Gene Panel Sequencing Identifies a Novel RYR1 p.Ser2300Pro Variant as Candidate for Malignant Hyperthermia with Multi-Minicore Myopathy.

Malignant hyperthermia (MH), a rare autosomal dominant pharmacogenetic disorder of skeletal muscle calcium regulation, is triggered by sevoflurane in susceptible individuals. We report a Korean having MH with multi-minicore myopathy functionally supported by RYR1-mediated intracellular Ca2+ release testing in B lymphocytes. A 14-year-old boy was admitted for the evaluation of progressive torticollis accompanied by cervicothoracic scoliosis. During the preoperative drape of the patient for the release of the sternocleidomastoid muscle under general anesthesia, his wrist and ankle were observed to have severe flexion contracture. The body temperature was 37.1 °C. To treat MH, the patient was administered a bolus of dantrolene intravenously (1.5 mg/kg) and sodium bicarbonate. After a few minutes, muscle rigidity, tachycardia, and EtCO2 all resolved. Next-generation panel sequencing for hereditary myopathy identified a novel RYR1 heterozygous missense variant (NM_000540.2: c.6898T > C; p.Ser2300Pro), which mapped to the MH2 domain of the protein, a hot spot for MH mutations. Ex vivo RYR1-mediated intracellular Ca2+ release testing in B lymphocytes showed hypersensitive Ca2+ responses to isoflurane and caffeine, resulting in an abnormal Ca2+ release only in the proband, not in his family members. Our findings expand the clinical and pathological spectra of information associated with MH with multi-minicore myopathy.

Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM.

Ryanodine Receptors (RyRs) are massive channels that release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological 'intermediate' conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions.

Magnesium sulfate - An effective agent could delay the progression of fulminant malignant hyperthermia.

Malignant hyperthermia (MH) is a life-threatening disease that occurs during general anaesthesia following exposure to succinylcholine (SCh), a depolarizing muscle relaxant, and volatile anaesthetics. Susceptibility to MH most commonly arises from mutations in the RyR1 gene, the Ca2+ release channel of skeletal muscle. Fulminant MH (f-MH) is the most dangerous form of MH, which presents a hypermetabolic cascade state, including very high temperature and carbon dioxide production, increased heart rate and oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis. Dantrolene is the only specific drug therapy for MH on the market. Without dantrolene, the reported mortality of f-MH is as high as 42.3%. Based on the participation of catecholamine in the hyperhaemodynamic response of f-MH and the demonstrated effective control of catecholamine release of magnesium sulfate, combined with the fact that magnesium and calcium have opposite effects on muscle contraction, I hypothesized that magnesium sulfate could be a choice for delaying the progression of f-MH while waiting for dantrolene treatment.

Junctional membrane Ca2+ dynamics in human muscle fibers are altered by malignant hyperthermia causative RyR mutation.

We used the nanometer-wide tubules of the transverse tubular (t)-system of human skeletal muscle fibers as sensitive sensors for the quantitative monitoring of the Ca2+-handling properties in the narrow junctional cytoplasmic space sandwiched between the tubular membrane and the sarcoplasmic reticulum cisternae in single muscle fibers. The t-system sealed with a Ca2+-sensitive dye trapped in it is sensitive to changes in ryanodine receptor (RyR) Ca2+ leak, the store operated calcium entry flux, plasma membrane Ca pump, and sodium-calcium exchanger activities, thus making the sealed t-system a nanodomain Ca2+ sensor of Ca2+ dynamics in the junctional space. The sensor was used to assess the basal Ca2+-handling properties of human muscle fibers obtained by needle biopsy from control subjects and from people with a malignant hyperthermia (MH) causative RyR variant. Using this approach we show that the muscle fibers from MH-susceptible individuals display leakier RyRs and a greater capacity to extrude Ca2+ across the t-system membrane compared with fibers from controls. This study provides a quantitative way to assess the effect of RyR variants on junctional membrane Ca2+ handling under defined ionic conditions.

Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.

