enter by Nav1.4 and depolarise the muscle cells. This depolarisation triggers the entry of calcium from the sarcoplasmic reticulum to cause contraction (tensing) of the muscle. To prevent the muscle from being perpetually contracted, the channel contains a fast inactivation gate that plugs the sodium pore very quickly after it opens. This prevents further entry of sodium. In time, potassium ions will leave the muscle cells, repolarising the cells and causing the pumping of calcium away from the contractile apparatus to relax the muscle. Mutations altering the usual structure and function of this sodium channel therefore disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate. The pathological mechanism of SCN4A mutations in hyperkalemic periodic paralysis is complex, but explains the autosomal dominant and hyperkalemia-related aspects of the disease. In patients with mutations in SCN4A, not all copies of the channel inactivate following the action potential. This results in a sodium leak and failure to return to the original resting membrane potential. In the presence of hyperkalemia, which causes an additional chronic depolarization of the membrane potential, this sodium leak raises the membrane potential to the point that all sodium channels, including channels produced from the wild-type allele and mutant channels that did inactivate, fail to be release from inactivation (enter depolarization block). Since the motor end plate is depolarised, further signals to contract have no effect (paralysis). Treatment Glucose or other carbohydrates can be given during an attack and may reduce the severity. Intravenous calcium decreases activity of sodium channels. It may stop sudden attacks. Diuretics such as furosemide may be needed to stop sudden attacks; acetazolamide and thiazide diuretics such as chlorothiazide are also effective. Intravenous glucose and insulin stimulates potassium uptake into the cell by the Na-K ATPase and may reduce weakness without a loss of total body potassium. A high-carbohydrate diet may be recommended. Avoidance of other known attack triggers. See also Hyperkalemic periodic paralysis (equine) References National Library of Medicine. Hyperkalemic periodic paralysis External links GeneReview/NIH/UW entry on Hyperkalemic Periodic Paralysis Type 1 Myoneural junction and neuromuscular diseases Channelopathies Rare diseases