Erythromelalgia - Knowledge

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incidence was 1.3/100,000, with a 1 : 5.6 male to female ratio in this study population, respectively. The incidence in this study of primary and secondary EM was 1.1 : 0.2 per 100 000 people per year, respectively. A study of a single centre in the south of Sweden in 2012, showed the overall annual population-based incidence was 0.36/100,000. In New Zealand (Dunedin) a study estimated that in 2013 the incidence of EM is 15/100,000, with a 1 : 3 male to female ratio in this study population, respectively. This last study has an estimation that is at least ten times higher than the prevalence previously reported. This study recruited individuals based on self-identification of symptoms (after self-identification, patients were invited for an assessment of an EM diagnosis), instead of participants that are identified through secondary and tertiary referrals as in the other studies.

237:, a painful deep-aching of the soft tissue (usually either radiating or shooting) and tenderness, along with a painful burning sensation primarily in the extremities. These symptoms are often symmetric and affect the lower extremities more frequently than the upper extremities. Symptoms may also affect the ears and face. For secondary erythromelalgia, attacks typically precede and are precipitated by the underlying primary condition. For primary erythromelalgia, attacks can last from an hour to months at a time and occur infrequently to frequently with multiple times daily. Attacks most frequently occur at night, thus having the potential to greatly interfere with sleep. Common triggers for daytime episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs. In some patients sugar and even 1220:

the application of cold, the conditions are relieved; on the other hand, warmth and summer weather increases pain; there is no loss of sensation, but there may be increased sensitiveness; the local temperature of the affected parts may be raised or lowered; gangrene does not occur; the affection is asymmetrical; there is a certain amount of swelling, sometimes allowing pitting on pressure, sometimes not; incisions over such swelling, even down to the bone, have proved useless; excessive pain on pressure upon the nerves supplying the parts affected is not found; muscular wasting is found, but explainable by the disuse of the limb, and is not at all as severe as in cases of disease of the peripheral nerves; a reaction of degeneration in the nerves of the affected parts has not been found; the deep reflexes, with few exceptions, are not reduced.

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characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. For temperature-related theory, the acral (foot and hand) small superficial arteries intensely constrict and dilate during the sharp decline of temperature, whereas a sharp increase of temperature, the intense expansion of capillaries irritate the nerve endings around, and thus lead to syndromes including (first and second degree) burning pain, increased temperature, erythema and swelling.

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work place, lack of mobility, depression, and is socially alienating; much greater education of medical practitioners is needed. As with many rare diseases, many people with EM end up taking years to get a diagnosis and to receive appropriate treatment.Research into the genetic mutations continues but there is a paucity of clinical studies focusing on living with erythromelalgia. There is much urgency within pharmaceutical companies to provide a solution to those who suffer with pain such as that with erythromelalgia.

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and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. Subsequently, a virus - erythromelalgia-related poxvirus (ERPV) - was repeatedly isolated from throat swabs of six separate patients from two different counties and Wuhan city in Hubei province. The genome of this virus has been sequenced and it appears that this virus is related to a strain of

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triggers to set off a 'flaring' episode that are inexplicable. Whilst a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is strongly discouraged. In pursuit of added relief sufferers can inadvertently cause tissue damage or death, i.e. necrosis. See comments at the end of the preceding paragraph regarding possible effectiveness of plastic food storage bags to avoid/reduce negative effects of submersion in cold water baths.

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higher. Furthermore, while current injection of 40pA for 950ms provokes an average of 6 action potentials in sympathetic neurons expressing wild-type channels this stimulation evokes only approximately 2 action potentials with reduced overshoots in sympathetic neurons expressing L858H mutant channels. Further investigation has demonstrated that the differences in response between DRG and sympathetic neurons is due to expression of Na

490:) than those expressing wild-type channels (124.1 ± 7.4 pA). Furthermore, while DRG neurons expressing wild-type channels only respond with a few action potentials, those expressing F1449V channels respond with a high-frequency train of action potentials. There is a similar effect in DRG neurons expressing the L858H and A863P mutants. Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 307:(neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily affected neurons in these fibers. This hyperexcitability results in the severe burning pain experienced by patients. While the neuropathological symptoms are a result of hyperexcitability, microvascular alterations in erythromelalgia are due to hypoexcitability. The 831:

their legs, and note the reversal (from red to pale) in skin color. Tests done at universities include quantitative sensory nerve testing, laser evoked potentials, sweat testing and epidermal sensory nerve fiber density test (which is an objective test for small fiber sensory neuropathy). Due to the aforementioned factors, patients may face delays in diagnosis.

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girls in middle schools. The disease is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. In the 1987 epidemic in Hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis.

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Some confusion was introduced when Smith and Allen suggested changing the name to erythermalgia in order to emphasise the symptoms of painful inflammation and warmth. In their paper they showed for the first time that when their patients used aspirin, this promptly relieved the burning pain for about

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An epidemic form of this syndrome occurs in secondary school students in rural areas of China. A large epidemic erythromelalgia was occurred in Hubei province of China in 1987 and the disease was characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion,

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In 1997 there was a study conducted in Norway that estimated that the annual incidence of 2/100,000, with a 1 : 2.4 male to female ratio in this study population, respectively. In 2009 there was a population-based study of EM in the USA (Olmsted County, Minnesota), that reported that the annual

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to place the affected limbs in cold water to relieve symptoms when flaring occurs. It may seem a good idea, but it precipitates problems further down the line causing damage to the skin and ulceration often intractable due to the damaged skin. A possible reduction in skin damage may be accomplished

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has been thought to reduce symptoms of erythromelalgia, it is rare to find evidence that this is effective. Mechanical cooling of the limbs by elevating them can help or managing the ambient environment frequently is often necessary constantly as flares occur due to sympathetic autonomic dysfunction

