Malignant Hyperthermia, Susceptibility To, 1

A number sign (#) is used with this entry because one form of malignant hyperthermia (MHS1) is caused by heterozygous mutation in the ryanodine receptor gene (RYR1; 180901) on chromosome 19q13.

Description

Malignant hyperthermia susceptibility (MHS), a skeletal muscle disorder most often inherited as an autosomal dominant trait, is one of the main causes of death due to anesthesia. In susceptible people, a malignant hyperthermia episode is triggered by exposure to commonly used volatile anesthetic agents such as halothane or depolarizing muscle relaxants such as succinyl choline. A fulminant MH crisis is characterized by any combination of hyperthermia, skeletal muscle rigidity, tachycardia or arrhythmia, respiratory and metabolic acidosis, and rhabdomyolysis. Except for this susceptibility to triggering agents, MHS patients are not clinically distinguishable from the general population (summary by Monnier et al., 1997).

Genetic Heterogeneity of Susceptibility to Malignant Hyperthermia

Other MHS loci include MHS2 (154275) on chromosome 17q; MHS3 (154276) on chromosome 7q; MHS4 (600467) on chromosome 3q; MHS5 (601887), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; and MHS6 (601888) on chromosome 5p.

Clinical Features

Denborough et al. (1962) observed a family in which 11 of 38 persons who had general anesthesia developed explosive hyperthermia and died. The 11 included father-daughter, mother-son, and mother-daughter combinations. Denborough et al. (1970, 1970) found that malignant hyperpyrexia was often associated with hypertonicity of the voluntary muscles and elevation of serum creatine phosphokinase (CPK), phosphate, and potassium, indicating severe muscle damage. Severe lactic acidosis also occurred. The authors suggested that 'leaky' cell membranes were involved. High levels of CPK were found in a patient who had survived malignant pyrexia and in his father, paternal aunt, and sister. Two of the relatives showed mild myopathy affecting mainly the legs. Wilson et al. (1967) noted that this condition is a pharmacogenetic disorder, and suggested that 'uncoupling of oxidative phosphorylation' is the defect.

In patients with malignant hyperpyrexia, King et al. (1972) found elevated levels of serum CPK and clinical findings of a dominantly inherited myopathy. King et al. (1972) referred to the condition as 'Evans myopathy,' which was the name of Denborough's original family which had at least 57 affected persons. King et al. (1972) found hyperpyrexia in a case of the dominant form of myotonia congenita (160800).

In a review, Nelson and Flewellen (1983) stated that half the patients who develop the syndrome have had previous anesthesia without recognized malignant hyperthermia.

Hopkins et al. (1991) suggested that heat stroke is one manifestation of malignant hyperthermia. They tested 2 men in military service who had episodes of exertional heat stroke and their immediate family members for susceptibility to malignant hyperthermia by in vitro contracture tests (IVCT) on skeletal muscle samples. Muscle from both index subjects had a normal response to caffeine, but an abnormal response to halothane. Muscle from the father of 1 patient had an abnormal response to halothane, and that from the father of the second patient had an abnormal response to ryanodine.

Severe rhabdomyolysis is a major clinical feature of anesthetic-induced malignant hyperthermia. Several nonanesthetic triggers of rhabdomyolysis have been described in susceptible persons: severe exercise in hot conditions, neuroleptic drugs, alcohol, and infections. Denborough et al. (1994) reported a patient who developed severe rhabdomyolysis after a viral infection, who was subsequently shown to be susceptible to malignant hyperthermia, and whose father and grandfather appeared to have died from rhabdomyolysis after viral infections. The father of the proband was a healthy 32-year-old man when he developed a flu-like illness in 1989. He developed evidence of rhabdomyolysis with acute renal failure requiring dialysis and severe swelling of both calves, which was intensely painful and associated with ischemic changes. Serum creatine was elevated. Despite fasciotomies of both the calves and thighs, he died 72 hours after admission to hospital. A 4-fold rise in the antibody titer to influenza B virus was demonstrated. The proband, then 13 years old, developed similar symptoms of viral illness associated with aching calves 2 days after his father's illness began. He showed markedly elevated creatine kinase but made a rapid recovery within 2 days. His creatine kinase remained persistently raised and his only sister also had a raised serum creatine kinase. The paternal grandfather of the proband, who had previously been healthy, died at the age of 33 years with renal failure after a similar flu-like illness. Although there was no family history of serious adverse response to anesthesia, in vitro muscle tests carried out on the proband at the age of 17 years showed that he was susceptible to MH. Muscle contracture occurred with both halothane and caffeine.

