TY - JOUR
T1 - Genotype-phenotype characterisation of long survivors with motor neuron disease in Scotland
AU - Lothian Birth Cohorts Group
AU - Leighton, Danielle J
AU - Ansari, Morad
AU - Newton, Judith
AU - Parry, David
AU - Cleary, Elaine
AU - Colville, Shuna
AU - Stephenson, Laura
AU - Larraz, Juan
AU - Johnson, Micheala
AU - Beswick, Emily
AU - Wong, Michael
AU - Gregory, Jenna
AU - Carod Artal, Javier
AU - Davenport, Richard
AU - Duncan, Callum
AU - Morrison, Ian
AU - Smith, Colin
AU - Swingler, Robert
AU - Deary, Ian J
AU - Porteous, Mary
AU - Aitman, Timothy J
AU - Chandran, Siddharthan
AU - Gorrie, George H
AU - Pal, Suvankar
N1 - Funding 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.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12/14
Y1 - 2022/12/14
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - Genetics
KW - Motor neuron disease
KW - Survival
U2 - 10.1007/s00415-022-11505-0
DO - 10.1007/s00415-022-11505-0
M3 - Article
C2 - 36515702
SN - 0340-5354
JO - Journal of Neurology
JF - Journal of Neurology
ER -