Therefore, early work in our laboratory was aimed at understanding the pathogenesis of rare monogenic disorders that are similar in their episodic nature. Attacks of weakness are precipitated in these patients by elevated serum potassium levels. Unlike hyperKPP, in which attacks are brought on by elevated potassium, hypoKPP attacks are precipitated by low serum potassium levels. These myotonic disorders are similar to PAM except that the phenotype is not potassium sensitive. We have identified CLCN1 mutations that segregate in a dominant fashion in some families and as a recessive trait in another.
Ongoing work is directed at trying to understand the basis of the variable mode of transmission.
We have recently identified another two ion channel genes that are mutated in patients with periodic paralysis. Efforts are under way to prove that these mutations are disease causing through electrophysiologic characterization of the normal and mutant channels. We and others have expressed many of the sodium channel mutants in vitro and characterized their biophysical properties. Shortly after the channel opens and allows sodium ions to move into the cell, it normally closes very quickly. All the SCN4A mutants studied to date reveal slowed channel inactivation.