Denborough et al. (1982) found susceptibility to malignant hyperpyrexia and accompanying muscle abnormalities in 5 of 15 parents whose children had died of sudden infant death syndrome (SIDS). A 28-year-old man, whose son had died of SIDS at age 16 months, had had 3 cardiac arrests after appendectomy at age 19 and his mother had severe hyperpyrexia after hysterectomy. A 26-year-old man, whose daughter died of SIDS at age 4 months, had a sister, aged 12, with a severe myopathy affecting the legs since birth which was diagnosed as arthrogryposis multiplex. A woman, aged 27, whose son died of SIDS at age 10 weeks, had a grandfather who nearly died during anesthesia for arterial graft on his leg at age 55. Denborough et al. (1982) cited reports suggesting that many babies dying of SIDS have a high body temperature and show pathologic changes in the bowel resembling those of heat stroke. Gericke (1991) suggested that hyperthermia and heat shock proteins may have teratogenic effects on collagen during fetal life.

Deufel et al. (1992) reported a patient with chronic myopathy beginning at age 2 years and characterized by marked muscle weakness, elevated serum creatine kinase, and a distinct enlargement and increase of muscle mitochondria on biopsy. The IVCT showed a particularly severe MHS condition. Both parents had MHS, suggesting that the child was homozygous for the disorder. The findings suggested a link between MHS and myopathy.

Eng et al. (1978) observed malignant hyperthermia in a child with autosomal dominant central core muscle disease (CCD; 117000). Islander et al. (1995) presented the results of IVCT on family members of a girl with CCD. Although none of the other family members had a myopathy either clinically or by biopsy, 6 relatives in antecedent generations had either positive or equivocal in vitro contracture tests in a pattern consistent with autosomal dominant transmission of MHS. Islander et al. (1995) suggested that healthy members of families with a proband with CCD could be at risk for being susceptible to malignant hyperthermia even though they themselves do not have central core myopathy. They also suggested that CCD and susceptibility to malignant hyperthermia could be pleiotropic effects of the same gene.

Fagerlund et al. (1996) described a kindred in which a 2-year-old girl was found to have a severe form of central core disease. Although she was not studied with a diagnostic IVCT because of her young age, other members of her family were studied. MHS was diagnosed if both the test with halothane and the test with caffeine were pathologic, and malignant hyperthermia equivocal (MHE) if only one of the tests was pathologic. The proband's father and paternal grandmother were designated MHE, whereas a brother and a sister of the grandmother were labeled MHS. Surprisingly, DNA studies conducted on available family members uncovered recombination between the MHS locus and RYR1 markers, and none of 5 specific RYR1 gene mutations could be identified in the family. Fagerlund et al. (1996) concluded that because of the known heterogeneity of MHS and the possible heterogeneity of CCD, it is possible that 2 independent disorders were segregating in the family.

Tobin et al. (2001) reported the case of a 12-year-old boy who had an episode of malignant hyperthermia after general anesthesia for a fractured arm. Eight months later, the boy presented after playing in a football game with stress-induced hyperpyrexia, including diaphoresis, muscle weakness and stiffness, seizure activity, respiratory arrest, ventricular fibrillation, and acidosis. Postmortem examination was unremarkable, but a mutation in the RYR1 gene (180901.0004) was identified. The patient's father also carried the mutation.

