Channelopathies.

Abstract

In patients with mutations in the genes that encode the chloride, sodium, and calcium channels in skeletal muscle, there is abnormal function of the muscle membrane, which can cause myotonia or attacks of weakness. Mutations in the chloride and sodium channels can lead to myotonia, which typically begins in early childhood. Mexiletine is usually effective in controlling myotonia in these patients. Mexiletine is also effective in preventing attacks of cold-provoked muscle paralysis in patients with paramyotonia congenita, a sodium channel disorder. Certain mutations in the sodium channel cause attacks of hyperkalemic periodic paralysis; these attacks are often controlled with thiazide diuretics. Mutations in the skeletal muscle calcium channel cause periodic attacks of weakness, but hypokalemia (not hyperkalemia) occurs during these episodes. The carbonic anhydrase inhibitors acetazolamide and dichlorphenamide prevent attacks of hypokalemic periodic paralysis, although the mechanism by which they produce this protective effect remains a mystery. Interestingly, the hypokalemic attacks with periodic weakness that occur in some thyrotoxic patients are made worse by acetazolamide. This undesirable response to treatment emphasizes that not all disorders associated with hypokalemic periodic paralysis will benefit from carbonic anhydrase inhibitor therapy. DNA analysis to search for a mutation in the genes that encode for chloride, sodium, or calcium channels in skeletal muscle is helpful to establish the diagnosis. Some patients may eventually require provocative testing, however, to evaluate the attack of weakness and to reach a final diagnosis. Fortunately, there are effective treatments for the channelopathies that affect the skeletal muscle membrane.