Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

Abstract

Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core–rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.

Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

“…Exposure to o,p 0 -DDE did not only sensitize myotubes to electrical stimulation, but it also produced abnormal patterns in fatigability. Currently, numerous RyR1 congenital myopathies, that typically confer a gain-of-function, have been identified (Lawal et al, 2018;Witherspoon and Meilleur, 2016), and they are well known to cause clinical neuromuscular issues. DDx has also been shown to impair myogenesis doseand time-dependently (Kim et al, 2017), and this in combination with its ability to modulate RyR1 activity to cause Ca 2þ dysregulation in muscle cells can lead to exacerbation of muscle impairments in not only populations with RyR1 congenital myopathies, but also in healthy individuals.…”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…RYR1 mutations cause a wide spectrum of dominant and recessive myopathies [32]. RYR1related myopathies are usually classified in several histological subtypes, including central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy and congenital fiber-type disproportion [33][34][35][36][37].…”

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

“…Previous work using these models identified potential therapeutic targets for RYR1-RM (for a comprehensive review, see Lawal et al, 2018) including anti-oxidants (Durham et al, 2008;Dowling et al, 2012;Michelucci et al, 2017), ER stress modulators (Lee et al, 2017), and chemicals that influence the binding of RyR1 to modifying partners (e.g. S107, which promotes RyR1/calstabin1 interaction) (Lehnart et al, 2008;Bellinger et al, 2008;Andersson et al, 2011).…”