Manning et al. (1998) reported 2 families with MHS. The proband in the first family had onset of an MH crisis at the age of 12 years while undergoing ophthalmic surgery. Ten minutes after initiation of anesthesia with halothane and succinylcholine, body temperature rose to 37.4 degrees C, accompanied by myoglobinuria, masseter spasm, and ventricular arrhythmia. The maximum potassium level was 4.8 mEq/l, and his maximum creatine kinase level rose dramatically. The patient survived without sequelae, although dantrolene therapy was not given. The proband in the second family had an MH crisis with halothane and succinylcholine while undergoing orthopedic surgery for the first time at age 27 years. The maximum temperature recorded during the crisis was 39.2 degrees C. The duration of anesthesia before development of the MH crisis was 90 minutes. Other characteristics of the crisis included masseter spasm, inappropriate tachypnea, and sinus tachycardia. The maximum heart rate was measured at 150 bpm and the maximal CK level was more than 2,500 U/l. Both patients had a mutation in the RYR1 gene (180901.0010).

Sambuughin et al. (2001) reported 2 unrelated families with MHS. The proband of 1 family developed life-threatening signs of MH when she was anesthetized for tonsillectomy at 9 years of age. Anesthesia was induced with thiopental sodium and maintained with halothane. On injection of succinylcholine to facilitate intubation of the trachea, the patient developed global skeletal muscle rigidity, and her mouth could not be opened. Two brothers had positive in vitro contracture tests, as did the patient. The proband in the second family developed signs of MH when she was anesthetized for maxillary-mandibular advancement-augmentation genioplasty at 15 years of age. Anesthesia was induced with propofol and fentanyl, and nasotracheal intubation was accomplished after topical application of lidocaine; anesthesia was maintained with isoflurane. Signs of MH developed between 1 and 2 hours after induction of anesthesia. Subsequently, the proband and her sister were found to have unequivocally MH-positive in vitro contracture responses to caffeine and to halothane. Affected members of both families had the same 3-bp deletion in the RYR1 gene (180901.0017).

Guis et al. (2004) reported a large family in which 17 patients were diagnosed with MHS by IVCT. The disorder was inherited in an autosomal dominant pattern. Muscle biopsy showed an unexpected presence of multiminicores in 16 of the 17 patients (95%). Multiminicore lesions were observed in both type 1 and type 2 fiber types. No central cores were identified. Genetic analysis detected compound heterozygosity for 2 missense mutations in the RYR1 gene (180901.0023 and 180901.0024) which segregated with the disease phenotype. Only 2 of the 17 patients had clinical muscle involvement. Guis et al. (2004) emphasized that the phenotype in this family was strikingly different from any reported phenotype, demonstrating a significant link between MHS and multiminicore myopathy.

Sambuughin et al. (2009) found that 3 of 6 African American men with exertional rhabdomyolysis had putative mutations in the RYR1 gene. Exertional rhabdomyolysis was defined as acute muscle necrosis with myalgias, swollen muscle, increased serum creatine kinase, and myoglobinuria after strenuous physical exercise. All 6 patients were diagnosed with MHS after the caffeine and halothane contracture test on skeletal muscle biopsy. Only 1 of the patients had a clinical episode of malignant hyperthermia during anesthesia, but he did not carry a pathogenic RYR1 mutation. The findings suggested that there may be a relationship between exertional rhabdomyolysis and MHS, and Sambuughin et al. (2009) suggested that some patients with unexplained exertional rhabdomyolysis may have a mutation in the RYR1 gene.

King Syndrome

King et al. (1972) reported a group of patients with myopathy and malignant hyperpyrexia who also had physical abnormalities, including short stature, cryptorchidism, pectus carinatum, lumbar lordosis, thoracic kyphosis, and unusual facies. They noted that this form of MH, termed King syndrome, was likely to come to attention during corrective surgery. King and Denborough (1973) described 4 unrelated boys with a slowly progressive myopathy, as well as ptosis, short stature, low-set ears, malar hypoplasia, skeletal deformities, and cryptorchidism. All had been identified following episodes of malignant hyperthermia in which 3 of the boys died. Intelligence was normal in all 4.

Isaacs and Barlow (1973) reported a family with dominant inheritance of malignant hyperpyrexia and dysmorphic features that included scoliosis, ptosis, strabismus, dislocation of shoulders and patellas, pes cavus, pectus deformity, below average IQ, and elevated creatine kinase.

Pinsky (1972) and Kaplan et al. (1977) noted that the dysmorphic features of persons with King syndrome and malignant hyperpyrexia resembled those observed in Noonan syndrome (163950).

