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Research Articles


Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling. PaulGeha,MD; YangYang, PhD; MarkEstacion,PhD; BetsyR.Schulman,PhD; HajimeTokuno, MD; A.VaniaApkarian,PhD; SulaymanD.Dib-Hajj,PhD; StephenG.Waxman,MD,PhD. Researchers' study demonstrates that pharmacotherapy guided by genomic analysis, molecular modeling and function profiling can diminish neuropathic pain in patients carrying the S241T mutation.. Journal of the American Medical Association (JAMA), April 2016.

Understanding Atomic Interactions to Achieve Well - Being.  Juan M. Pascual, MD, PhD.  Explanation of underlying molecular mechanism of sodium channels - read this in conjunction with the above article entitled Pharmacotherpy for Pain in a Family with Inherited EM. Journal of the American Medical Association (JAMA), Editorial. April 2016

Mutation in Sodium Channel SCN9A and the Pain Perception Disorders.  Markovic, Danica; Jankovic, Radmilo; Veslinovic, Ines. Pain perception disorders are very rare; however, the findings suggest that there is a high possibility that the allelic differences in the SCN9A gene affect the pain perception in general population. Advances in Anesthesiology, Volume 2015, Article 562378.

New Hope in the Fight Against Pain: Study (at McGill University) shows potential new therapy for neuropathic pain.  M.Lopez-Canul, E.Palazzo, S Dominguez-Lopez, L.Luongo, B.Lacoste, S.Comai, D.Angeloni, F.Fraschini, S.Boccella, G.Spadoni, A.Bedini, G.Tarzia, S.Maione, V. Granados-Soto, G.Gobbi., An international study led by scientists at McGill University reports, for the first time, that drugs that selectively target the melatonin MT2 receptor represent a novel class of analgesic drugs that could be used to treat patients with neuropathic pain.  2015 Feb.  

Erythromelalgia Mutation Q875E Stabilizes The Activated State Of Sodium Channel Nav1.7.  Theresa Stadler, Andrias O. O’Reilly, Angelika Lampert,  A study with the following significance:An inter-domain interaction is the structural basis for a novel mechanism underlying this pain disorder. JBC Papers in Press. Published on January 9, 2015 as Manuscript M114.605899

Facial Erythromelalgia: A rare entity to consider in a differential diagnosis of connective tissue diseases.  Patel, MD,  M., Femia, MD, A., Eastham, MD, A., Lin, MD, J., Canales, MD, MMSc, A., Vleugels, MD, MPH, R. A case that shows erythromelalgia can be mistaken for connective tissue disease.  PubFacts. December 2014.

Pain That Won't Quit.  Stephani Sutherland.  How discovery of molecular pathways specific to pain has revealed new targets for drug development. This article uses erythromelalgia as its lead-in to the subject. December 2014.

Collaboration with Stephen Waxman of Yale University to Evaluate Pharmacology of Nav 1.7 Mutations in Chronic Pain Disorder. PRNewswire via Comtex, Cambridge, England. Pharmacological evaluation of Nav 1.7 mutations in paroxysmal pain disorders to discover selective drug therapy matched to a pain genotype. October 6, 2014

The Nav1.7 sodium channel: from molecule to man, Sulayman Dib-Hajj, Yang Yang, Joel Black, Stephen Waxman.  Genetic and functional studies have added to the evidence that Nav1.7 is a major contributor to pain signalling in humans. Jan. 2013, Vol. 14

A Novel SCN9A Mutation Responsible for Primary Erythromelalgia and Is Resistant to the Treatment of Sodium Channel Blockers, Min-Tzu Wu., Po-Yuan Huang1., Chen-Tung Yen, Chih-Cheng Chen, Ming-Jen Lee, Recent discovery of novel mutation in Taiwanese patients. PlosOne, January 2013

The Pain Gate, David Dobbs.  A rare disorder (erythromelalgia) brings insight into the nature of pain - includes conversation with TEA member, Pam Costa.  Scientific American Mind, April/May 2007

Can robots patch-clamp as well as humans? Characterization of a novel sodium channel mutation M. Estacion, J. S. Choi, E. M. Eastman, Z. Lin, Y. Li, L. Tyrrell, Y. Yang, S. D. Dib-Hajj1 and S. G.Waxman.  Researchers compare a patch-clamp robot using planar-chip technology with human patch-clamp in a functional assessment of a previously undescribed Nav1.7 sodium channel mutation, S211P, which causes erythromelalgia.

