OMIA 000621-9615 : Malignant hyperthermia in Canis lupus familiaris

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

Possibly relevant human trait(s) and/or gene(s) (MIM number): 145600

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).

Inheritance: All dogs are potentially at risk because one copy of the mutant gene is sufficient to produce clinical signs and the mutation is not limited to specific breeds (Brunson et al., 2004).

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: 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, and sevoflurane) and depolarizing muscle relaxants such as succinylcholine (Roberts et al., 2001, Brunson et al., 2004).

Treatment involves cessation of the causative anesthetic, supportive care, cooling, and dantrolene administration. 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 et al., 2004).

Pathology: The ryanodine receptor is part of the calcium-releasing channel in skeletal muscle. In affected dogs, chemical triggers interact directly with the ryanodine receptor to increase and prolong sarcoplasmic calcium release. This increases muscle contraction and muscle metabolism, resulting in hyperthermia (Brunson et al., 2004). Dantrolene is a muscle relaxant that blocks calcium release inside myocytes (Brunson et al., 2004).

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, English Springer Spaniel, German Shepherd Dog, Greyhound, Labrador Retriever, Pointer, Saint Bernard.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
RYR1 ryanodine receptor 1 (skeletal) Canis lupus familiaris 1 NC_006583.3 (114579577..114461350) RYR1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Collie Doberman German Shepherd Dog Labrador Retriever Malignant hyperthermia RYR1 missense A302128 1 c.1640T>C p.V547A 2001 11575546