In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type-1 (RYR1Y522S/WT) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca2+ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1Y522S/WT and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1Y522S/WT and CASQ1-null mice, respectively, vs. 0% in wild-type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1Y522S/WT and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca2+-dependent activation of calpains and NF-κB by lowering myoplasmic Ca2+ concentration and nitro-oxidative stress, parameters that were elevated in RYR1Y522S/WT and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.-Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.

Dantrolene requires Mg2+ to arrest malignant hyperthermia.

Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca2+ transients elicited by MH triggers are unknown. Here, we show that Ca2+ release in the absence of Mg2+ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg2+] (free [Mg2+]cyto) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca2+ waves in the presence of resting levels of free [Mg2+]cyto (1 mM). However, an increase of free [Mg2+]cyto to 1.5 mM could increase the period between Ca2+ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg2+ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg2+ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.

Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy.

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.

Effect of caffeine on intrinsic mechanical properties of normal and malignant hyperthermia-susceptible muscle.

INTRODUCTION: Malignant hyperthermia (MH) is a potentially lethal anesthesic complication. Pathological symptoms develop after exposure to triggering substances. It remains uncertain whether cellular alterations pre-exist. Mechanical properties of isolated muscle bundles were examined before and after exposure to a triggering substance. METHODS: With prior written consent, muscle bundles of 12 MH-susceptible (MHS) and 56 MH-nonsusceptible (MHN) individuals were examined before and after exposure to incremental doses of caffeine. Mechanical properties (baseline tension, peak tension, time to peak tension, and relaxation time) were measured. Contraction and relaxation derivatives and contraction-relaxation coupling were calculated and analyzed. RESULTS: Mechanical properties were not different between the groups before caffeine application. Caffeine increased peak tension in both groups and baseline tension only in MHS muscle bundles; relaxation time/derivative and contraction-relaxation coupling were prolonged. CONCLUSIONS: Cellular changes seen in MH are not pre-existing. Exposure to triggering substance impairs relaxation in MHS muscle.

The effect of succinylcholine on malignant hyperthermia events in susceptible swine.

BACKGROUND: While the impact of volatile anaesthetics to induce malignant hyperthermia (MH) is abundantly clear, the role of succinylcholine still remains controversial. To evaluate the influence of succinylcholine on porcine MH events, the authors investigated the hemodynamic and metabolic responses in MH susceptible (MHS) and non-susceptible (MHN) swine following either succinylcholine or halothane application alone or a combination of both substances. METHODS: With approval of the local animal care committee 27 MHS and 30 MHN pigs were anaesthetized and mechanically ventilated. Fiberoptic probes for continuous PCO2 measurement were inserted into the femoral vein and the triceps muscle. Group A received succinylcholine 4 mg/kg, group B incremental doses of halothane (0.5, 1.0 vol%) and group C succinylcholine and halothane simultaneously. Vital signs were recorded continuously. RESULTS: Prior to drug application measured values did not differ between MHS and MHN. While MHN pigs did not show relevant alterations, succinylcholine, halothane and the combination of both lead to significant hemodynamic and metabolic changes in MHS swine. CONCLUSIONS: Hemodynamic and metabolic alterations following succinylcholine were similar to halothane in MHS pigs. The combination of both pharmacological agents potentiated the observed effects. According to these results succinylcholine acted as an independent and supportive factor during onset of an MH episode.

Exercise-induced rhabdomyolysis and stress-induced malignant hyperthermia events, association with malignant hyperthermia susceptibility, and RYR1 gene sequence variations.

Exertional rhabdomyolysis (ER) and stress-induced malignant hyperthermia (MH) events are syndromes that primarily afflict military recruits in basic training and athletes. Events similar to those occurring in ER and in stress-induced MH events are triggered after exposure to anesthetic agents in MH-susceptible (MHS) patients. MH is an autosomal dominant hypermetabolic condition that occurs in genetically predisposed subjects during general anesthesia, induced by commonly used volatile anesthetics and/or the neuromuscular blocking agent succinylcholine. Triggering agents cause an altered intracellular calcium regulation. Mutations in RYR1 gene have been found in about 70% of MH families. The RYR1 gene encodes the skeletal muscle calcium release channel of the sarcoplasmic reticulum, commonly known as ryanodine receptor type 1 (RYR1). The present work reviews the documented cases of ER or of stress-induced MH events in which RYR1 sequence variations, associated or possibly associated to MHS status, have been identified.

