Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature
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Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature Tokunbor A. Lawal1* , Joshua J. Todd1, Jessica W. Witherspoon1, Carsten G. Bönnemann2, James J. Dowling3, Susan L. Hamilton4, Katherine G. Meilleur1 and Robert T. Dirksen5
Abstract The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency. Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exerciseinduced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1[related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum. Keywords: Myopathy, Skeletal muscle, Clinical neurology, Ion channel defects, Neuromuscular disease, History
Introduction Congenital myopathies (CM), a term first coined by Victor Dubowitz [1], are a group of inherited, non-dystrophic neuromuscular disorders characterized by specific clinical features and skeletal muscle histopathology [2]. Pathogenic * Correspondence: [email protected] 1 Tissue Injury Branch, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA Full list of author information is available at the end of the article
variations in the RYR1 gene, a relatively large gene in the human genome, are the most common cause of CM and contribute to the clinical, histopathological, and genetic heterogeneity of
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