Ion channel diseases: episodic disorders of the nervous system

Electrical excitability of skeletal and cardiac muscle cells and neurons results from a balance of inhibitory and excitatory influences. Ionic concentration gradients established by adenosine 5'-triphosphate (ATP)-dependent pumps can be maintained because the lipid bilayer is an extremely good insulator. Once ionic concentrations are established, movement of one or more ions down their respective concentration gradients can establish voltage differences across a membrane. The Nernst equation allows prediction of membrane potentials based on the particular ion involved and the concentration gradient for that ion in the cell. A large number of voltage-gated ion channels, ligand-gated channels, and transporters are involved in maintaining this balance. The specific channels and transporters involved differ in various cell types. In any case, normal membrane excitability is tightly regulated by the balance of these opposing influences. It is not surprising that the disruption of the balance of excitability of various cells might lead to neurological phenotypes. However, large changes in excitability of muscle or nerve may well be lethal. Therefore, nature may select against such major changes. A growing body of evidence suggests that subtle changes in some ion channels can lead to a slight increase in membrane excitability that results in a neurological phenotype. Interestingly, these phenotypes are frequently episodic. That is, under many circumstances, the nerve or muscle may be functioning properly; however, under certain circumstances, a precipitating event can lead to abnormal excitability resulting in one of any number of phenotypes discussed below. In this chapter, discussion will be focused on a number of monogenic disorders of the nervous system where episodic phenotypes are known to result from specific mutations of ion channels. The similarities between a large group of seemingly disparate disorders will be emphasized. Finally, some energy will be directed at developing the hypothesis that more subtle variations in proteins regula ting membrane excitability-though not causing a Mendelian disorder-may yield a predisposition to certain episodic phenomenon such as seizures and migraine headache.