Ion channel diseases: Episodic disorders of the nervous system

Electrical excitability of skeletal and cardiac muscle cells and neurons re sults from a balance of inhibitory and excitatory influences. tonic concent ration gradients established by adenosine 5'-triphosphate (ATP)-dependent p umps can be maintained because the lipid bilayer is an extremely good insul ator. Once ionic concentrations are established, movement of one or more io ns down their respective concentration gradients can establish voltage diff erences across a membrane. The Nernst equation allows prediction of membran e potentials based on the particular ion involved and the concentration gra dient for that ion in the cell. A large number of voltage-gated ion channel s, 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 n eurological 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 io n channels can lead to a slight increase in membrane excitability that resu lts in a neurological phenotype. Interestingly, these phenotypes are freque ntly episodic. That is, under many circumstances, the nerve or muscle may b e functioning properly; however, under certain circumstances, a precipitati ng event can lead to abnormal excitability resulting in one of any number o f phenotypes discussed below. In this chapter, discussion will be focused o n a number of monogenic disorders of the nervous system where episodic phen otypes are known to result from specific mutations of ion channels. The sim ilarities between a large group of seemingly disparate disorders will be em phasized. Finally, some energy will be directed at developing the hypothesi s that more subtle variations in proteins regulating membrane excitability- though not causing a Mendelian disorder-may yield a predisposition to certa in episodic phenomenon such as seizures and migraine headache.