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Dependence produces considerable increase of the dusky red or violaceous tint of the extremity affected; the arteries in this position of the limb may pulsate forcibly; pain is common, sometimes constant, and more especially when the limb is dependent or parts pressed upon; in wintry weather, or on

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topical creams as a way of managing pain on a long-term basis. Feedback from some EM patients has led to reduction in usage as they believe it is only effective for short periods.Living with erythromelalgia can result in a deterioration in quality of life resulting in the inability to function in a

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is an effective way of reducing the stabbing pains and burning sensation symptoms of erythromelalgia in conjunction with the appropriate analgesia. In some cases, antihistamines may give some relief. Most people with erythromelalgia never go into remission and the symptoms are ever present at some

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Primary erythromelalgia management is symptomatic, i.e. treating painful symptoms only. Specific management tactics include avoidance of attack triggers such as: heat, change in temperature, exercise or over exertion, alcohol and spicy foods. This list is by no means comprehensive as there are many

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versus wild-type channel expressing cells. The situation is different, however, in sympathetic neurons expressing the L858H mutation. While L858H expressing sympathetic ganglion are depolarized ~5mV relative to wild-type expressing neurons, their threshold for action potential initiation is notably

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Epidemic erythromelalgia is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. In the 1987 epidemic in Hubei, 60.6% of patients had a common cold before the onset

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Because of the confusion in terminology, Norton and Zager and Grady classified erythromelalgia in 1998 as either: primary/idiopathic erythromelalgia or secondary erythromelalgia. The primary/idiopathic form of erythromelalgia is not associated with any other disease process and can be either early

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Epidemic EM appears quite common in female middle school students of southern China, most likely due to a sharp decline in temperature following by a rapid increase of temperature. It has been postulated that epidemic erythromelalgia might be related to a poxvirus (ERPV) infection. The disease was

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In rural areas of southern China, outbreaks of erythromelalgia have occurred during winter and spring at 3-5 year intervals among secondary school students. This epidemic form of erythromelalgia has been viewed as a different form of non-inherited primary erythromelalgia and affects mainly teenage

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manner. Both of these may be further classified as either juvenile or adult onset. The juvenile onset form occurs prior to age 20 and frequently prior to age 10. While the genetic cause of the juvenile and sporadic adult onset forms is often known, this is not the case for the adult onset familial

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Erythromelalgia is a difficult condition to diagnose as there are no specific tests available. However, reduced capillary density has been observed microscopically during flaring; and reduced capillary perfusion is noted in the patient. Another test that can be done is to have the patient elevate

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of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35 °C. Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling. While such

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An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels is unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At

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Since this virus has not yet been isolated from other outbreaks in other parts of southern China to date this putative association needs to be further investigated. The finding of the specific antibody conversion to ATIs of ERPV in patients' paired sera strengthens the evidence for a possible

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In 1994 Drenth, van Genderen and Michiels distinguished between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin. They established three categories: erythromelalgia (platelet-mediated and aspirin-sensitive), primary erythermalgia, and secondary erythermalgia.

464:. In many mutations, this shift of activation is accompanied by shifts in the voltage sensitivity of fast and/or slow inactivation, often in the depolarized direction. This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in 246:

is rare, but case studies of patients with both diagnoses have been reported in medical journals. Symptoms may present gradually and incrementally, sometimes taking years to become intense enough for patients to seek medical care. In other cases symptoms emerge full blown with onset.

838:(CRPS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely or primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CRPS. 171:

1.7 mutants channels, from families with inherited erythromelalgia (IEM), make dorsal root ganglion (DRG, peripheral and sensory), neurons hyper excitable, thereby demonstrating the mechanistic link between these mutations and pain, thereby firmly establishing

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Patients find relief by cooling the skin. All patients must be notified to not apply ice directly on to the skin, since this can cause maceration of the skin, nonhealing ulcers, infection, necrosis, and even amputation in severe cases.

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consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. The coexistence of erythromelalgia and

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What causes epidemic erythromelalgia in southern China remains unknown although several erythromelalgia-associated poxviruses were isolated from throat swabs of several patients at different counties and from two different seasons.

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ganglion neurons. Nine of these mutations have received further study and they have all shown to result in similar biophysical alterations, Table 1. As can be seen from table 1, the primary effect of erythromelalgia mutations is

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Davis MD, Weenig RH, Genebriera J, Wendelschafer-Crabb G, Kennedy WR, Sandroni P (Sep 2006). "Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density".

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alterations. How this occurs in secondary erythromelalgia is poorly understood and may be specific to the underlying primary condition. Primary conditions that have been shown to elicit erythromelalgia are listed in

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and has also seen cases of: hypertension, diabetes mellitus, rheumatoid arthritis, gout, systemic lupus erythematosus, multiple sclerosis, astrocytoma of the brain, vasculitis, and pernicious anemia.

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by enclosing the flaring limb in a commonly available, thin, heat transparent, water impermeable, plastic food storage bag. The advice of a physician is advised depending on specific circumstances.

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and altered response of this system to stimuli such as heat likely results in the observed microvascular symptoms. In both cases, these changes in excitability are typically due to mutation of the

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Once it has been established that it is not secondary erythromelalgia — see below — a programme of management can be put in place. Some diseases present with symptoms similar to erythromelalgia.

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three days. They also suggested a distinction between primary (idiopathic) erythromelalgia and secondary erythromelalgia (due to underlying neurologic, hematologic, or vascular problems).

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Because of the severity of the pain in erythromelalgia, and the lack of good pain medication then, there have been reports dating back to 1903 of amputation of the affected limb. In 1903

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Drenth, JP; van Genderen, PJ; Michiels, JJ (June 1994). "Thrombocythemic erythromelalgia, primary erythermalgia, and secondary erythermalgia: three distinct clinicopathologic entities".

