Combining cryoEM and x-ray crystal structure analyses can model effects of N-terminal disease mutations on RyR1 function and mechanisms of RYR1-related diseases, thereby clarifying mechanisms by which disease-causing mutations act to alter RyR1 function.
Parallels can be drawn between mechanisms by which RYR1 and RYR2 disease mutations alter excitation-contraction coupling that lead to diseases in skeletal muscle (MH) and cardiac muscle (CPVT).
Increasingly, the RYR1 gene mutations are implicated in various inherited myopathies, statin-induced myopathy, and heat/exercise-induced rhabdomyolysis.
Clarification of which RYR1-related myopathies predispose to MH is necessary.
Identification of genes other than RYR1 and CACNA1S that are involved in MH is required before comprehensive genetic testing for MH is possible.
The metabolic basis of MH needs to be understood.
More work needs to be done to clarify which RYR1-related myopathies predispose to MH
The diagnostic algorithm for MH was reviewed, with a focus on the characteristics of the clinical presentation, IVCT/CHCT, and genetic testing.
MH therapeutic options are expanding including a new formulation of dantrolene and the possible utility of newer drugs such as AICAR and carvedilol derivatives.
A diagnostic algorithm for myopathic patients was presented.
The continued evolution of genetic databases will be instrumental in advancing improved understanding of the genotype/phenotype relation in MH.
Next-generation sequencing has the potential to identify new MH-causative genes, improve the sensitivity and efficiency of MH genetic testing, and will be instrumental in a more accurate assessment of the MH susceptibility prevalence within the general population.
