L10 - CNS Channelopathies Flashcards
What is episodic ataxia?
Irregular, uncontrolled muscle contractions
< 1 in 100,000
At least 6 types - type I and II seen in multiple families
What is type 1 episodic ataxia?
Autosomal dominant
Onset of symptoms - 10-20 years
Ataxia, dizziness
Attack length - brief
Which channel mutation is type 1 episodic ataxia linked to?
Linked to mutations in KCNA1 (KV)
What is type 2 episodic ataxia?
Autosomal dominant
Onset of symptoms - childhood to teens
Ataxia, vertigo, nausea, headache
Attack length - 30 mins to 24 hours
Which channel mutation is type 2 episodic ataxia linked to?
Linked to mutations in CACNA1A (CaV)
What is the trigger for type 1 episodic ataxia?
Physical or emotional stress
Impacts on vestibular system
Abrupt changes in position
What are the symptoms of type 1 episodic ataxia?
Ataxia, dizziness, visual blurring
What are the causes of type 1 episodic ataxia?
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
What is the treatment for type 1 episodic ataxia?
Acetazolamide – carbonic anhydrase inhibitor
Phenytoin – Na+ channel blocker
Carbamazepine - Na+ channel blocker
What is the trigger for type 2 episodic ataxia?
Physical or emotional stress
What are the symptoms of type 2 episodic ataxia?
Ataxia Trunk instability Nystagmus Vertigo Nausea Vomiting Headache
What are the causes of type 2 episodic ataxia?
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
What is the treatment for type 2 episodic ataxia?
Acetazolomide – carbonic anhydrase inhibitor
What are the 3 allelic disorders caused by CACNA1A?
Mis-sense mutations – familial hemiplegic migraine
Repeat expansion C terminus - spinocerebellar ataxia type 6
Shows that mutation position and type determines the phenotype
Where are CACNA1A channels found?
Purkinje cells
Granule cells
Cell bodies central neurones
Ca channel role is - exocytotic neurotransmitter release triggered by increased Ca concentrations
What is the CACNA1A knockout mice phenotype?
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
What is the difference between WT or G293R mice?
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
What is epilepsy caused by?
Seizures caused by episodic neuronal discharges
Caused by infection, tumours, brain trauma, inherited
What are the different epilepsy phenotypes?
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
What are the roles of ion channels in inherited epilepsy?
Benign familial neonatal seizures
Absence epilepsy and episodic ataxia
Focal epilepsy and episodic ataxia
What are the roles of ion channels in acquired epilepsy?
Changes in ion channels in response to damage
Autoimmune diseases
What are the roles of inhibitory and excitatory neurones role?
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
Neuronal ion channels role
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
Where is NaV1.1 found?
In inhibitory interneurons
What is the structure of NaV1.1?
24 transmembrane spanning domains in four blocks of 6
4th transmembrane spanning domain of each block is a sensor
What is the wild type function in a NaV1.1 interneuron?
Action potential firing normal leading to release of inhibitory GABA
Suppression of activity in surrounding excitatory neurons
What happens in a +/- Nav1.1 interneuron?
Mimic Epilepsy – loss of suppression of excitatory neurons
Action potential firing reduced
What are the main two mutations found in NaV1.1?
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
Different NaV1.1 mutations have different severity
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
NaV1.1 summary
Location - inhibitory interneurons
Effect - loss and gain
Impact on excitatory output - increased due to loss of inhibition
GABAAR summary
Location - post synaptic membrane inhibitory neurones
Effect - loss
Impact on excitatory output - increased due to loss of inhibition
AchR summary
Location - post synaptic membrane excitatory neurones downstream of other excitatory neurones
Effect - gain
Impact on excitatory output - increased due to excessive AchR activity
NaV1.2 summary
Location - excitatory axons
Effect - gain
Impact on excitatory output - increased due to excessive Nav1.2 activity
HCN summary
Location - excitatory dendrites
Effect - loss
Impact on excitatory output - increased due to loss of firing control
KV7.2 summary
Location - excitatory axons
Effect - loss
Impact on excitatory output - increased due to loss of firing control
What are the benefits of pain?
Protective
Avoidance – to stop damage or warn of damage
- E.g. heat
What are the two types of rare inherited pain disorders?
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
