Title: Molecular Genetic Testing to Diagnose Malignant Hyperthermia Susceptibility
A healthy 3-year-old male without a history of general anesthesia or familial problems with anesthesia underwent strabismus repair. The child received a general anesthetic with sevoflurane and required succinylcholine for laryngospasm during induction. Soon after administration of succinylcholine, the anesthesiologist noted masseter muscle rigidity without difficult ventilation. Intubation was secured after administration of atracurium. Soon thereafter, the patient developed hypercapnia despite dramatic increases in minute ventilation. The patient’s esophageal temperature increased from 36.8 to 38.6 within 15 minutes. Malignant hyperthermia was then considered; therefore, sevoflurane was discontinued, and the procedure rapidly completed. ABG revealed pH 7.24, PaO2 575.3, PaCO2 64 mmHg, HCO3 27.6mmol/L, BE -0.6mmol/L, K 4.8 mEq/L. After discontinuation of sevoflurane, the PETCO2 dropped dramatically, and the temperature also decreased. Therefore, dantrolene was not administered. The patient was observed postoperatively, and did well, except for an increase in serum creatine kinase from 1504 U/L during anesthesia to 27,100 U/L 24 hours later. Myoglobinuria was not noted.
A sample of this patient’s blood was sent for molecular genetic testing, and upon looking for mutations in exon 39 of the ryanodine receptor, a new mutation, Gly2130Arg, was discovered. Therefore, this patient was then considered to have a MH susceptibility mutation.
Questions
1. What is currently considered to be the “gold standard” for diagnosing MH susceptibility?
a. Molecular genetic testing
b. Halothane-caffeine contracture testing
c. Masseter muscle rigidity with hypercarbia
d. 3-fold rise in CK following a rapid intraoperative temperature elevation
2. Which of the following is a disadvantage to using molecular genetic testing to diagnose MH susceptibility?
a. The sensitivity is probably less than 30%
b. The specificity is probably close to 100% when screening for known mutations
c. Any bodily tissue can be used for analysis
d. It can be used when the patient does not have access to a MH biopsy testing site
3. At the present time, how many known MH-causing mutations have been discovered on the ryanodine receptor gene (RYR1)?
a. 10
b. 15
c. 20
d. >25
4. The vast majority of cases of acute MH occur in patients that have which of the following conditions?
a. Central core myopathy
b. King-Denborough syndrome
c. Normal phenotype
d. Duchenne’s muscular dystrophy
References
1. Carroll JB: Increased incidence of masseter spasm in children with strabismus anesthetized with halothane and succinylcholine. Anesthesiology 1987; 67: 559-61
2. Larach MG, Rosenberg H, Gronert GA, Allen GC: Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Clin Pediatr 1997; 36: 9-16
3. O'Flynn RP, Shutack JG, Rosenberg H, Fletcher JE: Masseter muscle rigidity and malignant hyperthermia susceptibility in pediatric patients. An update on management and diagnosis. Anesthesiology 1994; 80: 1228-33
4. Meakin G: Underdosage with succinylcholine may lead to incorrect diagnosis of masseter spasm in children. Anesthesiology 1988; 69: 1025-6
5. Rosenberg H, Antognini JF, Muldoon S: Testing for malignant hyperthermia. Anesthesiology 2002; 96: 232-7
6. Girard T, Treves S, Voronkov E, Siegemund M, Urwyler A: Molecular genetic testing for malignant hyperthermia susceptibility. Anesthesiology 2004; 100: 1076-80
7. Litman RS, Rosenberg H: Malignant hyperthermia: update on susceptibility testing. JAMA 2005; 293: 2918-24
8. Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P: Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 2006; 27: 977-89
9. Urwyler A, Deufel T, McCarthy T, West S: Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. Br J Anaesth 2001; 86: 283-7
Answers
1. b At present, halothane-caffeine contracture testing is considered the best test with regard to sensitivity and specificity for diagnosing MH susceptibility. However, since only 6 centers in North American currently administer the test (for which a fresh muscle specimen is required), the test is not available to most persons with suspected MH susceptibility.
2. a At the present time, molecular genetic testing is only offered at two institutions in
3. d There are currently 29 known mutations on the ryanodine receptor gene that are causative for MH susceptibility (see http://www.emhg.org/index.php?option=com_ryr1&Itemid=66).
4. c Although central core myopathy and King-Denborough syndrome are known to be associated with MH susceptibility, the vast majority of MH susceptible persons are phenotypically normal. Duchenne’s muscular dystrophy patients may develop rhabdomyolysis and hyperkalemia when exposed to volatile agents or succinylcholine, but they are not at increased risk for MH over the general population.
Narrative
In the above case, an otherwise healthy child presented for correction of strabismus. “Experienced” pediatric anesthesiologists may remember a time when strabismus was considered a predisposing risk factor for MHS.1 This is no longer the case; children with strabismus are now routinely anesthetized with inhalational anesthetics without any apparent increase in the incidence of MH. The child in this case received succinylcholine to treat laryngospasm. Administration of succinylcholine to children is associated with a number of adverse effects, and like halothane, its routine use in children for routine, non-full stomach inductions has largely been abandoned in modern practice. The major reason for avoiding the elective use of succinylcholine in healthy children is the possible presence of an occult myopathy, especially in males. A number of cases of hyperkalemic cardiac arrest and death have been associated with such cases.2 The child in the case developed hypercarbia, which in the usual clinical practice is caused by hypoventilation. Although it is possible that is was the first sign of acute MH, hypoventilation is far more common in clinical practice. The anesthesiologists strongly considered the possibility of MH when the temperature also began to rise; however, hyperthermia commonly occurs during procedures of the head or neck when the remainder of the body is covered with warming blankets. The first blood gas demonstrated respiratory acidosis. Although the hallmark of MH is the development of both respiratory and metabolic acidosis, it is feasible that early in the process, myocyte death had not yet begun, and thus, metabolic acidosis was delayed. The only convincing clinical features of MH in this case were the dramatic decrease in PETCO2 when the sevoflurane was discontinued, and the unexpected marked elevation of creatine kinase (CK) postoperatively. Although masseter muscle rigidity (MMR) is often considered a harbinger of acute MH in some cases,3 it may also be caused by too small a dose of succinylcholine or not waiting long enough for a demonstrable effect.4
How should cases of unconvincing MH be subsequently evaluated? An open muscle biopsy with contracture test remains the gold standard for diagnosis of MH susceptibility in suspected susceptible probands.5 When contracture testing is not available, genetic analysis is a reasonable method with which to identify variants of the skeletal muscle ryanodine receptor gene (RYR1).6,7 The presence of a RYR1 mutation known to be causative for MH is diagnostic for MH susceptibility. When a new RYR1 variant is found, as it was in the case, it should not be automatically assumed to be a causative novel mutation. The RYR1 gene is known to be a polymorphic gene with more than 170 missense mutations, several of these having been identified as polymorphisms rather than causative mutations.8 A novel mutation must not be used diagnostically (in contrast to the case above) before it has been proven to be causative, either in extensive pedigree analysis comparing molecular genetic results with contracture testing data and/or using experimental techniques. Furthermore, it must be shown that the novel variant isn’t a normal polymorphism for the particular geographic area or ethnic background. A polymorphism may occur in as few as 1% of the population. Molecular genetic analysis of MH patients should be encouraged, but results should be analyzed with caution. Only causative RYR1 mutations are to be used for the diagnosis of MH susceptibility. Absence of such mutations does not exclude MH susceptibility and warrants eventual in-vitro contracture testing.7,9
Attending Anesthesiologist
The Children's
University of
