The periodic paralysis syndromes are characterized by episodic attacks of acute muscle weakness, typically due to rapid fluxes in the serum potassium concentration, based on an abnormality in intracellular potassium shift. While there have been several instances of inherited mutations that cause periodic paralysis, there is also a subset of individuals who have thyrotoxic periodic paralysis (TPP), in which the presence of hyperthyroidism predisposes to attacks of transient paralysis. An article in this month’s Cell by Ryan et al helps determine the molecular basis of TPP in many (but not all) cases, and characterizes this disorder as yet another example of a channelopathy: a disorder of ion channels.
Although thyrotoxicosis is a predisposing factor to this disease, there was also a clue that genetics was involved: Latin American and Asian populations appeared especially susceptible to TPP. The investigators identified a novel inward-rectifying potassium channel, Kir2.6 (interestingly, a gene which had escaped detection in all versions of the human genome thus far!), and sequenced this gene in affected individuals. In 33% of the unrelated patients in their sample, they identified mutations in Kir2.6 which appear to alter the function of this potassium channel and lead to an altered skeletal muscle excitability. Interestingly, the transcription of Kir2.6 was found to be altered by thyroid hormone, providing an explanation as to why the disease manifests itself most commonly during episodes of thyrotoxicosis.