CNS channelopathies

Question 1

What is episodic ataxia?

Answer 1

Irregular, uncontrolled muscle contractions 
Rare condition (<1 in 100,000) 
There are at least 6 types but type 1 and 2 are more understood

Question 2

What are the properties of episodic ataxia type 1?

Answer 2

Autosomal dominant
Inset between 10 -20 years ; symptoms will gradually appear
Causes brief attacks of ataxia and dizziness
Mutation in voltage gated potassium channel KCNA1

Question 3

What are the properties of episodic ataxia type 2?

Answer 3

Austosomal dominant
Onset child to teens
Ataxia, vertigo, nausea and headaches
Attacks are more severe thatn type 1 and can last from 30 minutes to 24 hours
Mutation in voltage gated calcium channel CACNAIA

Question 4

What are some of the common symptoms between episodic ataxia type 1 and 2?

Answer 4

Ataxia (Seen in ALL), trunk instability, vomiting, dizziness, nystagmus, nausea, headache and visual blirring
Patients can appear to look drunk

Question 5

What are the triggers of episodic ataxia type 1?

Answer 5

Triggers may be physical or emotional stress, impacts on the vestibular system or an abrupt change in position

Question 6

What is the structure of KCNA and where is it found?

Answer 6

4 subunits, each with 6 transmembrane spanning domains

Found in the cerebellum and at neuromuscular junctions

Question 7

What type of mutation occurs in KCNA and how does this affect the cell?

Answer 7

Loss of function mutation, causes a delay in repolarisation

Question 8

How can type 1 episodic ataxia be treated?

Answer 8

Acetazolomide - carbonic anhydrase inhibitor? works by disrupting pH of bodily fluids so the excitability is dampened down in cerebellar cells
Phenytoin - sodium channel blocker
Carbamazpine - sodium channel blocker

Question 9

What is the structure of CACNAIA (CaV)?

Answer 9

One subunit with 24 transmembrane spanning domains

Question 10

Which mutations in CACNAIA cause the most severe symptoms?

Answer 10

Those that cause truncation of the protein

Question 11

What 3 disorders can CACNAIA mutations cause?

Answer 11

1) episodic ataxia type 2
2) Familial hemiplegic migraine - causes migraines, inherited, missense mutations
3) Spinocerebellar ataxia - repeated expansion of the C terminus

Question 12

Where is CACNAIA located?

Answer 12

Purkinje cells, granule cells and cell bodies of central neurones

Question 13

Why might barium be used when calcium channels are being used experimentally?

Answer 13

Barium does not cause the calcium channels to close after it moves through like calcium does

Question 14

What is the effect of the mutation in CACNA1A in cells?

Answer 14

Reduced total flow of calcium ions into neurons, which disrupts the release of neurotransmitters in the brain.

Question 15

For the mutant CACNA1A what is the opening potential?

Answer 15

8mV - this means the channel is activated later on than normal

Question 16

Describe what happens in CACNA1A knockout mice

Answer 16

They are normal up to the first 10 days but after show balance problems; ataxia and falling with twisting movements
Death occurs 3-4 weeks after birth (no functioning protein at all unlike in humans)

Question 17

What are the possible causes of eilepsy?

Answer 17

Brain trauma, infection, tumours and inherited

Question 18

How can epilepsy be classified?

Answer 18

Partial or generalised (how big is the area of brain affected?)
Simple (no loss of consciousness) or complex (loss of consciousness)

Question 19

How can excitatory and inhibitory neurons cause epilepsy?

Answer 19

excitatory neurons = too much activity, inhibitory neurons = to little activity

Question 20

What are HCN channels?

Answer 20

Activated cyclic nucleotide gated channel
cAMP can change its open probability
When open they allow cations through to cause depolarisation

Question 21

Where is Nav1.1 found and what is its role?

Answer 21

It is found in inhibitory neurons and they mediate depolarisation for action potentials

Question 22

What happens when Nav1.1 channels open?

Answer 22

The CaV channels are activated causing vesicles to fuse and release GABA. GABA binds to receptors on the post synaptic membrane which causes a negative shift in the resting potential of an excitatory neuron so it is harder for it to reach threshold potential

Question 23

What mutations occur in the dendrites of the excitatory neuron to cause epilepsy?

Answer 23

CaV, HCN and Kv4.2

Question 24

What mutations occur in the axons of excitatory neurons to cause epilepsy?

Answer 24

Nav1.2, Kv1.1, Kv7.2 and Kv7.3

Question 25

What is the effect of a loss of function mutation in a heterozygous Nav1.1 knockout mouse?

Answer 25

In the wt AP firing is due to Nav1.1 and gets fired faster, however in the KO the firing is less often and the ability to fire gets worse
The KO releases less GABA so the excitatory neuron membrane potential is closer to the threshold - epilepsy is therefore mimiced

Question 26

What are febrile seizures?

Answer 26

Seizures caused by a rise in temperature, seen in children with infections and illness

Question 27

What is SME?

Answer 27

Severe myoclonic epilepsy

Question 28

What is the role of HCN in the excitatory dendrites?

Answer 28

Some channels have no role in action potential firing but they will ‘fine tune’ the resting potential
Activation of HCN in the dendrites controls firing by lowering membrane potential and therefore inhibits firing
KV7.2 also works in the same way

Question 29

What is the definition of pain?

Answer 29

An unpleasant sensory or emotional experience associated with actual or potential tissue damage

Question 30

What mutation causes the loss of pain?

Answer 30

Nav1.7 loss of function mutation in peripheral sensory neurons

Question 31

What may cause an enhancement of pain?

Answer 31

Gain of function mutation in Nav1.7

Question 32

Why may some people be more tolerable to pain?

Answer 32

There may be polymoprhisms in Nav7.1