Erythermalgia: molecular basis for an inherited pain syndrome Stephen G. Waxman 1,2 and Sulayman Dib-Hajj 1,2 1 Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA 2 Rehabilitation Research Center, VA Connecticut Healthcare, West Haven, CT 06516, USA Inherited erythermalgia (also termed erythromelalgia) is characterized by severe pain in the limbs in response to mild thermal stimuli or exercise. Its molecular basis has, until recently, been enigmatic. Studies of families with autosomal dominant erythermalgia have now demon- strated mutations in sodium channel Na v 1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. Erythermalgia, the first inherited painful neuropathy to be understood at a molecular level, is a model disease that could hold lessons for other painful conditions and for the development of rational, mechanism-based treatments for pain. The enigma of erythermalgia Pain is one of the most frequent symptoms experienced by humans, but its molecular basis is incompletely under- stood and there is a need for more effective treatments. Over the past five years, it has become clear that altered expression of sodium channels in first and higher order sensory neurons along the pain pathway contributes to acquired neuropathic pain following nerve injury and spinal cord injury [1–3], raising the possibility that sodium channels also participate in the pathophysiology of inherited pain disorders. Over the past two years, mole- cular studies on one such disorder whose pathophysiology was previously enigmatic – erythermalgia – have demon- strated that it is in fact a genetic channelopathy. Here, we provide a brief review of the molecular pathophysiology of hereditary erythermalgia, which is now known to be caused by mutations in a specific, well-defined molecular target, the Na v 1.7 sodium channel. This recent progress could point the way toward rational, mechanism- and molecule-based therapies, and suggests that eryther- malgia is a model disease that holds more general lessons about the role of sodium channels in pain. First described in 1878 by the American neurologist Silas Weir Mitchell [4], this disorder was originally termed erythromelalgia (erythros Z red; melos Z extremities; algos Z pain) because it is characterized by red, painful extremities. The inherited form is often termed primary erythermalgia (although some refer to it as inherited or primary erythromelalgia). This autosomal dominant disorder is characterized by burning pain and redness of the skin of the extremities in response to warm stimuli or moderate exercise [5]. Secondary, non-inherited forms of erythermalgia are seen in association with myeloproli- ferative diseases, such as polycythemia vera, and other disorders, such as cutaneous vasculitis, systemic lupus erythematosus, hypertension, rheumatoid arthritis and diabetes mellitus, and secondary forms have also been reported as possible complications of treatment with drugs, such as verapamil, nifedipine, nicardipine, pergo- lide and bromocriptine [6,7]. Occasionally, patients who do not have an obvious predisposing illness develop eryther- malgia without an apparent familial pattern of inheri- tance. Although the underlying cause is not known for these sporadic cases, some of them could be caused by de novo mutations, as discussed below. Until recently, the etiology and molecular patho- physiology of erythermalgia were enigmatic. Vascular, microvascular, inflammatory and neuropathic causes have been entertained [8–10], but the cellular or molecular underpinnings of the disorder were not under- stood and none of these etiologies was well established. In parallel with these multiple views of etiology, treatment of patients with erythermalgia has been provided by dermatologists, vascular medicine specialists, pain specialists and neurologists, among others. Treatment has been empirical and has included aspirin, nonsteroidal anti-inflammatory drugs, vasodilators, vasoconstrictors, antihistamines, capsaicin, adrenergic blockers, antimitotic agents, calcium channel blockers, phenytoin, carbamaze- pine, plasma exchange, sympathetic block or sympathec- tomy [11,12], but in most cases there has been only a partial response to treatment, at best, and there is a need for more effective therapies. Clinical profile of erythermalgia Erythermalgia presents a striking picture of episodic pain and redness in the limbs. Clinical onset of familial erythermalgia has been reported as early as 1 year of age and generally occurs before the end of the first decade. Attacks are characterized by burning pain and redness in the extremities, often triggered by mild warmth or Corresponding author: Waxman, S.G. (stephen.waxman@yale.edu). Available online 8 November 2005 Review TRENDS in Molecular Medicine Vol.11 No.12 December 2005 www.sciencedirect.com 1471-4914/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2005.10.004