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

Abstract

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.

Keywords: Magnesium; Muscle weakness; Myotonia; Paramyotonia congenita; Periodic paralysis; Sodium channel.

Figure 1

Clinical and laboratory findings over time (A–D). Clinical severity score (A) was adapted from the GBS disability scoring system (0: A healthy state, 1: Minor symptoms and capable of running, 2: Needs help with walking, 3: Chair bound or bedridden). Average monthly CSA (B), Mg²⁺ (C) and Ca²⁺ (D) concentrations. Monthly data are shown in box and whiskers format with 5% and 95% confidence intervals. Light and dark lines indicate the normal laboratory reference range for divalent cations and therapeutic range for CSA. Heavy dark line (C) defines critically low magnesium level.

Figure 2

Computerized model of action potential firing in single muscle fibers (AD). Voltage gated ion channels in the model were described using Hodgkin-Huxley kinetics[5]. Panels show membrane potential from a fiber stimulated at 30 Hz for 400 ms. (A) shows normal firing of action potentials in a fiber with activation curve midpoint (m₅₀) = −41.1; representing the “normal state”. (B) shows a burst of myotonia lasting over 6 seconds in a fiber with m₅₀ shifted by 9 mV in hyperpolarizing direction from −41.1 to −50.1 mV along with a 5-fold increased rate of recovery from slow inactivation; representing the ”Nav1.4 I693T” effects. (C–D) show results of m₅₀ shifts in fibers with the “Nav1.4 I693T” effects. (C) shows myotonia precipitating in inexcitable state in a fiber with m₅₀ shifted by 0.6 mV in the hyperpolarizing direction from −50.1 mV to −50.7 mV; representing subnormal levels of divalent cations. (D) shows return to normal excitability state in a fiber with m₅₀ shifted by 0.6 mV in the depolarizing direction from −50.1 mV to −49.5 mV; representing response to magnesium administration.