Background: Variants in the ryanodine receptor 1 (RYR1) gene have been linked to a range of disorders, from congenital myopathy to adult-onset manifestations, with phenotypes varying from mild to severe. Methods: A retrospective review was conducted on an Israeli cohort of 36 individuals with RYR1 variants, identified through genetic testing as part of a national collaboration among multiple pediatric and adult neuromuscular clinics. Clinical features, molecular data, laboratory results, electromyographic findings, and muscle histology were analyzed. Each variant was classified according to its respective domain within the RYR1 gene. Results: Thirty-six cases were included in the analysis; 31 were from 11 unrelated families, and 5 were sporadic. Nine individuals were asymptomatic with normal CK levels. Most of the 27 affected patients presented with variable degrees of perinatal weakness, often accompanied by respiratory impairment or arthrogryposis. Weakness was predominantly proximal, with clinical courses that included deterioration, improvement, or stabilization. Three cases of King-Denborough syndrome were identified. Additional presentations included malignant hyperthermia and, in isolated cases, periodic paralysis. Muscle biopsies demonstrated considerable histologic heterogeneity, including fiber-size variation, internal nuclei, multiminicores, and fibrosis or dystrophic features. The pathogenic RYR1 variants included five compound-heterozygous genotypes, two homozygous variants, and two heterozygous variants. There was a positive correlation between variants located in the Bsol domain and disease severity. Conclusions: This cohort confirms and expands the clinical and histological diversity associated with RYR1 variants in Israel. Variants in the Bsol domain appear to be indicative of disease severity.

King-Denborough Syndrome (KDS) is a congenital myopathy (CM) characterised by myopathy, dysmorphic features and susceptibility to malignant hyperthermia. The objective of this study was to investigate the genotype-phenotype correlation in Black African patients presenting with CM, specifically those with KDS-like phenotypes, who remained undiagnosed for over 25 years. A cohort of 67 Black African patients with CM was studied, of whom 44 were clinically evaluated and diagnosed with KDS. Whole-exome sequencing (WES) was performed as part of an international genomics study (ICGNMD) to identify potential pathogenic mutations. Genomic assessments focused on identifying relevant genes, including RYR1 and STAC3, and establishing genotype-phenotype correlations. The study identified RYR1 and STAC3 mutations as the predominant genetic causes of KDS in this cohort, with mutations in both genes exhibiting autosomal recessive inheritance. While RYR1 has previously been linked to autosomal dominant mutations, STAC3, which was formerly associated exclusively with Native American Myopathy/Bailey-Bloch Myopathy, congenital hypotonia, and susceptibility to malignant hyperthermia, is now newly associated with CM-KDS in this study. This establishes the first genotype-phenotype correlation for 44 Black African individuals with KDS. This study marks a significant milestone in research on understudied African populations with CM, emphasising the lengthy diagnostic journey these patients endured. The findings highlight the pressing need for improved access to genomic medicine in underserved regions and underscore the importance of expanding research and diagnostic capabilities in Africa. This work contributes to the advancement of genetic medicine in underrepresented populations, facilitating better diagnostic and therapeutic outcomes.

Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.

Ryanodine receptor type 1-related disorder (RYR1-RD) is the most common subgroup of congenital myopathies with a wide phenotypic spectrum ranging from mild hypotonia to lethal fetal akinesia. Genetic testing for myopathies is imperative as the diagnosis informs counseling regarding prognosis and recurrence risk, treatment options, monitoring, and clinical management. However, diagnostic challenges exist as current options are limited to clinical suspicion prompting testing including: single gene sequencing or familial variant testing, multi-gene panels, exome, genome sequencing, and invasive testing including muscle biopsy. The timing of diagnosis is of great importance due to the association of RYR1-RD with malignant hyperthermia (MH). MH is a hypermetabolic crisis that occurs secondary to excessive calcium release in muscles, leading to systemic effects that can progress to shock and death if unrecognized. Given the association of MH with pathogenic variants in RYR1, a diagnosis of RYR1-RD necessitates an awareness of medical team to avoid potentially triggering agents. We describe a case of a unique fetal presentation with bilateral diaphragmatic eventrations who had respiratory failure, dysmorphic facial features, and profound global hypotonia in the neonatal period. The diagnosis was made at several months of age, had direct implications on her clinical care related to anticipated need to long-term ventilator support, and ultimately death secondary an arrhythmia as a result of suspected MH. Our report reinforces the importance of having high suspicion for a genetic syndrome and pursuing early, rapid exome or genome sequencing as first line testing in critically ill neonatal intensive care unit patients and further evaluating the pathogenicity of a variant of uncertain significance in the setting of a myopathic phenotype.

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.