Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life

Frank Lehmann-Horn, Adele D'Amico, Enrico Bertini, Mauro LoMonaco, Luciano Merlini, Kevin R. Nelson, Heike Philippi, Gabriele Siciliano, Frank Spaans, Karin Jurkat-Rott

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Introduction. Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Methods. Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. Results. In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our frst myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features agedependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. Discussion. Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the frst genetically clarifed case series from newborn period to adulthood and therefore helpful for counselling.

Original languageEnglish
Pages (from-to)125-134
Number of pages10
JournalActa Myologica
Issue number3
StatePublished - Sep 2017

Bibliographical note

Funding Information:
We thank Drs H. Lerche and P.A. Iaizzo for fruitful discussions and Drs C. Gill and B. Reitter for help to recruit patients for the study and the families for their collaboration. This work is dedicated to Dr. K. Ricker. This study was supported by the IonNeurOnet of the German BMBF Ministry of Research, the German DGM Muscle Disease Society, and the non-profit Hertie-Foundation.


  • Muscular and respiratory tract diseases
  • Neonate
  • Stridor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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