Abstract
Variants in the skeletal muscle ryanodine receptor 1 gene (RYR1) result in a spectrum of RYR1-related disorders. Presentation during infancy is typical and ranges from delayed motor milestones and proximal muscle weakness to severe respiratory impairment and ophthalmoplegia. We aimed to elucidate correlations between genotype, protein structure and clinical phenotype in this rare disease population. Genetic and clinical data from 47 affected individuals were analyzed and variants mapped to the cryo-EM RyR1 structure. Comparisons of clinical severity, motor and respiratory function and symptomatology were made according to the mode of inheritance and affected RyR1 structural domain(s). Overall, 49 RYR1 variants were identified in 47 cases (dominant/de novo, n = 35; recessive, n = 12). Three variants were previously unreported. In recessive cases, facial weakness, neonatal hypotonia, ophthalmoplegia/paresis, ptosis, and scapular winging were more frequently observed than in dominant/de novo cases (all, p < 0.05). Both dominant/de novo and recessive cases exhibited core myopathy histopathology. Clinically severe cases were typically recessive or had variants localized to the RyR1 cytosolic shell domain. Motor deficits were most apparent in the MFM-32 standing and transfers dimension, [median (IQR) 85.4 (18.8)% of maximum score] and recessive cases exhibited significantly greater overall motor function impairment compared to dominant/de novo cases [79.7 (18.8)% vs. 87.5 (17.7)% of maximum score, p = 0.03]. Variant mapping revealed patterns of clinical severity across RyR1 domains, including a structural plane of interest within the RyR1 cytosolic shell, in which 84% of variants affected the bridging solenoid. We have corroborated genotype-phenotype correlations and identified RyR1 regions that may be especially sensitive to structural modification.
Highlights
First described as a single entity in 1956 [43], congenital myopathies are considered a spectrum of rare, slowlyprogressive neuromuscular disorders with overlapping symptoms and histopathology [31]
An autosomal dominant/de novo (AD/DN) mode of inheritance is most frequently associated with malignant hyperthermia susceptibility (MHS) whereas autosomal recessive (AR)
For participants born before the advent of massively parallel sequencing in 2004 (n = 35) [79], the median (IQR) age of ryanodine receptor 1 gene (RYR1)-RD diagnosis was 36.0 (23.4) years compared to 4.5 (3.8) years in those born after 2004, p < 0.001
Summary
First described as a single entity in 1956 [43], congenital myopathies are considered a spectrum of rare, slowlyprogressive neuromuscular disorders with overlapping symptoms and histopathology [31]. Malignant hyperthermia (MH) crises have been reported, albeit less often, in AR cases and all RYR1-RD affected individuals should be considered as potentially susceptible [1, 33, 40]. Examples include CCD, multi-minicore disease (MmD), centronuclear myopathy (CNM), core-rod myopathy (CRM), and congenital fibertype disproportion (CFTD) [53]. These histopathological features are not unique to RYR1-RD, and are variable over time. There is an expanding spectrum of RYR1-associated clinical phenotypes, including RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, and King-Denborough syndrome [15, 48, 88]
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