Basal bioenergetic abnormalities in skeletal muscle from ryanodine receptor malignant hyperthermia-susceptible R163C knock-in mice.

Malignant hyperthermia (MH) and central core disease in humans have been associated with mutations in the skeletal ryanodine receptor (RyR1). Heterozygous mice expressing the human MH/central core disease RyR1 R163C mutation exhibit MH when exposed to halothane or heat stress. Considering that many MH symptoms resemble those that could ensue from a mitochondrial dysfunction (e.g. metabolic acidosis and hyperthermia) and that MH-susceptible mice or humans have a higher than normal cytoplasmic Ca(2+) concentration at rest, we evaluated the role of mitochondria in skeletal muscle from R163C compared with wild type mice under basal (untriggered) conditions. R163C skeletal muscle exhibited a significant increase in matrix Ca(2+), increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number. These changes, in conjunction with lower myoglobin and glycogen contents, Myh4 and GAPDH transcript levels, GAPDH activity, and lower glucose utilization suggested a switch to a compromised bioenergetic state characterized by both low oxidative phosphorylation and glycolysis. The shift in bioenergetic state was accompanied by a dysregulation of Ca(2+)-responsive signaling pathways regulated by calcineurin and ERK1/2. Chronically elevated resting Ca(2+) in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like phenotype as part of a metabolic adaptation to the R163C RyR1 mutation.

Ryanodine receptor type 1 (RyR1) possessing malignant hyperthermia mutation R615C exhibits heightened sensitivity to dysregulation by non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95).

Malignant hyperthermia (MH) susceptibility is conferred by inheriting one of >60 missense mutations within the highly regulated microsomal Ca(2+) channel known as ryanodine receptor type 1 (RyR1). Although MH susceptible patients lack overt clinical signs, a potentially lethal MH syndrome can be triggered by exposure to halogenated alkane anesthetics. This study compares how non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95), a congener identified in environmental and human samples, alters the binding properties of [(3)H]ryanodine to RyR1 in vitro. Junctional sarcoplasmic reticulum (SR) was isolated from skeletal muscle dissected from wild type pigs ((Wt)RyR1) and pigs homozygous for MH mutation R615C ((MH)RyR1), a mutation also found in humans. Although the level of (Wt)RyR1 and (MH)RyR1 expression is the same, (MH)RyR1 shows heightened sensitivity to activation and altered regulation by physiological cations. We report here that (MH)RyR1 shows more pronounced activation by Ca(2+), and is less sensitive to channel inhibition by Ca(2+) and Mg(2+), compared to (Wt)RyR1. In a buffer containing 100nM free Ca(2+), conditions typically found in resting cells, PCB 95 (50-1000nM) enhances the activity of (MH)RyR1 whereas it has no detectable effect on (Wt)RyR1. PCB 95 (2microM) decreases channel inhibition by Mg(2+) to a greater extent in (MH)RyR1 (IC(50) increased nine-fold) compared to (Wt)RyR1 (IC(50) increased by 2.5-fold). PCB95 reduces inhibition by Ca(2+) two-fold more with (MH)RyR1 than (Wt)RyR1. Our data suggest that non-coplanar PCBs are more potent and efficacious toward (MH)RyR1 than (Wt)RyR1, and have more profound effects on its cation regulation. Considering the important roles of Ca(2+) and Mg(2+) in regulating Ca(2+) signals involving RyR channels, these data provide the first mechanistic evidence that a genetic mutation known to confer susceptibility to pharmacological agents also enhances sensitivity to an environmental contaminant.

Malignant hyperthermia: a pharmacogenetic disease of Ca++ regulating proteins.