McPherson and Taylor (1981) reported a case of King syndrome in a girl and noted that all earlier cases had been in males. Saul et al. (1984) reported an affected female. Steenson and Torkelson (1987) reported a case of the King syndrome in which there was no pectus carinatum or cryptorchidism; the patient had mental retardation.

Isaacs and Badenhorst (1992) described what they referred to as King-Denborough syndrome in a white male teenager who from birth had been noted to have low-set ears, high-arched palate, undescended testes, and bilateral pes cavus. The patient reportedly had unexplained high fever in the immediate postoperative period after surgery for undescended testes and pes cavus. During tonsillectomy at age 14 years, the patient had a hyperthermic crisis. Physical examination at that time showed pectus deformity, kyphoscliosis, downslanting palpebral fissures, long upper lip, protuberant nose, and decreased IQ. Serum creatine kinase was increased, and muscle biopsy showed a variation in fiber size and some de- and regenerating fibers. Muscle tension studies confirmed increased susceptibility to malignant hyperthermia. The patient's mother also had increased serum creatine kinase, high-arched feet, and a positive muscle tension test.

Chitayat et al. (1992) described an isolated case in a 9-year-old boy who had, in addition to the usual features of the King syndrome, dilatation of the cardiac ventricles, aorta, and pulmonary artery. Although he was thought to have a congenital myopathy and had transient increase in creatine kinase levels during anesthesia, malignant hyperthermia did not occur. Chitayat et al. (1992) concluded that the manifestations of the King syndrome can result from different congenital myopathies and that in all cases there is probably an increased risk of malignant hyperthermia.

Graham et al. (1998) reviewed the cases of 14 previously reported patients and described a new patient, a 7-year-old girl, with the King syndrome and the unique findings of diaphragmatic eventration, tethered spinal cord, and severe paucity of type 2 skeletal muscle fibers. They suggested that the King syndrome represents a phenotype that is common to several different slowly progressive congenital myopathies. Graham et al. (1998) commented that although there is considerable overlap with the Noonan syndrome, no King syndrome patient had been reported with the Noonan combination of hypertelorism, epicanthic folds, lymphedema, bleeding diathesis, and characteristic heart defects.

D'Arcy et al. (2008) reported a 27-year-old woman with King-Denborough syndrome and susceptibility to malignant hyperthermia. She was born at term after a pregnancy complicated by decreased fetal movements and breech presentation. At birth, she was noted to have hypotonia, ptosis, high-arched palate, prominent philtrum, and scaphocephaly. The father and paternal grandfather had congenital ptosis, but no other signs of neuromuscular disease. She underwent surgery for ptosis at ages 2 and 9 years without complications. Facial and proximal limb weakness became more apparent with age, and she developed kyphoscoliosis, myopathic facies with flat midface, prominent columella, and webbed neck. An EMG was myopathic and serum creatine kinase was increased. At age 15 years, she developed hyperthermia during surgery for scoliosis repair, and subsequent muscle testing confirmed susceptibility to malignant hyperthermia. Genetic analysis identified a heterozygous mutation in the RYR1 gene (K33E; 180901.0038), indicating that RYR1 mutations account for some proportion of patients with this syndrome.

Inheritance

Kalow (1970) reported an extensively affected kindred exhibiting autosomal dominant inheritance of malignant hyperpyrexia and referred to 11 other instances of familial occurrence. He noted that muscular rigidity is a feature of the syndrome.

McPherson and Taylor (1982) reported 12 Wisconsin families segregating MHS, some of which were extensively affected in a dominant pedigree pattern.

Ellis et al. (1978) and Nelson and Flewellen (1983) concluded that malignant hyperthermia exhibits multifactorial inheritance.

Diagnosis

Denborough (1977) developed an in vitro contracture test (IVCT) for malignant hyperpyrexia using a small segment of skeletal muscle from patients. Caffeine, halothane, succinylcholine, and increased potassium induced exaggerated contractions. A dilantin-like drug inhibited the halothane response and the basal twitch in vitro, and presumably could have prophylactic value in vivo. Denborough (1977) noted that high CPK and muscle wasting were useful in identifying subclinical affected persons.

