Muscle channelopathies

Question 1

What is the autosomal dominant inheritance for myotonia congenita

Answer 1

Thompsen’s

Question 2

What is the autosomal recessive inheritance for myotonia congenita

Answer 2

Becker’s

Question 3

What is the animal model for CLC1 ion channel mutations

Answer 3

Fainting goats

Myotonic mice - Same mutation in same gene - inappropriate muscle contraction

Question 4

What is the role of ClC1 in the muscle action potential

Answer 4

Vitally important in establishing muscle resting membrane potential - passive movement down conc grad - Drives negative muscle resting membrane potential

Question 5

What is the G200R mutation of the CLC1 channel

Answer 5

Glycine to arginine transition mutation
Changes the voltage dependence of the channel - don’t open until much more positive Vm
This decreases the open probability
Resting membrane is therefore more depolarised
Only need to activate a small number of Ach receptors to reach action potential threshold

Question 6

What is the drug used to treat myotonia congenita

Answer 6

Mexilitene - Inhibits v gated Na channels - gives a submaximal concentration to block some action potentials

Question 7

What is the mutation needed to cause paramyotonia and K aggravated myotonia

Answer 7

Gain of function in the Nav1.4 channel (SCN4A gene)
Causes an issue with the inactivation of the channel - Depolarised longer - More calcium influx means more contractions occur

Question 8

What happens when a patient suffers from malignant hyperthermia

Answer 8

Abnormal response to general anaesthetic
Increased Ca influx from sarcoplasmic reticulum causes mitochondria to have an oxidative burst - Increased contractility so patient goes rigid - increased need for oxygen so tachypnea - low plasma O2 but high CO2 so a respiratory and lactic acidosis - Rapid rise in temperature (1/5mins) Breakdown of muscle tissue leads to release of K so hyperkalemia - cardiac and neural excitability - death

Question 9

What is the mutation that causes malignant hyperthermia

Answer 9

Ryanodine receptor type 1 - skeletal muscle ryanodine receptor -
Mechanically coupled with L-type calcium channels
Increases open probability of the channel due to the gain of function mutation that presents itself with the trigger of GAs

Question 10

Why did farmers select pigs with pig malignant hyperthermia

Answer 10

Increased muscle mass due to increased amount of contraction

Question 11

What is used to trigger malignant hyperthermia

Answer 11

Dantrolene - inhibits ryanodine receptor - blocking calcium influx and muscle contraction
IV hydration to replace lost water due to sweating
Diuretics to stop kidney damage as a result of toxic metabolites from muscle breakdown
NaHCO3 to counter acidosis
Mechanical hyperventilation to remove CO2