Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature

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 (RYR1-RM) 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, exercise-induced 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: Clinical neurology; History; Ion channel defects; Myopathy; Neuromuscular disease; Skeletal muscle.

Fig. 1

Timeline of significant discoveries/milestones in the evolution of RYR1-RD. 1900s to present: In the twentieth century, congenital myopathy diagnoses were based primarily on muscle biopsy histopathologic features. Advancements in next-generation sequencing enabled more precise identification of RYR1-related phenotypes. Solving of the RyR1 structure at near-atomic resolution provided valuable insight into RyR1 channel function and disease mechanisms. These advances paved the way for the first RYR1-RM clinical trial completed in 2018 and the Phase 1 Rycal trial which began enrolling participants in 2020

Fig. 2

Overview of the RYR1 disease spectrum. At time of presentation, clinical severity can vary according to mode of inheritance (dominant, de novo, recessive), histopathologic features, and phenotypes ranging from severe neonatal onset to mild non-progressive muscle weakness. Recessive cases are typically more severe than dominant cases. The majority of histopathological features are associated with more severe clinical phenotypes, though this may not hold true for the core myopathies. Emerging clinical phenotypes associated with RYR1 variations also vary in severity

Fig. 3

Distinct and overlapping features of the RYR1-RD spectrum. Individuals with RYR1-RD present with both myopathic and non-myopathic features. Histopathology can overlap among the different subtypes. Additionally, some phenotypes manifest following exposure to pharmacologic, physiologic, or environmental triggers. A classification system based on three distinct and overlapping categories (myopathic, non-myopathic, and triggered) accommodates current and most future subtypes of RYR1-RD