Muscle Channelopathies

Question 1

Malignant Hyperthermia

Answer 1

Autosomal dominant
Abnormal response to general anaesthetic - halothane
80% death rate and 10% death rate in those treated

Question 2

Symptoms of malignant hyperthermia

Answer 2

Tachypnea
Tachycardia
Low plasma O2
High plasma CO2
Rigidity
Sweating
Shifts in blood pressure

Question 3

What happens if malignant hyperthermia is not treated and why does this lead to death?

Answer 3

Get respiratory and lactic acidosis
Go into anaerobic respiration which leads to metabolic acidosis
Muscular rigidity which leads to the breakdown of muscles, this releases K+
Severe hyperkalaemia
Cardiac and neuronal excitability
Leads to death because:
Uncontrolled muscle contraction
Excessive ATP hydrolysis
Hypermetabolic state of muscles

Question 4

What causes malignant hyperthermia?

Answer 4

Gain of function mutation in RyR1 on skeletal muscle SR

Position 614

Question 5

Describe what happens when a patient with a 614 gain of function mutation in the RyR1 receptor is exposed to halothane

Answer 5

1. RyR1 has increased sensitivity to halothane and so will cause excess release of Ca2+ from SR
2. Enhanced contraction leads to rigidity
3. Also leads to increased ATP hydrolysis - resulting in heat and hyperthermia
4. Lactic acid production - metabolic acidosis
5. Increased use of oxygen to make ATP leading to low plasma O2 concentrations
6. Increased production of CO2
7. Increase ventilation rate to remove CO2
8. Increased HR to supply O2

Question 6

What are the treatments for malignant hyperthermia

Answer 6

Bantrolene - inhibits RyR1
IV hydration
Diuretics to stop kidney damage
NaHCO3 to counteract acidosis
Mechanical ventilation to remove CO2

Question 7

Myotonia

Answer 7

Hyperexcitability in skeletal muscle
Muscle stiffness
Runs of action potentials with delayed relaxation
Myotonic seizures

Question 8

What are the two forms of myotonia?

Answer 8

Myotonia congenita and paramyotonia

Question 9

Myotonia congenita

Answer 9

Thomson’s autosomal dominant
Becker’s autosomal recessive
Both these mutations are on the same gene but at different locations
Loss of function in CLC1

Question 10

Describe the normal function of CLC1

Answer 10

4 CLC1 come together to form one functional channel - a voltage dependent chloride channel
CLC1 channels are kept open at rest to keep negative membrane potential

Question 11

Describe the loss of function CLC1 mutation effects

Answer 11

1. Loss of contribution of CLC1 to the Vm
2. Channels function but there is a change in the voltage dependence
3. This leads to a less negative membrane potential
4. Resting potential is slightly depolarised and so there is increased excitability
5. Smaller depolarisation needed to reach threshold
6. Number of action potentials per unit time is higher
7. Contraction

Question 12

Treatments for myotonia congenita

Answer 12

Moxilitene - inhibits voltage gated Na+ channels so reduce the depolarisation phase, however a submaximal dose must be given

Question 13

Paramyotonia

Answer 13

Issues with the inactivation gate
Channels do not close when they should
Depolarisation phase is prolonged and therefore there is prolonged contraction
SCN4A Nav1.4 gain of function mutation