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street performer and some of his family members. He felt no pain, walked on hot coals and stabbed himself to entertain crowds. By 2013, nearly a dozen gain-of-function mutations of Na

2887:"Combined computer assisted capillary microscopy and laser Doppler imaging used to assess redistribution changes in skin of erythromelalgic patients during treatment with misoprostol" 927:

of the capillaries. The pain that accompanies it is severe and treated separately (the pain is similar to CRPS, phantom limb or thalamic pain syndrome). Patients are strongly advised

104:. Erythromelalgia may occur either as a primary or secondary disorder (i.e. a disorder in and of itself or a symptom of another condition). Secondary erythromelalgia can result from 460:

1.7 channels act largely as threshold sensors and initiate action potentials. Consequently, this shift in their activation profile results in channels that open closer to the

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Ma JE, Lee JU, Sartori-Valinotti JC, Rooke TW, Sandroni P, Davis MD (January 2023). "Erythromelalgia: A Review of Medical Management Options and Our Approach to Management".

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Yang, Yang; Huang, Jianying; Mis, Malgorzata A.; Estacion, Mark; Macala, Lawrence; Shah, Palak; Schulman, Betsy R.; Horton, Daniel B.; Dib-Hajj, Sulayman D. (2016-07-13).

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Cox, James J.; Reimann, Frank; Nicholas, Adeline K.; Thornton, Gemma; Roberts, Emma; Springell, Kelly; Karbani, Gulshan; Jafri, Hussain; Mannan, Jovaria; Raashid, Yasmin;

5762: 2350:"Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons" 413:. Serological characterization can easily distinguish human ERPV from ectromelia virus and vaccinia virus by cross-neutralization and plaque reduction assays 2954:

Sandroni P, Davis MD (March 2006). "Combination gel of 1% amitriptyline and 0.5% ketamine to treat refractory erythromelalgia pain: a new treatment option?".

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Lewis, Thomas (1933). "Clinical observations and experiments relating to burning pain in the extremities, and to so-called "erythromelalgia" in particular".

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Caldito EG, Kaul S, Caldito NG, Piette W, Mehta S (March 2024). "Erythromelalgia. Part I: Pathogenesis, clinical features, evaluation, and complications".

2594:"A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity" 5440: 1113:

onset (in children) or adult onset. In their paper they described secondary erythromelalgia as being associated with another disease, often related to a

1494:; Hamamy, Henan; Valente, Enza Maria; Gorman, Shaun; Williams, Richard; McHale, Duncan P.; Wood, John N.; Gribble, Fiona M.; Woods, C. Geoffrey (2006). 1053:

of all the studies combined results in an EM estimation incidence of 4.7/100,000 with a mean of 1 : 3.7 of the male to female ratio, respectively.

1041:) has also proven to be useful in controlling pain, but many EM patients have found this combination has side effects that they are unable to tolerate. 2198:"Presence of specific IgG antibody to the A type inclusions of erythromelalgia-related poxvirus in the sera of patients with epidemic erythromelalgia" 188:

1.7 had been linked to IEM. The multi-decades search which identified gene SCN9A as the cause of inherited erythomelalgia is documented in a book by

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Alhadad, A; Wollmer, P; Svensson, A; Eriksson, KF (January 2012). "Erythromelalgia: Incidence and clinical experience in a single centre in Sweden".

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Saviuc PF, Danel VC, Moreau PA, Guez DR, Claustre AM, Carpentier PH, Mallaret MP, Ducluzeau R (2001). "Erythromelalgia and mushroom poisoning".

5757: 5632: 4860: 2830:"Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli" 2453:

Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC (2007). "Characterization of a familial case with primary erythromelalgia from Taiwan".

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1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.

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Smith, L.A.; Allen, F.V. (1938). "Erythermalgia (erythromelalgia) of the extremities. A syndrome characterized by redness, heat and pain".

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He distinguished it from the painful red limbs seen in some patients with gout or rheumatoid arthritis. It is derived from the Greek words

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Dib-Hajj, Sulayman D.; Yang, Yang; Black, Joel A.; Waxman, Stephen G. (2012-12-12). "The NaV1.7 sodium channel: from molecule to man".

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Mitchell, Silas Weir (July 1878). "On a rare vasomotor neurosis of the extremities and on maladies with which it may be confounded".

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Zheng, Z. M.; Zhang, J. H.; Hu, J. M.; Liu, S. F.; Zhu, W. P. (1988). "Poxviruses isolated from epidemic erythromelalgia in China".

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Caldito EG, Caldito NG, Kaul S, Piette W, Mehta S (March 2024). "Erythromelalgia. Part II: Differential diagnoses and management".

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EM episode in a foot triggered by dipping it in warm water. The EM in this case is caused by an underlaying small fiber neuropathy.

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reported that in three cases the pain was so severe, and that the affected extremities so useless, that amputation was performed.

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Erythromelalgia is sometimes caused by other disorders. A partial list of diseases known to precipitate erythromelalgia is below.

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Michiels, JJ; Drenth, JP; Van Genderen, PJ (February 1995). "Classification and diagnosis of erythromelalgia and erythermalgia".

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Dib-Hajj, S. D.; Rush, A. M.; Cummins, T. R.; Hisama, F. M.; Novella, S.; Tyrrell, L.; Marshall, L.; Waxman, S. G. (2005-06-15).

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Zhang JH, Zheng ZM, Zhu WP, Cai AM (1990). "Investigation and virus isolation of reappeared epidemic erythromelalgia in Wuhan".

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Zheng ZM, Hu JM, Liu SF, Zhang JH, Zhu WP (1987). "Survey of epidemic erythromelalgia in Hanchuan and Puqi of Hubei Province".

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For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment. Although

4325: 2643:"Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7" 5538: 5401: 4330: 2785:

Han C, Rush AM, Dib-Hajj SD, et al. (2006). "Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7".

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Choi JS, Dib-Hajj SD, Waxman SG (2006). "Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy".

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who suggested the term erythromelalgia to describe a syndrome of red congestion and burning pain in the hands and feet.

