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

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 145600 (trait) , 180901 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2004

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

Species-specific symbol: RYR1, MH

Species-specific description: Malignant hyperthermia (MH) is a potentially life-threatening disorder in horses that can be triggered by halogenated anaesthetics and other non-aesthetic factors that may include exercise, stress, breeding, illnesses, and concurrent myopathies. It has an estimated mortality rate of 34% when halothane anaesthesia is administered (cited by Aleman et al., 2009). MH occurs primarily in Quarter horses, but has been reported in other breeds including Thoroughbred, Appaloosa, Arabian horses, and ponies (Aleman et al., 2004). Horses are generally mature before exhibiting clinical signs. [IT thanks Hailey Anderson, working under the guidance of Professor Ernie Bailey, for contributions to this entry in April 2022]

History: The first report of the disease in horses occurred in 1975 (cited by Aleman et al., 2004). A likely causal variant was identified in 2004 (Aleman et al., 2004). A synergistic relationship between MH and PSSM1 was reported by McCue et al. (2009).

Inheritance: As noted by Aleman et al. (2004), the fact that the two affected animals with which they dealt were heterozygous suggests autosomal dominant inheritance. However, a pedigree analysis has still to be conducted.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous disorder in other species, especially pigs and humans), Aleman et al. (2004) characterised the molecular basis of this disorder in two affected horses: a base substitution (C7360G) in exon 46 of the RyR1 gene results in an amino-acid substitution (R2454G). This codon is also mutated in two of the five exon-46 RyR1 mutations in humans.

Clinical features: “Mutations in the RYR1 gene cause dysfunction of the calcium release channel of the sarcoplasmic reticulum in skeletal muscle, resulting in excessive release of calcium into the myoplasm and a hypermetabolic state characterized by intense heat, hypercapnia [elevated carbon dioxide (CO2) levels in the blood], lactic acidosis, and, in many cases, death” (Aleman et al., 2004) Malignant hyperthermia episodes can include signs such as muscle contracture (rigidity), elevated body temperature, elevated heart rate, irregular heart rhythm, excessive sweating, and shallow breathing. Horses with the MH likely causal variant can exhibit more severe clinical symptoms if they also have a PSSM1 mutation (McCue et al., 2009) (see also OMIA 001158-9796 : Polysaccharide storage myopathy/PSSM1/Exertional rhabdomyolysis in Equus caballus).

Genetic testing: Genetic testing for the reported likely causal variant is available.

Breeds: Appaloosa (Horse) (VBO_0000904), Arab (Horse) (VBO_0000905), Quarter Horse (Horse) (VBO_0001057), Thoroughbred (Horse) (VBO_0001083).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: