The Genetics of Malignant Hyperthermia

Malignant hyperthermia is a severe reaction to specific drugs used for general anesthesia. This response involves a dangerously high body temperature, muscle rigidity, and a rapid heart rate. Without immediate treatment, this rare condition can be fatal. The underlying cause is a genetic disorder known as malignant hyperthermia susceptibility (MHS), an inherited condition where an individual carries a gene alteration that puts them at risk when exposed to certain anesthetic agents.

The Genetic Basis of Malignant Hyperthermia

Malignant hyperthermia susceptibility is primarily caused by mutations in genes responsible for muscle function. The most commonly affected gene is the ryanodine receptor 1 gene, or RYR1. This gene provides the instructions for making a protein that functions as a calcium channel in skeletal muscle cells. These channels are part of the process of muscle contraction and relaxation.

In individuals with an RYR1 mutation, these calcium channels are structurally altered. When certain anesthetic gases or the muscle relaxant succinylcholine are administered, these drugs can trigger the faulty channels to open and release an uncontrolled flood of calcium into the muscle cells. This sudden and massive increase in intracellular calcium causes the muscles to contract forcefully and continuously, leading to rigidity and spasms.

This intense muscle activity generates an immense amount of heat, causing a rapid and dangerous rise in body temperature. The body’s metabolic rate skyrockets as it tries to manage the calcium overload and sustained muscle contraction. While RYR1 mutations account for the majority of MHS cases, a smaller percentage are caused by mutations in another gene, CACNA1S, which also plays a part in muscle cell calcium regulation.

Inheritance Patterns and Family Risk

Malignant hyperthermia susceptibility is inherited in a pattern known as autosomal dominant. This means that a person only needs to inherit one copy of the altered gene from one parent to be at risk for the condition. The gene is on an autosome (a non-sex chromosome), so it can be passed from either parent and can affect both male and female children.

If a parent has the gene mutation that causes MHS, each of their children has a 50% chance of inheriting that same gene. If an individual is diagnosed with MHS, it is a strong indicator that other close relatives may also carry the genetic trait.

MHS also exhibits variable penetrance. This means that not everyone who inherits the gene will have the same reaction, or any reaction at all, upon exposure to trigger agents. Some individuals may experience a severe, life-threatening episode, while others might have a milder, less obvious reaction. It is even possible for a person to have a triggering anesthetic without a reaction on one occasion, only to have a severe episode during a subsequent surgery.

Genetic Testing and Diagnosis

One primary method for diagnosis is molecular genetic testing, which is performed on a blood sample. This test analyzes a person’s DNA to identify the presence of known pathogenic variants in the RYR1, CACNA1S, and other less commonly associated genes like STAC3. Identifying a known MH-causative mutation can definitively establish the diagnosis.

The other diagnostic standard is an in vitro contracture test (IVCT), often referred to as the Caffeine Halothane Contracture Test (CHCT). This procedure is more invasive as it requires a surgical muscle biopsy, where a small piece of thigh muscle is removed. In the laboratory, the muscle sample is exposed to triggering agents like halothane and caffeine, and its contractile response is measured. An abnormally strong contraction in response to these substances confirms MHS.

Testing is recommended for individuals who have a close relative with a confirmed MHS diagnosis. It is also considered for patients who have experienced a suspected MH-like event during a previous anesthetic procedure.

Clinical Management for Gene Carriers

For individuals confirmed to carry an MHS-related gene mutation, the focus of clinical management is on prevention. The primary step is to ensure all healthcare providers, particularly anesthesiologists and surgeons, are aware of the diagnosis. This information allows them to avoid all known triggering anesthetic agents for any future surgical or medical procedures.

Safe alternatives are available, and anesthesiologists can use a total intravenous anesthetic technique, ensuring the anesthesia machine is free from any residual triggering agents. Many individuals with an MHS diagnosis choose to wear a medical alert bracelet or necklace to inform emergency medical personnel of their condition.

Hospitals are also prepared for the possibility of an MH crisis. They maintain stock of an antidote drug called dantrolene sodium. While the goal is to prevent an episode by avoiding triggers, having dantrolene readily available is a safety measure.