Malignant hyperthermia susceptibility (MHS) is a subclinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. While in vitro contracture testing (IVCT) is the gold standard for defining MHS, molecular analysis is increasingly used to diagnosis MHS. Mutations associated with MHS have been reported in two genes: RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here the results of correlation studies performed with molecular, pharmacological, histological, and functional data obtained in 175 families (referred to as confirmed (129) or potential (46) MHS families). Extensive molecular analysis allowed us to identify a variant in 60% of the confirmed MHS families, and resulted in the characterization of 11 new variants in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed us to assign a causative role for seven MHS mutations that we propose to add to the panel of MHS mutations used for genetic testing. The use of genetic data to determine MHS status led to a 99.5% sensitivity for IVCT. IVCT-positive/mutation-negative diagnoses were analyzed not only in terms of specificity for IVCT, but also to assess the presence of a second MHS trait in families, and the genetic heterogeneity of the disease. Histological analyses revealed the presence of cores in more than 20% of muscle biopsies originating from 242 genotyped and tested MHS patients who did not present with clinical symptoms. This indicates that these patients must be considered as MHS patients with cores, and are clearly differentiated from CCD patients who have been tested positive for MHS.

Purpose Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population. Methods In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families. Results Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations. Conclusions The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing. RésuméObjectif L'hyperthermie maligne (HM) est une maladie pharmacoge´ne´tique he´re´ditaire dominante autosomique qui se manifeste lors de l'exposition des personnes susceptibles a`des anesthe´siques haloge´ne´s ou à la succinylcholine. E´tant donne´que l'HM est principalement associe´e aux mutations au niveau du ge`ne des re´cepteurs de ryanodine de type 1 (RYR1), l'objectif de cette e´tude e´tait de de´terminer la distribution et la fre´quence des mutations RyR1 causant une HM chez la population canadienne susceptible a`l'HM (SHM). Méthode Dans cette e´tude, nous avons examine´une cohorte repre´sentative de 36 personnes canadiennes SHM This article is accompanied by an editorial. Please see Can J Anesth 2011; 58: 6.

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Because there are no differences in RYR1 transcript structure between muscle and leukocytes, aside from those that may be ascribed to RNA splicing aberrations during processing, leukocytes seem to be an adequate substitute tissue for screening the RYR1 gene for previously undiscovered mutations in families with malignant hyperthermia or central core disease.

Application of a protein kinase C inhibitor, H7 (10, 30 and 100 JAM) or calphostin C (1 JiM), reduced the high K+ contraction but not that caused by an equi-osmolar concentration of mannitol. 6 The data suggest that hypertonic K+-induced contraction differs from that caused by hypertonicity or depolarization per se and invokes membrane enzyme activation.

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PURPOSE: To report a genotype-phenotype association between the presence of two novel mutations in the Calcium Release Channel gene, RYR1, in a patient with a history of both anaesthetic related malignant hyperthermia and frequent episodes of muscular rigidity in the absence of any anaesthetic. CLINICAL FEATURES: An 18 year old patient was referred for assessment with a past history of masseter muscle rigidity (MMR) during inguinal herniorraphy at the age of 6 years. Postoperative Creatine Kinase (CK) rose to 5362 IU/L, but there was no associated fever, metabolic nor respiratory acidosis. At that time, the patient had not reached minimum weight criteria for muscle biopsy testing. At the age of 15 years the patient experienced episodes of generalized body rigidity, producing dyspnoea associated with chest rigidity, and painful calf spasms. Up to 100 episodes were reported by the patient to have occurred over a 3 year period, and though not associated with any anaesthetic, were apparently associated with hot weather and emotional stress, such as awaiting injection for vaccination. Resting CK levels were normal. EMG and EEG examinations were unable to distinguish between seizures and psuedoseizures, so the patient was placed on antiepileptic therapy (valproate and lamotrigene) by a specialist neurologist. At the age of 18 years, the patient submitted to skeletal muscle biopsy. Caffeine-halothane contracture testing (CHCT) showed a 2.6 gram weight contracture response to 2mM caffeine [Normal < 0.3 gm wt]; and 6.8 gram weight contracture response to 3% halothane [Normal < 0.5 gm wt]. The CHCT result was interpreted as Malignant Hyperthermia Susceptibility. Histopathology confirmed normal skeletal muscle architecture, and failed to demonstrate central cores. Following institutional REB approval and individual informed consent for genetic study and scientific publication, DNA and RNA were isolated from muscle and blood samples of the patient and RYR1 transcript was analyzed following an established method