Severe case and literature review of primary erythromelalgia: Novel SCN9A gene mutation  Nedaa Skeik, Thom W. Rook, Mark Denis P Davis, Dawn Marie R Davis, Henna Kalsi, Ingo Kurth and Randal C Richardson, Vascular Medicine Journal  A severe case of progressive primary erythromelalgia caused by a new de novo heterozygous missense mutation of the SCN9A gene.

Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia  J. Genebriera, J.D. Michaels, P. Sandronit and M.D.P.Davis, Department of Dermatology, College of Medicine and Department of Neurology, Mayo Clinic, Rochester, MN, USA.  Clinical & Experimental Dermatology, British Association of Dermatologists, 2012.   Finding of quantitative sensory testing of patients with EM.

Scientists Discover Chronic Pain Gene (Reuters)British scientists have identified a gene responsible for regulating chronic pain, called HCN2, and say their discovery should help drug researchers in their search for more effective, targeted pain-killing medicines.

Genetic switch discovered that turns on pain.  MacKenzie, Alasdair, News Details, Communications Team, Office of External Affairs, University of Aberdeen, Kings College, Aberdeen, Dec. 21, 2010. Researchers have discovered a "switch" that turns on a gene that lets us feel pain, in a finding that could be a step towards the development of new painkilling drugs.

Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders Drenth, Joost P.H. and Waxman, Stephen G., The Journal of Clinical Investigation, Dec. 2007, Vol. 117, pp. 3603-3609. Recent genetic studies have identified Nav1.7 dysfunction in three different human pain disorders

Thermoregulatory sweat testing in patients with erythromelalgia. Davis MD, Genebriera J, Sandroni P, Fealey RD. Ar-chives of Dermatology 2006, 142(12):1583-1588. Absence of sweating, damaged small nerve fibers are prevalent in EM.

Histopathological findings in primary erythromelalgia show a decrease in small nerve fiber density. Davis MD, Weenig RH, Genebriera J, Wendelschafer-Crabb G, Kennedy WR, Sandroni P. Journal of American Academy of Dermatology 2006, 55(3):519-522. Skin biopsies of EM patients show a decrease in nerve density.

Neurobiology: a channel sets the gain on pain. Waxman SG. Nature 2006, 444(7121):831-832. Different mutations of sodium channel Na1.7 can trigger intense pain of EM or prevent all pain sensation.

Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, Fan J, Bu D, Liu B, Fan Z, Wu G, Jin J, Ding B, Zhu X, Shen Y. Journal of Medical Genetics 2004, 41:171-174. Discovery of 2 mutations in sodium channel 1.7 gene in Chinese family.

Autosomal dominant erythromelalgia. Finley WH, Lindsey JR, Fine JD, Dixon GA, Burbank MK. American Journal of Medical Genetics 1992, 42:310-315. Study of Alabama family with inherited EM.

Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Davis MD, Sandroni P, Rooke TW, Low PA. Archives of Dermatology 2003, 139:1337-1343. Abstract only. Detailed study of nerve abnormalities in EM patients.

SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channelsDrenth JP, Te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB. Journal of Investigative Dermatology 2005, 124:1333-1338. So-dium channel mutations cause neuropathic pain of EM.

Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermal-gia. Burns TM, Te Morsche RH, Jansen JB, Drenth JP. British Journal of Dermatology 2005, 153:174-177.

Discovery of a second gene for EM? Gain-of-function mutation in Nav 1.7 in familial erythromelalgia induces bursting of sensory neurons Dib-Hajj SD, Rush AM, Cummins TR, Hisama FM, Novella S, Tyrrell L, Marshall L, Waxman SG. Brain 2005, 128:1847-1854. Study of third mutation in the gene for sodium channel 1.7 in Alabama family.

