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Characterizing SOD1 mutations in Spain: The impact of genotype,age and sex in the natural history of the disease |
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| Authors: | Juan F. Vázquez-Costa,Daniel Borrego-Hernández,Carmen Paradas,María Teresa Gómez-Caravaca,Ricardo Rojas-Garcia,Luis Varona,Mónica Povedano,Tania García-Sobrino,Ivonne Jericó Pascual,Antonio Gutiérrez,Javier Riancho,Janina Turon-Sans,Abdelilah Assialioui,Jordi Pérez-Tur,Teresa Sevilla,Jesús Esteban Pérez,Alberto García-Redondo,ALSGESCO |
| Affiliation: | 1. Neuromuscular Unit, Hospital Universitario y Politécnico la Fe, IIS La Fe, Valencia, Spain;2. Neurology Department, Hospital Universitario 12 de Octubre and Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain;3. Hospital Universitario Virgen del Rocío and Instituto Biomedicina de Sevilla, Sevilla, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;4. Hospital Universitario Reina Sofía, Córdoba, Spain;5. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain Motor Neuron Diseases Clinic, Department of Neurology, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain;6. Department of Neurology, Hospital Universitario de Basurto, Bilbao, Spain;7. Department of Neurology, Hospital de Bellvitge and Idibell, Barcelona, Spain;8. Department of Neurology, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela (A Coruña), Spain;9. Hospital Universitario de Navarra (HUN) and IdisNA, Pamplona, Spain;10. Complejo Hospitalario Universitario Insular-Materno-Infantil de Gran Canaria, Gran Canaria, Spain;11. Hospital Sierrallana-IDIVAL. Departamento de Medicina y Psiquiatría. Universidad Cantabria, Cantabria, Spain;12. Motor Neuron Diseases Clinic, Department of Neurology, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain;13. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;14. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain Neurology Department, Hospital Universitario 12 de Octubre and Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain;15. See Appendix 16. 1 for all members of ALSGESCO. |
| Abstract: | Background and purposeThe aim of this study was to describe the frequency and distribution of SOD1 mutations in Spain, and to explore factors contributing to their phenotype and prognosis.MethodsSeventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers.ResultsIn 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all five exons of SOD1, including seven novel mutations. A total of 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. The frequency of this mutation varied considerably among regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp[Estimate] = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (hazard ratio 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated with faster disease progression (exp[Estimate] = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs. 301 months).ConclusionsThese data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments. |
| Keywords: | amyotrophic lateral sclerosis motor neuron disease mutation prevalence prognosis SOD1 |