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Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V

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He J, Zhao L, Wang B, Zheng J, Lin G, et al. (1995). "Outbreak of epidemic erythromelalgia in Fujian Province".

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Only a small number of studies that have investigated the prevalence of EM, with four studies conducted to date. The

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1.7 sodium channels, which are preferentially expressed within peripheral neurons. One year later, in an article in

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Mendez-Rios, J. D.; Martens, C. A.; Bruno, D. P.; Porcella, S. F.; Zheng, Z. M.; Moss, B. (2012). Xiang, Yan (ed.).

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Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an

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to no avail. (This delay in appropriate pain management can be a result of insurer-mandated or legally-required

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from France, has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.

159:, Cummins et al., demonstrated, using voltage clamp recordings, that these mutations enhanced the function of Na 5712: 5666: 5227: 5023: 4874: 4431: 1210: 835: 3614:"The Morbid Anatomy of Erythromelalgia Based Upon the Examination of the Amputated Extremities of Three Cases" 1839:

Long T, Yang Z, Wang H, Jin D, Qin M (2005). "Epidemiology study of an outbreak of epidemic erythromelalgia".

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may also be effective, but no further testing was carried out as newer research superseded this combination.

1969:"Further characterization of the biological and pathogenic properties of erythromelalgia-related poxviruses" 5322: 5213: 4980: 4807: 4548: 4468: 4173: 3153: 5594: 5377: 4759: 4563: 4558: 4285: 4275: 3039:

Liu, T; Zhang, Y; Lin, H; Lv, X; Xiao, J; Zeng, W; Gu, Y; Rutherford, S; Tong, S; Ma, W (30 March 2015).

2507:"SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels" 1765:

Wei, J. Y. (1984). "An epidemiological survey and clinical analysis of erythromelalgia in Nanning City".

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Diaz, James H. (February 2005). "Syndromic diagnosis and management of confirmed mushroom poisonings".

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mutation with chronic neuropathic pain, when its link to the SCN9A gene was initially published in the

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In 2004 erythromelalgia became the first human disorder in which it has been possible to associate an

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Michiels, JJ; van Joost, T (January 1990). "Erythromelalgia and thrombocythemia: a causal relation".

2242:"Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons" 1443:"Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons" 1345:"Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia" 113: 3103:"Erythromelalgia? A clinical study of people who experience red, hot, painful feet in the community" 2936: 2738:"Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy" 2288:"A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons" 1394:"Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy" 295:

disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of

5747: 5307: 4674: 4487: 4441: 4436: 4260: 4238: 3906: 96:. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, 5159: 4729: 4711: 4193: 4188: 4152: 4122: 2139:"Genome Sequence of Erythromelalgia-Related Poxvirus Identifies it as an Ectromelia Virus Strain" 1214: 1014:

drugs. Opana ER has been found to be effective for many in the US, whilst in the UK slow-release

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Xie F, Ning H, Lei Y, Lei S (2010). "A brief report of an outbreak epidemic erythromelalgia".

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1.7 gain-of-function mutations as the molecular basis for IEM. Conversely, in December 2006 a

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Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG (2007). "A case of inherited erythromelalgia".

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level, whilst others get worse, or the EM is eventually a symptom of another disease such as

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Berlin AL, Pehr K (March 2004). "Coexistence of erythromelalgia and Raynaud's phenomenon".

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drugs may be prescribed to patients only after they have tried almost every other type of

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Mann N, King T, Murphy R (July 2019). "Review of primary and secondary erythromelalgia".

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Norton, JV; Zager, E; Grady, JF (1998). "Erythromelalgia: diagnosis and classification".

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team reported an SCN9A mutation that resulted in a complete lack of pain sensation in a

5647: 5637: 5470: 4610: 4520: 4102: 3889: 3638: 3613: 3478: 3466: 3241: 3216: 3194: 3129: 3102: 3073: 3040: 3014: 2862: 2829: 2810: 2762: 2737: 2618: 2593: 2571: 2559: 2478: 2430: 2401: 2374: 2349: 2322: 2287: 2173: 2138: 2119: 2107: 2076: 1942: 1693: 1637: 1592: 1536: 1495: 1418: 1393: 1369: 1344: 1320: 1266: 1239: 877: 867: 465: 292: 234: 205: 121: 3514: 3398: 3341: 1930: 1890: 5484: 5387: 5312: 5288: 5175: 4401: 4350: 4250: 3917: 3830: 3801: 3766: 3737: 3708: 3679: 3643: 3591: 3518: 3470: 3432: 3345: 3281: 3246: 3232: 3217:"Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota" 3186: 3172: 3134: 3078: 3006: 2971: 2918: 2867: 2849: 2802: 2767: 2715: 2674: 2669: 2623: 2563: 2528: 2523: 2506: 2470: 2435: 2379: 2327: 2263: 2219: 2178: 2111: 2068: 1990: 1934: 1894: 1774: 1747: 1720: 1685: 1625: 1615: 1584: 1576: 1541: 1523: 1472: 1464: 1423: 1374: 1312: 1271: 969:

Strong anecdotal evidence from EM patients shows that a combination of drugs such as

872: 125: 109: 44: 3482: 3198: 3018: 2814: 2575: 2123: 2080: 1946: 1324: 5526: 5431: 5382: 5363: 5317: 5274: 5260: 5246: 5071: 5066: 5052: 5004: 4893: 4841: 4836: 4831: 4406: 4055: 3958: 3822: 3791: 3758: 3729: 3700: 3671: 3633: 3625: 3583: 3510: 3462: 3424: 3394: 3337: 3273: 3236: 3228: 3176: 3168: 3124: 3114: 3068: 3060: 2998: 2963: 2910: 2857: 2845: 2841: 2794: 2757: 2753: 2749: 2705: 2664: 2654: 2613: 2605: 2555: 2518: 2482: 2462: 2425: 2415: 2402:"Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7" 2369: 2365: 2361: 2317: 2307: 2253: 2209: 2168: 2158: 2103: 2060: 1980: 1926: 1886: 1697: 1677: 1596: 1568: 1531: 1515: 1491: 1454: 1413: 1409: 1405: 1364: 1356: 1302: 1261: 1251: 893: 483: 482:. In DRG neurons expressing the F1449V mutation, a lower threshold is required for 1213:

had already summarized with great detail the contrast between erythromelalgia and

