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An update on the malignant hyperthermia syndrome
1Department of Anesthesiology, Hahnemann University, Philadelphia, PA 19102-1192, USA.
Abstract:
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In humans, MH is inherited in an autosomal dominant fashion; in swine, the principal model for MH, it is in a recessive fashion. Those with MH susceptibility usually are asymptomatic except in the presence of certain "triggering" anaesthetic agents such as isoflurane, enflurane and the muscle relaxant succinylcholine. Upon such exposure hypermetabolism, increased CO2 production, acidosis, muscle rigidity, rhabdomyolysis and hyperthermia occur. Untreated, death may result in 70% of patients. With prompt diagnosis and treatment with dantrolene sodium, the mortality is less than 10%. The overall incidence of MH is low (perhaps 1:50,000 anaesthetics), but it is more common in children. Children also display a paradoxical increase in jaw muscle tone to succinylcholine which often presages MH, but confusing clinically, may also be a normal response to succinylcholine. The pathophysiology of MH centres around a defect in calcium flux in skeletal muscle. A specific base pair change in the gene that codes for the ryanodine receptor calcium channel in muscle has been demonstrated in susceptible swine, but occurs rarely in humans. It is hoped that the understanding of the molecular genetics of MH will lead to a simpler diagnostic test than is currently available, and enhance our understanding of MH and its relation to other myopathies.
Insights
Malignant hyperthermia (MH) is a rare genetic disorder affecting skeletal muscle. Understanding its molecular genetics may lead to better diagnostic tests and treatments for this serious condition.
Area of Science:
- Pharmacogenetics
- Skeletal Muscle Physiology
- Anesthesiology
Background:
- Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, inherited differently in humans (autosomal dominant) and swine (recessive).
- Susceptibility to MH is typically asymptomatic until exposure to specific anesthetic agents like isoflurane, enflurane, or succinylcholine.
- Exposure triggers a hypermetabolic state, leading to acidosis, muscle rigidity, rhabdomyolysis, and potentially fatal hyperthermia, with mortality rates up to 70% if untreated.
Purpose of the Study:
- To explore the pathophysiology of malignant hyperthermia, focusing on calcium flux defects in skeletal muscle.
- To investigate the genetic basis of MH, particularly the role of the ryanodine receptor calcium channel.
- To highlight the need for improved diagnostic methods and a deeper understanding of MH and related myopathies.
Main Methods:
- Review of existing literature on malignant hyperthermia genetics and pathophysiology.
- Comparison of MH inheritance patterns and clinical presentations in humans and swine models.
- Analysis of the role of specific gene mutations, such as those in the ryanodine receptor, in MH susceptibility.
Main Results:
- MH pathophysiology involves a defect in skeletal muscle calcium flux.
- A specific mutation in the ryanodine receptor gene is identified in susceptible swine but is rare in humans.
- MH is more prevalent in children, who may exhibit paradoxical jaw muscle hypertonia to succinylcholine.
Conclusions:
- Prompt diagnosis and dantrolene sodium treatment significantly reduce MH mortality to less than 10%.
- Understanding the molecular genetics of MH is crucial for developing simpler diagnostic tests.
- Further research into MH genetics can enhance our understanding of this disorder and its relationship to other myopathies.