Malignant hyperthermia (MH) is a pharmacogenetic, life-threatening hypermetabolic syndrome in genetically predisposed individuals exposed to certain anesthetic agents. Discovered by Denborough and Lovell [1] in 1960, MH was associated with high mortality and morbidity as the cause was unknown and an effective treatment was unavailable. There is no classic clinical presentation of the syndrome, and the onset and signs of MH are dependent upon known and unknown environmental and genetic factors. Initial theories involved central temperature regulation defects or uncoupling of oxidative phosphorylation in mitochondria [2], but later investigations targeted skeletal muscle as the affected organ. Subsequently freshly biopsied skeletal muscle was used for in vitro pharmacologic contracture testing to discriminate between normal and MH-affected muscle and remains the "gold standard" for MH diagnosis. Spontaneous, genetic models for MH were discovered in pigs and dogs and substantial knowledge about MH was gained from these valuable resources. The abnormal contracture response of MH skeletal muscle evoked a focus on calcium regulation, and abnormalities in calcium release (as opposed to calcium sequestration) mechanisms were discovered. About this same time the major calcium release channel in the skeletal muscle sarcoplasmic reticulum membrane was purified and named the ryanodine receptor [3]. Although the ryanodine receptor represents one of the largest functional proteins, the enormous gene encoding the 5021 amino acids comprising the ryanodine receptor subunit was eventually cloned [4,5]. Patient and dedicated work on the ryanodine receptor gene has found linkage to MH in the pig [6], dog [7], and among several different mutations and MH in unrelated human families [8,9]. Expression of these mutations in HEK cells has resulted in abnormal calcium release [10,11], supporting but not proving a causal basis for MH. In this review each of the areas mentioned above is discussed in detail revealing a wonderful success story that changed the anesthesiologist's "worst nightmare" from a syndrome with high mortality and morbidity to a reasonably well managed disease today. This success story includes unraveling the molecular basis for the disease and brings its pathoetiologic and diagnostic aspects toward molecular genetic resolution.

Malignant hyperthermia and excitation-contraction coupling.

Malignant hyperthermia (MH) is a state of elevated skeletal muscle metabolism that may occur during general anaesthesia in genetically pre-disposed individuals. Malignant hyperthermia results from altered control of sarcoplasmic reticulum (SR) Ca2+ release. Mutations have been identified in MH-susceptible (MHS) individuals in two key proteins of excitation-contraction (EC) coupling, the Ca2+ release channel of the SR, ryanodine receptor type 1 (RyR1) and the alpha1-subunit of the dihydropyridine receptor (DHPR, L-type Ca2+ channel). During EC coupling, the DHPR senses the plasma membrane depolarization and transmits the information to the ryanodine receptor (RyR). As a consequence, Ca2+ is released from the terminal cisternae of the SR. One of the human MH-mutations of RyR1 (Arg614Cys) is also found at the homologous location in the RyR of swine (Arg615Cys). This animal model permits the investigation of physiological consequences of the homozygously expressed mutant release channel. Of particular interest is the question of whether voltage-controlled release of Ca2+ is altered by MH-mutations in the absence of MH-triggering substances. This question has recently been addressed in this laboratory by studying Ca2+ release under voltage clamp conditions in both isolated human skeletal muscle fibres and porcine myotubes.

Pharmacological distinction between dantrolene and ryanodine binding sites: evidence from normal and malignant hyperthermia-susceptible porcine skeletal muscle.

