In humans, the most common underlying genetic cause is one of several possible point mutations in the gene SCN4A. This gene codes for a voltage-gated sodium channel Nav1.4 found at the neuromuscular junction. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause it. Action potentials from the central nervous system cause end-plate potentials at the NMJ which causes sodium ions to 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<unk> . 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<unk>  is complex, but explains the autosomal dominant and<unk> -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<unk> , 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<unk> .
Hyperkalemic periodic paralysis
Hypokalemic periodic paralysis
Potassium-aggravated myotonia
Thyrotoxic periodic paralysis
Paroxysmal exercise-induced dystonia
Myotonia congenita
Glycine encephalopathy
Thyrotoxic myopathy