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Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia

From the Department of Neurology and Program in Neuroscience, UT Southwestern Medical Center, Dallas, TX.

Address correspondence and reprint requests to Dr Cannon, Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8813 Steve.cannon{at}utsouthwestern.edu

Background: Missense mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. The mechanistic basis for the phenotypic variability of these allelic disorders of muscle excitability remains unknown. An atypical phenotype with cold-induced hypokalemic paralysis and myotonia at warm temperatures was reported to segregate with the P1158S mutation.

Objective: This study extends the functional characterization of the P1158S mutation and tests the specific hypothesis that impairment of Na channel slow inactivation is a common feature of periodic paralysis.

Methods: Mutant NaV1.4 channels (P1158S) were transiently expressed in human embryonic kidney cells and characterized by voltage-clamp studies of Na currents.

Results: Wild-type and P1158S channels displayed comparable behavior at 37 °C, but upon cooling to 25 °C, mutant channels activated at more negative potentials and slow inactivation was destabilized.

Conclusions: Consistent with other NaV1.4 mutations associated with a paralytic phenotype, the P1158S mutation disrupts slow inactivation. The unique temperature sensitivity of the channel defect may contribute to the unusual clinical phenotype.

Abbreviations: HEK = human embryonic kidney; HyperPP = hyperkalemic periodic paralysis; HypoPP2 = hypokalemic periodic paralysis type 2; NaV1.4 = human skeletal muscle sodium channel; PAM = potassium aggravated myotonia; PMC = paramyotonia congenita; WT = wild-type.

Supplemental data at www.neurology.org

Editorial, page 746

e-Pub ahead of print on September 26, 2007, at www.neurology.org.

Supported by the NIAMS (RO1-42730) of the NIH and the Medical Scientist Training Program (5 T32 GM08014).

Disclosure: The authors report no conflict of interest

Received February 5, 2007. Accepted in final form June 27, 2007.