Malignant hyperthermia (MH) is a rare, potentially life-threatening condition triggered by exposure to certain drugs used during general anesthesia. It is characterized by a severe reaction of the skeletal muscles to specific medications, particularly volatile anesthetics (such as halothane, isoflurane, and sevoflurane) and the muscle relaxant succinylcholine.
Malignant hyperthermia genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of malignant hyperthermia include:
- Muscle Rigidity: The condition leads to a rapid and sustained increase in skeletal muscle contraction (muscle rigidity), which can cause difficulty with ventilation.
- Hypermetabolism: Malignant hyperthermia rapidly increases body temperature and metabolism, leading to a dangerous elevation in body heat.
- Elevated Carbon Dioxide Levels: The increased muscle activity and metabolism contribute to elevated carbon dioxide levels in the blood (hypercapnia), leading to respiratory acidosis.
- Tachycardia: The heart rate may increase significantly (tachycardia), and other cardiovascular manifestations can occur.
- Rhabdomyolysis: Severe muscle breakdown can release myoglobin into the bloodstream, leading to rhabdomyolysis. Myoglobin can cause kidney damage, and its release can be detected in the urine.
- Hyperkalemia: Elevated potassium levels in the blood (hyperkalemia) may occur, contributing to cardiac arrhythmias.
Malignant hyperthermia is typically an inherited condition, and genetic testing can identify mutations in the RYR1 gene (most commonly associated with MH) or the CACNA1S gene. However, MH can also occur sporadically without a family history.
Management and treatment of malignant hyperthermia involve several critical steps:
- Discontinuation of Triggering Agents: Immediate discontinuation of the triggering agents, such as volatile anesthetics and succinylcholine.
- Administration of Dantrolene: Dantrolene is the specific antidote for malignant hyperthermia. It blocks calcium release from the muscle's sarcoplasmic reticulum, preventing muscle contractions. Dantrolene should be administered promptly.
- Supportive Measures include cooling the patient to lower the body temperature, addressing acidosis and electrolyte imbalances, and providing respiratory support.
- Monitoring and Further Treatment: Continuous monitoring of vital signs and laboratory parameters is crucial. In severe cases, additional interventions, such as hemodialysis, may be necessary to manage myoglobin-induced kidney damage.
Healthcare providers must be aware of a patient's susceptibility to malignant hyperthermia before administering triggering agents. Preoperative genetic testing and a thorough medical history can help identify at-risk individuals.
Individuals with known susceptibility to malignant hyperthermia should wear a medical alert bracelet or carry a card indicating their condition to ensure rapid and appropriate management in case of exposure to triggering agents during medical procedures.
More Information
Malignant hyperthermia is a pharmacogenetic disorder of skeletal muscle that presents a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, and the depolarizing muscle relaxant succinylcholine, and, rarely in humans, in response to stressful situations such as intense exercise and heat. This adverse reaction is estimated to occur between 1:10.000 and 1:150.000 general anesthesia.
In most cases, the affected gene is RYR1, which codes for ryanodine, a calcium ion transporter in muscle cells and neurons. So far, at least 100 pathogenic variants in RYR1 have been identified. Its inheritance pattern is autosomal dominant, i.e., one copy of a pathogenic variant related to MH susceptibility would be sufficient to markedly increase the risk of suffering an adverse reaction during anesthesia.
The RYR1 variant most frequently reported in the scientific literature is c.1840C>T (p.Arg614Cys), followed by c.14693T>C (p.Ile4898Thr) and c.487C>T (p.Arg163Cys).
The c.6502G>A variant (p.Val2168Met) is one of Europe's most common pathogenic variants. The amino acid change from valine to methionine at position 2168 of the protein increases its sensitivity to certain anesthetics such as halothane.
As previously indicated, variants that could cause MH have been identified in RYR1 and two other genes, CACNA1S and STAC3, which this test does not analyze.
Malignant hyperthermia genetic testing analyzes the 28 most frequent pathogenic mutations of the RYR1 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
