Genotype–phenotype characterisation of long survivors with motor neuron disease in Scotland
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Published:2022-12-14
Issue:3
Volume:270
Page:1702-1712
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ISSN:0340-5354
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Container-title:Journal of Neurology
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language:en
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Short-container-title:J Neurol
Author:
Leighton Danielle J.ORCID, Ansari Morad, Newton Judith, Parry David, Cleary Elaine, Colville Shuna, Stephenson Laura, Larraz Juan, Johnson Micheala, Beswick Emily, Wong Michael, Gregory Jenna, Carod Artal Javier, Davenport Richard, Duncan Callum, Morrison Ian, Smith Colin, Swingler Robert, Deary Ian J., Porteous Mary, Aitman Timothy J., Chandran Siddharthan, Gorrie George H., Pal Suvankar, Harris Sarah, Prendergast James, Russ Tom, Taylor Adele, Deary Ian, Bethell Andrew, Byrne Suzanne, Craig Gillian, Flett Moira, Haagendrud Hanne, Hafezi Katarzyna, Hatrick Janice, Hutchison Aidan, Lennox Helen, Marshall Laura, McAleer Dympna, McEleney Alison, Millar Kitty, Murrie Louise, Perry David, Saravanan Gowri, Starrs Martin, Stewart Susan, Storey Dorothy, Stott Gill, Thompson David, Thornton Carol, Van Der Westhuizen Tanya, Webber Carolyn, ,
Abstract
Abstract
Background
We investigated the phenotypes and genotypes of a cohort of ‘long-surviving’ individuals with motor neuron disease (MND) to identify potential targets for prognostication.
Methods
Patients were recruited via the Clinical Audit Research and Evaluation for MND (CARE-MND) platform, which hosts the Scottish MND Register. Long survival was defined as > 8 years from diagnosis. 11 phenotypic variables were analysed. Whole genome sequencing (WGS) was performed and variants within 49 MND-associated genes examined. Each individual was screened for C9orf72 repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls.
Results
58 long survivors were identified. Median survival from diagnosis was 15.5 years. Long survivors were significantly younger at onset and diagnosis than incident patients and had a significantly longer diagnostic delay. 42% had the MND subtype of primary lateral sclerosis (PLS). WGS was performed in 46 individuals: 14 (30.4%) had a potentially pathogenic variant. 4 carried the known SOD1 p.(Ile114Thr) variant. Significant variants in FIG4, hnRNPA2B1, SETX, SQSTM1, TAF15, and VAPB were detected. 2 individuals had a variant in the SPAST gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic C9orf72 repeat expansions.
Conclusions
Long survivors are characterised by younger age at onset, increased prevalence of PLS and longer diagnostic delay. Genetic analysis in this cohort has improved our understanding of the phenotypes associated with the SOD1 variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of C9orf72 is likely a poor prognostic marker. Genetic screening using targeted MND and/or HSP panels should be considered in those with long survival, or early-onset slowly progressive disease, to improve diagnostic accuracy and aid prognostication.
Funder
UK Dementia Research Institute
Publisher
Springer Science and Business Media LLC
Subject
Neurology (clinical),Neurology
Reference45 articles.
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