Malignant Hyperthermia Susceptibility and Related Diseases.

TLDR: A body of data that has linked specific genotypic or phenotypic findings with susceptibility to malignant hyperthermia is built upon and summarized and suggestions to anesthesiologists about the types of patients that should or should not receive a trigger-free general anesthetic are offered.

Abstract: <zdoi;10.1097/ALN.0000000000001877> Anesthesiology, V 128 • No 1 159 January 2018 M ALIGNANT hyperthermia (MH) is an inherited disorder of skeletal muscle that manifests clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent or succinylcholine.1–3 The clinical signs that ensue from this exposure in susceptible individuals include hypercapnia, masseter muscle and/or generalized muscle rigidity, acidosis, peaked T waves that indicate hyperkalemia, and hyperthermia and are caused by the dysregulated entry of myoplasmic calcium, which results in a hypermetabolic cascade involving sustained muscular contractures, depletion of adenosine triphosphate, and muscle cell death.4 The inheritance of pathogenic variants (i.e., mutations) in three genes are primarily associated with MH susceptibility and account for the genetic basis of approximately 70% of patients investigated (fig. 1). The majority of MH–associated variants are found within the RYR1 gene that encodes the skeletal muscle ryanodine receptor type I protein.2,5–7 This protein regulates the movement of calcium from the sarcoplasmic reticulum into the intracellular space of the muscle cell. In MH–susceptible individuals, abnormalities of the ryanodine receptor result in the accumulation of excessive myoplasmic calcium in the presence of one of the anesthetic triggering agents. Nearly 700 variants have been identified in RYR1; however, only 35 have been functionally validated as MH–causative pathogenic variants (an up-to-date list as well as the criteria for causality may be found at the European Malignant Hyperthermia Group website).8 The remainder await validation studies. The most common RYR1 variants that confer susceptibility to MH result from gain-of-function mutations in specific amino acids and regions of the RYR1 protein. These mutations may arise de novo or may be inherited, and the MH phenotype manifests variable expressivity and incomplete penetrance. Inheritance of MH causative pathogenic variants is suspected in individuals with a history of a likely MH clinical event or in those patients with a family history of MH susceptibility or a likely MH event. The mainstay of prevention of MH is the identification of these genetically susceptible individuals so that clinicians can then avoid triggering anesthetic agents. There is a wide range of both dominant and recessive disorders associated with RYR1 pathogenic variants, and many of these inherited myopathies and related conditions have been linked with MH susceptibility.9–11 Therefore, in clinical anesthesia practice, MH susceptibility has often been assumed in patients with nonspecific muscle weakness but without a definitive diagnosis. This shotgun approach is less than ideal because most causes of muscle weakness are not associated with MH susceptibility, and this process then only results in the inaccurate labeling of patients (and their families) who would otherwise be able to safely receive volatile anesthetic agents and succinylcholine. In this article, we build upon and summarize a body of data that have linked specific genotypic or phenotypic findings with susceptibility to MH and offer suggestions to anesthesiologists about the types of patients that should or should not receive a trigger-free general anesthetic. We discuss anesthetic management of certain congenital myopathies that may predispose to MH–like symptoms during general anesthesia, and we offer an approach to the anesthetic management of the undiagnosed patient with muscle weakness.