CHANNELOPATHIES - ION-CHANNEL DISORDERS OF MUSCLE AS A PARADIGM FOR PAROXYSMAL DISORDERS OF THE NERVOUS-SYSTEM

Some of the most common diseases in humans occur intermittently in peo ple who are otherwise healthy and active. Such disorders include migra ine headache, epilepsy, and cardiac arrythymias. Because electrical si gnals an critical to the function of neurons, muscle cells, and heart cells, proteins that regulate electrical signaling in these cells are logical sites where abnormalities might lend to disease, All of these diseases have prominent genetic components. Difficulty in understandin g these diseases arises from the complexity of the clinical phenotypes as well as from the genetic heterogeneity that is almost certain to e xist. Therefore, early work in my laboratory was aimed at understandin g the pathogenesis of rare disorders that are similar in their episodi c nature. These disorders of muscle (the periodic paralyses), lead to attacks of weakness that occur intermittently in otherwise normal peop le. We, and others, have shown that hyperkalemic periodic paralysis (h yperKPP) and paramyotonia congenita (PC) result from mutations in a ge ne encoding a skeletal muscle sodium channel. We have also shown that hypokalemic periodic paralysis (hypoKPP) is caused by mutations in a g ene encoding a voltage-gated calcium channel. The characterization of these diseases as channelopathies has served as a paradigm for other e pisodic disorders. One example is periodic ataxia, which results from mutations in voltage-gated potassium calcium channels, Long QT syndrom e, an episodic cardiac dysrhythmia syndrome, is known to result from m utations in either voltage-gated sodium or potassium channels. We have recently mapped genes that cause a familial paroxysmal dyskinesia (no n-kinesiogenic paroxysmal dystonia/choreoathetosis) in humans and a re flex epilepsy in mice. The similarities among all these disorders, inc luding their episodic nature, precipitating factors, and therapeutic r esponses, are striking. Understanding gained from work in these rare m onogenic episodic disorders is not only allowing characterization of t he molecular and physiologic basis of these diseases, but may ultimate ly shed light on our understanding of the pathophysiology of more comm on and genetically complex disorders of the central nervous system. (C ) 1997 Elsevier Science B.V.