World Journal of Emergency Medicine, 2024, 15(1): 70-72 doi: 10.5847/wjem.j.1920-8642.2024.006

Case Letter

Recurrent malignant hyperthermia after scoliosis correction surgery

Junfeng Su1,2, Man Huang,1,2

1Department of General Intensive Care Unit, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310052, China

2Key Laboratory of Early Warning and Intervention of Multiple Organ Failure, Ministry of Education of the People's Republic of China, Hangzhou 310052, China

Corresponding authors: Man Huang, Email:huangman@zju.edu.cn

Received: 2023-06-10   Accepted: 2023-10-18  

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Junfeng Su, Man Huang. Recurrent malignant hyperthermia after scoliosis correction surgery. World Journal of Emergency Medicine, 2024, 15(1): 70-72 doi:10.5847/wjem.j.1920-8642.2024.006

Malignant hyperthermia (MH) is a genetic disorder of skeletal muscle cells that affects muscle cytoplasmic calcium homeostasis, with high mortality and low morbidity. Generally, it presents with non-specific signs of a hypermetabolic response, including high fever, tachycardia, and elevated end-tidal carbon dioxide (ETCO2). The successful treatment lies in the timely recognition and early use of dantrolene.[1] As an inhibitor of Ca2+ release through ryanodine receptor (RYR) channels, the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca2+ signaling and a lifesaving treatment for MH.[2] Dominant mutations in the skeletal muscle RYR1 gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD).[3] CCD is an inherited neuromuscular disorder characterized by central cores on muscle biopsy and clinical features of a congenital myopathy. It typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness, especially in the hip girdle.[4] MH phenotypes may be affected significantly by mutation type.[5] Recurrence occurred in 20% of patients surviving a clinical MH episode in the North American Malignant Hyperthermia Registry, and it was not associated with the initial dose of dantrolene.[6]

CASE

A 15-year-old boy (weight 43 kg, body mass index [BMI] 25.95 kg/m2) underwent posterior spinal osteotomy, correction, and fusion fixation for congenital scoliosis. He was otherwise healthy and took no medication routinely. He underwent safe anesthesia for surgical extension of the right Achilles tendon last year. There was no family history of anesthesia side effects, and his father had undergone a safe anesthesia process for posterior spinal osteotomy, correction, and fusion fixation for congenital scoliosis. His preoperative blood pressure was 107/70 mmHg (1 mmHg=0.133 kPa), heart rate was 113 beats/min (sinus rhythm), and body temperature was 36.6 °C. A rapid sequence induction was performed with 10 mg lidocaine, 2 mg midazolam, 30 μg sufentanil, 12 mg etomidate, and 40 mg rocuronium.

Three hours after the beginning of operation, an unexplained and unexpected increase in ETCO2 (maximum 61 mmHg), heart rate (maximum 102 beats/min), and temperature (maximum 39.2 ℃) (supplementary Figure 1) alerted the anesthesiologist to the possibility of MH onset because conventional medication therapy proved ineffective. The patient only showed shivering; neither hemodynamic instability nor severe acidosis occurred on arterial blood gas analysis. Since MH was suspected, the anesthesiologist changed the sodium lime and the anesthesia apparatus, the blood samples were examined for complete blood count, cardiac enzyme panel, coagulation spectrum, electrolyte analysis, and blood gas analysis, and dantrolene was obtained from outside the hospital when the operation had been over for 25 min. Dantrolene 40 mg was given for intravenous injection. After 20 min, the ETCO2 decreased to 38 mmHg, his body temperature dropped to 38.3 ℃, his muscles were relaxed, his vital signs returned to normal, and he was transferred to the intensive care unit (ICU) for further treatment. The patient’s MH clinical grading score (CGS), which indicates a suspected clinical MH event, was 63 (> 50). The likelihood of MH is almost certain.[7]

After ICU admission, his shivering recurred, accompanied by a fever, an increased level of ETCO2, increased creatine kinase (CK), prolonged prothrombin time (PT), increased heart rate and blood pressure, and decreased oxygenation. The dantrolene dose was increased from 40 mg every 6 h to 60 mg every 6 h to improve symptoms during the administration of propofol and midazolam for sedation and sufentanil for analgesia. Cough difficulty and mild limb muscle weakness (upper limb muscle strength level 4, lower limb muscle strength level 3) occurred after the tracheal intubation was removed on the 8th day after the operation.

