Channelopathies of muscle contraction

Question 1

Types of molecular pathologies

Answer 1

Genetic channelopathies (mutated genes). Neuromuscular disorders

Autoimmune/toxic (antibodies, toxins). Myasthenia gravis (AchR)

Transcriptional (abnormal transcription). Multiple sclerosis (Na+ channel)

Question 2

Myokomia

Answer 2

Spontaneous muscle contractions
Nerve cell left in depolarised state and poised to fire AP
AP prolonged (excessive release of neurotransmitter)

Mild facial muscle twitching is most common
Mutation in Kv1.1 expressed in synaptic terminals (reduced K+ channel activity)

Question 3

Myotonia

Answer 3

Prolonged muscle contraction
Mutation in CLC1 chloride channel gene (expressed in skeletal muscle and required for membrane repolarisation)

Mutated Cl- channel less open so Cl- influx impaired
Hyperexcitability of muscle and multiple action potentials

Question 4

Wild type/myotonic T tubules

Answer 4

In wild type, Cl- accounts for 70-80% of membrane conductance

In myotonic, K+ is dominant conductance. K+ accumulation depolarises the membrane and triggers further APs

Question 5

Myotonia in humans

Answer 5

CLC1 loss of function mutation
Muscle stiffness from continued AP firing
Autosomal recessive (generalised myotonia) is more severe form
Autosomal dominant (myotonia congenita) is milder form

Symptoms relieved by warming up (exercise)

CLC4 may compensate for CLC1 (explains why recessive form is not lethal)

Question 6

Hypokalemic periodic paralysis

Answer 6

Flaccid muscles and muscle weakness lasting several hours

L-type VGCC mutation in skeletal muscle. Most common in S4 domain (voltage sensor)
VGCC fails to sense AP and doesn’t open
Also results from malfunctioning Na+ channel

Question 7

Human malignant hyperthermia

Answer 7

Abnormal reaction to volatile anaesthetics (halothane)
High fever, skeletal muscle rigidity, hypoxia

Autosomal dominant gain of function in RyR1 (ryanodine receptor)
Arg614Cys most common

Question 8

Mutant RYR channel

Answer 8

Regulation of the channel gating by Ca2+, ryanodine, ATP is affected.
Channel activity is elevated (more open)
Excessive cytosolic Ca2+ elevations leading to glucose depletion, heat, muscle contraction

Treated with Dantrolene (inhibits Ca2+ release from SR)

Question 9

Central core disease

Answer 9

Muscle biopsy. Manifests in infants
Autosomal dominant gain of function
Muscle core is unstructured, inactive and devoid of mitochondria

Mutation in RYR (Arg2435His) leading to persistent Ca2+ leakage and muscle atrophy

Question 10

Long QT syndrome

Answer 10

Cardiac disorder
LQT1/2 arise from mutations VG K+ channels
LQT3 from VG Na+ channel

Prolonged QT interval (APs can overlap with next)

Question 11

Types of long QT syndrome

Answer 11

LQT1 loss of function of KCNQ1 K+ channel
LQT2 loss of function of HERG K+ channel (reduced K+ efflux)
LQT3 most severe. Gain of function of VG Na+ channel (enhanced Na+ influx)

Question 12

Familial hemiplegic migraine

Answer 12

Migraine and paralysis
Mutated P-type VGCC
Autosomal dominant

Increased rate of inactivation of VGCC. Increases channel availability and Ca2+ influx into neurons. Altered neurotransmitter release