Channelopathies

Question 1

What are neurological ion channelopathies?

Answer 1

Neurological ion channelopathies are a group of heterogeneous disorders that can be broadly grouped into 3 areas:

1) . Cerebellar Ataxia and Excessive Startle.
2) . Neuromuscular Disorders.
3) . Epilepsy and Migraine.

What they have in common is that the expression of these disorders are all thought to be influenced by genetic variations in genes encoded by ion channels and expressed in the central nervous system or peripheral nervous system.

Question 2

Outline ion channel structure.

Answer 2

• Many ion channels are commonly composed of alpha helix transmembrane units which form 4 structures which then form a pore through which ions travel.
• There are also auxiliary subunits (beta and alpha subunits) which are also needed for ion channel function.

Question 3

What are the different types of ion channel? What channels are usually associated with channelopathy disease?

Answer 3

There are 3 types of ion channel:

1) . Voltage Gated.
2) . Inward Rectifying.
3) . Others such as ligand gated - e.g. G-protein coupled receptors.

Many channels associated with channelopathy disease are indeed the voltage gated ones - e.g. Sodium channels, Potassium channels, Calcium channels.

Mutations in the subunits that form these channels do give rise to different phenotypes.

Question 4

What is the underlying biology of channelopathies?

Answer 4

• Voltage gated ion channels affect ionic charge. This will have important consequences for the transition of information along nerve cells - that is, action potential propagation along neurons.
• Action potentials are produced by an in flow of sodium ions through open sodium voltage gated channels which then close when the polarity of a plasma membrane changes which then activates the opening of potassium channels which leads to repolarisation. Any disruption in ion channel opening will affect the actual action potential.
• Ion channels are also important for neurotransmitter release into the synaptic cleft and neurotransmitter receptor function at synapses and indeed neuromuscular synapses.
• Another characteristic of channelopathies is that they are episodic in nature - i.e. they occur in episodes rather than being progressive. Why do such symptoms come and go? Why do people get ill and then get better?
• Episodic disorders are thought to be caused by the increased relative stability of / decreased barrier of entry into an aberrant state. Precipitating factors that are thought to push the system into such an aberrant state include emotional/physical stress, excitement, exertion, diet, hormones (hormonal cycles).
• Research into such env. factors which may interact with genetic factors is a very active topic of research.

Question 5

Outline the genetics of neurological channelopathies.

Answer 5

• It is clear that some disorders that come under the headings of neuromuscular or ataxia type channelopathies are monogenic and are caused by very rare or intermediate rare familial mutations.
• These channel subunit mutations were first identified by positional cloning in large pedigrees and are the sort of mutations screened for by clinical diagnostic labs.
• There is also evidence that some of these disorders are more of a common sporadic type - really talking about the epilepsy and migraine type of channelopathies here. There is a hypothesis that such common sporadic diseases are caused by many common variants, each with a small effect - this is known as the common disease variant model.
• Evidence supporting the common disease variant model comes from very large case control GWAS studies which have shown significant association signals between common SNPs, often in such ion channel genes, and these common complex diseases such as generalised epilepsies.
• However, there are issues - recently there has been some very strong suggestion that ataxia and traits such as pain (in the neuromuscular type channelopathies) may be influenced or even caused by many common genetic risk factors. This would imply that ataxia and neuromuscular type channelopathies are not simple mendeelian diseases and further suggests that they may have a genetic architecture possible much more like a common complex disorder spectrum type disease.
• This leads us now to ask:
• What is the underlying architecture of such disorders - does it involve complex, simple, mixed modes of inheritance?
• Are modifier genes involved?
• What are the modes of transmission and types of mutations?
• Will the genetic modes currently being revealed to be true for other neurological disorders such as Alzheimers and Parkinsons disease also be shown to be true for channelopathies? Both show early onset familial and late onset sporadic forms.
• What approaches will be used to unravel these issues and what are the implications of the findings for clinical diagnostic screening and the information given to subjects?