Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation

Jean François Desaphy, Roberta Carbonara, Adele D'Amico, A. Modoni, Julien Roussel, Paola Imbrici, Serena Pagliarani, Sabrina Lucchiari, M. Lo Monaco, Diana Conte Camerino

Research output: Contribution to journalArticlepeer-review


Objective: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype. Methods: Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp. Results: The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition. Conclusions: Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.

Original languageEnglish
Pages (from-to)2100-2108
Number of pages9
Issue number22
Publication statusPublished - May 31 2016

ASJC Scopus subject areas

  • Clinical Neurology


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