5697: 5465: 5446: 5199: 5090: 4990: 4855: 4812: 4783: 4598: 4593: 4505: 4228: 4063: 3911: 3762: 2609: 2163: 3277: 2659: 2642: 1985: 1968: 4958: 4647: 4497: 4360: 4320: 4255: 4216: 4127: 3733: 3704: 3675: 3428: 2967: 2914: 2406: 426: 341: 322: 276: 189: 133: 89: 31: 3922: 3874: 2989:

Cohen, JS (November 2000). "Erythromelalgia: new theories and new therapies".

2694:"Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating" 2466: 1629: 1392:

Cummins, Theodore R.; Dib-Hajj, Sulayman D.; Waxman, Stephen G. (2004-09-22).

1240:"Erythromelalgia: An Uncommon Presentation Precipitated by Aspirin Withdrawal" 1120:

The following table shows the history of the nomenclature of Erythromelalgia:

5741: 5498: 4775: 4515: 4178: 2853: 1580: 1527: 1468: 1007: 897: 373: 65: 4342: 3002: 2312: 1360: 1030:, or merely overly-cautious prescribing on the part of sufferers' doctors.) 5506: 4744: 4656: 4568: 4383: 4073: 4016: 3834: 3805: 3770: 3741: 3712: 3683: 3647: 3629: 3595: 3522: 3285: 3250: 3138: 3082: 3010: 2975: 2922: 2871: 2806: 2771: 2719: 2710: 2693: 2678: 2627: 2567: 2532: 2474: 2439: 2383: 2331: 2267: 2258: 2241: 2182: 2115: 2072: 1898: 1689: 1588: 1545: 1476: 1459: 1442: 1427: 1378: 1316: 1275: 1027: 267: 225:

Erythromelalgia in hands of a Scandinavian male, 52, after holding a book).

221: 85: 69: 3666:

Zahn C, Puga C, Malik A, Khanna D (May 2024). "Painful Raynaud's mimics".

3474: 3436: 3349: 3190: 3119: 2505:

Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB (2005).

2420: 2223: 2064: 1994: 1967:

Zheng, Z. M.; Specter, S.; Zhang, J. H.; Friedman, H.; Zhu, W. P. (1992).

1938: 1778: 1751: 1724: 1256: 5706: 4721: 4117: 1681: 959: 951: 909: 318: 146: 2899: 1519: 4637: 4627: 4588: 4532: 4525: 4355: 3181: 2214: 2197: 1738:

Zhu, W. F. (1989). "A case-control study on epidemic erythromelalgia".

1496:"An SCN9A channelopathy causes congenital inability to experience pain" 1038: 1034: 974: 970: 955: 947: 440: 365: 337: 304: 3857: 3826: 3796: 3779: 3587: 3448: 3446: 3064: 2798: 1307: 1291:"Erythromelalgia: A hereditary pain syndrome enters the molecular era" 1290: 1081: 80:, are episodically blocked (frequently on and off daily), then become 4391: 4132: 4068: 4024: 4007: 4002: 3941: 3536:

Gerhardt, Carl Jakob Adolf Christian (1892). "über erythromelalgie".

3368: 2286:

Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (2006).

1201: 1023: 1019: 963: 943: 905: 901: 632: 377: 361: 312: 280: 132:. Primary erythromelalgia is caused by mutation of the voltage-gated 81: 73: 1572: 5579: 4605: 4207: 4144: 4078: 4029: 3443: 1015: 1003: 986: 887: 503:

1.8 channels in sympathetic neurons also expressing L858H mutant Na

410: 230: 181: 97: 93: 49: 2592:

Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR (2007).

1612:

Chasing men on fire : the story of the search for a pain gene

1767:

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi

1740:

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi

1713:

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi

1711:

Mo, Y. M. (1989). "An epidemiological study on erythromelalgia".

923: 3900: 3574:

HUIZINGA, J (1957). "Hereditary acromelalgia or restless legs".

3410: 3408: 456:

1.7 channels that activate at more hyperpolarized potentials. Na

380:, have been associated with medication-induced erythromelalgia. 5561: 5520: 5409: 5395: 5153: 5147: 5141: 5127: 5121: 4887: 4868: 4849: 4825: 4801: 3998: 3869: 2136: 1011: 487: 479: 435: 325: 229:

The most prominent symptoms of erythromelalgia are episodes of

138: 3323: 3321: 3319: 3263: 3221:

Journal of the European Academy of Dermatology and Venereology

2640: 5547: 5492: 5478: 5459: 5371: 5330: 5296: 5282: 5268: 5254: 5235: 5221: 5207: 5193: 5079: 5060: 5046: 5017: 4998: 4974: 3405: 417:

aetiological role of human ERPV in epidemic erythromelalgia.

369: 238: 3496: 3494: 3492: 2691: 2504: 332:. These differences in excitability alterations between the 194:

Chasing Men on Fire: The Story of the Search for a Pain Gene

5679: 5660: 5656: 5626: 5612: 5357: 4931: 4912: 4374: 3748: 3316: 2591: 1667: 1050: 1018:

has proved to be effective. These powerful and potentially-

517: 491: 77: 3452: 3414: 3299: 3297: 3295: 1489: 1237: 3489: 2641:

Michiels JJ, te Morsche RH, Jansen JB, Drenth JP (2005).

1966: 1440: 1238:

Khalid F, Hassan S, Qureshi S, Qureshi W, Amer S (2012).

