Dokumentdetails
ID
doi:10.1007/s00415-022-11505-0...
Autor
Leighton, Danielle J. 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 the Lothian Birth Cohorts Group and the CARE-MND ConsortiumLangue
enEditor
Springer
Kategorie
Medicine & Public Health
Jahr
2022
Auflistungsdatum
21.12.2022
Schlüsselwörter
motor neuron disease amyotrophic lateral sclerosis survival genetics survival diagnosis pathogenic diagnostic variant mndZusammenfassung
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.
Leighton, Danielle J.,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,the Lothian Birth Cohorts Group,and the CARE-MND Consortium, 2022, Genotype–phenotype characterisation of long survivors with motor neuron disease in Scotland, Springer
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