Muscle Na channelopathies

Background: Muscle channelopathies such as paramyotonia, hyperkalemic periodic paralysis, and potassiumaggravated myotonia are caused by gain-of-function Na channel mutations. Methods: Implementation of a threedimensional radial Na magnetic resonance (MR) sequence with ultra-short echo times allowed the authors to quantify changes in the total muscular Na signal intensity. By this technique and T2-weighted H MRI, the authors studied whether the affected muscles take up Na and water during episodes of myotonic stiffness or of coldor exercise-induced weakness. Results: A 22% increase in the Na signal intensity and edema-like changes on T2-weighted H MR images were associated with cold-induced weakness in all 10 paramyotonia patients; signal increase and weakness disappeared within 1 day. A 10% increase in Na, but no increase in the T2-weighted H signal, occurred during coldor exerciseinduced weakness in seven hyperkalemic periodic paralysis patients, and no MR changes were observed in controls or exercise-induced stiffness in six potassium-aggravated myotonia patients. Measurements on native muscle fibers revealed provocation-induced, intracellular Na accumulation and membrane depolarization by 41 mV for paramyotonia, by 30 mV for hyperkalemic periodic paralysis, and by 20 mV for potassium-aggravated myotonia. The combined in vivo and in vitro approach showed a close correlation between the increase in Na MR signal intensity and the membrane depolarization (r 0.92). Conclusions: The increase in the total Na signal intensity reflects intracellular changes, the coldinduced Na shifts are greatest and osmotically relevant in paramyotonia patients, and even osmotically irrelevant Na shifts can be detected by the implemented Na MR technique. NEUROLOGY 2006;67:1–1 Paramyotonia congenita (PC), hyperkalemic periodic paralysis (HyperPP), and potassium-aggravated myotonia (PAM) are channelopathies caused by mutations in the SCN4A gene coding for the Nav1.4 muscle sodium channel.1-3 In PC, muscle exertion in cold environment causes muscle stiffness, which is usually followed by flaccid weakness lasting for up to 12 hours. Rest after exhausting exercise or potassium-rich food causes muscle stiffness in PAM and flaccid weakness in HyperPP. In these disorders, a gating defect of the Na channels, which are essential for the generation of the muscle action potential, destabilizes the inactivated state. The incomplete channel inactivation results in a persistent inward Na current and causes the muscle fibers to depolarize and to generate repetitive action potentials. During an attack of weakness, the persistent inward current is so large that the progressing membrane depolarization leads to loss of membrane excitability because it renders the population of normal sodium channels inactivated. Since the mutant channels exert an effect on cell excitability, the mutations produce a gain of function leading to a dominantly inherited disease. Studies on heterologously expressed channels have revealed that the persistent current is large in HyperPP, moderate in PAM, and small in PC, which typically shows slowing of fast inactivation instead.4-9 However, these patch clamp studies gave no information whether the persistent current leads to an intracellular Na accumulation or if [Na ]i is normal due to activated ion transporters or the Na pump. A slight Na accumulation has been described in few HyperPP fibers as measured with Na sensitive microelectrodes.10 No Na concentration values Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of