3719: 3690: 3380: 3378: 3376: 3292: 1558: 1289:

Waxman, Stephen G.; Dib-Hajj, Sulayman D. (June 2005).

3100: 2348:

Harty TP, Dib-Hajj SD, Tyrrell L, et al. (2006).

2285: 2240:

Dib-Hajj SD, Rush AM, Cummins TR, et al. (2005).

3152:

Kalgaard, OM; Seem, E; Kvernebo, K (September 1997).

2735: 2692:

Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG (2006).

2050: 1803:

Chinese Journal of Experimental and Clinical Virology

1391: 1196: 471:

Some of these mutant channels have been expressed in

3988: 3847: 3373: 3151: 2827: 2452: 2347: 2195: 1002:

Mild sufferers may find sufficient pain relief with

939:

One clinical study has demonstrated the efficacy of

516:

cooling is unlikely to affect neuronal cell bodies,

3777: 3665: 2239: 88:. There is severe burning pain (in the small fiber 2943:. NORD - National Organization for Rare Disorders. 2545: 712:Creation of a window current, slowed deactivation 425:There are 10 known mutations in the voltage-gated 16:Inflammation due to periodic blood vessel blockage 3327: 3101:Friberg, D; Chen, T; Tarr, G; van Rij, A (2013). 3096: 3094: 3092: 693:Slowed deactivation, enhanced slow inactivation, 499:1.8 in the former. Consequently, expression of Na 388:The consumption of two species of related fungi, 5763:Diseases of arteries, arterioles and capillaries 5739: 3778:Raef HS, Williams M, Fedeles F (November 2022). 3500: 2235: 2233: 2196:Zheng, Z. M.; Specter, S.; Friedman, H. (1991). 2032:Ichimura, J (1918). "A new poisonous mushroom". 2012: 275:In general, erythromelalgia seems to consist of 3154:"Erythromelalgia: a clinical study of 87 cases" 3145: 2784: 2731: 2729: 2400:Han C, Lampert A, Rush AM, et al. (2007). 1916: 1838: 1819: 1800: 291:Primary erythromelalgia is a better understood 3812: 3330:Journal of the American Academy of Dermatology 3210: 3208: 3089: 2991:Journal of the American Academy of Dermatology 2587: 2585: 2500: 2498: 2496: 2494: 2492: 2399: 1663: 1661: 1659: 1657: 1655: 1653: 1288: 631:Creation of a large window current, decreased 251:of erythromelalgia and 91.2% had pharyngitis. 4760: 3974: 3567: 3529: 3038: 3034: 3032: 3030: 3028: 2953: 2634: 2343: 2341: 2230: 2008: 2006: 2004: 1857: 1796: 1794: 1792: 1790: 1788: 1483: 4774: 3607: 3605: 3257: 2726: 2685: 2281: 2279: 2277: 1642:: CS1 maint: multiple names: authors list ( 801:, the linker between transmembrane segments 535:1.7 associated with primary erythromelalgia 403: 355: 3205: 2736:Cummins TR, Dib-Hajj SD, Waxman SG (2004). 2582: 2489: 2395: 2393: 2130: 1650: 1338: 1336: 1334: 4767: 4753: 4554:Chronic cerebrospinal venous insufficiency 3981: 3967: 3548: 3384: 3107:International Journal of Vascular Medicine 3025: 2982: 2338: 2189: 2001: 1876: 1785: 1343:Yang Y, Wang Y, Li S, et al. (2004). 1342: 552:Shift of inactivation (fast and/or slow) V 30: 5672:Progressive symmetric erythrokeratodermia 3795: 3637: 3602: 3240: 3214: 3180: 3128: 3118: 3072: 2884: 2861: 2761: 2709: 2668: 2658: 2617: 2539: 2522: 2429: 2419: 2373: 2321: 2311: 2274: 2257: 2213: 2172: 2162: 1984: 1832: 1535: 1458: 1417: 1368: 1306: 1265: 1255: 439:. This channel is expressed primarily in 5686:Clouston's hidrotic ectodermal dysplasia 3780:"Topical treatments for erythromelalgia" 3573: 3535: 3306:American Journal of the Medical Sciences 3303: 2778: 2446: 2390: 2031: 1962: 1960: 1958: 1956: 1912: 1910: 1908: 1851: 1331: 1200: 1080: 266: 258: 220: 3266:VASA. Zeitschrift für Gefässkrankheiten 1813: 1074:The first reported case was in 1878 by 167:, Dib-Hajj et al., demonstrated that Na 5740: 5633:Keratitis–ichthyosis–deafness syndrome 5452:Congenital absence of the vas deferens 1060: 985:Some suffering with EM are prescribed 5758:Vascular-related cutaneous conditions 4748: 4326:Hereditary hemorrhagic telangiectasia 3962: 3554: 3503:The Journal of Foot and Ankle Surgery 2988: 1953: 1905: 653:Slowed deactivation and inactivation 383: 216: 4331:Generalized essential telangiectasia 3611: 3455:International Journal of Dermatology 3215:Reed, KB; Davis, MD (January 2009). 2093: 594:Faster entry into fast-inactivation 155:. Later that year, in an article in 5753:Peripheral nervous system disorders 2202:Archives of Dermatological Research 1764: 1758: 1737: 1731: 13: 5303:Jervell and Lange-Nielsen syndrome 5242:Jervell and Lange-Nielsen syndrome 3658: 3576:Acta Genetica et Statistica Medica 3467:10.1111/j.1365-4362.1995.tb03587.x 2560:10.1212/01.wnl.0000231514.33603.1e 2108:10.1097/01.CCM.0000153531.69448.49 1710: 1704: 1670:Nature Clinical Practice Neurology 1609: 1197:Differences with Raynaud's disease 1170:L.A. Smith and F.N. Allen in 1938 420: 340:is due to different expression of 14: 5779: 3843: 2885:Mørk, Cato; Asker, Claes (2013). 