Ball and Johnson (1993) suggested that only about 50% of families with malignant hyperthermia have a mutation of the skeletal muscle RYR1 gene on 19q13.1-q13.2. Thus, presymptomatic testing based on DNA markers can be offered only to a limited number of families where linkage to markers from that region has clearly been shown.

Hogan (1997) pointed out that normothermia does not rule out the diagnosis of malignant hyperthermia. Hyperthermia may be a late sign, as in the proband described by Monnier et al. (1997).

Anetseder et al. (2002) proposed a minimally invasive test for susceptibility to malignant hyperthermia as a substitute for the contracture test, which requires an open muscle biopsy sample. They postulated that intramuscular injection of caffeine increases local carbon dioxide pressure in individuals susceptible to hyperthermia but not in those who are nonsusceptible or in healthy individuals. They measured carbon dioxide pressure in the rectus femoris muscle during local stimulation with caffeine injections in 12 patients susceptible to malignant hyperthermia, in 8 nonsusceptible individuals, and in 7 healthy controls. A clean separation was observed in carbon dioxide pressure values between susceptible and nonsusceptible individuals.

Monnier et al. (2005) reported the results of correlation studies performed with molecular, pharmacologic, histologic, and functional data obtained from 129 IVCT-confirmed MHS families and 46 potential MHS families. Extensive molecular analysis identified a variant in 60% of the MHS families with positive IVCT tests. Using functional analysis, Monnier et al. (2005) assigned a causative role for 7 RYR1 mutations that they proposed to add to the panel of MHS mutations used for genetic testing. IVCT testing in 196 genetically-confirmed MHS patients resulted in 99.5% sensitivity. IVCT-positive/mutation-negative diagnoses were established in 3.1% of 160 tested patients who did not carry the family mutation, although the authors suggested the possibility of a second MHS trait in such families.

Clinical Management

Nelson and Flewellen (1983) noted that dantrolene sodium is the primary specific therapeutic agent for malignant hyperthermia. 'Dantrium' can be given intravenously. Oral administration of dantrolene has been approved by the FDA for prophylactic oral administration before surgery. Dantrolene is used for chronic spasticity and its effectiveness in malignant hyperthermia appears to be related to its action on skeletal muscle where it associates the excitation-contraction coupling, probably by interfering with the release of Ca(2+) from the sarcoplasmic reticulum.

Biochemical Features

Schmitt et al. (1974) reported a family in which 2 children had died from malignant hyperpyrexia. Skeletal muscle biopsy from the father and brother of the propositi showed a decrease of muscle adenylate kinase (AK2; 103020). Schmitt et al. (1974) suggested that malignant hyperpyrexia may develop in patients with decreased AK2 due to an inability to regenerate ATP. In 3 survivors of malignant hyperthermia and in 5 relatives of survivors who showed a positive caffeine contracture test, Cerri et al. (1981) found no deficiency of muscle adenylate cyclase. In contrast, Willner et al. (1981) found that the activity of adenylate cyclase and the content of cyclic AMP was abnormally high in skeletal muscle of patients with malignant hyperthermia. They suggested that secondary modification of protein phosphorylation could explain observed abnormalities of phosphorylase activation and sarcoplasmic reticulum function in the disorder.

Mapping

Noting that MHS in the pig (see ANIMAL MODEL) is linked to glucose phosphate isomerase (GPI; 172400) which belongs to a linkage group conserved in vertebrates, McCarthy et al. (1989, 1990) investigated human chromosome 19, which carries the GPI gene, in several families with MHS. They found that MHS is tightly linked to CYP2A (122720) (maximum lod of 5.65 at theta = 0) and is flanked by APOC2 (608083) and DNA marker S9. The authors concluded that both human and porcine MHS are due to mutations in homologous genes.

MacLennan et al. (1990) reported linkage of several MHS families to chromosome 19 markers, including markers within the RYR1 gene (lod score of 4.20) at a linkage distance of 0.0 cM. The authors concluded that the basic defect in MHS resides in the RYR1 gene. Noting that the RYR1 gene maps to chromosome 19q, which is syntenic to the candidate gene for malignant hyperthermia on porcine chromosome 6, MacKenzie et al. (1990) also suggested that the RYR1 gene may be the cause of human MHS.

