Malignant Hyperthermia and HyperKPP/PMC

Submitted by deb on Mon, 06/27/2011 – 20:16

Patients with Sodium channel HyperKPP and PMC mutations are at increased risk of Malignant Hyperthermia;

It has long been recognized that patients with hyperkalemic periodic paralysis are at increased risk for Malignant Hyperthermia (MH) during surgery, showing as fulminant muscle rigidity as seen in the jaw muscles, rhabdomyolysis, hypercarbia, and acidosis. Elevated core temperature is common, and hyperthermia may be a late sign. Ventricular dysrhythmia is the believed cause of death in fatal attacks and renal failure and neurologic injury may occur in survivors.

MH a leading cause of death with anesthetics

MH is one of the leading causes of death with anesthetics. Malignant hyperthermia susceptibility (MHS) is found to be due to different genetic causes (genetic heterogeneity) and is usually a dominantly inherited trait. Studies indicate that MHS is due to a malfunction in the mechanisms regulating sarcoplasmic calcium-ion fluxes. Ackerman and Clapham gave a comprehensive review of the role of ion channel defects in disease. They referred to masseter-muscle rigidity induced by succinylcholine in patients with a mutation of the sodium channel gene SCN4A.¹

Both MH and HyperKPP linked to the SCN4A

Moslehi et al. studied a large kindred in which both hyperkalemic periodic paralysis and malignant hyperthermia appeared to be linked to the SCN4A locus. This was suggested by earlier research of Levitt et al. and Olckers et al. (both 1992) who found that a polymorphism within the SCN4A gene gave a cumulative LOD score of 2.1 at theta = 0.0 in 3 MH families that were informative for polymorphisms within the SCN4A gene. ^2,3,4

Prior uneventful history no guarantee

A prior history of an uneventful anesthetic using triggering drugs does not assure that a subsequent anesthetic will be safe. Uncertainties were resolved with introduction of the in vitro halothane contracture test, IVCT. All halogenated ethers in contemporary clinical practice (isoflurane, ethrane, sevoflurane, and desflurane), as well as halothane, an alkane, are potential triggers. These substances are very precise and rapid in control over depth of anesthesia thus their frequent use. As a class, they produce skeletal, cardiac, and smooth-muscle relaxation in normal patients, in stark contrast to the rigidity and contracture observed in those susceptible to MH.

Succinylcholine, a depolarizing muscle relaxant, is the other drug that is a trigger to MH. Prompt intervention with Dantrolene is life-saving in 90% of cases. Dantrolene is highly lipid soluble inhibiting calcium release from the skeletal muscle sarcoplasmic reticulum rather than acting at the neuromuscular muscular junction or the t-tubule. A receptor for dantrolene has been proposed as a possible constituent of the skeletal muscle triad at the apposition of terminal cisternae of the SR and the sarcolemmal t-tubules. ⁵

Additionally patients with hyperkalemic periodic paralysis who undergo anaesthesia require special attention to prevent anesthesia-induced paralysis. It is important that temperature be maintained and carbohydrates in the form of glucose be supplied. ⁶

Patients at special risk

Internationally, the incidence of MH is estimated at 1:50,000 anesthetics. Children are at special risk with about 1:5,000-10,000 anesthetics.⁷ The higher incidence is encountered in geographically defined populations, residents of north-central Wisconsin ⁸, aboriginal inhabitants of North Carolina ^{9, 10} valley dwellers in parts of Austria, and descendants of French settlers in Quebec.¹¹

For further information You may want to refer to our overview on Malignant Hyperthermia which covers testing procedures, treatment in the O.R., Recovery Room and Intensive Care, and includes contacts which provide testing.

References:

1. Ackerman, M. J.; Clapham, D. E. : Ion channels — basic science and clinical disease. New Eng. J. Med. 336: 1575-1586, 1997.

2. Moslehi, R.; Langlois, S.; Yam, I.; Friedman, J. M. : Linkage of malignant hyperthermia and hyperkalemic periodic paralysis to the adult skeletal muscle sodium channel (SCN4A) gene in a large pedigree. Am. J. Med. Genet. 76: 21-27, 1998.

3. Levitt, R. C.; Olckers, A.; Meyers, S.; Levitt, M. K.; Rosenberg, H.; Fletcher, J. E.; Isaacs, H.; Meyers, D. A. : Evidence for the localization of a malignant hyperthermia susceptibility locus to human chromosome 17q. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A46 only, 1992.

4. Olckers, A.; Meyers, D. A.; Meyers, S.; Taylor, E. W.; Fletcher, J. E.; Rosenberg, H.; Isaacs, H.; Levitt, R. C. : Adult muscle sodium channel alpha-subunit is a gene candidate for malignant hyperthermia susceptibility. Genomics 14: 829-831, 1992.

5. Nelson, T. E.; Flewellen, E. H. : The malignant hyperthermia syndrome. New Eng. J. Med. 309: 416-418, 1983

6. Reddy VG, Singapore Med J 1998; Vol 39(11): 511-516 Hogan, K. To fire the train: a second malignant-hyperthermia gene. Am J Hum Genet. 60:1303-1308:1997. (Editorial)

7. McPherson, E. W.; Taylor, C. A., Jr. : The genetics of malignant hyperthermia: evidence for heterogeneity. Am. J. Med. Genet. 11: 273-285, 1982.

8. Berry, B.: Almost White. New York: Macmillan (pub.) 1963. Pp. 152-159;

9. Stewart, C. R.; Kahler, S. G.; Gilchrist, J. M. : Congenital myopathy with cleft palate and increased susceptibility to malignant hyperthermia: King syndrome? Pediat. Neurol. 4: 371-374, 1988.

10. Monnier et al, op. cit.