863:Small fiber peripheral neuropathy 524:1.7 and are present in the skin. 199: 106:small fiber peripheral neuropathy 5713:Nephrogenic diabetes insipidus 2 5101:Congenital insensitivity to pain 5096:Paroxysmal extreme pain disorder 5024:Hypokalemic periodic paralysis 2 4875:Hypokalemic periodic paralysis 1 4481:Cerebral venous sinus thrombosis 3538:Berliner Klinische Wochenschrift 3233:10.1111/j.1468-3083.2008.02938.x 3173:10.1046/j.1365-2796.1997.00185.x 2524:10.1111/j.0022-202X.2005.23737.x 1614:. Cambridge, MA: The MIT Press. 64:) is a rare vascular peripheral 5605:Hypoplastic left heart syndrome 5416:Thyrotoxic periodic paralysis 2 5029:Hyperkalemic periodic paralysis 4880:Thyrotoxic periodic paralysis 1 3356: 2947: 2929: 2893: 2878: 2821: 2087: 2044: 2025: 1973:The Journal of General Virology 1870: 1044: 360:Several medications, including 5667:Erythrokeratodermia variabilis 5619:Charcot–Marie–Tooth disease X1 5323:Familial atrial fibrillation 3 5228:Spinocerebellar ataxia type-13 5214:Familial atrial fibrillation 7 4981:Familial hemiplegic migraine 3 4808:Familial hemiplegic migraine 1 4432:Hepatic veno-occlusive disease 2846:10.1523/JNEUROSCI.0462-16.2016 2754:10.1523/JNEUROSCI.2695-04.2004 2366:10.1523/JNEUROSCI.3424-06.2006 1603: 1552: 1434: 1410:10.1523/jneurosci.2695-04.2004 1385: 1282: 1231: 993: 954:, while other have shown that 836:Complex regional pain syndrome 285: 1: 5513:Vitelliform macular dystrophy 5039:Potassium-aggravated myotonia 4818:Spinocerebellar ataxia type-6 4244:Aneurysm of sinus of Valsalva 4098:Monckeberg's arteriosclerosis 3668:Best Pract Res Clin Rheumatol 3515:10.1016/s1067-2516(99)80060-x 3399:10.1016/S0002-8703(38)90693-3 3342:10.1016/s0190-9622(08)80005-9 1931:10.1016/S0140-6736(88)90372-8 1891:10.1016/S0190-9622(03)02121-2 1860:Practical Preventive Medicine 1184: 1033:The combination of Cymbalta ( 750:Increased spontaneous firing 538: 60:or Mitchell's disease (after 4549:Chronic venous insufficiency 4174:Aortoiliac occlusive disease 3763:10.1016/j.mayocp.2022.08.005 3161:Journal of Internal Medicine 2610:10.1113/jphysiol.2006.127027 2292:Proc. Natl. Acad. Sci. U.S.A 2164:10.1371/journal.pone.0034604 1610:G., Waxman, Stephen (2018). 1224: 917: 819: 39:Erythromelalgia in left hand 7: 5600:Hallermann–Streiff syndrome 5595:Oculodentodigital dysplasia 5160:Pseudohypoaldosteronism 1AR 4564:Inferior vena cava syndrome 4559:Superior vena cava syndrome 4286:Vertebral artery dissection 4276:Intracranial berry aneurysm 2660:10.1001/archneur.62.10.1587 1986:10.1099/0022-1317-73-8-2011 1822:Chinese Journal of Zoonoses 1561:Nature Reviews Neuroscience 1115:myeloproliferative disorder 511:16 °C the activation V 157:The Journal of Neuroscience 152:Journal of Medical Genetics 10: 5784: 4665:Hypertensive heart disease 4316:Arteriovenous malformation 4291:Familial aortic dissection 3734:10.1016/j.jaad.2023.02.070 3705:10.1016/j.jaad.2023.02.071 3676:10.1016/j.berh.2024.101948 3612:Shaw, HB (21 March 1903). 3429:10.1177/000331979404500606 2968:10.1001/archderm.142.3.283 2915:10.1016/j.jaad.2006.04.067 1069: 892:Some medications, such as 848:Myeloproliferative disease 823: 462:resting membrane potential 334:sympathetic nervous system 309:sympathetic nervous system 5723: 5696: 5578: 5537: 5430: 5347: 5183: 5174: 5111: 4966: 4957: 4904: 4791: 4782: 4720: 4690:Renovascular hypertension 4655: 4646: 4633:Hepatic artery thrombosis 4581: 4541: 4496: 4400: 4382: 4373: 4341: 4301: 4281:Carotid artery dissection 4234:Abdominal aortic aneurysm 4206: 4166: 4143: 4084:Intermittent claudication 4054: 4047:Peripheral artery disease 4045: 4015: 3997: 3932: 3851: 3278:10.1024/0301-1526/a000162 2670:10067/1027200151162165141 2467:10.1007/s00415-006-0328-3 765:, linker between domains 756: 404:Possible infectious cause 356:Side effect of medication 271:Toes during an EM flareup 114:essential thrombocythemia 43: 38: 29: 24: 4776:Diseases of ion channels 4675:Hypertensive nephropathy 4488:Post-thrombotic syndrome 4469:Paget–Schroetter disease 4261:Coronary artery aneurysm 4239:Thoracic aortic aneurysm 1244:Case Reports in Medicine 781:, transmembrane segment 254: 5378:Andersen–Tawil syndrome 4730:Orthostatic hypotension 4712:White coat hypertension 4189:Fibromuscular dysplasia 4153:Carotid artery stenosis 