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Erythromelalgia – A dramatic pain of genetic origin, revealing pain mechanisms with implications for neuropathic pain in general
Scandinavian Journal of Pain 5 (2014) 215–216
Contents lists available at ScienceDirect
Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com
Editorial comment
Erythromelalgia – A dramatic pain of genetic origin, revealing pain mechanisms with implications for neuropathic pain in general Harald Breivik ∗ University of Oslo and Oslo University Hospital, Departments of Anaesthesiology and of Pain Management and Research, Nydalen PB 4950, 0424 Oslo, Norway
In this issue of the Scandinavian Journal of Pain Zhiping Zhang and co-workers from the research groups of Martin Schmelz, Ellen Jørum, and the Translational Science Centre of AstraZeneca publish a highly interesting and important paper on genetics and neurophysiological research of the pain of erythromelalgia [1].
feet. Many avoid wearing shoes or socks because the warmth this generates can be enough to start pain attacks. There are now 10 known mutations in this gene. It is fascinating that another mutation of the SCN9A-gene causes an inborn genetic error with inability to feel pain [2]. It is also interesting the NaV 1.7 channel is where our local anaesthetic drugs have their blocking effect.
1. What is erythromelalgia For readers who have not seen a case, or maybe even have not heard of patients suffering from attacks of painful red feet (and hands), here is a brief description of a patient with an attack of this rare (1:100 000) erythromelalgia – derived from three Greek words erythros (“red”), melos (“limb”), and algos (“pain”): A young adult woman (as always more women with pain than men), in the middle of the winter, sits with her feet and hands in a bucket of ice-water, complaining that her red feet and hands are burning painfully. The name erythromelalgia was coined by Silas Weird Mitchell (who also described causalgia) in 1878. In 2004 erythromelalgia became the first human neuropathic pain disorder known to be caused by an ion channel mutation, in the gene SCN9A encoding the voltage-gated sodium channel ␣-subunit of NaV 1.7. This voltage gated sodium channel is expressed in C-fibres of peripheral nerves and in nerves of the sympathetic autonomic nervous system. Vaso-dilatation causes the red skin of erythromelalagia. A similar painful disease, secondary eythromelalgia, can be caused by side-effects of medication, e.g. verapamil and nifedipin. The attacks of erythromelalgia pain, lasting from hours to months, arise from hyperexcitability of nociceptive C-fibres and their neurons in the dorsal root ganglia and autonomic ganglia, and can be precipitated by exertion, heating of the affected extremities, or pressure to the
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2014.09.002. ∗ Correspondence to: University of Oslo and Oslo University Hospital, Department of Pain Management and Research, Nydalen PB 4950, 0424 Oslo, Norway. Tel.: +47 23073691; fax: +47 23073690. E-mail address: [email protected]
2. New pieces of knowledge about genetics and clinic of erythromelalgia The highly qualified scientists behind this paper investigated clinically and neurophysiologically 350 patients suspected of erythromelalgia in Oslo. Only 48 patients were confirmed to have erythromelalgia, still a significant number considering how rare this pain condition is (1 in 100 000). These 48 patients were screened for mutation in the Nav 1.7 channel and 29 other known pain-related genes (e.g. genes that express other voltage gated sodium channels, sodium channel subunits, transient receptor potential channels, and neurotrophic factors), using next generation sequencing and classical Sanger sequencing. They found the expected mutations of Nav 1.7 in 5 patients and two patients with new mutations in Nav 1.7. They also found new, rare variants of other sodium channel alpha-subunits and betasubunits. In 20 patients, they found new mutations in several of the other 10 known voltage gated sodium channels. In Nav 1.8 (found in peripheral nervous system), Nav 1.9 (also found in peripheral nervous system), Nav 1.6 (found in central nervous system, it is the most abundant sodium channel), Nav 1.5 (found in the heart), Nav 2.1, and the genes SCN1B and SCN3B. They found mutations in transient receptor potential channels (TRPA1 and TRPV1), and in other pain-related targets (NGFR and WNK1). Thus, they found more than 20 new mutations that have not been reported before [1]. They identified clinically important aspects of four patients with the I848T mutation in the Nav 1.7 gene: they typically had early onset of erythromelalgia with sever symptoms and signs. No clinical characteristics differentiated the other patients with other Nav 1.7 mutations from the patients without such mutations.
