Potassium Channel Mutations Underlie TPP

The rare condition thyrotoxic hypokalemic periodic paralysis, or TPP, causes people with normal muscle strength to experience episodes of paralysis and weakness. Until recently, TPP was known to be associated with attacks of high thyroid hormone secretion (thyrotoxicosis), but new information shows that in some cases the condition also has a genetic component -- mutations in a newly identified potassium channel that helps control the flow of potassium ions into and out of muscle fibers.

Muscle contraction occurs when a neurotransmitter called acetylcholine is releqased from the nerve cell and stimulates the opening of ion channels in the muscle cell.

“TPP may be a genetically conditioned disorder unmasked by thryrotoxicosis,” the TPP researchers reported in the journal Cell on Jan. 8, 2010.  In other words, in some instances TPP requires a combination of nongenetic and genetic factors to make itself known. The nongenetic factor is high circulating thyroid hormone (thryrotoxicosis), and the genetic factor is an abnormality in a type of potassium channel that exists in muscle fibers.

Importantly, increased understanding of TPP's origin and mechanism also may increase understanding of various other muscle diseases.

About the new findings

The new findings describe six mutations in a gene that carries the instructions for a previously unrecognized potassium channel called KIR2.6.

KIR2.6 is one of a family of channels that governs potassium flow into and out of cells. The "IR" in its name signifies its designation as a type of channel called an "inward rectifier," which channels potassium (K) into cells much more readily than in the outward direction.

The mutations identified in the study alter a variety of KIR2.6 channel properties and can lead to incorrect (too much or too little) levels of potassium flow into or out of cells, or current flow to the wrong location. The resulting effects on muscle membrane excitability result in the extreme weakness and paralysis experienced by people with TPP. 

In the study population, the identified mutations were found to be responsible for TPP in one-third of patients studied in the United States, France, Canada and Brazil; in one-quarter of patients from Singapore; in only 2 percent of those from Hong Kong; and in none of those from Thailand. Therefore, the researchers wrote, it's likely that there are additional, as yet uncovered, gene defects that can cause TPP.

Although MDA did not directly fund this study, researcher Louis J. Ptacek, a neurologist and muscle physiologist at the University of California San Francisco and a former longtime MDA grantee, acknowledged the Association for another grant to study Anderson-Tawil Syndrome (one of several forms of periodic paralysis for which his group previously identified a related potassium channel gene and causative mutations).

In that study, researchers identified the previously unreported gene responsible for KIR2.6 channels, mutations in which are characterized in the current study as responsible for TPP.

Three other forms of periodic paralysis, which are also genetic but aren't related to levels of thyroid hormone, have previously been found to be caused by defects in sodium and calcium channels, and another type of potassium channel (see In Focus: Periodic Paralysis).

Meaning for people with TPP

It's now possible, in theory, to test for KIR2.6 mutations, though no commercial test is yet available. However, Ptacek noted, treating the high thyroid levels (thyrotoxicosis) that trigger TPP is a definitive cure for the condition, so there is not much benefit in knowing a patient's particular mutation.

Even so, a greater understanding of KIR2.6 function and dysfunction may lead to a broader benefit that translates to a number of other diseases.

"Further study of this newly recognized channel will lead to new insights into the biology and physiology of muscle," Ptacek said, "which may ultimately lead to benefits for patients with muscle disease."

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