Genotype–phenotype characterisation of long survivors with motor neuron disease in Scotland

Leighton, D. J. et al. (2023) Genotype–phenotype characterisation of long survivors with motor neuron disease in Scotland. Journal of Neurology, 270(3), pp. 1702-1712. (doi: 10.1007/s00415-022-11505-0) (PMID:36515702) (PMCID:PMC9971124)

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.

• Item Type: Articles
• Additional Information: DL received funding for PhD study at the inception of this study from the Chief Scientist Office for Scotland, the Motor Neuron Disease Association and Motor Neuron Disease Scotland (CAF/MND/15/01). This work is also supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.
• Keywords: Amyotrophic lateral sclerosis, motor neuron disease, genetics, survival.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leighton, Dr Danielle and CHANDRAN, Professor SIDDHARTHAN and Gorrie, Dr George
• Authors: Leighton, D. J., Ansari, M., Newton, J., Parry, D., Cleary, E., Colville, S., Stephenson, L., Larraz, J., Johnson, M., Beswick, E., Wong, M., Gregory, J., Carod Artal, J., Davenport, R., Duncan, C., Morrison, I., Smith, C., Swingler, R., Deary, I. J., Porteous, M., Aitman, T. J., Chandran, S., Gorrie, G. H., and Pal, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Journal of Neurology
• Publisher: Springer
• ISSN: 0340-5354
• ISSN (Online): 1432-1459
• Published Online: 14 December 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Journal of Neurology 270(3): 1702-1712
• Publisher Policy: Reproduced under a Creative Commons License