http://dx.doi.org/10.1016/j.sjpain.2014.09.001 1877-8860/© 2014 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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H. Breivik / Scandinavian Journal of Pain 5 (2014) 215–216
3. Important implications of these new research findings The authors conclude that functionally characterized mutations of Nav 1.7 are present only in a minority of patients with erythromelalgia. However, they found rare protein-modifying mutations in a majority (27) of their 48 patients with neuropathic pain. They emphasize that possible roles of rare variants of sodium channels, that provoke neuropathic chronic pain, are important fields of future pain research. But already I am convinced that functioning abnormal mutations in channels and receptors must be part of, or possibly even the most significant, explanation for why some unlucky patients develop severe chronic pain after trauma (e.g. neck trauma), after surgery (e.g. persistent post-thoracotomy pain), or after infection (e.g. post-herpes zoster neuralgia), while most patients do not. This paper is an excellent mini-review of the highly complex science of genetics of pain. The pieces of new knowledge they have added to the existing body of knowledge of erythromelalgia, will
eventually help clarify the conundrums of this dramatic disease, but I am hopeful that our present meagre understanding of neuropathic pain in general, will benefit from this research in Martin Schmelz’s and Ellen Jørum’s research teams, and from research that will have to follow in their path. Conflict of interest No conflict of interest. References [1] Zhang Z, Schmelz M, Segerdahl M, Quiding H, Centerholt C, Juréus A, Hedley Carr T, Whiteley J, Salter H, Kvernebo M, Ørstavik K, Helås T, Kleggetveit I-P, Lunden LK, Jørum E. Exonic mutations in SCN9A (Nav 1.7) are found in a minority of patients with Erythromelalgia. Scand J Pain 2014;5:217–25. [2] Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444:894–8.
Contents lists available at ScienceDirect
Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com
Editorial comment
Erythromelalgia – A dramatic pain of genetic origin, revealing pain mechanisms with implications for neuropathic pain in general Harald Breivik ∗ University of Oslo and Oslo University Hospital, Departments of Anaesthesiology and of Pain Management and Research, Nydalen PB 4950, 0424 Oslo, Norway
In this issue of the Scandinavian Journal of Pain Zhiping Zhang and co-workers from the research groups of Martin Schmelz, Ellen Jørum, and the Translational Science Centre of AstraZeneca publish a highly interesting and important paper on genetics and neurophysiological research of the pain of erythromelalgia [1].
feet. Many avoid wearing shoes or socks because the warmth this generates can be enough to start pain attacks. There are now 10 known mutations in this gene. It is fascinating that another mutation of the SCN9A-gene causes an inborn genetic error with inability to feel pain [2]. It is also interesting the NaV 1.7 channel is where our local anaesthetic drugs have their blocking effect.