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2017 Thrift, E., Wimpole, J.A., Child, G., Brown, N., Gandolfi, B., Malik, R. :
Exercise-induced hyperthermia syndrome (canine stress syndrome) in four related male English springer spaniels. Vet Med (Auckl) 8:59-68, 2017. Pubmed reference: 30050857. DOI: 10.2147/VMRR.S123836.
2012 Adami, C., Axiak, S., Raith, K., Spadavecchia, C. :
Unusual perianesthetic malignant hyperthermia in a dog. J Am Vet Med Assoc 240:450-3, 2012. Pubmed reference: 22309018. DOI: 10.2460/javma.240.4.450.
2004 Brunson, DB., Hogan, KJ. :
Malignant hyperthermia: a syndrome not a disease. Vet Clin North Am Small Anim Pract 34:1419-33, 2004. Pubmed reference: 15474681. DOI: 10.1016/j.cvsm.2004.05.010.
2002 Nelson, T.E. :
Malignant hyperthermia: a pharmacogenetic disease of Ca++ regulating proteins. Curr Mol Med 2:347-69, 2002. Pubmed reference: 12108947.
2001 Roberts, M.C., Mickelson, J.R., Patterson, E.E., Nelson, T.E., Armstrong, P.J., Brunson, D.B., Hogan, K. :
Autosomal dominant canine malignant hyperthermia is caused by a mutation in the gene encoding the skeletal muscle calcium release channel (RYR1) Anesthesiology 95:716-725, 2001. Pubmed reference: 11575546.
1998 Xu, L., Eu, J.P., Meissner, G., Stamler, J.S. :
Activation of the cardiac calcium release channel (ryanodine receptor) by poly-s-nitrosylation Science 279:234-237, 1998. Pubmed reference: 9422697.
1997 Duncan, K.L., Hare, W.R., Buck, W.B. :
Malignant hyperthermia-like reaction secondary to ingestion of hops in five dogs Journal of the American Veterinary Medical Association 210:51 ff., 1997.
Sudo, R.T., Nelson, T.E. :
Changes in ryanodine-induced contractures by stimulus frequency in malignant hyperthermia susceptible and malignant hyperthermia nonsusceptible dog skeletal muscle Journal of Pharmacology & Experimental Therapeutics 282:1331-1336, 1997.
1992 Cosgrove, S.B., Eisele, P.H., Martucci, R.W., Gronert, G.A. :
Evaluation of Greyhound Susceptibility to Malignant Hyperthermia Using Halothane-Succinylcholine Anesthesia and Caffeine-Halothane Muscle Contractures Laboratory Animal Science 42:482-485, 1992. Pubmed reference: 1460848.
1991 Nelson, T.E. :
Malignant hyperthermia in dogs. J Am Vet Med Assoc 198:989-94, 1991. Pubmed reference: 2032926.
1990 Obrien, P.J., Pook, H.A., Klip, A., Britt, B.A., Kalow, B.I., Mclaughlin, R.N., Scott, E., Elliott, M.E. :
Canine Stress Syndrome Malignant Hyperthermia Susceptibility - Calcium-Homeostasis Defect in Muscle and Lymphocytes Research in Veterinary Science 48:124-128, 1990. Pubmed reference: 2300706.
1987 O'Brien, P.J., Fletcher, T.F., Metz, A.L., Kurtz, H.J., Reed, B.K., Rempel, W.E., Clark, E.G., Louis, C.F. :
Malignant hyperthermia susceptibility: cardiac histomorphometry of dogs and young and market-weight swine. Can J Vet Res 51:50-5, 1987. Pubmed reference: 3567752.
O'brien, P.J. :
Malignant hyperthermia in dogs. Can Vet J 28:302-3, 1987. Pubmed reference: 17422791.
Rand, J.S., O'Brien, P.J. :
Exercise-induced malignant hyperthermia in an English springer spaniel. J Am Vet Med Assoc 190:1013-4, 1987. Pubmed reference: 3570952.
1986 Cribb, P.H., Olfert, E.A., Reynolds, F.B. :
Erythrocyte osmotic fragility testing and the prediction of canine malignant hyperthermia susceptibility. Can Vet J 27:517-22, 1986. Pubmed reference: 17422730.
1985 O'Brien, P.J., Rand, J.S. :
Canine stress syndrome. J Am Vet Med Assoc 186:432-3, 1985. Pubmed reference: 3972704.
1984 Kirmayer, A.H., Klide, A.M., Purvance, J.E. :
Malignant hyperthermia in a dog: case report and review of the syndrome. J Am Vet Med Assoc 185:978-82, 1984. Pubmed reference: 6511640.
O'Brien, P.J., Forsyth, G.W., Olexson, D.W., Thatte, H.S., Addis, P.B. :
Canine malignant hyperthermia susceptibility: erythrocytic defects--osmotic fragility, glucose-6-phosphate dehydrogenase deficiency and abnormal Ca2+ homeostasis. Can J Comp Med 48:381-9, 1984. Pubmed reference: 6150753.
1983 Leary, S.L., Anderson, L.C., Manning, P.J., Bache, R.J., Zweber, B.A. :
Recurrent malignant hyperthermia in a Greyhound. J Am Vet Med Assoc 182:521-2, 1983. Pubmed reference: 6833093.
O'brien, P.J., Cribb, P.H., White, R.J., Olfert, E.D., Steiss, J.E. :
Canine malignant hyperthermia: diagnosis of susceptibility in a breeding colony. Can Vet J 24:172-7, 1983. Pubmed reference: 17422267.
1978 Bagshaw, R.J., Cox, R.H., Knight, D.H., Detweiler, D.K. :
Malignant hyperthermia in a Greyhound. J Am Vet Med Assoc 172:61-2, 1978. Pubmed reference: 624662.
Cohen, C.A. :
Malignant hyperthermia in a greyhound. J Am Vet Med Assoc 172:1254, 1256, 1978. Pubmed reference: 659305.
1973 Short, C.E., Paddleford, R.R. :
Letter: Malignant hyperthermia in the dog. Anesthesiology 39:462-3, 1973. Pubmed reference: 4758363.

Edit History


  • Created by Frank Nicholas on 12 Sep 2005
  • Changed by Martha MaloneyHuss on 10 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 18 Sep 2012