Carsana A (2017) Statin-Induced Myopathy, RYR1 Gene Sequence Variations and Association with Malignant Hyperthermia Susceptibility. Int J Clin Anesthesiol 5(3): 1074.

Statins (3-hydroxy-3-methylglutaryl coenzyme-A or HMG Co-A reductase inhibitors) are a very established class of drugs for the treatment of hypercholesterolemia. However, 10%-15% of patients report statin-induced miopathy (SIM) [1]; myotoxicity is dose-dependent and resolves after discontinuation of therapy. SIM has a highly variable clinical presentation including muscle fatigability, moderate or strong myalgia with normal or increased creatine kinase (CK) activity, and rarely rhabdomyolysis. Several mechanisms have been proposed to explain SIM, e.g., reduced synthesis of mevalonate and consequently of production of isoprenoids such as coenzyme Q10 and prenylated proteins, reduced function in drug metabolizing or transporting enzymes, and alteration of calcium homeostasis in muscle cells. Genetic factors can predispose to develop SIM. Sequence variants (SVs) in the CoQ2 gene encoding the enzyme polyprenyltransferase involved in the synthesis of coenzyme Q10, in genes encoding the cytochrome P450 enzymes superfamily (CYP2D6 (coumarin 7 hydroxylase), CYP3A4 (glucocorticoid inducible p450) and MDR1 (multidrug resistance 1, ABCB1 transporter) genes), and in the SLCO1B1 gene encoding a membrane-bound sodium-independent organic anion transporter protein (OATP1B1), involved in active cellular influx of many endogenous and xenobiotic compounds, have been proposed to be associated with SIM [2]. One year ago, the Pharmacogenomics Knowledgebase (PharmGKB) published a summary on the RYR1 gene and analyzed the impact of SVs on drug-induced myopathies following inhalation of volatile anesthetics or treatment with statins [3, https://www.pharmgkb. org/gene/PA34896]. The RYR1 gene (OMIM * 180901) encodes the Ca2+ release channel of the sarcoplasmic reticulum in skeletal muscles, also known as ryanodine receptor isoform 1 (RYR1). The RYR1 channel and the voltage-dependent L-type calcium channel Cav1.1 are the two principal channels involved in the excitation-contraction coupling in skeletal muscle. SVs in RYR1 are the primary cause of malignant hyperthermia susceptibility (MHS), an autosomal dominant pharmacogenetic disorder triggered in genetically predisposed subjects by commonly used volatile anesthetics and/or the neuromuscular blocking agent succinylcholine during general anesthesia. Triggering agents cause an altered calcium regulation in muscle cells that result in a hypermetabolic status. A malignant hyperthermia attack, unless immediately recognized and treated, is often fatal. The MHS status can be diagnosed by an in vitro test, based on the differential contractile response of normal and MHS muscles to caffeine and halothane. Protocols for contracture testing of human skeletal muscle have been developed by the European [4], and North American [5]. Malignant Hyperthermia Groups, namely, in vitro contracture test (IVCT) and caffeine halothane contracture test (CHCT), respectively. Moreover, RYR1 SVs associated or possibly associated with MHS status have been identified in patients who experienced exertional or stress-induced rhabdomyolysis [6,7] and in patients with several distinct skeletal muscle disorders [8]. Furthermore, it has been suggested that RYR1 SVs are also involved in the development of SIM [9] associated with the risk of MHS [10-13]. In fact, some patients who exhibited myotoxic effect following statin treatment have been diagnosed with MHS by IVCT [10-12], indicating an alteration of calcium homeostasis induced by statin therapy. Five RYR1 SVs have been identified, each in one SIM case [9,14]. The p.Arg614Cys substitution has already been demonstrated to be causative of MHS (www.emhg.org ), while the other SVs have been already reported in MHS patients or are of uncertain pathogenicity. Moreover, a transgenic mouse model of MHS, harboring the missense mutation Tyr524Ser in the RYR1 channel, exhibited a malignant hyperthermia-like response to simvastatin in a dose-dependent manner [15]. The drug-induced hypermetabolic response detected in this mouse model can explain many clinical symptoms associated with SIM in humans, i.e., muscle fatigue, cramping, CK increase. Therefore, some MHS genotypes were suspected to predispose patients to SIM, with statins unmasking latent RYR1-related myopathy.

The association of SIM with MHS status and with RYR1 SVs indicated that at least a proportion of patients who experienced SIM should be considered as candidates for MHS and non triggering anesthetic agents should be used when necessary u definitive diagnostic IVCT and possibly genetic analysis can be performed.

1. Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011; 10: 373-387.

2. Vrablik M, Zlatohlavek L, Stulc T, Adamkova V, Prusikova M, Schwarzova L, et al. Statin-associated myopathy: from genetic predisposition to clinical management. Physiol Res. 2014; 63: S327-S334.

3. Alvarellos ML, Krauss RM, Wilke RA, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for RYR1. Pharmacogenet Genomics. 2016; 26: 138-144.

4. Ording H, Brancadoro V, Cozzolino S, Ellis FR, Glauber V, Gonano EF, et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta Anaesthesiol Scand. 1997; 41: 955-966.

5. Larach MG. Standardization of the caffeine halothane muscle contracture test. North American Malignant Hyperthermia Group. Anesth Analg. 1989; 69: 511-515.

6. Carsana A. Exercise-induced rhabdomyolysis and stress-induced malignant hyperthermia events, association with malignant hyperthermia susceptibility, and RYR1 gene sequence variations. Scientific World J. 2013a: 531465.

7. Carsana A. Exertional rhabdomyolysis, RYR1 gene sequence variations and association with malignant hyperthermia susceptibility. Int J Clin Anesthesiol. 2013; 1: 1004.

8. Carsana A. RYR1-related myopathies and anesthesiological implications. Int J Clin Anesthesiol. 2014; 2: 1037.

9. Vladutiu GD, Isackson PJ, Kaufman K, Harley JB, Cobb B, Christopher Stine L, et al. Genetic risk for malignant hyperthermia in non anesthesia-induced myopathies. Mol Genet Metab. 2011; 104: 167- 173.

10. Guis S, Bendahan D, Kozak-Ribbens G, Figarella-Branger D, Mattei JP, Pellissier JF, et al. Rhabdomyolysis and myalgia associated with anticholesterolemic treatment as potential signs of malignant hyperthermia susceptibility. Arthritis Rheum. 2003; 49: 237-238.

11. Krivosic-Horber R, Dépret T, Wagner JM, Maurage CA. Malignant hyperthermia susceptibility revealed by increased serum creatine kinase concentrations during statin treatment. Eur J Anaesthesiol. 2004; 21: 572-574.

12. Guis S, Figarella-Branger D, Mattei JP, Nicoli F, Le Fur Y, Kozak Ribbens G, et al. In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects. Arthritis Rheum. 2006; 55: 551-557.

13. Hedenmalm K, Granberg AG, Dahl M. Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-based case-control study including 1st and 2nd degree relatives. Eur J Clin Pharmacol. 2015; 71: 117-124.

14. Snoeck M, van Engelen BG, Küsters B, Lammens M, Meijer R, Molenaar JP, et al. RYR1-related myopathies: a wide spectrum of phenotypes throughout life. Eur J Neurol. 2015; 22: 1094-1112.

15. Knoblauch M, Dagnino-Acosta A, Hamilton SL. Mice with RyR1 mutation (Y524S) undergo hypermetabolic response to simvastatin. Skelet Muscle. 2013; 3: 22.