Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy

• DOI: 10.1016/j.nmd.2015.08.007
• Publication Date: 2015-08-20T16:15:10Z
• Authors: Ami Mankodi; Christopher Gruns...; Martin Skov; Lisa Cook; Georg Aue; Enkhtsetseg Purev; Dara Bakar; Tanya Lehky; Karin Jurkat-Rott; Thomas H. Pedersen; Richard W. Childs
• Keywords: Adult; Male; Muscles; Models, Biological; 03 medical and health sciences; 0302 clinical medicine; Cations; Humans; Paralysis; Computer Simulation; NAV1.4 Voltage-Gated Sodium Channel; Oligopeptides; Myotonic Disorders

We report a patient with paramyotonia congenita/hyperkalemic periodic paralysis due to Nav1.4 I693T mutation who had worsening of myotonia and muscle weakness in the setting of hypomagnesemia and hypocalcemia with marked recovery after magnesium administration. Computer simulations of the effects of the I693T mutation were introduced in the muscle fiber model by both hyperpolarizing shifts in the Nav1.4 channel activation and a faster recovery from slow channel inactivation. A further shift in the Nav1.4 channel activation in the hyperpolarizing direction as expected with low divalent cations resulted in myotonia that progressed to membrane inexcitability. Shifting the channel activation in the depolarizing direction as would be anticipated from magnesium supplementation abolished the myotonia. These observations provide clinical and biophysical evidence that the muscle symptoms in sodium channelopathy are sensitive to divalent cations. Exploration of the role of magnesium administration in therapy or prophylaxis is warranted with a randomized clinical trial.