Heterogeneity

Genetic Heterogeneity

In 3 unrelated families with MHS, Levitt et al. (1991) excluded linkage of the MHS phenotype to loci on 19q13.1, indicating genetic heterogeneity. Fagerlund et al. (1992) studied 8 Swedish MH families with respect to a BanI RFLP of the RYR1 gene (called by them CRC for calcium release channel of the sarcoplasmic reticulum). Three of the families were informative for genetic linkage and 2 of them showed recombinants, indicating that the mutation in those families was not in the RYR1 gene. Deufel et al. (1992) and Iles et al. (1992) excluded close linkage to RYR1 in 2 Bavarian MHS families with MHS and in 2 additional MHS families, respectively. The work of Levitt et al. (1992) suggested that at least 3 separate loci are responsible for susceptibility to malignant hyperthermia.

Because in some pedigrees phenotypic and genotypic data are discordant, Robinson et al. (2000) suggested that susceptibility to malignant hyperthermia is dependent upon the effects of more than one gene. Using the transmission disequilibrium test in a study of 130 MH nuclear families, they assessed the involvement of 8 malignant hyperthermia candidate loci: RYR1, CACNA1S (114208), CACNA2D1 (114204), MHS4 (600467), MHS6 (601888), LIPE (151750), DM1 (160900), and dystrophin (300377). The authors concluded that the results pointed to variation in more than one gene as influencing MH susceptibility in individual families. Using family stratification data, Robinson et al. (2003) confirmed a role in MH susceptibility for loci on chromosomes 5 and 7 in RYR1-linked families, with the influence of chromosomes 1 and 3 being less clear.

Molecular Genetics

In several porcine breeds that exhibited inheritance of malignant hyperthermia, Otsu et al. (1991) and Fujii et al. (1991) identified an A615R mutation in the Ryr1 gene. In 1 of 35 Canadian families with malignant hyperthermia, Gillard et al. (1991) identified heterozygosity for the same mutation, which is A614R (180901.0001) in humans.

In patients with malignant hyperthermia, Manning et al. (1998) identified 4 adjacent mutations in the RYR1 gene: R2163C (180901.0010), R2163H (180901.0011), V2168M (180901.0013), and T2206M (180901.0014).

Monnier et al. (2005) identified 11 new variants in the RYR1 gene in affected members of families with MHS1. Most mutations clustered in the MH1 and MH2 domains of the RYR1 gene.

King-Denborough Syndrome

In a patient with King-Denborough syndrome, D'Arcy et al. (2008) identified a heterozygous mutation in the RYR1 gene (180902.0038).

Population Genetics

Nelson and Flewellen (1983) cited a frequency of malignant hyperthermia of 1 in 15,000 anesthetic administrations to children and 1 in 50,000 to 100,000 in adults.

The international incidence of malignant hyperthermia was stated by Hogan (1997) to be 1 in 50,000 anesthetics. Children are at special risk, with approximately 1 in 5,000 to 10,000 pediatric anesthetics using trigger drugs complicated by malignant hyperthermia. A higher incidence is encountered in geographically defined populations, such as residents of north-central Wisconsin, aboriginal inhabitants of North Carolina, valley dwellers in parts of Austria, and descendants of settlers in Quebec.

History

Ohnishi and Ohnishi (1994) edited a comprehensive multiauthored treatise on malignant hyperthermia. The history of the Malignant Hyperthermia Association of the United States and the British Malignant Hyperthermia Association was recounted in separate chapters.

Animal Model

The malignant hyperthermia that occurs on the basis of a genetic defect in Landrace pigs is not only clinically identical with the human syndrome, but also identical in many of the biochemical features (Britt and Kalow, 1970). Smith and Bampton (1977) concluded that the malignant hyperthermia syndrome is autosomal recessive in pigs.

Foster et al. (1989) showed that the sarcoplasmic reticulum from muscle of swine with susceptibility to malignant hyperpyrexia was deficient in inositol 1,4,5-trisphosphate phosphatase, which leads to high intracellular concentrations of inositol 1,4,5-trisphosphate phosphatase and calcium ions. Halothane inhibited the enzyme and further increased myoplasmic inositol 1,4,5-trisphosphate and calcium ion concentrations, which produced the clinical features of malignant hyperpyrexia.