1. Pickled Pigs and Hyperthermia
By: Long Xin Chen, Yi Min Liang, Alena Tran, Michelle Yee
October 10th, 2017
PHM Metabolic Biochemistry & Immunology
PHM Fall 2017
Instructor: Dr. Jeffrey Henderson

2. Presentation Outline Introduction Genetics of Malignant Hyperthermia
Pickled Pigs & How it Relates to Humans
Pathophysiology
Diagnostics, Preventions and Treatments
Presentation Summary
Presentation Outline

3. Hyperthermia What is it?
Risen in body temperature (above 38.5 °C) due to failed thermoregulation
Most severe form is heat stroke
Can be deadly, function of proteins in cell membranes can be adversely affected
Causes:
Dehydration from not drinking enough water
Confined in poorly ventilated environment
Drugs can influence ex) Alcohol
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What is it? Rise in body temperature due to failed thermoregulation (body produces or absorbs more head than it dissipates) Causes Commonly caused by heat strokes, adverse drug reactions (CNS; rare) Special case: Malignant hyperthermia - rare complication on some types of general anesthesia Symptoms
Introduction

4. Malignant Hyperthermia
Rare, inherited disorder, life-threatening
Mutation that results buildup of calcium in muscle, leads to massive metabolic reaction
Most people are unaware that they have this mutation
Result of severe reaction to triggering agents
Triggering agents:
Halogenated anesthetic gases
Muscle relaxant succinylcholine
Other drugs
May experience:
Rapid heart rate
Muscle Spasms
Acidosis
Organ dysfunction and failure
Special case: Malignant hyperthermia - rare complication on some types of general anesthesia Symptoms
Introduction

5. Pickled Pigs How it relates to humans
MH in pigs is termed “porcine stress syndrome”
Triggered by stress, anaesthesia or intense exercise
Autosomal recessive disorder due to a defective ryanodine receptor
Death from porcine stress syndrome = pickled pigs
Pale, soft, exudative meat due to drop in muscle pH and degradation of muscle proteins
How it relates to humans
Pig models are used for research
Similar mutations in pigs that led researchers to discover the mutation in humans
What is it? Rise in body temperature due to failed thermoregulation (body produces or absorbs more head than it dissipates) Causes Commonly caused by heat strokes, adverse drug reactions (CNS; rare) Special case: Malignant hyperthermia - rare complication on some types of general anesthesia Symptoms
Introduction

6. Genetics of Malignant Hyperthermia
Autosomal dominant inheritance pattern
Different genetic mutations are categorized into at least 6 forms of malignant hyperthermia susceptibility (MHS)
Mutated genes are associated with calcium channels of skeletal muscles
Calcium-release channels
Dihydropyridine receptors
Brandom (2006) Sci World J
Rosenberg et al. (2015) Orphanet J Rare Dis
NIH U.S. National Library of Medicine (2016)
Large genetic component associated with MH. MH follows an autosomal dominant inheritance pattern, hence one copy of the gene associated with MH is already sufficient to display the disease symptoms and severe reaction to certain drugs during surgery. Associated genes that are mutated are involved in skeletal muscle function. There are at least 6 forms of malignant hyperthermia susceptibility (MHS), which are categorized by gene mutations. Mutations observed in RYR1, CACNA1S and CACNA2D1 have been linked to MHS1, 5 and 3 respectively. The remainder forms are still under investigation.
Genetics

7. RYR1
Located on 19q13.2
Encodes for homotetrameric ryanodine receptor (RYR1) channel
MHS1, MHS2, and MHS3
At least 217 mutations identified to increase risk of malignant hyperthermia
Mostly single amino acid point mutations in important gene regions
Mutations alter the structure of the RYR1 channels, leading to overaccumulation of Ca2+ in skeletal muscles
Brandom (2006) Sci World J
Rosenberg et al. (2015) Orphanet J Rare Dis
NIH U.S. National Library of Medicine (2016)
Located on the long arm of chromosome 19 at the 13.2 position. The gene expresses ryanodine receptor 1 proteins, which are involved with the formation of channels transporting Ca ions into cells.
Image from
Genetics

8. CACNA1S
Located on 1q32.1
Encodes for calcium voltage-gated channel subunit alpha1 S
Forms dihydropyridine receptor, which activate RYR1 channels
MHS5
2 mutations linked to malignant hyperthermia:
Arg1086Cys
Arg1086His
Mutations cause improper activation of RYR1 channels
Image from
Brandom (2006) Sci World J
Rosenberg et al. (2015) Orphanet J Rare Dis
NIH U.S. National Library of Medicine (2016)
Located on long arm of chromosome 1, position 32.1.
Genetics

9. Genetics Summary Genetic Mutation
Mutated RYR1: Structural Alteration of RYR1 channel
Mutated CACNA1S: Improper activation of RYR1 channels (response to certain drugs)
Overaccumulation of Ca2+ in skeletal muscles
Malignant Hyperthermia Symptoms
Brandom (2006) Sci World J
Rosenberg et al. (2015) Orphanet J Rare Dis
NIH U.S. National Library of Medicine (2016)
Mutation
Open more easily and close slowly in response to drug
Symptoms such as:
Abnormalities in skeletal muscle contractability leading to muscle rigidity, heat generation, and excess acid production leading to acidosis.
Genetics

