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.
Very interesting.
ReplyDeleteI saw a case of TPP as an intern. 19 yo asian male college student recently diagnosed with Grave's who was brought in flaccid by his roommates. He had played basketball then had a massive Chipotle burrito just hours prior. K was 1.8.
I wonder if insulin and catechols have potentiating effects on this Kir2.6 channel as they do on the Na/K ATPase?
Logical hypothesis involving Kir2.6 regulation by insulin and/or catechols. The paper focused on thyroid hormone I imagine because thyrotoxicosis is such an important part of the disease and also because they found a thyroid response element in the promoter of the Kir2.6 gene.
ReplyDeleteIt's also possible insulin/catechols do NOT have any direct Kir2.6 regulatory effects--but instead help precipitate flaccid paralysis due to their ability to independently lower K via intracellular shift. Perhaps the combination of Kir2.6 mutation and eating a giant Chipotle burrito (mmmm!) could do this.
Thanks for your comments.
Here is a link to more information about the genetics of Hypokalemic Periodic Paralysis that was prepared by our genetic counselor and which has links to some useful resources for those dealing with this condition: http://www.accessdna.com/condition/Hypokalemic_Periodic_Paralysis/199. There is also a phone number listed if you need to speak to a genetic counselor by phone. I hope it helps. Thanks, AccessDNA
ReplyDeleteexcuse me but I think I need illumination here. Is this kir 2.6 one of many gene that regulate the function of Na/K-ATPase or is it a whole different channel?
ReplyDelete