Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy.
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.
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA. Electronic address: Ami.Mankodi@nih.gov.
Ami
A
Mankodi
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Christopher
C
Grunseich
Department of Biomedicine, University of Aarhus, 8000 Aarhus, Denmark.
Martin
M
Skov
Section of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Lisa
L
Cook
Section of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Georg
G
Aue
Section of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Enkhtsetseg
E
Purev
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Dara
D
Bakar
Clinical Neurophysiology Program, EMG Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Tanya
T
Lehky
Division of Neurophysiology, University of Ulm, 89069 Ulm, Germany.
Karin
K
Jurkat-Rott
Department of Biomedicine, University of Aarhus, 8000 Aarhus, Denmark.
Thomas H
TH
Pedersen
Section of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Richard W
RW
Childs
D000328:Adult; D002412:Cations / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D008297:Male; D008954:Models, Biological; D009132:Muscles / Q000166:cytology / Q000503:physiopathology; D020967:Myotonic Disorders / Q000235:genetics / Q000503:physiopathology*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides; D010243:Paralysis / Q000235:genetics / Q000503:physiopathology*
D002412:Cations; C096894:MUT 1 peptide; D062553:NAV1.4 Voltage-Gated Sodium Channel; D009842:Oligopeptides; C106251:SCN4A protein, human
Magnesium; Muscle weakness; Myotonia; Paramyotonia congenita; Periodic paralysis; Sodium channel