CNS channelopathies Flashcards
What is episodic ataxia?
Irregular, uncontrolled muscle contractions Rare condition (<1 in 100,000) There are at least 6 types but type 1 and 2 are more understood
What are the properties of episodic ataxia type 1?
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
What are the properties of episodic ataxia type 2?
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
What are some of the common symptoms between episodic ataxia type 1 and 2?
Ataxia (Seen in ALL), trunk instability, vomiting, dizziness, nystagmus, nausea, headache and visual blirring
Patients can appear to look drunk
What are the triggers of episodic ataxia type 1?
Triggers may be physical or emotional stress, impacts on the vestibular system or an abrupt change in position
What is the structure of KCNA and where is it found?
4 subunits, each with 6 transmembrane spanning domains
Found in the cerebellum and at neuromuscular junctions
What type of mutation occurs in KCNA and how does this affect the cell?
Loss of function mutation, causes a delay in repolarisation
How can type 1 episodic ataxia be treated?
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
What is the structure of CACNAIA (CaV)?
One subunit with 24 transmembrane spanning domains
Which mutations in CACNAIA cause the most severe symptoms?
Those that cause truncation of the protein
What 3 disorders can CACNAIA mutations cause?
1) episodic ataxia type 2
2) Familial hemiplegic migraine - causes migraines, inherited, missense mutations
3) Spinocerebellar ataxia - repeated expansion of the C terminus
Where is CACNAIA located?
Purkinje cells, granule cells and cell bodies of central neurones
Why might barium be used when calcium channels are being used experimentally?
Barium does not cause the calcium channels to close after it moves through like calcium does
What is the effect of the mutation in CACNA1A in cells?
Reduced total flow of calcium ions into neurons, which disrupts the release of neurotransmitters in the brain.
For the mutant CACNA1A what is the opening potential?
8mV - this means the channel is activated later on than normal
Describe what happens in CACNA1A knockout mice
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)
What are the possible causes of eilepsy?
Brain trauma, infection, tumours and inherited
How can epilepsy be classified?
Partial or generalised (how big is the area of brain affected?)
Simple (no loss of consciousness) or complex (loss of consciousness)
How can excitatory and inhibitory neurons cause epilepsy?
excitatory neurons = too much activity, inhibitory neurons = to little activity
What are HCN channels?
Activated cyclic nucleotide gated channel
cAMP can change its open probability
When open they allow cations through to cause depolarisation
Where is Nav1.1 found and what is its role?
It is found in inhibitory neurons and they mediate depolarisation for action potentials
What happens when Nav1.1 channels open?
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
What mutations occur in the dendrites of the excitatory neuron to cause epilepsy?
CaV, HCN and Kv4.2
What mutations occur in the axons of excitatory neurons to cause epilepsy?
Nav1.2, Kv1.1, Kv7.2 and Kv7.3
What is the effect of a loss of function mutation in a heterozygous Nav1.1 knockout mouse?
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
What are febrile seizures?
Seizures caused by a rise in temperature, seen in children with infections and illness
What is SME?
Severe myoclonic epilepsy
What is the role of HCN in the excitatory dendrites?
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
What is the definition of pain?
An unpleasant sensory or emotional experience associated with actual or potential tissue damage
What mutation causes the loss of pain?
Nav1.7 loss of function mutation in peripheral sensory neurons
What may cause an enhancement of pain?
Gain of function mutation in Nav1.7
Why may some people be more tolerable to pain?
There may be polymoprhisms in Nav7.1