Erythromelalgia: a hereditary pain syndrome enters the molecular era. Waxman SG, Dib-Hajj SD. Annals of Neurology 2005, 57:785-788. Painful symptoms of EM caused by defective sodium ion nerve channel 1.7.

Erythromelalgia: studies on pathogenesis and therapy. Mork C. Thesis. Publisher: Unipub AS, Oslo 2004. Summary of earlier research in Norway on vascular and neurological causes of EM. Useful list of 200 other EM papers.

Microvascular arteriovenous shunting is a probable pathogenetic mechanism in erythromelalgia. Mork C, Asker CL, Salerud EG, Kvernebo K. Journal of Investigative Dermatology 2000, 114:643-646. Abnormal blood flow in the skin (shunting vessels) of EM patients. A comment by Mark Davis and reply by Cato Mork follow this article.

Skin perfusion in patients with erythromelalgia Littleford RC, Khan F, Belch JJ. European Journal of Clinical Investiga-tion 1999, 29:588-593. Detailed study of blood flow in the skin of EM patients.

Impaired neurogenic control of skin perfusion in erythromelalgia. Mork C, Kalgaard OM, Kvernebo K. Journal of Investi-gative Dermatology 2002, 118:699-703. Nerve regulation of skin blood flow in EM patients.

Skin blood flow in adult human thermoregulation: how it works, when it does not, and why. Charkoudian N. Mayo Clinic Proceedings 2003, 78:603-612. Review of many studies on temperature regulation of blood flow in the skin. Long techni-cal paper.

Red skin re-read. Schechner J. Journal of Investigative Dermatology 2002, 119:781-782. Short summary of findings by Kvernebo and Mork on skin blood flow in EM.

Impaired skin vasomotor reflexes in patients with erythromelalgia. Littleford RC, Kahn F, Belch JJ. Clinical Science (London) 1999, 96:507-512. The effect of the sympathetic nerves on skin blood flow in EM patients. (Continued from page 9)

Pathological C-fibres in patients with a chronic painful condition. Orstavik K, Weidner C, Schmidt R, Schmelz M, Hil-liges M, Jorum E, Handwerker H, Torebjork E. Brain 2003, 126:567-578. Abstract only. Changes in nerve conduction in chronic EM.

A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. Proceedings of National Academy of Sciences USA 2006, 103(21):8245-8250. The EM sodium channel acts differently in 2 types of nerves.

Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as p Mork C, Kvernebo K, Asker CL, Salerud EG. Journal of Investigative Dermatology 2002, 119:949-953. Abstract only. Abnormal blood flow in the skin (capillary vessels) of EM patients.

A Sodium Channel Gene SCN9A Polymorphism That Increases Nociceptor Excitability Mark Estacion, PhD, T. Patrick Harty, PhD, Jin-Sung Choi, PhD,Lynda Tyrrell, MA,Sulayman D. Dib-Hajj, PhD, and Stephen G. Waxman, MD, PhD. 

Early- and late-onset inherited erythromelalgia: genotype–phenotype correlation Chongyang Han, Sulayman D. Dib-Hajj, Zhimiao Lin, Yan Li,Emmanuella M. Eastman,
Lynda Tyrrell, Xianwei Cao, Yong Yang,* and Stephen G. Waxman

Erythromelalgia mutation L823R shifts activation and inactivation of threshold sodium channel Nav1.7 to hyperpolarized potentials Angelika Lampert Sulayman D. Dib-Hajj, Emmanuella M. Eastman, Lynda Tyrrell, Zhimiao Lin d, Yong Yang d, Stephen G. Waxman

Can robots patch-clamp as well as humans? Characterization of a novel sodium channel mutation. M. EstacionJ. S. Choi1,2,3, E. M. Eastman, Z. Lin, Y. Li, L. Tyrrell1, Y. Yang, S. D. Dib-Hajj and S. G.Waxman

Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel NaV1.7 produce distinct pain disorders Xiaoyang Cheng, Sulayman D Dib-Hajj, Lynda Tyrrell, Dowain A Wright, Tanya Z Fischer and Stephen G Waxman