Atypical periodic paralysis and myalgia

Matthews, Emma; Neuwirth, Christoph; Jaffer, Fatima; Scalco, R.; Fialho, Doreen; Parton, Matt; Rayan, Dipa Raja; Suetterlin, Karen; Sud, Richa; Spiegel, Roland; Mein, Rachel; Houlden, Henry; Schaefer, Andrew M.; Healy, Estelle; Palace, J; Quinlivan, R.; Treves, Susan; Holton, Janice L.; Jungbluth, Heinz; Hanna, Michael G.

doi:10.1212/wnl.0000000000004894

Cited by 40 publications

(43 citation statements)

References 23 publications

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“…However, these histopathological features are not unique to RYR1 -RD, and are variable over time. In addition, 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]. …”

Section: Introductionmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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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.Electronic supplementary materialThe online version of this article (10.1007/s00415-018-9033-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

et al. 2018

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“…Interestingly, RYRs are involved in signal transduction in osteoclasts and nerves (reviewed in Lanner et al, 2010). This may explain why RYR mutations can result in skeletal and nerve abnormalities such as kyphoscoliosis and periodic paralysis (Matthews et al, 2018). Furthermore, vascular abnormalities, including increased bleeding times, have been reported in some core myopathy patients (Lopez et al, 2016).…”

Section: Ryr1 Genotype-phenotype Discordancementioning

confidence: 99%

Cored in the act: the use of models to understand core myopathies

Fusto

Moyle

Gilbert

et al. 2019

Disease Models &Amp; Mechanisms

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The core myopathies are a group of congenital myopathies with variable clinical expressionranging from early-onset skeletal-muscle weakness to later-onset disease of variable severitythat are identified by characteristic 'core-like' lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies.

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“…Mutations in the RYR1 gene are the most common cause of non-dystrophic muscle disease in humans (Colombo et al, 2015;Jungbluth et al, 2018). RYR1 mutations are associated with a wide range of clinical phenotypes, collectively referred to as RYR1-related myopathies (RYR1-RM), that can include wheelchair and ventilator dependence, and dynamic symptoms such as exercise induced myalgias, heat stroke, and malignant hyperthermia (Klein et al, 2012;Amburgey et al, 2013;Snoeck, et al, 2015;Jungbluth et al, 2016;Matthews et al, 2018). Despite their relatively high prevalence and associated morbidities, there are currently no approved pharmacological therapies for patients with RYR1-RM.…”

Section: Introductionmentioning

confidence: 99%

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

Volpatti

Endo

Knox

et al. 2020

eLife

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Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed large-scale drug screens in C. elegans which uncovered 74 hits. Targeted testing in zebrafish yielded positive results for two p38 inhibitors. Using mouse myotubes, we found that either pharmacological inhibition or siRNA silencing of p38 impaired caffeine-induced Ca2+ release from wild type cells while promoting intracellular Ca2+ release in Ryr1 knockout cells. Lastly, we demonstrated that p38 inhibition blunts the aberrant temperature-dependent increase in resting Ca2+ in myotubes from an RYR1-RM mouse model. This unique platform for RYR1-RM therapy development is potentially applicable to a broad range of neuromuscular disorders.

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Atypical periodic paralysis and myalgia

Cited by 40 publications

References 23 publications

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

Cored in the act: the use of models to understand core myopathies

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

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