Genetic Variants in the SCN9A Gene are Detected in a Minority of Erythromelalgia Patients
DOI:
https://doi.org/10.2340/actadv.v105.42022Keywords:
Erythromelalgia, NAV1.7 voltage gated sodium channel, Genetics, etiologyAbstract
Gain-of-function variants in the voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, have previously been identified in patients with erythromelalgia, a clinical diagnosis defined by intermittent attacks of painful, hot, swollen, and red skin, predominantly involving the hands and feet. Symptoms are induced or aggravated by warming and relieved by cooling. In primary erythromelalgia there is no known underlying disease. This study investigated the frequency of SCN9A variants in a cohort of primary erythromelalgia patients collected at a single centre, and examined the clinical signs and symptoms associated with identified variants. One hundred patients with possible erythromelalgia were collected prospectively and evaluated by clinical examination. Thirty-five patients fulfilling the clinical criteria of primary erythromelalgia were screened for variants in SCN9A. Five were found to carry likely causal variants, including a variant found in 2 related individuals and a variant not previously described in patients with erythromelalgia. The clinical findings differed significantly between the patients. Overall, in this cohort only 4/34 (11.7%) of unrelated patients had erythromelalgia likely caused by gain-of-function variants in SCN9A. Variants in SCN9A are therefore likely to cause or contribute to primary erythromelalgia in only a small proportion of patients.
Downloads
References
Kvernebo K. Erythromelalgia. A condition caused by microvascular arteriovenous shunting. VASA 1998; 51.
Kalgaard OM, Seem E, Kvernebo K. Erythromelalgia: a clinical study of 87 cases. J Intern Med 1997; 242: 191-197.
https://doi.org/10.1046/j.1365-2796.1997.00185.x DOI: https://doi.org/10.1046/j.1365-2796.1997.00185.x
Davis MP, O'Fallon W, Rogers IR, Rooke TW. Natural history of erythromelalgia: Presentation and outcome in 168 patients. Arch Dermatol 2000; 136: 330-336.
https://doi.org/10.1001/archderm.136.3.330 DOI: https://doi.org/10.1001/archderm.136.3.330
Mork C, Kvernebo K. Erythromelalgia - a mysterious condition? Arch Dermatol 2000; 136: 406-409.
https://doi.org/10.1001/archderm.136.3.406 DOI: https://doi.org/10.1001/archderm.136.3.406
Mork C, Asker CL, Salerud EG, Kvernebo K. Microvascular arteriovenous shunting is a probable pathogenetic mechanism in erythromelalgia. J Invest Dermatol 2000; 114: 643-646.
https://doi.org/10.1046/j.1523-1747.2000.00944.x DOI: https://doi.org/10.1046/j.1523-1747.2000.00944.x
Alhadad A, Wollmer P, Svensson A, Eriksson KF. Erythromelalgia: Incidence and clinical experience in a single centre in Sweden. Vasa 2012; 41: 43-48.
https://doi.org/10.1024/0301-1526/a000162 DOI: https://doi.org/10.1024/0301-1526/a000162
Reed KB, Davis MD. Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota. J Eur Acad Dermatol Venereol 2009; 23: 13-15.
https://doi.org/10.1111/j.1468-3083.2008.02938.x DOI: https://doi.org/10.1111/j.1468-3083.2008.02938.x
Friberg D, Chen T, Tarr G, van Rij A. Erythromelalgia? A clinical study of people who experience red, hot, painful feet in the community. Int J Vasc Med 2013; 2013: 864961.
https://doi.org/10.1155/2013/864961 DOI: https://doi.org/10.1155/2013/864961
Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet 2004; 41: 171-174.
https://doi.org/10.1136/jmg.2003.012153 DOI: https://doi.org/10.1136/jmg.2003.012153
Drenth JP, Te Morsche RH, Mansour S, Mortimer PS. Primary erythermalgia as a sodium channelopathy: screening for SCN9A mutations: exclusion of a causal role of SCN10A and SCN11A. Arch Dermatol 2008; 144: 320-324.
https://doi.org/10.1001/archderm.144.3.320 DOI: https://doi.org/10.1001/archderm.144.3.320
Klein CJ, Wu Y, Kilfoyle DH, Sandroni P, Davis MD, Gavrilova RH, et al. Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia. J Neurol Neurosurg Psychiatry 2013; 84 :386-391.
https://doi.org/10.1136/jnnp-2012-303719 DOI: https://doi.org/10.1136/jnnp-2012-303719
McDonnell A, Schulman B, Ali Z, Dib-Hajj SD, Brock F, Cobain S, et al. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile. Brain 2016; 139: 1052-1065.
https://doi.org/10.1093/brain/aww007 DOI: https://doi.org/10.1093/brain/aww007
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci 2010; 33: 325-347.
https://doi.org/10.1146/annurev-neuro-060909-153234 DOI: https://doi.org/10.1146/annurev-neuro-060909-153234
Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker. Pain 2012; 153: 80-85.
https://doi.org/10.1016/j.pain.2011.09.008 DOI: https://doi.org/10.1016/j.pain.2011.09.008
Burns TM, Te Morsche RH, Jansen JB, Drenth JP. Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia. Br J Dermatol 2005; 153: 174-177.
