Allele Frequencies and Genotypes for the Ryanodine Receptor 1 Variant Causing Malignant Hyperthermia and Fatal Rhabdomyolysis With Hyperthermia in Horses.
Abstract: Fatal anesthesia-induced malignant hyperthermia (MH) and rhabdomyolysis with hyperthermia documented in Quarter Horses (QH) breeds are caused by a missense variant in the ryanodine receptor 1 gene (RYR1: XP_023505430.1.:p.(R2454G), designated as MH). The reported cases to date have all been heterozygous, and the allele frequency is suspected to be low. Objective: To determine an accurate estimate of MH allele frequency in multiple horse breeds and investigate whether homozygous animals exist in the population. Methods: In total, 159 227 horses from 16 breeds who were either submitted for clinical evaluation (n = 1500) or genetic testing (n = 157 727) were included. Methods: Prospective study using banked DNA samples from two diagnostic laboratories determined the presence, zygosity, and estimated population MH allele frequencies. Results: The MH allele was exclusively detected in 391 QH, 18 Paints (PT), one Appaloosa (AP), and one QH-Clydesdale cross with similar allele frequencies (QH = 0.0013 and PT and AP = 0.0012). In cases submitted for clinical evaluation, death occurred as anesthesia-induced MH or severe acute rhabdomyolysis with hyperthermia (≥ 42°C, 107.6°F) in 51% of N/MH horses. Nineteen of the 20 fatal cases were young males (median: 9 years old, range: 9 months-14 years). No MH homozygotes were detected in either cohort evaluated. Conclusions: Homozygotes for the MH allele were not identified, and thus might be incompatible with life, but additional testing is needed to confirm. Although the allele frequency was low, being heterozygous poses a risk of death if anesthesia, stress, concurrent illness, breeding, or other stresses occur.
© 2025 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.
Publication Date: 2025-04-29 PubMed ID: 40298507PubMed Central: PMC12038935DOI: 10.1111/jvim.70081Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research article focuses on the study of the frequency of the gene variant causing malignant hyperthermia (MH) and lethal rhabdomyolysis (muscle breakdown) with hyperthermia in horses. The researchers also aim to find out if homozygous animals (animals with two copies of the variant gene) exist in the population.
Objectives and Methods
- The research aimed to determine the accurate estimate of the frequency of the MH gene in multiple horse breeds and to investigate the existence of homozygous animals in the population.
- The study included 159,227 horses from 16 breeds who were either submitted for clinical evaluation or genetic testing.
- The researchers used DNA samples from two diagnostic laboratories to determine the presence, zygosity (whether horses have one copy (heterozygous) or two copies (homozygous) of the variant gene), and estimated population MH allele frequencies.
Results
- The MH allele was predominantly detected in Quarter Horses, with a few instances in Paints, one Appaloosa, and one Quarter Horse-Clydesdale cross. The allele frequencies among these breeds were similar.
- Among the cases submitted for clinical evaluation, in more than half of the cases, death occurred due to anesthesia-induced MH or severe acute rhabdomyolysis with hyperthermia, predominantly in young males.
- No homozygous animals were detected in the study population, suggesting that carrying two copies of the MH allele may not be compatible with life.
Conclusions
- The research concluded that there were no homozygous animals detected for the MH allele, meaning carrying two copies of the MH gene may not be compatible with life.
- Additional testing is recommended to confirm the hypothesis about the non-existence of homozygotes.
- Though the allele’s frequency was found to be low, horses carrying a single copy (being heterozygous) are at risk of death if they undergo anesthesia, stress, concurrent illness, breeding, or face other stresses.
The study emphasizes the potential risks associated with the MH gene, and although it is found in a low frequency, it carries significant risk factors, particularly in specific horse breeds. Therefore, understanding this genetic variant’s patterns can help manage and possibly reduce these risks in horse populations.
Cite This Article
APA
Aleman M, McCue M, Bellone RR.
(2025).
Allele Frequencies and Genotypes for the Ryanodine Receptor 1 Variant Causing Malignant Hyperthermia and Fatal Rhabdomyolysis With Hyperthermia in Horses.
J Vet Intern Med, 39(3), e70081.
https://doi.org/10.1111/jvim.70081 Publication
Researcher Affiliations
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California, USA.
- Comparative and Molecular Biosciences, Department of Veterinary Population Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.
MeSH Terms
- Animals
- Horses
- Ryanodine Receptor Calcium Release Channel / genetics
- Rhabdomyolysis / veterinary
- Rhabdomyolysis / genetics
- Malignant Hyperthermia / genetics
- Malignant Hyperthermia / veterinary
- Horse Diseases / genetics
- Horse Diseases / mortality
- Genotype
- Gene Frequency
- Male
- Prospective Studies
- Female
Grant Funding
- UC Davis Veterinary Genetics Laboratory
- #V435AM2 / UC Davis Equine and Comparative Neurology Research Group
Conflict of Interest Statement
Rebecca R. Bellone is affiliated with the University of California, Davis, Veterinary Genetics Laboratory, a facility that offers genetic testing for malignant hyperthermia and other veterinary genetics diagnostic testing. The other authors declare no conflicts of interest.
