David B. Brunson

Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1 )

BackgroundMalignant hyperthermia (MH) is an inherited disorder of skeletal muscle characterized by hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac dysrhythmia, and renal failure, that develops on exposure to succinylcholine or volatile anesthetic agents. All swine and up to 50% of human MH events are thought to be associated with mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor (RYR1). Events resembling MH have been reported in other species, but none have undergone genetic investigation to date. MethodsTo determine the molecular basis of canine MH, a breeding colony was established with a male, mixed-breed, MH-susceptible (MHS) dog that survived an in vivo halothane–succinylcholine challenge. He was mated to three unaffected females to produce four litters and back-crossed to an affected daughter to produce one litter. One of his MHS sons was mated to an unaffected female to produce an additional litter. Forty-seven dogs were phenotyped with an in vitro contracture test and diagnosed as MHS or MH normal based on the North American in vitro contracture test protocol. Nine microsatellite markers in the vicinity of RYR1 on canine chromosome 1 (CFA01) were tested for linkage to the MHS phenotype. Mutational analysis in two MHS and two MH-normal dogs was performed with direct sequencing of polymerase chain reaction products and of cloned fragments that represent frequently mutated human RYR1 regions. A restriction fragment length polymorphism was chosen to detect the candidate mutation in the pedigree at large. ResultsPedigree inspection revealed that MHS in this colony is transmitted as an autosomal dominant trait. FH2294, the marker closest to RYR1, is linked to MHS at a &thgr; = 0.03 with a LOD score of 9.24. A T1640C mutation gives rise to an alanine for valine substitution of amino acid 547 in the RYR1 protein, generating a maximum LOD score of 12.29 at &thgr; = 0.00. All dogs diagnosed as MHS by in vitro contracture test were heterozygous for the mutation, and all MH-normal dogs were homozygous for the T1640 allele. ConclusionsThese results indicate that autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel and that the MHS trait in this pedigree of mixed-breed dogs is in perfect cosegregation with the RYR1 V547A mutation.

Anesthesia in Ophthalmic Surgery

Ophthalmic surgical patients can be routinely anesthetized without complications if the surgeon has a thorough understanding of the effects of anesthetic agents on ocular physiology. The regulation of intraocular pressure is important for successful ophthalmic surgery and can be greatly affected by the anesthetic procedure. Agents utilized to intentionally decrease intraocular pressure are often employed for intraocular procedures. These agents have profound systemic effects that must be anticipated. Adverse drug interactions between sympathomimetic mydriatics and halogenated inhalation anesthetics also must be considered.

Use of Halothane and Isoflurane in the Horse

When compared with halothane, isoflurane has several distinct characteristics. Vaporizer settings are higher because of its lower potency. Respiratory rates will be slower, and intraoperative changes in depth and recovery from surgical depth of anesthesia will be more rapid, although total recovery times frequently will not be different. Halothane and isoflurane appear similar in their effects on ocular reflexes and mean arterial blood pressure. Recovery from isoflurane should be managed to provide added sedation or physical support if the horse attempts to stand prematurely.

Doxacurium and mivacurium do not trigger malignant hyperthermia in susceptible swine

The role of succinylcholine in the precipitation of malignant hyperthermia (MH) necessitates the testing of new neuro-muscular relaxants for their ability to trigger MH in MH-susceptible swine before general human use. We tested doxacurium and mivacurium, two new nondepolarizing bis-benzylisoquinolinium neuromuscular relaxants, at ED95 and at four times ED95 doses in swine previously documented to be MH-susceptible. In none of the 16 animals was MH triggered after administration of these relaxants, whereas all animals developed fatal MH after administration of halothane or halothane plus succinylcholine. Muscle biopsy specimens taken before administration of the relaxant confirmed that all animals had increased sensitivity to halothane, caffeine, or both. Thus, we conclude that doxacurium and mivacurium are not triggering agents of malignant hyperthermia in MH-susceptible swine.