Until the 10th day, the shivering was relieved, and the dose of dantrolene was reduced to 40 mg every 6 h. On the 11th day after the procedure, his spirit and oxygen improved, without trembling, and the dantrolene injection was stopped. Thus far, the total dantrolene dosage was 2,440 mg (Table 1).

Table 1.   Patient's condition after operation

Date (after operation)Shivering frequencyTmax (℃)ETCO2max
(mmHg)
CKmaxSedationRespiratory supportDantrolene usageDantrolene dose (mg)
D0 (ICU admission)No shivering37.1451,591Propofol+remifentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 100%, PEEP: 5 cmH2O, SpO2 ≥94%40 mg iv. Q6h (1 iv)40
D15 times, continued for 1 min per time37.7436,450Propofol+remifentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 5 cmH2O, SpO2 ≥94%40 mg iv. Q6h (4 iv) & 40 mg bolus200
D25 times, continued for 1 min, 1 min, 2 min, 1 min, and 10 min, respectively39.5548,310Midazolam+remifentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 5 cmH2O, SpO2 ≥94%40 mg iv. Q6h (4 iv)160
D32 times, continued for 10 min, and 30 min, respectively38.5568,060Midazolam+remifentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94%40 mg bolus (2 iv) & 40 mg iv. Q6h (3 iv)200
D44 times, continued for 30 min, 30 min, 30 min, and 50 min, respectively38.0584,210Propofol+midazolam+remifentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94%60 mg iv. Q6h (4 iv) & 60 mg bolus300
D51 time, continued for 15 min38.8553,500Propofol+midazolam+sufentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94%60 mg iv. Q6h (4 iv)240
D64 times, continued for 5 min, 6 min, 5 min, and 5 min, respectively38.6512,700Propofol+midazolam+sufentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94%60 mg iv. Q6h (3 iv) & iv.vp. 10 mg/h for 3 h210
D75 times, continued for 7 min, 20 min, 10 min, 10 min, and 12 min respectively38.9562,700Propofol+midazolam+sufentanil
RASS score: -4 to -2
Mechanical ventilation with FiO2: 40%, PEEP: 8 cmH2O, SpO2 ≥94%iv.vp. 10 mg/h for 7 h & 60 mg iv. Q6h (4 iv)310
D83 times, continued for 12 min, 6 min, and 8 min, respectively38.05312,330Desist from sedationRemoval of endotracheal intubation & high-flow oxygen therapy (flow rate 35 L/min, oxygen concentration 40%, SpO2 ≥94%)60 mg iv. Q6h (4 iv)240
D9Persistent weak shivering for 120 min39.3-12,800-High-flow oxygen therapy (flow rate 35L/min, oxygen concentration 50%-100%, SpO2 ≥94%)60 mg iv. Q6h (4 iv)240
D10Shivering for 10 min, persistent weak shivering for hours38.9-8,020-Sat beside the bed (for rehabilitation exercise) for 30 min in the late morning with nasal catheter oxygen inhalation 5 L /min, SpO2 91%-95%, and continued to tremble in the afternoon, then high-flow oxygen therapy (flow rate 25 L/min, oxygen concentration 50%-55%, SpO2 ≥94%)60 mg iv. Q6h (2 iv) & 40 mg iv. Q6h (2 iv)200
D11No shivering37.7-3,700-Nasal catheter oxygen inhalation 5 L /min, SPO2 ≥94%60 mg bolus & 40 mg bolus then stop dosing100
D12No shivering37.3---Nasal catheter oxygen inhalation 5 L/min, SpO2 ≥94%-0
D13No shivering36.9---Nasal catheter oxygen inhalation 5 L/min, SpO2 ≥94%-0
D14 (left ICU)Weak shivering (head and limbs) improved automatically in a few minutes37.4---Nasal catheter oxygen inhalation 5 L/min, SpO2 ≥94%
Transfered to orthopedic ward
-0
D15-D35No shivering<37.5-D15 (920) D19 (645)Nasal catheter oxygen inhalation 3 L/min, SpO2 ≥94% (D15); no oxygen inhalation (D16-D35)-0

ICU: intensive care unit; ETCO2: end-tidal carbon dioxide; T: temperature; CK: creatine kinase; RASS: Richmond Agitation-Sedation Scale; PEEP: positive end-expiratory pressure; FiO2: fraction of inspiration O2; SpO2: peripheral capillary oxygen saturation; iv: intravenous.

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Genetic detection of his peripheral blood samples during hospitalization showed a heterozygous missense mutation of the RYR1 gene (NM_000540.3): c.7523G > A (p. Arg2508His), exon 47. The same mutation was detected in his father’s peripheral blood samples. Electromyography (EMG) suggested myogenic changes. He was diagnosed with CCD caused by the RYR1 mutation, treated with idebenone, and finally discharged from the hospital on the 35th day of hospitalization without complications. Wang et al[8] reported that the clinical diagnostic scale of MH can provide clues for clinical diagnosis. Caffeine-halothane contracture tests (CHCTs) can also be used to confirm the diagnosis of MH in Chinese individuals, although they have different genetic backgrounds from Westerners. However, the patient and his family refused further testing for CHCT.

DISCUSSION

MH is rare, but the mortality was high until dantrolene was identified as an effective medication. The morbidity is estimated to be between 1/30,000 and 1/10,000 in adults or between 1/250,000 and 1/100,000 in children, depending on location and age, with no difference regarding ethnicity, but men are more common than women. The prevalence of gene mutations ranges from 1/3,000 to 1/2,000, and individuals do not exhibit MH events before administering multiple anesthetics.[9] Dantrolene was synthesized in 1967[10] and initially used for muscle relaxation treatment of skeletal muscle spasms.[11] It has been approved for clinical therapy for MH since animal experiments in the 1970s found that it has a beneficial effect. ETCO2’s universal detection and patient counseling and testing have reduced MH mortality from 80% in the 1960s to less than 5% in the 1970s in European countries and the USA.[9,12] The situation improved until October 2020, when dantrolene for injection, China’s first generic drug, was approved for sale in China.

In contrast, in Wu et al’s study, limb muscle weakness was present in all patients with C-terminal mutations.[13] In this case, the patient, who was detected as having a non-C-terminal mutation, as his father did, was asymptomatic before the surgery but showed cough difficulty and mild limb muscle weakness without muscle atrophy after recurrent MH and using sedation and dantrolene. The recurrence was marked by shivering, increased body temperature, higher ETCO2, and tachycardia (supplementary video), with CGS >4.[7,14] Short et al[14] suggested two possibilities: shivering may indicate the initiation of MH or reactivation of the MH response in association with subtherapy or the absence of dantrolene. We eliminated interference factors, that is, an electroencephalogram showed no seizure activity. A head CT scan excluded hemorrhage or other intracranial etiologies. Thyroid studies were normal. We failed to prevent and stop the recurrence, even though we gave a repeat dose of dantrolene, approximately 1.0-1.4 mg/kg, every 6 h after the first dose according to the drug’s elimination half-life, until two weeks later.[15] However, we are unable to detect its blood concentration and are unsure whether the effective plasma concentration of dantrolene can prevent the recurrence of MH according to this case.

Most individuals susceptible to MH have a defect in the RYR1 gene (MHS1 form) on chromosome 19, which regulates the synthesis of the ryanodine receptor one protein. There are more than 400 mutations associated with this gene, 34 of which are linked to MH.[9] Specific genetic defects that are prone to MH may affect the likelihood of recurrence. Robinson et al[5] reported the influence of specific RYR1 mutations on the severity of the MH phenotype. RYR1 mutations are clustered geographically; this genetic susceptibility to recurrence has implications for the applicability to Asian patients because these findings were based on North American patients.[16] The patient’s MH phenotype in our case may be related to his RYR1 mutations (c.7523G > A). More data will be needed to verify this hypothesis in the future.

CONCLUSIONS

The prompt recognition and proper management of MH are critical in preventing life-threatening complications, with particular attention needed to recurrence. Non-C-terminal mutations (c.7523G >A) may increase the likelihood of recurrence. The relationship between effective plasma concentrations of dantrolene and recurrence is worthy of further exploration.

Funding: None.

Ethical approval: The patient gave his informed consent.

Conflicts of interest: None.

Contributors: All authors contributed significantly to the writing and revision of this manuscript and approved the final version.

All the supplementary files in this paper are available at http://wjem.com.cn.

Reference

Riazi S, Kraeva N, Hopkins PM.

Updated guide for the management of malignant hyperthermia

Can J Anesth. 2018; 65(6):709-21.

DOI:10.1007/s12630-018-1108-0      [Cited within: 1]

Zhao F, Li P, Chen SR, Louis CF, Fruen BR.

Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity

J Biol Chem. 2001; 276(17):13810-6.

DOI:10.1074/jbc.M006104200      PMID:11278295      [Cited within: 1]

As an inhibitor of Ca(2+) release through ryanodine receptor (RYR) channels, the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca(2+) signaling and a lifesaving treatment for the pharmacogenetic disorder malignant hyperthermia. However, the molecular basis and specificity of the actions of dantrolene on RYR channels have remained in question. Here we utilize [(3)H]ryanodine binding to further investigate the actions of dantrolene on the three mammalian RYR isoforms. The inhibition of the pig skeletal muscle RYR1 by dantrolene (10 microm) was associated with a 3-fold increase in the K(d) of [(3)H]ryanodine binding to sarcoplasmic reticulum (SR) vesicles such that dantrolene effectively reversed the 3-fold decrease in the K(d) for [(3)H]ryanodine binding resulting from the malignant hyperthermia RYR1 Arg(615) --> Cys mutation. Dantrolene inhibition of the RYR1 was dependent on the presence of the adenine nucleotide and calmodulin and reflected a selective decrease in the apparent affinity of RYR1 activation sites for Ca(2+) relative to Mg(2+). In contrast to the RYR1 isoform, the cardiac RYR2 isoform was unaffected by dantrolene, both in native cardiac SR vesicles and when heterologously expressed in HEK-293 cells. By comparison, the RYR3 isoform expressed in HEK-293 cells was significantly inhibited by dantrolene, and the extent of RYR3 inhibition was similar to that displayed by the RYR1 in native SR vesicles. Our results thus indicate that both the RYR1 and the RYR3, but not the RYR2, may be targets for dantrolene inhibition in vivo.

Zhou HY, Jungbluth H, Sewry CA, Feng L, Bertini E, Bushby K, et al.

Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies

Brain. 2007; 130(8): 2024-36.

DOI:10.1093/brain/awm096      URL     [Cited within: 1]

Jungbluth H.

Central core disease

Orphanet J Rare Dis. 2007; 2: 25.

PMID:17504518      [Cited within: 1]

Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ, et al.

RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes

Hum Mutat. 2002; 20(2):88-97.

PMID:12124989      [Cited within: 2]

Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH. Mutations in RYR1 (19q13.1), encoding a skeletal muscle calcium release channel (ryanodine receptor), account for the majority of MH and CCD cases. Fifteen RYR1 N-terminal mutations are considered causative of MH susceptibility, five of which are also associated with CCD. In the first extensive UK population survey, eight of 15 mutations were detected in 85 out of 297 (29%) unrelated MH susceptible cases, with G2434R detected in 53 cases (18%). Mutation type was shown to affect significantly MH phenotypes (in vitro contracture test (IVCT) response to caffeine, halothane, and ryanodine). RYR1 mutations associated with both CCD and MH (R163C, R2163H, R2435H) had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the amino terminal (R163C, G341R) had a relatively greater effect on responses to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in seven families (nine individuals), with five false-positives and four false-negatives. This represents the most extensive study of MH patient clinical and genetic data to date and demonstrates that RYR1 mutations involved in CCD are those associated with one end of the spectrum of MH IVCT phenotypes.Copyright 2002 Wiley-Liss, Inc.

Burkman JM, Posner KL, Domino KB.

Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions

Anesthesiology. 2007; 106(5):901-6;quiz1077.

DOI:10.1097/01.anes.0000265148.86566.68      URL     [Cited within: 1]

Some patients develop recrudescence after a malignant hyperthermia (MH) reaction, but it is not clear which patients are at risk. The authors analyzed clinical variables associated with recrudescence after a clinical MH episode.

Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, et al.

A clinical grading scale to predict malignant hyperthermia susceptibility

Anesthesiology. 1994; 80(4):771-9.

