The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation-contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype-phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions.

Mutations in RYR1 in malignant hyperthermia and central core disease.

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1002/cpt.1319

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes

Malignant hyperthermia (MH) is a rare, potentially lethal, clinically and genetically heterogeneous pharmacogenic myopathy, which during or after general anesthesia manifests as MH crisis (MHC) in genetically predisposed, but otherwise mostly normal, individuals (MH susceptibles) in response to anesthetic-triggering agents. MHC can also occur in patients with central core disease. MCH-like crises have been reported in those with Duchenne/Becker muscular dystrophy, myotonic dystrophy, mitochondriopathy, and various other conditions. MH susceptibility is diagnosed if there is an MHC in the individual or family history or by the in vitro caffeine-halothane contracture test. Although screening for mutations in the ryanodine-receptor-1 gene and the dihydropyridine-receptor gene, respectively, could further substantiate the diagnosis, the caffeine-halothane-contracture test still remains the gold standard for diagnosing MH susceptibility. The most well-known triggers of an MHC are depolarizing muscle relaxants and volatile anesthetics. Therapy of an MHC comprises discontinuation of triggering agents, oxygenation, and correction of the acidosis and electrolyte disturbances, treatment of arrhythmias, cooling, and dantrolene. If MH susceptibility is not known preoperatively and an MHC unexpectedly interrupts anesthesia, consultation by a specialist in MH susceptibility after anesthesia is essential to investigate the patient for MH susceptibility or subclinical myopathy, guide laboratory investigations, manage therapy, and counsel the family on further risk. To further reduce morbidity and mortality of those with MHC, anesthesiologists and neurologists should be well educated and should strengthen their clinical vigilance. Research should be intensified and extended with regard to the development of new in vitro tests to further elucidate the heterogeneous genetic background of MH susceptibility.

Current concepts in malignant hyperthermia.

One case of congenital myopathy caused by new mutation of RYR1 gene and literature review.

The human body generates heat capable of raising body temperature by approximately 1°C per hour. Normally, this heat is dissipated by means of a thermoregulatory system. Disorders resulting from abnormally high or low body temperature result in neurologic dysfunction and pose a threat to life. In response to thermal stress, maintenance of normal body temperature is primarily maintained by convection and evaporation. Hyperthermia results from abnormal temperature regulation, leading to extremely elevated body temperature while fever results from a normal thermoregulatory mechanism operating at a higher set point. The former leads to specific clinical syndromes with inability of the thermoregulatory mechanism to maintain a constant body temperature. Heat related illness encompasses heat rash, heat cramps, heat exhaustion and heat stroke, in order of severity. In addition, drugs can induce hyperthermia and produce one of several specific clinical syndromes. Hypothermia is the reduction of body temperature to levels below 35°C from environmental exposure, metabolic disorders, or therapeutic intervention. Management of disorders of body temperature should be carried out decisively and expeditiously, in order to avoid secondary neurologic injury.

Disorders of body temperature

Malignant hyperthermia (MH) is a potentially lethal inherited pharmacogenetic syndrome due to a dysfunction of the intracellular calcium regulation of skeletal muscle following administration of volatile anaesthetics and depolarizing muscle relaxants The ryanodine receptor of skeletal muscle (RYR1), which is an intracellular calcium release channel, has been proposed to be a candidate structure for the MH defect In some families with a history of MH a C1840-T nucleotide exchange has been found in the RYR1 gene which cosegregates with the MH susceptible phenotype

Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family.

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Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family.