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Periodic Paralysis News Desk

Resources for the Periodic Paralysis Community since 1995

PHYSICIAN'S INFORMATION SHEET

Malignant Hyperthermia in Hypokalemic Periodic Paralysis

Malignant Hyperthermia is one of the leading causes of death with anesthetics

Certain types of inhaled anesthetics and the injection of depolarizing muscle relaxants used during the course of surgery can result in Malignant Hyperthermia (MH) resulting in fulminant muscle rigidity in the jaw muscles, rhabdomyolysis, hypercarbia, and acidosis. Elevated core temperature is common. Hyperthermia may be a late sign. Ventricular arrhythmia may result in death and renal failure and neurological injury may occur in survivors.

Malignant hyperthermia susceptibility (MHS) is usually a dominantly inherited trait. Studies indicate that MHS is due to a malfunction in the mechanisms regulating sarcoplasmic calcium-ion fluxes. The first genetic locus for MHS (MHS1) was found to correspond to the skeletal muscle ryanodine receptor (RYR1) at chromosome location 19q12-13.2.

MH and Hypokpp map to same gene and are allelic

In a new study researchers show that in a large French family MHS was mapped to the CACNL1A3 gene at chromosome location 1q31 encoding the alpha1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel (VDCC). (1) Mutations of this same gene responsible for MH located in a different part of the gene have been linked to Hypokalemic Periodic Paralysis (HypoKPP) and thus these two diseases may be considered to be allelic (different forms of the same gene). HypoKPP is an autosomally dominant disease characterized by episodic weakness associated with decreased serum potassium concentration. (2,3,4)

Prior Unevent History No Guarantee of Safety

A prior history of an uneventful anaesthetic using triggering drugs does not assure that a subsequent anaesthetic 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)

Internationally, the incidence of MH is estimated at 1:50,000 anaesthetics. Children are at special risk with about 1:5,000-10,000 anaesthetic.(6) The higher incidence is encountered in geographically defined populations, residents of north-central Wisconsin (7), aboriginal inhabitants of North Carolina (8,9) valley dwellers in parts of Austria, and descendants of French settlers in Quebec.(10)

You may want to read the Physician's Sheet: Malignant Hyperthermia which covers testing procedures, treatment in the O.R., Recovery Room and Intensive Care, and includes contacts which provide tests.

Patients with Periodic Paralysis also have difficulties with local anaesthetics, for information see our Physician's Sheet: Local Anaesthesia.

References:

  1. Monnier, N., et al. Malignant-Hyperthermia susceptibility is associated with a mutation of the alpha1- subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. American Journal Human Genetics. 60:1316-1325:1997
  2. Manning, B. M.; Quane, K. A.; Lynch, P. J.; et al: Novel mutations at a CpG dinucleotide in the ryanodine receptor in malignant hyperthermia. Hum. Mutat. 11: 45-50, 1998.
  3. Manning, B. M.; Quane, K. A.; Ording, H.; et al: Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. Am. J. Hum. Genet. 62: 599-609, 1998.
  4. Ptacek, L. J.; Tawil, R.; Griggs, R. C.; et al: Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77: 863-868, 1994.
  5. Nelson, T. E.; Flewellen, E. H. : The malignant hyperthermia syndrome. New Eng. J. Med. 309: 416-418, 1983.
  6. Hogan, K. : To fire the train: a second malignant-hyperthermia gene. (Editorial) Am. J. Hum. Genet. 1303-1308, 1997.
  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.

Where can I get more information?
Visit our web site at http://www.hkpp.org