DOI:10.1097/00000542-199404000-00008      PMID:8024130      [Cited within: 2]

The diagnosis of an acute malignant hyperthermia reaction by clinical criteria can be difficult because of the nonspecific nature and variable incidence of many of the clinical signs and laboratory findings. Development of a standardized means for estimating the qualitative likelihood of malignant hyperthermia in a given patient without the use of specialized diagnostic testing would be useful for patient management and would promote research into improved means for diagnosing this disease.Using the Delphi method and an international panel of 11 experts on malignant hyperthermia, a multifactor malignant hyperthermia clinical grading scale comprising standardized clinical diagnostic criteria was developed for classification of existing records and for application to new patients.This scale ranks the qualitative likelihood that an adverse anesthetic event represents malignant hyperthermia (malignant hyperthermia event rank) and that, with further investigation of family history, an individual patient will be diagnosed as malignant hyperthermia susceptible (malignant hyperthermia susceptibility rank). The assigned rank represents a lower bound on the likelihood of malignant hyperthermia. The clinical grading scale requires the anesthesiologist to judge whether specific clinical signs are appropriate for the patient's medical condition, anesthetic technique, and surgical procedure.The malignant hyperthermia clinical grading scale is recommended for use as an aid to the objective definition of this disease. It use may improve malignant hyperthermia research by allowing comparisons among well-defined groups of patients. This clinical grading system provides a new and comprehensive clinical case definition for the malignant hyperthermia syndrome.

Wang YL, Luo AL, Tan G, Cui XL, Guo XY.

Clinical features and diagnosis for Chinese cases with malignant hyperthermia: a case cluster from 2005 to 2007

Chin Med J (Engl). 2010; 123(10):1241-5.

[Cited within: 1]

Ellinas H, Albrecht MA.

Malignant hyperthermia update

Anesthesiol Clin. 2020; 38(1):165-81.

DOI:S1932-2275(19)30092-8      PMID:32008650      [Cited within: 3]

Malignant hyperthermia (MH) is a rare but potentially lethal skeletal muscle disorder affecting calcium release channels. It is inherited in a mendelian autosomal dominant pattern with variable penetration. The initial clinical manifestations are of a hypermetabolic state with increased CO2 production, respiratory acidosis, increased temperature, and increased oxygen demands. If diagnosed late, MH progresses to multi-organ system failure and death. Current data suggest that mortality has improved to less than 5%. The gold standard for ruling out MH is the contracture test. Genetic testing is also available. MH-susceptible individuals should be clearly identified for safe administration of future anesthetics.Copyright © 2019 Elsevier Inc. All rights reserved.

Snyder HR, Davis CS, Bickerton RK, Halliday RP.

1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants

J Med Chem. 1967; 10(5):807-10.

PMID:6048486      [Cited within: 1]

Dykes MH.

Evaluation of a muscle relaxant: dantrolene sodium (Dantrium)

JAMA. 1975; 231(8):862-4.

DOI:10.1001/jama.1975.03240200058032      URL     [Cited within: 1]

Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K.

Malignant hyperthermia: a review

Orphanet J Rare Dis. 2015; 10: 93.

DOI:10.1186/s13023-015-0310-1      PMID:26238698      [Cited within: 1]

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The incidence of MH reactions ranges from 1: 10,000 to 1: 250,000 anesthetics. However, the prevalence of the genetic abnormalities may be as great as one in 400 individuals. MH affects humans, certain pig breeds, dogs and horses. The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue. In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive. Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. Less than 1 % of variants have been found in CACNA1S but not all of these are causal. Diagnostic testing involves the in vitro contracture response of biopsied muscle to halothane, caffeine, and in some centres ryanodine and 4-chloro-m-cresol. Elucidation of the genetic changes has led to the introduction of DNA testing for susceptibility to MH. Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered. Increased understanding of the clinical manifestation and pathophysiology of the syndrome, has lead to the mortality decreasing from 80 % thirty years ago to <5 % in 2006.

Wu SW, Ibarra MCA, Malicdan MCV, Murayama K, Ichihara Y, Kikuchi H, et al.

Central core disease is due to RYR1 mutations in more than 90% of patients

Brain. 2006; 129(6):1470-80.

DOI:10.1093/brain/awl077      URL     [Cited within: 1]

Short JA, Cooper CM.

Suspected recurrence of malignant hyperthermia after post-extubation shivering in the intensive care unit, 18 h after tonsillectomy

Br J Anaesth. 1999; 82(6):945-7.

DOI:10.1093/bja/82.6.945      URL     [Cited within: 2]

Harrison GG.

Dantrolene—dynamics and kinetics

Br J Anaesth. 1988; 60(3):279-86.

DOI:10.1093/bja/60.3.279      URL     [Cited within: 1]

Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P.

Mutations in RYR1 in malignant hyperthermia and central core disease

Hum Mutat. 2006; 27(10):977-89.

DOI:10.1002/humu.20356      PMID:16917943      [Cited within: 1]

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.

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