References
This article includes 43 references
- Denborough M, Lovell RRH. Anaesthetic Deaths in a Family. Lancet II (1960): 45.
- Hopkins PM, Girard T, Dalay S. Malignant Hyperthermia 2020: Guideline From the Association of Anaesthetists. Anaesthesia 76 (2021): 655–664.
- Mullins MF. Malignant Hyperthermia: A Review. Journal of Perianesthesia Nursing 33 (2018): 582–589.
- Greenbaum I, Weigl Y, Pras E. The Genetic Basis of Malignant Hyperthermia. Israel Medical Association Journal 9 (2007): 39–41.
- Denborough M, Hopkinson KC, O'Brien RO, Foster PS. Overheating Alone Can Trigger Malignant Hyperthermia in Piglets. Anaesthesia and Intensive Care 24 (1996): 348–354.
- Biesecker LG, Dirksen RT, Girard T. Genomic Screening for Malignant Hyperthermia Susceptibility. Anesthesiology 133 (2020): 1277–1282.
- McCarthy TV, Healy JM, Heffron JJ. Localization of the Malignant Hyperthermia Susceptibility Locus to Human Chromosome 19q12‐13.2. Nature 343 (1990): 562–564.
- Fujii J, Otsu K, Zorzato F. Identification of a Mutation in Porcine Ryanodine Receptor Associated With Malignant Hyperthermia. Science 253 (1991): 448–451.
- Roberts MC, Mickelson JR, Patterson EE. Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1). Anesthesiology 95 (2001): 716–725.
- Aleman M, Riehl J, Aldridge BM, Lecouteur RA, Stott JL, Pessah IN. Association of a Mutation in the Ryanodine Receptor 1 Gene With Equine Malignant Hyperthermia. Muscle & Nerve 30 (2004): 356–365.
- Denborough M. Malignant Hyperthermia. Lancet 352 (1998): 1131–1136.
- Groom L, Muldoon SM, Tang ZZ. Identical de Novo Mutation in the Type 1 Ryanodine Receptor Gene Associated With Fatal, Stress‐Induced Malignant Hyperthermia in Two Unrelated Families. Anesthesiology 115 (2011): 938–945.
- Zvaritch E, Gillies R, Kraeva N, Richer M, Jungbluth H, Riazi S. Fatal Awake Malignant Hyperthermia Episodes in a Family With Malignant Hyperthermia Susceptibility: A Case Series. Canadian Journal of Anaesthesia 66 (2019): 540–545.
- Harrison GG. Pale, Soft Exudative Pork, Porcine Stress Syndrome and Malignant Hyperpyrexia—An Identity?. Journal of the South African Veterinary Association 43 (1972): 57–63.
- Klein L. A Hot Horse. Veterinary Anaesthesia and Analgesia 2 (1975): 41–42.
- Hildebrand SV, Howitt GA. Succinylcholine Infusion Associated With Hyperthermia in Ponies Anesthetized With Halothane. American Journal of Veterinary Research 44 (1983): 2280–2284.
- Waldron‐Mease E, Klein LV, Rosenberg H, Leitch M. Malignant Hyperthermia in a Halothane‐Anesthetized Horse. Journal of the American Veterinary Medical Association 179 (1981): 896–898.
- Aleman M, Brosnan RJ, Williams DC. Malignant Hyperthermia in a Horse Anesthetized With Halothane. Journal of Veterinary Internal Medicine 19 (2005): 363–366.
- Aleman M, Nieto JE, Magdesian KG. Malignant Hyperthermia Associated With Ryanodine Receptor 1 (C7360G) Mutation in Quarter Horses. Journal of Veterinary Internal Medicine 23 (2009): 329–334.
- Nieto JE, Aleman M. A Rapid Detection Method for the Ryanodine Receptor 1 (C7360G) Mutation in Quarter Horses. Journal of Veterinary Internal Medicine 23 (2009): 619–622.
- Aleman M, Scalco R, Malvick J, Grahn RA, True A, Bellone RR. Prevalence of Genetic Mutations in Horses With Muscle Disease From a Neuromuscular Disease Laboratory. Journal of Equine Veterinary Science 118 (2022): 104129.
- McCue ME, Valberg SJ, Jackson M, Borgia L, Lucio M, Mickelson JR. Polysaccharide Storage Myopathy Phenotype in Quarter Horse‐Related Breeds Is Modified by the Presence of an RYR1 Mutation. Neuromuscular Disorders 19, no. 1 (2009): 37–43.
- Fletcher JE, Calvo PA, Rosenberg H. Phenotypes Associated With Malignant Hyperthermia Susceptibility in Swine Genotyped as Homozygous or Heterozygous for the Ryanodine Receptor Mutation. British Journal of Anaesthesia 71 (1993): 410–417.
- Gallant EM, Lentz LR. Excitation‐Contraction Coupling in Pigs Heterozygous for Malignant Hyperthermia. American Journal of Physiology 262 (1992): C422–C426.
- Richter A, Gerdes C, Löscher W. Atypical Reactions to Halothane in a Subgroup of Homozygous Malignant Hyperthermia(MH)‐Susceptible Pigs: Indication of a Heterogenous Genetic Basis for the Porcine Syndrome. Deutsche Tierärztliche Wochenschrift 99 (1992): 401–406.
- Rrt H, Olthoff D, Deutrich C, Thamm B, Froster UG. Homozygous and Heterozygous Arg614Cys Mutations (1840C‐‐>T) in the Ryanodine Receptor Gene Co‐Segregate With Malignant Hyperthermia Susceptibility in a German Family. British Journal of Anaesthesia 87 (2001): 240–245.
- Wolak S, Rücker B, Kohlschmidt N. Homozygous and Compound Heterozygous RYR1 Mutations. New Findings on Prevalence and Penetrance of Malignant Hyperthermia. Anaesthesist 63 (2014): 643–650.
- Miller DM, Daly C, Aboelsaod EM. Genetic Epidemiology of Malignant Hyperthermia in the UK. British Journal of Anaesthesia 121 (2018): 944–952.
- Locke MM, Ruth LS, Millon LV, Penedo MC, Murray JD, Bowling AT. The Cream Dilution Gene, Responsible for the Palomino and Buckskin Coat Colours, Maps to Horse Chromosome 21. Animal Genetics 32 (2001): 340–343.
- Wilson EB. Probable Inference, the Law of Succession, and Statistical Inference. Journal of the American Statistical Association 22 (1927): 209–212.
- Brown L, Cai T, DasGupta A. Interval Estimation for a Binomial Proportion. Statistical Science 16, no. 2 (2001): 101–133.
- Liu H, Hu Y. Hardy‐Weinberg Equilibrium in Genetic Epidemiology. Zhong Nan Da Xue Xue Bao. Yi Xue Ban 35 (2010): 90–93.
- McCarthy TV, Quane KA, Lynch PJ. Ryanodine Receptor Mutations in Malignant Hyperthermia and Central Core Disease. Human Mutation 15 (2000): 410–417.
- Brandt A, Schleithoff L, Jurkat‐Rott K, Klingler W, Baur C, Lehmann‐Horn F. Screening of the Ryanodine Receptor Gene in 105 Malignant Hyperthermia Families: Novel Mutations and Concordance With the In Vitro Contracture Test. Human Molecular Genetics 8 (1999): 2055–2062.
- Manning BM, Quane KA, Lynch PJ. Novel Mutations at a CpG Dinucleotide in the Ryanodine Receptor in Malignant Hyperthermia. Human Mutation 11 (1998): 45–50.
- Truong KM, Pessah IN. Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild‐Type and Malignant Hyperthermia‐Susceptible Ryanodine Receptors and Heat Stress Intolerance. Toxicological Sciences 167 (2019): 509–523.
- Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical Presentation, Treatment, and Complications of Malignant Hyperthermia in North America From 1987 to 2006. Anesthesia and Analgesia 110 (2010): 498–507.
- Riazi S, Larach MG, Hu C, Wijeysundera D, Massey C, Kraeva N. Malignant Hyperthermia in Canada: Characteristics of Index Anesthetics in 129 Malignant Hyperthermia Susceptible Probands. Anesthesia and Analgesia 118 (2014): 381–387.
- Yuen B, Boncompagni S, Feng W. Mice Expressing T4826I‐RYR1 Are Viable but Exhibit Sex‐ and Genotype‐Dependent Susceptibility to Malignant Hyperthermia and Muscle Damage. FASEB Journal 26 (2012): 1311–1322.
- Yang T, Riehl J, Esteve E. Pharmacologic and Functional Characterization of Malignant Hyperthermia in the R163C RyR1 Knock‐In Mouse. Anesthesiology 105 (2006): 1164–1175.
- Chelu MG, Goonasekera SA, Durham WJ. Heat‐ and Anesthesia‐Induced Malignant Hyperthermia in an RyR1 Knock‐In Mouse. FASEB Journal 20 (2006): 329–330.
- Manley SV, Kelly AB, Hodgson D. Malignant Hyperthermia‐Like Reactions in Three Anesthetized Horses. Journal of the American Veterinary Medical Association 183 (1983): 85–89.
- Wappler F, Fiege M, Steinfath M. Evidence for Susceptibility to Malignant Hyperthermia in Patients With Exercise‐Induced Rhabdomyolysis. Anesthesiology 94 (2001): 95–100.
Citations
This article has been cited 0 times.Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