Dantrolene inhibits and ryanodine stimulates calcium release from skeletal-muscle sarcoplasmic reticulum (SR), the former by an unknown mechanism, and the latter by activating the ryanodine receptor (RyR), the primary Ca2+-release channel of SR. Dantrolene is used to treat malignant hyperthermia (MH), a genetic predisposition to excessive intracellular Ca2+ release upon exposure to volatile anaesthetics. Porcine MH results from a point mutation in the SR RyR that alters the open probability of the channel, and is reflected in altered [3H]ryanodine binding parameters. Specific binding sites for [3H]dantrolene and [3H]ryanodine co-distribute on SR that has been isolated by discontinuous sucrose gradient centrifugation. If the two drug-binding sites are functionally linked, [3H]dantrolene binding might be affected both by pharmacological and by genetic modulators of the functional state of the RyR. Accordingly, we compared the characteristics of [3H]dantrolene binding to porcine malignant-hyperthermia-susceptible and normal-skeletal-muscle SR, and examined the effects of RyR modulators on [3H]dantrolene binding to these membranes. Additionally, the feasibility of separating the SR binding sites for [3H]dantrolene and [3H]ryanodine was investigated. No significant differences in [3H]dantrolene binding characteristics to SR membranes from the two muscle types were detected, and the Bmax ratio for [3H]dantrolene/[3H]ryanodine was 1.4(+/-0.1):1 in both muscle types. [3H]Dantrolene binding is unaffected by the RyR modulators caffeine, ryanodine, Ruthenium Red and calmodulin, and neither dantrolene nor azumolene have any effect on [3H]ryanodine binding. Additionally, distinct peaks of [3H]dantrolene and [3H]ryanodine binding are detected in SR membranes fractionated by linear sucrose centrifugation, although no differences in protein patterns are detected by SDS/PAGE or Western-blot analysis. We suggest that the binding sites for these two drugs are pharmacologically distinct, and may exist on separate molecules.

Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects.

Malignant hyperthermia (MH) is a disorder of skeletal muscle in which certain anesthetic agents trigger a sustained elevation in myoplasmic Ca2+ concentration that activates metabolic and contractile activity. This review focuses on the biochemical and physiological alterations in the skeletal muscle of MH-susceptible (MHS) pigs and humans that appear responsible for this inherited disorder. In porcine MH, these studies identified the skeletal muscle sarcoplasmic reticulum Ca2+ release channel gene (RYR1) as the site of the defect. A mutation in this protein results in altered excitation-contraction coupling and secondary changes in porcine muscle structure and function. Although RYR1 mutations have been reported in many MHS human families, there is also significant genetic heterogeneity, and much less is known as to the underlying mechanism responsible for altered human myoplasmic Ca2+ regulation. The effects of caffeine and anesthetic agents on MHS and normal muscle are also discussed to better understand the basis for the in vitro clinical test for this disorder and mechanisms responsible for the initiation and maintenance of MH episodes in susceptible individuals. Finally, we examine the possiblity of a defect in Ca2+ regulation in tissues other than skeletal muscle. Current understanding of the molecular basis of MH elegantly illustrates the successful integration of knowledge obtained from all fields of biological and clinical science.

Masseter muscle rigidity and malignant hyperthermia susceptibility in pediatric patients. An update on management and diagnosis.

BACKGROUND: Controversy exists regarding the definition of masseter muscle rigidity (MMR) and anesthetic management after MMR. This study reports current anesthetic management after MMR, estimates the incidence of clinical malignant hyperthermia (MH) in patients with MMR, and is the first to evaluate the coincidence of MMR with malignant hyperthermia susceptibility (MHS) according to the 1987 North American Malignant Hyperthermia Group protocol. METHODS: Practicing anesthesiologists referred pediatric patients for biopsy between 1986 and 1991 based on evidence of MMR after succinylcholine (1975-1991). The clinical scenario was described as MMR alone or MMR followed by signs of MH, including arterial CO2 tension > 50 mmHg, arterial pH < or = 7.25, and base deficit > 8. Patients had caffeine-halothane muscle contracture testing to determine MHS. RESULTS: Seventy patients (50 boys and 20 girls) were evaluated. Eighty-three percent (58 of 70) of anesthetics were halothane-succinylcholine. In 68% (48 of 70) of cases, the anesthetic was discontinued, whereas anesthesia was continued with nontriggering agents in 11% (8 of 70) and with triggering agents in 13% (9 of 70). Fifty-nine percent (41 of 70) of patients were diagnosed as MHS by muscle biopsy. In 7% (5 of 70) of patients, clinical MH developed within 10 min of MMR. CONCLUSIONS: This study, by using the current North American Malignant Hyperthermia Group protocol, reaffirms the high incidence (59%, 41 of 70) of MHS associated with MMR as confirmed by muscle biopsy. Of the MHS patients, 5 developed signs of clinical MH. Most anesthesiologists in this study, when confronted with MMR, discontinued anesthesia. Because of the potential lethality of MH and the > 50% concordance between MMR and MHS, the most conservative course of action after MMR is to discontinue the anesthetic and observe the patient for clinical evidence of MH. An acceptable alternative, depending on the urgency of the surgery, would be to continue anesthesia with nontriggering agents for MH, with appropriate monitoring.

Chronic myopathy in a patient suspected of carrying two malignant hyperthermia susceptibility (MHS) mutations.

Malignant hyperthermia (MH) is a pharmacogenetic myopathy triggered by a variety of anaesthetic agents and muscle relaxants. In humans, susceptibility to MH is inherited as an autosomal dominant trait, and susceptible patients do not show a clinically relevant myopathy unless having suffered from a MH crisis. Homozygosity for the MHS trait is thought to be an uncommon finding, and so far only a few cases of patients suggested to be homozygous for MH on the basis of pedigree information were reported and described as having a more severe form of this condition resulting in clinical symptoms also in the absence of triggering agents. We report clinical findings in a patient with chronic myopathy beginning at the age of 2 yr and associated with a number of unique features, the most important being a family history of MHS present in both parents. She became symptomatic with marked muscular weakness and elevated serum CK levels. A muscle biopsy showed a distinct enlargement and increase of muscle mitochondria. In the in vitro contracture test the patient's muscle responded with unusually high contractures already at basal levels of triggering agents indicating a particularly severe MHS condition. DNA markers for the MHS1 locus, described previously on chromosome 19q12-13.2 in Irish and Canadian pedigrees, could not be used to confirm her homozygous state because our molecular genetic studies had previously excluded the MHS trait in this pedigree from this locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of otolaryngic patients susceptible to malignant hyperthermia without dantrolene.

Malignant hyperthermia (MH) is an adverse reaction most frequently associated with the administration of halogenated inhalational anesthetic agents and the depolarizing muscle relaxant succinylcholine. Characteristic findings are a hypermetabolic state accompanied by extreme hyperpyrexia, acidosis, rhabdomyolysis, and generalized muscle rigidity, often involving the masseter muscles. Dantrolene sodium, which was approved in 1979 by the FDA for use in the prevention of MH in high-risk patients, has neurologic and gastrointestinal side effects. At the Children's National Medical Center (CNMC), 24 children identified as being at risk for the development of a MH reaction were anesthetized for otolaryngic procedures by using "non-triggering" anesthetics and without use of dantrolene sodium. These patients represent 56% of all patients at risk for MH or masseter muscle rigidity (MMR) reactions during an 8-year period at the CNMC. There were no complications. Concomitant muscle biopsies were performed, and caffeine/halothane contracture studies were completed in 18 of these patients, demonstrating 11 susceptible or equivocal responses. The data suggest that children undergoing common otolaryngic procedures who are at risk for development of MH may be safely anesthetized without the use of prophylactic dantrolene sodium.

Clinical and muscle biopsy findings in malignant hyperthermia susceptibility.

Patients (155) were investigated for malignant hyperthermia susceptibility (MHS), by in vitro testing of muscle taken from the vastus medialis muscle. Histopathological and histochemical investigation of muscle was also performed. Ultrastructural investigation was performed in 13 MHS patients; 90% of the patients replied to a questionnaire concerning present or previous neuromuscular symptoms. The majority of MHS and MH negative (MHN) patients had no or only minor histopathological and histochemical abnormalities. Core-targetoid fibres were the only potentially important abnormalities found in MHS patients. There were no differences in neuromuscular symptoms between MHS, MHN and control patients, and most patients in both the MHS and MHN group were normal on clinical examination.