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.

Keywords: 4PBA; Central core disease; Myopathies; N-acetylcysteine; RYR1; Rycal; Salbutamol; Therapeutics.

Fig. 1

Schematic diagram of the typical pattern in RYR1-related myopathies. (A) In the thighs, the rectus femoris (RF), adductor longus (AL), and gracilis (G) are spared and in some patients hypertrophied; the adductor magnus (AM), sartorius (S), vastus lateralis (VL), vastus intermedius (VIM), and vastus medialis (VM) are affected; the hamstrings are less affected; and the involvement of semimembranosus (SM) and semitendinosus (ST) is nonspecific. BF = biceps femoris. (B) In the calf, the most affected muscle is the soleus (SO), followed by the gastrocnemius lateralis (GL) and to a lesser effect the gastrocnemius medialis (GM). In the anterior compartment, which is less affected than the posterior, the peroneal group (PG) is more affected than the tibialis anterior (TA). EDL = extensor digitorum longus; FDL = flexor digitorum longus; TP = tibialis posterior. (From: Klein et al., 2011, JAMA Neurology, with permission)

Fig. 2

RyR1 channel in the open and closed state. Purported mechanisms of action of various therapies: salbutamol increases SERCA expression levels to facilitate reuptake of cytosolic Ca²⁺ into the SR lumen; NAC works in the sarcoplasm to reduce levels of mitochondrially derived oxidative stress via restoring redox balance; rycals increase FKBP12 binding to RyR1, which in turn maintains the RyR1 channel in the closed state, reducing Ca²⁺ leak into the sarcoplasm; dantrolene antagonizes the RyR1 channel and thus reduces Ca²⁺ leak; 4PBA reduces ER stress markers/UPR and cytosolic Ca²⁺ levels and reduces calpain activation while increasing SR Ca²⁺ content. (Adapted from Witherspoon and Meilleur, 2017 and https://www.biozentrum.uni-wuerzburg.de/humangenetik/forschung/emeritus/prof-mueller-reible/ with permission from Dr. M. Anetseder and Dr. A. Hoyer, Dept. of Anesthesiology, University of Wuerzburg, Germany)