variant A-T receive the correct diagnosis only in adulthood (van Os et al, 2019).…”

Adult-onset variant ataxia-telangiectasia diagnosed by exome and cDNA sequencing

“…4 It has been suggested that mainly the mutation type predicts the clinical course with missense variants leading to a milder phenotype but an increased risk of cancer. 5…”

“…4 The broad phenotypic spectrum of A-T now becomes gradually disentangled owing to the increased availability of comprehensive genetic testing. 5…”