Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept

Sheila Riazi, M.Sc., M.D.; Natalia Kraeva, Ph.D.; Philip M. Hopkins, M.D., F.R.C.A.


Anesthesiology. 2018;128(1):168-180. 

In This Article

Abstract and Introduction


This article reviews advancements in the genetics of malignant hyperthermia, new technologies and approaches for its diagnosis, and the existing limitations of genetic testing for malignant hyperthermia. It also reviews the various RYR1-related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, and examines the connection between these disorders and malignant hyperthermia.


MALIGNANT hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered by volatile anesthetics or succinylcholine. It manifests as a potentially lethal hypermetabolic crisis associated with a rapid and uncontrolled increase in myoplasmic Ca2+ in skeletal muscle cells.[1,2] Advances in anesthesia monitoring and the discovery of the therapeutic efficacy of dantrolene have reduced the mortality and morbidity of MH substantially.[3] However, over the past decade, studies have reported evidence that deaths associated with MH still occur, despite treatment.[4–6]

In parallel, our knowledge of the molecular and genetic etiology of MH has been advanced over the last three decades. Three genes, RYR1,,[7,8]CACNA1S,[9–11] and STAC3,[12] have been associated with MH susceptibility and the severe dysregulation of skeletal muscle Ca2+ homeostasis that results in the clinical features of an MH reaction under anesthesia. A recent report of a bleeding disorder associated with an RYR1 variant implicated in MH susceptibility[13] expands the range of clinical defects, already including myopathies[14,15] and exertional rhabdomyolysis,[16–19] that may be present in MH–susceptible individuals. These findings emphasize that the phenotypes associated with genetic defects predisposing to MH are not confined to reactions to volatile anesthetics and imply a common or overlapping pathophysiology of these disorders.

In this review, we summarize the latest evidence on the genetics of MH susceptibility, and its connection to non–anesthesia-related disorders. We review the guidelines for genetic diagnosis of MH susceptibility and discuss the limitations of current genetic screening. We also discuss the nonanesthetic phenotypes associated with RYR1-related disorders.