L13 - Myontonia and Malignant Hyperthermia

Question 1

What is Myotonia?

Answer 1

Hyper-excitability of skeletal muscle
Muscle stiffness
Runs of action potentials with delayed relaxation
Myotonic seizures – body wide contraction of skeletal muscle

Question 2

What is the prevalence of myotonia?

Answer 2

1:23,000 to 1: 50,000

Varies depending on type and location

Question 3

What mutations causes myotonia congenita?

Answer 3

Loss of function mutations in CLCN1 gene

- This makes a CLC1 protein – found in skeletal muscle

Question 4

What are the two types of myotonia congenita?

Answer 4

2 types depending on where the mutation lies in the protein

• Thomsen’s autosomal dominant
• Becker’s autosomal recessive

Question 5

What are fainting goats?

Answer 5

Symptoms mimic those seen in human patients with myotonia congenita

Question 6

What mutations causes paramyotonia?

Answer 6

Gain of function mutations in SCN4A gene

- This makes a Nav1.4 protein – found in skeletal muscle

Question 7

What does paramyotonia cause?

Answer 7

Issues with inactivation gate

• Channels do not close
• More Na+ enters muscle leading to prolonged depolarisation
• Leads to excessive contraction of muscle

Question 8

What channels are involved in the muscle action potential?

Answer 8

EK ~ -90 mV
ECl ~ -70 mV
- If you open up Cl channels membrane potential driven towards -70 mV
- Both K and Cl channels open in membrane at rest
- They set the resting membrane potential

Question 9

What are the characteristics of the Cl channel in myotonia congenita?

Answer 9

12 transmembrane spanning domains
4 domains come together to make a functional channel
No pattern of where we see mutations in the protein

Question 10

What does the CLC1 mutations in myotonia congenita cause?

Answer 10

Voltage dependent Cl channel – its open potential increases as the membrane potential depolarises
CLC1 channels open half the time at the resting membrane potential
Mutant CLC1 channels barley open at the resting membrane potential
- Resting membrane potential less negative in mutant cells
- Need a bigger depolarisation to reach the same open probability as wild type

Question 11

How does the CLC1 mutation affect threshold and Cl conductance in myotonia congenita?

Answer 11

In CLC1 mutant depolarised resting membrane potential is closer to threshold
Smaller depolarisation required to reach threshold
Ach receptors that produce a depolarisation are more likely to fire an action potential
- Increased frequency of action potential firing
- Increased excitability and muscle contraction

Question 12

What is the treatment for Myotonia congenita?

Answer 12

Mexilitene

• Inhibits Na+ channel – stops depolarisation phase of action potential
• Give a sub-maximal dose

Question 13

In paramyotonia with Nav1.4 mutations what can be used to trigger muscle stiffness?

Answer 13

The cold
In wild type fibres – rise in intracellular Na
- The cold slows down the kinetics of the channel
In mutant fibres – greater rise in intracellular Na
- Channels more sensitive to the cold

Question 14

What is malignant hyperthermia?

Answer 14

Autosomal dominant

They have an abnormal response to general anaesthesia – halothane

Question 15

What is the prevalence of malignant hyperthermia?

Answer 15

1 in 10,000 to 1 in 50,000 individuals

• 80% death rate
• Treatment death rate 10%

Question 16

What are the symptoms of malignant hyperthermia?

Answer 16

Tachypnea - rapid breathing
Low plasma O2
High plasma CO2
Tachycardia
Hyperthermia - can be 1oC every 5 mins
Rigidity
Sweating
Shifts in blood pressure

Question 17

What is the treatment for malignant hyperthermia?

Answer 17

No treatment
Anaerobic respiration leading to respiratory and lactic acidosis
Muscular rigidity leading to muscle breakdown
- Release of K+ –> hyperkalaemia –> cardiac and neuronal excitability
Leads to death

Question 18

What is the reasoning behind the symptoms of malignant hyperthermia?

Answer 18

Uncontrolled muscle contraction
Excessive ATP hydrolysis releasing heat
- Due to lots of cross bridge formation
Hypermetabolic state of muscles – replace ATP and sustain ATP stores

Question 19

What 2 receptors are involved in malignant hyperthermia?

Answer 19

RyR1 - skeletal muscle ryanodine receptor

CICR – sarcoplasmic reticulum

Question 20

What mutations cause malignant hyperthermia?

Answer 20

Gain of functions mutations in RyR1

• Increased open probability in mutant channels
• Greater currents with more Ca leaving the sarcoplasmic reticulum

Question 21

What is the mutation causing pig hyperthermia?

Answer 21

Mutation - Arg 615 to Cysteine

Question 22

What are the symptoms of pig hyperthermia?

Answer 22

Same as those seen in humans 
Triggered by physical stress and halothane
Increase in muscle mass
- These pigs were selected by farmers
- Lead to an increase in incidence

Question 23

What is the mutation causing pig hyperthermia?

Answer 23

RyR1 614 mutation

Question 24

In malignant hyperthermia rabbit exposure to halothane and caffeine leads to?

Answer 24

A rise in intracellular Ca

This is monitored as changes in Ca concentration change the fluorescence

Question 25

In malignant hyperthermia the excess release of Ca from the sarcoplasmic reticulum leads to?

Answer 25

Enhanced contraction - rigidity
Excess ATP hydrolysis – heat and hyperthermia
Lactic acid production – metabolic acidosis
Increased use of O2 to make ATP – low plasma O2
Increased production of CO2 – high plasma CO2
Increase ventilation – to try to remove CO2
Increase heart rate – to supply O2

Question 26

What is the treatment for malignant hyperthermia?

Answer 26

Dantrolene – inhibits RyR1 blocking Ca
IV hydration
Diuretics - stop kidney damage from muscle breakdown products)
NaHCO3 - to counter acidosis
Mechanical hyperventilation - to remove CO2