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Muscle at the junction: Where next generation sequencing is sending us

Skeletal muscle membrane stability is dependent on the actions of sodium, calcium, and chloride channels to appropriately gate ion activity. The sodium channel Nav1.4 in particular has been recognized as having a critical role in the gating of ion current in skeletal muscle.1 Mutations in Nav1.4 due to variants in the SCN4A gene result in a variety of phenotypes including hyperkalemic and hypokalemic periodic paralysis, paramyotonia congenita, and congenital myasthenic syndrome with mixed dominant and recessive inheritance. Dominantly inherited disorders such as hypokalemic periodic paralysis result in leaky sodium channels that in turn results in transient episodic weakness that often presents early in childhood.2 Eventually, many of these patients develop myopathic features including fixed proximal weakness. Dominant mutations in SCN4A that result in increased sodium influx cause hyperkalemic periodic paralysis and paramyotonia congenita phenotypes.3 In contrast, loss-of-function mutations in SCN4A result in a more severe congenital myasthenic syndrome with disruption of the neuromuscular junction. This constellation of rare disorders, as the result of either loss of function or gain of function of the sodium channel, shares several characteristic features: (1) transient, fluctuating symptoms (either weakness or myotonia); (2) progression to fixed weakness; and (3) rare occurrence. What is distinct between the gain-of-function and loss-of-function mutations are those disorders that involve muscle excitability (such as paramyotonia congenita) and those disorders that impair muscle contraction, either at the neuromuscular junction or muscle membrane itself (congenital myasthenic syndrome and hypokalemic periodic paralysis). With the constellation of syndromes affected by mutations in SCN4A, it is not clear if we have completely identified the spectrum of allelic disorders caused by mutations in SCN4A. In addition, the mechanism separating the gain-of-function from loss-of-function mutations is incompletely understood.



from Neurology recent issues https://ift.tt/2uu7Es1

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