cns channelopathies

Question 1

Type I episodic ataxia

Answer 1

short duration of episodes

KCN1A mutation = voltage gated K+ channel

Question 2

what allelic disorders are CACNA1A mutations associated with?

Answer 2

type II episodic ataxia - caused by truncation mutations
familial hemiplegic migraine - caused by missense mutations
spinocerebellar ataxia type 6 - caused by repeat expansion of c terminus

Question 3

what are the acquired causes of epilepsy?

Answer 3

damage to brain causing changes in ion channels

autoimmune diseases targeting ion channels

Question 4

DEFINE: febrile seizures

Answer 4

seizures in response to increase in body temperature

Question 5

SMEI

Answer 5

severe myoclonic epilepsy of infancy

Question 6

which voltage gated Na+ channels are mutated in epilepsy?

Answer 6

Nav1.1 - located on inhibitory interneurons

Nav1.2 - located on excitatory axons

Question 7

how does a GABAa receptor mutation cause epilepsy?

Answer 7

• LOF GABAa receptor mutation
• GABAa receptor located on post-synaptic excitatory neuron but cannot respond to GABA released by interneuron
• No Cl- entry into cell no hyperpolariation
• membrane potential of excitatory neuron closer to threshold –> easier to fire APs

Question 8

how does a nicotinic ACh receptor mutation cause epilepsy?

Answer 8

• GOF nicotinic ACh receptor mutation
• nicotinic ACh receptor located on post-synaptic membrane of excitatory neuron downstream of 1st excitatory neuron
• excess nicotinic ACh receptor activation
• increased excitatory output

Question 9

how does a Nav1.2 mutation cause epilepsy?

Answer 9

• GOF Nav1.2 mutation
• Nav1.2 located on excitatory axon
• channel activated at more negative membrane potentials so smaller depolarisation required to fire APs
• increase in excitatory output

Question 10

how does a HCN mutation cause epilepsy?

Answer 10

• LOF HCN mutation
• located on excitatory dendrites (post-synaptic)
• depolarises membrane

Question 11

how does a Kv7.2 mutation cause epilepsy?

Answer 11

• LOF Kv7.2 mutation
• located on excitatory axons (pre-synaptic)
• usually hyperpolarises membrane

Question 12

what mutation causes loss of pain?

Answer 12

• LOF Nav7.2 mutation on nociceptive neurons

lose ability to fire APs in nociceptive neurons

Question 13

what mutation causes enhancement of pain?

Answer 13

• GOF Nav7.2 mutation on nociceptive neurons

inappropriate firing of APs with NO trigger