https://doi.org/10.1111/j.1365-2133.2005.06441.x DOI: https://doi.org/10.1111/j.1365-2133.2005.06441.x
Zhang Z, Schmelz M, Segerdahl M, Quiding H, Centerholt C, Jureus A, et al. Exonic mutations in SCN9A (NaV1.7) are found in a minority of patients with erythromelalgia. Scand J Pain 2014; 5: 217-225.
https://doi.org/10.1016/j.sjpain.2014.09.002 DOI: https://doi.org/10.1016/j.sjpain.2014.09.002
Faber CGea. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012: 71: 26-39.
https://doi.org/10.1002/ana.22485 DOI: https://doi.org/10.1002/ana.22485
Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G, Drenth JP, et al. Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7. Mol Pain 2011; 7: 92.
https://doi.org/10.1186/1744-8069-7-92 DOI: https://doi.org/10.1186/1744-8069-7-92
Eijkenboom I, Sopacua M, Hoeijmakers JGJ, de Greef BTA, Lindsey P, Almomani R, et al. Yield of peripheral sodium channels gene screening in pure small fibre neuropathy. J Neurol Neurosurg Psychiatry 2019; 90: 342-352.
https://doi.org/10.1136/jnnp-2018-319042 DOI: https://doi.org/10.1136/jnnp-2018-319042
Namer B, Orstavik K, Schmidt R, Kleggetveit IP, Weidner C, Mork C, et al. Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7. Pain 2015; 156: 1637-1646.
https://doi.org/10.1097/j.pain.0000000000000229 DOI: https://doi.org/10.1097/j.pain.0000000000000229
Han C, Dib-Hajj SD, Lin Z, Li Y, Eastman EM, Tyrrell L, et al. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain 2009; 132: 1711-1722.
https://doi.org/10.1093/brain/awp078 DOI: https://doi.org/10.1093/brain/awp078
Wu MT, Huang PY, Yen CT, Chen CC, Lee MJ. A novel SCN9A mutation responsible for primary erythromelalgia and is resistant to the treatment of sodium channel blockers. PloS one 2013; 8: e55212.
https://doi.org/10.1371/journal.pone.0055212 DOI: https://doi.org/10.1371/journal.pone.0055212
Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst 2014; 19: 53-65.
https://doi.org/10.1111/jns5.12071 DOI: https://doi.org/10.1111/jns5.12071
Fertleman CR, Ferrie CD, Aicardi J, Bednarek NA, Eeg-Olofsson O, Elmslie FV, et al. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome). Neurology 2007; 69: 586-595.
https://doi.org/10.1212/01.wnl.0000268065.16865.5f DOI: https://doi.org/10.1212/01.wnl.0000268065.16865.5f
Persson AK, Liu S, Faber CG, Merkies IS, Black JA, Waxman SG. Neuropathy-associated Nav1.7 variant I228M impairs integrity of dorsal root ganglion neuron axons. Ann Neurol 2013; 73: 140-145.
https://doi.org/10.1002/ana.23725 DOI: https://doi.org/10.1002/ana.23725
Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 2006; 6: 108-113.
https://doi.org/10.1016/j.coph.2005.11.003 DOI: https://doi.org/10.1016/j.coph.2005.11.003
Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev 2014: 2014: CD010958.
https://doi.org/10.1002/14651858.CD010958.pub2 DOI: https://doi.org/10.1002/14651858.CD010958.pub2
Samuels ME, te Morsche RH, Lynch ME, Drenth JP. Compound heterozygosity in sodium channel Nav1.7 in a family with hereditary erythermalgia. Mol Pain 2008; 4: 21.
https://doi.org/10.1186/1744-8069-4-21 DOI: https://doi.org/10.1186/1744-8069-4-21
Michiels JJ, Drenth JP, Van Genderen PJ. Classification and diagnosis of erythromelalgia and erythermalgia. Int J Dermatol 1995; 34: 97-100.
https://doi.org/10.1111/j.1365-4362.1995.tb03587.x DOI: https://doi.org/10.1111/j.1365-4362.1995.tb03587.x
Mork C, Kvernebo K, Asker CL, Salerud EG. Reduced skin capillary density during attacks of erythromelalgia implies arteriovenous shunting as pathogenetic mechanism. J Invest Dermatol 2002; 119: 949-953.
https://doi.org/10.1046/j.1523-1747.2002.00218.x DOI: https://doi.org/10.1046/j.1523-1747.2002.00218.x
Lebwohl M, Heymann WR, Berth-Jones J, Coulson I. Treatment of skin disease : comprehensive therapeutic strategies. 4th ed. ed. Edinburgh?: Saunders; 2014.
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63: S240-S252.
https://doi.org/10.1002/acr.20543 DOI: https://doi.org/10.1002/acr.20543
Additional Files
Published
How to Cite
License
Copyright (c) 2025 Mari Skystad Kvernebo, Celene Grayson, Ioannis M. Stylianou, Virginia Woloshen, Christopher Radomski, Cato Mørk, Knut Kvernebo
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All digitalized ActaDV contents is available freely online. The Society for Publication of Acta Dermato-Venereologica owns the copyright for all material published until volume 88 (2008) and as from volume 89 (2009) the journal has been published fully Open Access, meaning the authors retain copyright to their work.
Unless otherwise specified, all Open Access articles are published under CC-BY-NC licences, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for non-commercial purposes, provided proper attribution to the original work.
