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Inherited erythermalgia

Limb pain from an S4 charge-neutral Na channelopathy

From the Department of Neurology and Center for Neuroscience and Regeneration Research Yale University School of Medicine, New Haven, and Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT.

Address correspondence and reprint requests to Dr Waxman, Department of Neurology, Yale University School of Medicine, 333 Cedar St., LCI-707, New Haven, CT 06510; e-mail: Stephen.Waxman{at}yale.edu

Background: Inherited erythermalgia (also termed "erythromelalgia"), characterized by episodic burning pain in the distal extremities evoked by warmth, has been causally linked with mutations of the Na_v1.7 sodium channel, which is preferentially expressed in nociceptors. Thus far, Na_v1.7 mutations within intracellular linker parts of the channel have been physiologically characterized.

Objective: To investigate a Na_v1.7 erythermalgia mutation that substitutes one uncharged amino acid for another within an S4 segment.

Methods: Whole-cell patch-clamp analysis was used to study biophysical properties of wild-type and mutant (F216S) Na_v1.7 channels in mammalian cells.

Results: The F216S mutation hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation, and enhances the response to slow, small depolarizations.

Conclusion: These results provide a physiologic basis for the linkage to erythermalgia of an Na_v1.7 mutation that substitutes one uncharged residue for another within an S4 segment of the channel. These changes should increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain.

Editorial, see page 1538

This article was previously published in electronic format as an Expedited E-Pub on September 20, 2006, at www.neurology.org.

Supported in part by grants from the National Multiple Sclerosis Society, the Rehabilitation Research Service and Medical Research Service, Department of Veterans Affairs, and the Erythromelalgia Association. The Center for Neuroscience and Regeneration Research is a Collaboration of the Paralyzed Veterans of America and the United Spinal Association with Yale University.

Disclosure: The authors report no conflicts of interest.

Received March 15, 2006. Accepted in final form May 30, 2006.

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