1. What is erythromelalgia For readers who have not seen a case, or maybe even have not heard of patients suffering from attacks of painful red feet (and hands), here is a brief description of a patient with an attack of this rare (1:100 000) erythromelalgia – derived from three Greek words erythros (“red”), melos (“limb”), and algos (“pain”): A young adult woman (as always more women with pain than men), in the middle of the winter, sits with her feet and hands in a bucket of ice-water, complaining that her red feet and hands are burning painfully. The name erythromelalgia was coined by Silas Weird Mitchell (who also described causalgia) in 1878. In 2004 erythromelalgia became the first human neuropathic pain disorder known to be caused by an ion channel mutation, in the gene SCN9A encoding the voltage-gated sodium channel ␣-subunit of NaV 1.7. This voltage gated sodium channel is expressed in C-fibres of peripheral nerves and in nerves of the sympathetic autonomic nervous system. Vaso-dilatation causes the red skin of erythromelalagia. A similar painful disease, secondary eythromelalgia, can be caused by side-effects of medication, e.g. verapamil and nifedipin. The attacks of erythromelalgia pain, lasting from hours to months, arise from hyperexcitability of nociceptive C-fibres and their neurons in the dorsal root ganglia and autonomic ganglia, and can be precipitated by exertion, heating of the affected extremities, or pressure to the
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2014.09.002. ∗ Correspondence to: University of Oslo and Oslo University Hospital, Department of Pain Management and Research, Nydalen PB 4950, 0424 Oslo, Norway. Tel.: +47 23073691; fax: +47 23073690. E-mail address: [email protected]
2. New pieces of knowledge about genetics and clinic of erythromelalgia The highly qualified scientists behind this paper investigated clinically and neurophysiologically 350 patients suspected of erythromelalgia in Oslo. Only 48 patients were confirmed to have erythromelalgia, still a significant number considering how rare this pain condition is (1 in 100 000). These 48 patients were screened for mutation in the Nav 1.7 channel and 29 other known pain-related genes (e.g. genes that express other voltage gated sodium channels, sodium channel subunits, transient receptor potential channels, and neurotrophic factors), using next generation sequencing and classical Sanger sequencing. They found the expected mutations of Nav 1.7 in 5 patients and two patients with new mutations in Nav 1.7. They also found new, rare variants of other sodium channel alpha-subunits and betasubunits. In 20 patients, they found new mutations in several of the other 10 known voltage gated sodium channels. In Nav 1.8 (found in peripheral nervous system), Nav 1.9 (also found in peripheral nervous system), Nav 1.6 (found in central nervous system, it is the most abundant sodium channel), Nav 1.5 (found in the heart), Nav 2.1, and the genes SCN1B and SCN3B. They found mutations in transient receptor potential channels (TRPA1 and TRPV1), and in other pain-related targets (NGFR and WNK1). Thus, they found more than 20 new mutations that have not been reported before [1]. They identified clinically important aspects of four patients with the I848T mutation in the Nav 1.7 gene: they typically had early onset of erythromelalgia with sever symptoms and signs. No clinical characteristics differentiated the other patients with other Nav 1.7 mutations from the patients without such mutations.
http://dx.doi.org/10.1016/j.sjpain.2014.09.001 1877-8860/© 2014 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
216
H. Breivik / Scandinavian Journal of Pain 5 (2014) 215–216
3. Important implications of these new research findings The authors conclude that functionally characterized mutations of Nav 1.7 are present only in a minority of patients with erythromelalgia. However, they found rare protein-modifying mutations in a majority (27) of their 48 patients with neuropathic pain. They emphasize that possible roles of rare variants of sodium channels, that provoke neuropathic chronic pain, are important fields of future pain research. But already I am convinced that functioning abnormal mutations in channels and receptors must be part of, or possibly even the most significant, explanation for why some unlucky patients develop severe chronic pain after trauma (e.g. neck trauma), after surgery (e.g. persistent post-thoracotomy pain), or after infection (e.g. post-herpes zoster neuralgia), while most patients do not. This paper is an excellent mini-review of the highly complex science of genetics of pain. The pieces of new knowledge they have added to the existing body of knowledge of erythromelalgia, will
eventually help clarify the conundrums of this dramatic disease, but I am hopeful that our present meagre understanding of neuropathic pain in general, will benefit from this research in Martin Schmelz’s and Ellen Jørum’s research teams, and from research that will have to follow in their path. Conflict of interest No conflict of interest. References [1] Zhang Z, Schmelz M, Segerdahl M, Quiding H, Centerholt C, Juréus A, Hedley Carr T, Whiteley J, Salter H, Kvernebo M, Ørstavik K, Helås T, Kleggetveit I-P, Lunden LK, Jørum E. Exonic mutations in SCN9A (Nav 1.7) are found in a minority of patients with Erythromelalgia. Scand J Pain 2014;5:217–25. [2] Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444:894–8.