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

TY - JOUR

T1 - Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy

AU - Mankodi, Ami

AU - Grunseich, Christopher

AU - Skov, Martin

AU - Cook, Lisa

AU - Aue, Georg

AU - Purev, Enkhtsetseg

AU - Bakar, Dara

AU - Lehky, Tanya

AU - Jurkat-Rott, Karin

AU - Pedersen, Thomas H

AU - Childs, Richard W

N1 - Published by Elsevier B.V.

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

U2 - 10.1016/j.nmd.2015.08.007

DO - 10.1016/j.nmd.2015.08.007

M3 - Journal article

C2 - 26494408

SN - 0960-8966

VL - 25

SP - 908

EP - 912

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

IS - 11

ER -