L10 - CNS Channelopathies

Question 1

What is episodic ataxia?

Answer 1

Irregular, uncontrolled muscle contractions
< 1 in 100,000
At least 6 types - type I and II seen in multiple families

Question 2

What is type 1 episodic ataxia?

Answer 2

Autosomal dominant
Onset of symptoms - 10-20 years
Ataxia, dizziness
Attack length - brief

Question 3

Which channel mutation is type 1 episodic ataxia linked to?

Answer 3

Linked to mutations in KCNA1 (KV)

Question 4

What is type 2 episodic ataxia?

Answer 4

Autosomal dominant
Onset of symptoms - childhood to teens
Ataxia, vertigo, nausea, headache
Attack length - 30 mins to 24 hours

Question 5

Which channel mutation is type 2 episodic ataxia linked to?

Answer 5

Linked to mutations in CACNA1A (CaV)

Question 6

What is the trigger for type 1 episodic ataxia?

Answer 6

Physical or emotional stress
Impacts on vestibular system
Abrupt changes in position

Question 7

What are the symptoms of type 1 episodic ataxia?

Answer 7

Ataxia, dizziness, visual blurring

Question 8

What are the causes of type 1 episodic ataxia?

Answer 8

Caused by loss of function mutations in KCNA1 (KV)
- Only need 1 subunit to stop working to produce disease
- Increased excitability due to low K channel function
Expressed in neurons in the cerebellum and neuromuscular junction

Question 9

What is the treatment for type 1 episodic ataxia?

Answer 9

Acetazolamide – carbonic anhydrase inhibitor
Phenytoin – Na+ channel blocker
Carbamazepine - Na+ channel blocker

Question 10

What is the trigger for type 2 episodic ataxia?

Answer 10

Physical or emotional stress

Question 11

What are the symptoms of type 2 episodic ataxia?

Answer 11

Ataxia
Trunk instability
Nystagmus
Vertigo
Nausea
Vomiting
Headache

Question 12

What are the causes of type 2 episodic ataxia?

Answer 12

Caused by point mutations in CACNA1A (CaV)
- 1A Ca2+ channel – part of the P/Q type Ca2+ channels
- Most truncation mutations - severe
- Some non-truncating – less severe
Expressed in neurons in the cerebellum – degenerative neuron disease
Loss of function mutations means a reduction Ca2+ influx
- Problems neurotransmitter release
- Problems control skeletal muscle

Question 13

What is the treatment for type 2 episodic ataxia?

Answer 13

Acetazolomide – carbonic anhydrase inhibitor

Question 14

What are the 3 allelic disorders caused by CACNA1A?

Answer 14

Mis-sense mutations – familial hemiplegic migraine
Repeat expansion C terminus - spinocerebellar ataxia type 6
Shows that mutation position and type determines the phenotype

Question 15

Where are CACNA1A channels found?

Answer 15

Purkinje cells
Granule cells
Cell bodies central neurones
Ca channel role is - exocytotic neurotransmitter release triggered by increased Ca concentrations

Question 16

What is the CACNA1A knockout mice phenotype?

Answer 16

Up to 10 days after birth - normal
10 days after birth - balance problems and ataxia begin
Falls with twisting movements
Death 3-4 weeks after birth

Question 17

What is the difference between WT or G293R mice?

Answer 17

Barium current – goes through Ca channel pore but unlike Ca does not cause the channel to close giving more stable recordings
Small barium currents recorded in mutant – loss of function of Ca channel
As open probability increases as do the currents
In WT – maximum current recorded at 0mV
In mutant – maximum current recorded at 3mV
- Needs a bigger depolarisation to get the same open probability as in the wild type
- Smaller current and they take longer to open

Question 18

What is epilepsy caused by?

Answer 18

Seizures caused by episodic neuronal discharges

Caused by infection, tumours, brain trauma, inherited

Question 19

What are the different epilepsy phenotypes?

Answer 19

Areas of brain affected determine symptoms
Partial – only small parts of brain affected
Generalised – larger areas of brain affected
Simple – no loss of consciousness
Complex – loss of consciousness

Question 20

What are the roles of ion channels in inherited epilepsy?

Answer 20

Benign familial neonatal seizures
Absence epilepsy and episodic ataxia
Focal epilepsy and episodic ataxia

Question 21

What are the roles of ion channels in acquired epilepsy?

Answer 21

Changes in ion channels in response to damage

Autoimmune diseases

Question 22

What are the roles of inhibitory and excitatory neurones role?

Answer 22

Inhibitory neurones release neurotransmitter which supress activity in the excitatory neurones
Seizure caused by
- Too much activity in excitatory neuron
- Too little activity in inhibitory neuron

Question 23

Neuronal ion channels role

Answer 23

Nav - depolarisation
Kv - repolarisation
Cav - neurotransmitter release synapse
AchR – post synaptic membrane activation
GABAA – post synaptic membrane inhibition
- Chloride channel hyperpolarising membrane
HCN – hyperpolarisation-activated cyclic nucleotide gated channel - depolarisation

Question 24

Where is NaV1.1 found?

Answer 24

In inhibitory interneurons

Question 25

What is the structure of NaV1.1?

Answer 25

24 transmembrane spanning domains in four blocks of 6 | 4th transmembrane spanning domain of each block is a sensor

Question 26

What is the wild type function in a NaV1.1 interneuron?

Answer 26

Action potential firing normal leading to release of inhibitory GABA Suppression of activity in surrounding excitatory neurons

Question 27

What happens in a +/- Nav1.1 interneuron?

Answer 27

Mimic Epilepsy – loss of suppression of excitatory neurons | Action potential firing reduced

Question 28

What are the main two mutations found in NaV1.1?

Answer 28

Loss of function - Too much activity in excitation neurones - Too little activity in inhibitory neurones Gain of function - No clear reason why these mutations lead to epilepsy

Question 29

Different NaV1.1 mutations have different severity

Answer 29

``` Mild – missense - Febrile seizures Moderate – missense - Febrile and generalised seizures Severe – missense - Febrile and generalised seizures Truncation – loss of function - Febrile, generalised and myoclonic seizures - Ataxia - Cognitive impairment ```

Question 30

NaV1.1 summary

Answer 30

Location - inhibitory interneurons Effect - loss and gain Impact on excitatory output - increased due to loss of inhibition

Question 31

GABAAR summary

Answer 31

Location - post synaptic membrane inhibitory neurones Effect - loss Impact on excitatory output - increased due to loss of inhibition

Question 32

AchR summary

Answer 32

Location - post synaptic membrane excitatory neurones downstream of other excitatory neurones Effect - gain Impact on excitatory output - increased due to excessive AchR activity

Question 33

NaV1.2 summary

Answer 33

Location - excitatory axons Effect - gain Impact on excitatory output - increased due to excessive Nav1.2 activity

Question 34

HCN summary

Answer 34

Location - excitatory dendrites Effect - loss Impact on excitatory output - increased due to loss of firing control

Question 35

KV7.2 summary

Answer 35

Location - excitatory axons Effect - loss Impact on excitatory output - increased due to loss of firing control

Question 36

What are the benefits of pain?

Answer 36

Protective Avoidance – to stop damage or warn of damage - E.g. heat

Question 37

What are the two types of rare inherited pain disorders?

Answer 37

``` Nav1.7 peripheral sensory neurones Loss of pain - Loss of function Nav1.7 – can’t fire action potentials - Symptoms - injuries and early death Enhancement of pain - Gain of function Nav1.7 - Symptoms – redness, heat and burning pain - E.g. Erythromelalgia ```