{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:33:09Z","timestamp":1787869989676,"version":"build-2784847793"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>We investigated the phenotypes and genotypes of a cohort of \u2018long-surviving\u2019 individuals with motor neuron disease (MND) to identify potential targets for prognostication.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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\u2009&gt;\u20098\u00a0years 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 <jats:italic>C9orf72<\/jats:italic> repeat expansions. Data from ancestry-matched Scottish populations (the Lothian Birth Cohorts) were used as controls.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>58 long survivors were identified. Median survival from diagnosis was 15.5\u00a0years. 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 <jats:italic>SOD1<\/jats:italic> p.(Ile114Thr) variant. Significant variants in <jats:italic>FIG4<\/jats:italic><jats:italic>, hnRNPA2B1, SETX, SQSTM1, TAF15,<\/jats:italic> and <jats:italic>VAPB<\/jats:italic> were detected. 2 individuals had a variant in the <jats:italic>SPAST<\/jats:italic> gene suggesting phenotypic overlap with hereditary spastic paraplegia (HSP). No long survivors had pathogenic <jats:italic>C9orf72<\/jats:italic> repeat expansions.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>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 <jats:italic>SOD1<\/jats:italic> variant p.(Ile114Thr). Our findings confirm that pathogenic expansion of <jats:italic>C9orf72<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00415-022-11505-0","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T10:02:56Z","timestamp":1671012176000},"page":"1702-1712","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Genotype\u2013phenotype characterisation of long survivors with motor neuron disease in Scotland"],"prefix":"10.1007","volume":"270","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2015-7198","authenticated-orcid":false,"given":"Danielle 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The Scottish MND DNA Bank and the Scottish Regenerative Neurology Tissue Bank are approved by MREC\/98\/0\/56 1989\u20132010, 10\/MRE00\/77 2011 to 2013, 13\/ES\/0126 2013\u20132015, 15\/ES\/0094 2015-present. Ethical permission for the LBC1936 study protocol was obtained from the Multi-Centre Research Ethics Committee for Scotland (Wave 1: MREC\/01\/0\/56), the Lothian Research Ethics Committee (Wave 1: LREC\/2003\/2\/29), and the Scotland A Research Ethics Committee (Waves 2, 3,4 and 5: 07\/MRE00\/58). Ethical permission for the LBC1921 study protocol was obtained from the Lothian Research Ethics Committee (Wave 1: LREC\/1998\/4\/183; Wave 2: LREC\/2003\/7\/23; Wave 3: LREC1702\/98\/4\/183), the Scotland A Research Ethics Committee (Waves 4 and 5: 10\/MRE00\/87).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All participants provided informed consent before contributing to the Scottish MND Register\/CARE-MND Platform, Scottish MND DNA Bank and the Scottish Regenerative Neurology Tissue Bank and Lothian Birth Cohorts.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}