10. Normal Muscle Physiology
Ach released, binds to receptors
Action potential reaches T-tubules
Conformation change at DHP is transmitted to RYR1
Calcium released from SR, muscle contracts
Reuptake of calcium into SR via calcium-ATPase pump
DHP = dihydropyrimidine receptor RYR1 = ryanodine receptor subtype 1
Normal Muscle Physiology

11. Pathophysiology Trigger agents induce prolonged opening of RYR1
Uncontrolled release of calcium → continuous muscle activation
Excessive stimulation of aerobic and anaerobic metabolism→ metabolic acidosis
Increased oxygen consumption→ hypoxemia
Increase in ATP usage → heat production
Depletion of ATP→ muscle rigidity, rhabdomyolysis
Pathophysiology

12. Treatment
Prepare and administer dantrolene. This is a direct-acting skeletal muscle relaxant through inhibiting the release of calcium ions from the sarcoplasmic reticulum
Begin cooling measures
Treat cardiac arrhythmias as needed
Correct hyperkalemia with hyperventilation, glucose and insulin.
MacLennan, 1992
Rosenberg et al., 2003
Treatment

13. Diagnostic/Prevention
Muscle Contracture Test: Caffeine Halothane Contracture Test:
Skeletal muscle biopsy from patient’s thigh
Access muscle contractile properties upon exposure to ryanodine receptor agonists: caffeine, halothane
Abnormally high levels of contractile force indicate malignant hyperthermia sensitivity
Sensitivity > Specificity
Malignant Hyperthermia Association of US
Diagnostic/Prevention

14. Diagnostic/Prevention
Muscle Contracture Test: Caffeine Halothane Contracture Test
Genetic Testing (RYR1 gene sequencing)
Thorough anesthetic history should be considered before undergoing anesthesia.
Individuals undergoing general anesthetics for more than 30 minutes should have their temperature monitored.
Rosenberg et al., 2003
Diagnostic/Prevention

15. Summary Summary Introduction
Hyperthermia is the result of body temperature rise due to poor thermoregulation
Malignant Hyperthermia is an inherited mutation that alters function of Ca2+ release channels in SR
Malignant Hyperthermia in pigs is called “porcine stress syndrome” and is autosomal recessive
Genetics in Humans
Malignant Hyperthermia in humans is autosomal dominant, and genetic mutation lead to different forms of malignant hyperthermia susceptibility
Genetic mutations are often associated with calcium channels of skeletal muscles such as Ca2+-release channels in the sarcoplasmic reticulum and dihydropyridine receptors (adjacent voltage-gated channels)
Examples of genetic mutations include RYR1 and CACNA1S
Pathophysiology
Prolonged opening of RYR1→ uncontrolled release of calcium→ sustained muscle activity
Diagnostics, Preventions & Treatments
Dantrolene is used to immediately treat MH, it is a direct-acting skeletal muscle relaxant through inhibiting the release of calcium ions from the sarcoplasmic reticulum
Diagnostic tools include: muscle contracture test using caffeine and halothane & genetic testing (RYR1 gene sequencing)
Summary

16. References References
Farley R. Inherited diseases of Ion Transport.Cell Physiology Source Book doi: /B Schneiderbanger D, Johannsen S, Roewer N, Schuster F. Management of malignant hyperthermia: diagnosis and treatment. Therapeutics and Clinical Risk Management. 2014;10: doi: /TCRM.S Silverthorn D. Human Physiology: An Integrated Approach 7th edition. San Francisco: Pearson Education Anon. The Chiropractic Office. Available from: [Accessed from 9th October 2017]. Ording H. Pathophysiology of malignant hyperthermia. Ann Fr Anesth Reanim 8, (1989). Kolh, M.E., Horne, M.L., Martz, R. Dantrolene in human malignant hyperthermia. Aneshesiology 56, (1982). MacLennan, D.H. The genetic basis of malignant hyperthermia.TiPS 13, (1992). Anon. Testing for malignant hyperthermia susceptibility: how do I counsel my patients? Available from: [Access from 9th October 2017] Rosenberg, H., Sambuughin, N., Riazi, S., Dirksen, R. Malignant hyperthermia susceptibility. Gene Reviews (2003). Rosenberg, H., Pollock, N., Schiemann, A., Bulger, T., Stowell, K. Malignant hyperthermia: a review. Orphanet J Rare Dis 10: 93. DOI /s (2015) Brandom, B.W., Genetics of malignant hyperthermia. Sci World J 6, DOI /tsw (2006) NIH U.S. National Library of Medicine. Malignant hyperthermia. Available from: [Accessed from 9th October 2017] NIH U.S. National Library of Medicine. CACNA1S gene. Available from: [Accessed from 9th October 2017] NIH U.S. National Library of Medicine. RYR1 gene. Available from: [Accessed from 9th October 2017]
References

17. Thank you!