A recessive Na(v)1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis

作者：Habbout Karima; Poulin Hugo; Rivier Francois; Giuliano Serena; Sternberg Damien; Fontaine Bertrand; Eymard Bruno; Morales Raul Juntas; Echenne Bernard; King Louise; Hanna Michael G; Maennikkoe Roope; Chahine Mohamed; Nicole Sophie; Bendahhou Said^*

来源：Neurology, 2016, 86(2): 161-169.

DOI：10.1212/WNL.0000000000002264

Objective:To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient.Methods:The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed. Functional characterization of the candidate mutation was done in mammalian cell background using whole cell patch clamp technique.Results:The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis. We identified a novel homozygous SCN4A mutation (p.R1454W) linked to this recessively inherited phenotype. The p.R1454W substitution induced an important enhancement of fast and slow inactivation, a slower recovery for these inactivated states, and a frequency-dependent regulation of Na(v)1.4 channels in the heterologous expression system.Conclusion:We identified a novel loss-of-function mutation of Na(v)1.4 that leads to a recessive phenotype combining clinical symptoms and signs of congenital myasthenic syndrome and periodic paralysis, probably by decreasing channel availability for muscle action potential genesis at the neuromuscular junction and propagation along the sarcolemma.

• 出版日期2016-1-12