A Proposed North American Approach for Genetic Testing of Individuals at Risk for Malignant Hyperthermia

Area of Science:

• Anesthesiology
• Pharmacogenetics
• Skeletal Muscle Physiology

Background:

• Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder of skeletal muscle.
• Triggered by volatile anesthetics and succinylcholine, MH presents a significant anesthetic risk.
• Current genetic testing for MH susceptibility (RYR1, CACNA1S, STAC3) has limitations in sensitivity, reaching only up to 70%.

Purpose of the Study:

• To outline a stepwise diagnostic approach for malignant hyperthermia susceptibility.
• To integrate clinical history, assessment, and genetic variant interpretation for risk-benefit analysis.
• To provide guidance for managing individuals at risk of MH.

Main Methods:

• Review and synthesis of clinical guidelines and genetic testing data for MH.
• Development of a stepwise protocol incorporating clinical evaluation.
• Interpretation framework for genetic variants associated with MH.

Main Results:

• Genetic testing alone has suboptimal sensitivity for MH susceptibility.
• Contracture testing can aid in ruling out MH in some cases.
• A combined approach of clinical assessment and genetic interpretation offers a balanced risk-benefit strategy.

Conclusions:

• A stepwise approach integrating clinical assessment and genetic variant interpretation is crucial for managing MH susceptibility.
• This strategy aims to optimize diagnosis and patient management for this pharmacogenetic disorder.
• The proposed approach has received recognition from major anesthesiology societies.