In other species: domestic cat , cattle , horse , pig , rabbit , deer , turkey

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 145600 (trait) , 180901 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2001

Cross-species summary: A progressive increase in body temperature, muscle rigidity and metabolic acidosis, leading to rapid death.

Species-specific symbol: MHS

Species-specific description: Malignant hyperthermia is a disorder of skeletal muscle characterized by hypercapnea, tachycardia, and hyperthermia in response to a chemical trigger, and can be fatal. It is an autosomal dominant trait caused by a mutation in the skeletal muscle ryanodine receptor. This mutation has been identified in several breeds. Affected dogs show no clinical signs until exposed to chemical triggers, which are common anesthetic agents.

Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

History: Malignant hyperthermia was first reported in humans in 1960 and in dogs in 1973 (Short and Paddleford, 1973).

Mapping: CFA1

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the known molecular cause of the same disorder in pigs and humans, and reinforced by showing the candidate gene to be very tightly linked to MHS in dogs), Roberts et al. (2001) identified the causative mutation as a T to C substitution that changes an amino acid codon from valine to alanine (V547A) in a highly conserved region of the canine RYR1 gene.

Clinical features: MH is a pharmacogenetic clinical syndrome that affects multiple species. Dogs with malignant hyperthermia present as an outwardly healthy dog, but develop hypercapnea, tachycardia, and hyperthermia during general anesthesia. Signs can progress to cardiac dysrhythmia, rhabdomyolysis, renal failure, and death if the anesthetic is not discontinued. Common triggers of clinical signs include volatile inhalants (halothane, isoflurane, desflurane and sevoflurane) and depolarizing muscle relaxants such as succinylcholine (Roberts et al., 2001, Brunson and Hogan, 2004).

Treatment involves cessation of the causative anesthetic, supportive care, cooling, and dantrolene administration. Dantrolene is a muscle relaxant that blocks calcium release inside myocytes (Brunson and Hogan, 2004). Unlike affected humans or pigs (Nelson et al., 2002), affected dogs develop signs primarily in response to chemical triggers and exhibit less severe metabolic acidosis and muscle rigidity during a clinical episode (Roberts et al., 2001). Alternative anesthetic protocols for affected dogs can include nitrous oxide, benzodiazepines, phenothiazines, barbiturates, etomidate, propofol, dissociative agents, opioids, nondepolarizing neuromuscular blockers, or a combination of intravenous and local or regional anesthesia. Sufficient premedication is important, since stress can be a contributing factor to development of clinical signs (Brunson and Hogan, 2004).

[IT thanks DVM student Jianjian Gong for suggested changes in April 2022]

Pathology: A missense mutation in the RYR1 gene causes the function alteration in the ryanodine receptors (a part of the calcium releasing channel in skeletal muscle) in affected dogs and leads to defects in the calcium release channel located in the sarcoplasmic reticulum (Roberts et al., 2001). The calcium channels present prolonged opening when being stimulated by the triggering factors (such as certain general anaesthesia agents). This increases muscle contraction and muscle metabolism, resulting in hyperthermia (Brunson and Hogan, 2004), and eventually can lead to a life-threatening hypermetabolic state (the MH episodes).

[IT thanks DVM student Jianjian Gong for suggested changes in April 2022]

Prevalence: Although prevalence is thought to be low, it is difficult to estimate because affected dogs appear normal unless they are exposed to a trigger, and some may die before diagnosis is achieved.

Control: Relatives of affected dogs should be tested. Breeding of affected dogs is discouraged. Because dogs with this mutation are often not identified before undergoing anesthesia, it is recommended that dantrolene be stocked in the surgical suite.

Genetic testing: There is a test for this mutation in dogs (Roberts et al., 2001).

Breeds: Collie, Doberman Pinscher, English Springer Spaniel, German Shepherd Dog, Greyhound, Labrador Retriever, Pointer, Saint Bernard.

Associated gene: