King-Denborough syndrome

Causes

King-Denborough syndrome results from a gene–environment interaction, where susceptible individuals typically have no symptoms unless exposed to triggering agents. The most common triggers are volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane, and enflurane, or depolarizing muscle relaxants like suxamethonium and decamethonium. In rare instances, physical exercise or heat may provoke a reaction. The condition is inherited in an autosomal dominant pattern with variable penetrance.

The defect most often involves the ryanodine receptor gene (RYR1) on chromosome 19q13.2, with over 25 mutations linked to malignant hyperthermia susceptibility. These mutations cluster in three domains (MH1, MH2, MH3) within the protein. Chromosomes 7q and 17 have also been implicated. King-Denborough syndrome may be allelic with central core disease, allowing co-inheritance.

Pathophysiology

In a large proportion of cases (50–70%), the propensity for malignant hyperthermia in King-Denborough syndrome is due to a mutation in the ryanodine receptor type 1 (RYR1) on the sarcoplasmic reticulum. RYR1 normally opens in response to L-type calcium channel conformational changes after membrane depolarization, causing a rise in intracellular calcium and muscle contraction. The receptor has two calcium-binding sites: a high-affinity A-site that mediates opening and a lower-affinity I-site that mediates closing.

Triggering agents like caffeine and halothane increase A-site affinity for calcium and decrease I-site affinity in mutant proteins. Calcium also affects RYR1 activity, causing closure via the A- or I-sites; in MH mutants, calcium affinity at these sites is reduced. These alterations lead to excessive calcium release due to a lowered activation threshold and heightened deactivation threshold. Sequestering this excess calcium consumes large amounts of ATP, generating excessive heat.

Muscle cell damage releases potassium, myoglobin, creatine, phosphate, and creatine kinase into the circulation. The other known causative gene is CACNA1S, encoding an L-type calcium channel α-subunit; two mutations at residue R1086 increase channel sensitivity to caffeine and halothane, raising basal cytosolic calcium and muscle excitability.

Diagnosis

Diagnosis of King-Denborough syndrome is based on clinical grounds, with early signs including masseter muscle contracture after succinylcholine, rising end-tidal carbon dioxide despite increased ventilation, unexplained tachycardia, and muscle rigidity. Elevated body temperature is often a late sign but may appear early in severe cases. Respiratory acidosis is universal, and many patients have metabolic acidosis at diagnosis. Other features include fast breathing, cyanosis, hypertension, abnormal heart rhythms, and high blood potassium.

Laboratory investigations may confirm the diagnosis: raised creatine kinase, elevated potassium, increased phosphate, decreased calcium, and raised myoglobin due to muscle damage. Severe rhabdomyolysis can lead to acute kidney failure.

The standard test for susceptibility is the caffeine-halothane contracture test (CHCT) on a muscle biopsy, with sensitivity of 97% and specificity of 78%. Negative biopsies are not definitive, so patients with a suggestive history are treated with non-triggering anesthetics even if the biopsy is negative. Some researchers advocate adding a calcium-induced calcium release test for greater specificity.

Prevention

For individuals with King-Denborough syndrome undergoing general anesthesia, avoidance of triggering agents is essential. Volatile anesthetic concentrations above 5 parts per million and succinylcholine must be avoided. Most other drugs, including nitrous oxide, are safe, as are regional anesthetic techniques. Prophylactic dantrolene is no longer recommended due to questionable benefits and possible adverse effects such as nausea, vomiting, muscle weakness, and prolonged action of nondepolarizing neuromuscular blocking agents.

Anesthesia machines can be prepared by flushing: remove or disable vaporizers, flush with fresh gas flow of 10 L/min or greater for at least 20 minutes (60 minutes for modern machines with more rubber and plastic components), periodically ventilate a new breathing circuit, and replace soda lime. Alternatively, charcoal filters can be used to prepare a machine in less than 60 seconds; these filters prevent residual anesthetic from triggering MH for up to 12 hours.

Before placing charcoal filters, the machine should be flushed with fresh gas flows greater than 10 L/min for 90 seconds.

Did You Know?

• The syndrome was first recognized at Royal Melbourne Hospital, Australia in an affected family by Denborough et al. in 1962.
• Dantrolene, the only known antidote, was discovered as a treatment by South African anesthesiologist Gaisford Harrison and reported in a 1975 article.
• In the Manawatū region of New Zealand, up to 1 in 200 people are at high risk of malignant hyperthermia.