Segarra Casas, AlbaIruzubieta, PabloKapetanovic, SolangeHernández-Laín, AurelioJericó, IvonneFernández Torrón, RobertoManeiro, MirenMarco Moreno, PabloZelaya Huerta, M. VictoriaRodríguez Santiago, BenjamínCalafell i Majó, FrancescTöpf, AnaStraub, VolkerVallejo Illarramendi, AinaraLópez de Munain, AdolfoGallano, PíaGonzalez-Quereda, Lidia2025-02-212025-02-212025Segarra-Casas A, Iruzubieta P, Kapetanovic S, Hernández-Laín A, Jericó I, Fernández-Torrón R, et al. A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps. Eur J Neurol. 2025 Jan;32(1):e16471. DOI: 10.1111/ene.164711351-5101http://hdl.handle.net/10230/69666Background and purpose: Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant. Methods: Families harbouring the p.Leu2286 RYR1 variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives. Results: Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non-specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional RYR1 variant. Three individuals carrying an in trans RYR1 variant presented with an earlier onset and more severe phenotype. Conclusion: Here, it is shown that the dominantly inherited p.Leu2286Val RYR1 founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia.application/pdfeng© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1111/ene.16471RYR1‐related myopathiesExercise intoleranceHyperCKemiaMyalgiainfo:eu-repo/semantics/openAccess