3618:British Medical Journal 3003:10.1067/mjd.2000.109301 2834:Journal of Neuroscience 2313:10.1073/pnas.0602813103 1398:Journal of Neuroscience 1361:10.1136/jmg.2003.012153 883:Obstructive Sleep Apnea 531:Summary of mutations Na 178:University of Cambridge 5643:Bart–Pumphrey syndrome 5034:Paramyotonia congenita 4919:Malignant hyperthermia 4702:Pulmonary hypertension 4685:Secondary hypertension 4680:Essential hypertension 4670:Hypertensive emergency 4511:Portacaval anastomosis 4447:Portal vein thrombosis 4089:Critical limb ischemia 3990:Cardiovascular disease 3630:10.1136/bmj.1.2203.662 2711:10.1074/jbc.M607637200 2096:Critical Care Medicine 2053:J Toxicol Clin Toxicol 1206: 1086: 757:Region nomenclature: D 520:and termini express Na 486:creation (93.1 ± 12.0 272: 264: 226: 5568:Mucolipidosis type IV 5113:Constitutively active 4707:Systolic hypertension 4452:Renal vein thrombosis 4311:Arteriovenous fistula 4303:Vascular malformation 4271:Intracranial aneurysm 4158:Renal artery stenosis 2421:10.1186/1744-8069-3-3 2065:10.1081/CLT-100105162 2015:Wuhan Medical Journal 1879:J. Am. Acad. Dermatol 1841:Occupation and Health 1204: 1084: 826:Burning feet syndrome 546:Shift of activation V 391:Clitocybe acromelalga 270: 262: 224: 5499:Osteopetrosis A2, B4 5308:Romano–Ward syndrome 4924:Central core disease 4621:Paradoxical embolism 4616:Cholesterol embolism 4442:May–Thurner syndrome 4437:Budd–Chiari syndrome 4420:Deep vein thrombosis 4415:primarily lower limb 4194:Raynaud's phenomenon 2259:10.1093/brain/awh514 1682:10.1038/ncpneuro0425 1460:10.1093/brain/awh514 1178:J. Huizinga in 1957 980:systemic scleroderma 853:Hypercholesterolemia 473:dorsal root ganglion 445:dorsal root ganglion 397:Clitocybe amoenolens 372:derivatives such as 301:dorsal root ganglion 244:Raynaud's phenomenon 130:autoimmune disorders 118:hypercholesterolemia 5053:Long QT syndrome 10 4697:Benign hypertension 3120:10.1155/2013/864961 3057:2015NatSR...5E9525L 2511:J. Invest. Dermatol 2304:2006PNAS..103.8245R 2155:2012PLoSO...734604M 1520:10.1038/nature05413 1512:2006Natur.444..894C 1295:Annals of Neurology 1257:10.1155/2012/616125 1138:Silas Weir Mitchell 1129:Author(s) and year 1085:Silas Weir Mitchell 1076:Silas Weir Mitchell 1061:Prevalence in China 858:Autoimmune disorder 536: 433:1.7 encoding gene, 62:Silas Weir Mitchell 5648:Vohwinkel syndrome 5638:Ichthyosis hystrix 5527:Bartter syndrome 3 5471:Myotonia congenita 5383:Long QT syndrome 7 5364:Bartter syndrome 2 5318:Long QT syndrome 1 5275:Brugada syndrome 5 5261:Long QT syndrome 6 5247:Long QT syndrome 5 5091:Febrile seizure 3B 5072:Long QT syndrome 3 5067:Brugada syndrome 1 5005:Brugada syndrome 6 4991:Febrile seizure 3A 4894:Brugada syndrome 4 4842:Long QT syndrome 8 4837:Brugada syndrome 3 4611:Pulmonary embolism 4521:Esophageal varices 4459:upper limb / torso 4103:Arteriolosclerosis 3933:External resources 3722:J Am Acad Dermatol 3693:J Am Acad Dermatol 3045:Scientific Reports 2903:J Am Acad Dermatol 2215:10.1007/BF00371930 1207: 1145:Gerhardt's disease 1087: 878:Mushroom poisoning 527: 466:membrane potential 384:Mushroom poisoning 293:autosomal dominant 273: 265: 227: 217:Symptoms and signs 206:autosomal dominant 5735: 5734: 5426: 5425: 5388:Short QT syndrome 5313:Short QT syndrome 5289:Short QT syndrome 5200:Episodic ataxia 1 5176:Potassium channel 5170: 5169: 5134:Liddle's syndrome 4953: 4952: 4856:Ocular albinism 2 4813:Episodic ataxia 2 4742: 4741: 4738: 4737: 4582:Arteries or veins 4577: 4576: 4402:Venous thrombosis 4369: 4368: 4351:Cherry hemangioma 4251:Aortic dissection 4202: 4201: 4037:Buerger's disease 3956: 3955: 3827:10.1111/ced.13891 3815:Clin Exp Dermatol 3797:10.1111/dth.15860 3588:10.1159/000150945 3065:10.1038/srep09525 2997:(5 Pt 1): 841–7. 2941:rare diseases.org 2840:(28): 7511–7522. 2799:10.1002/ana.20776 2604:(Pt 3): 1019–31. 2252:(Pt 8): 1847–54. 1506:(7121): 894–898. 1492:Al-Gazali, Lihadh 1404:(38): 8232–8236. 1308:10.1002/ana.20511 1215:Raynaud's disease 1205:Sir Thomas Barlow 1182: 1181: 873:Mercury poisoning 817: 816: 277:neuropathological 126:mercury poisoning 110:polycythemia vera 74:lower extremities 72:, usually in the 55: 54: 19:Medical condition 5775: 5432:Chloride channel 5349:Inward-rectifier 5181: 5180: 4964: 4963: 4832:Timothy syndrome 4789: 4788: 4769: 4762: 4755: 4746: 4745: 4653: 4652: 4464:Mondor's disease 4407:Thrombophlebitis 4380: 4379: 4056:Arteriosclerosis 4052: 4051: 4013: 4012: 3983: 3976: 3969: 3960: 3959: 3849: 3848: 3838: 3809: 3799: 3774: 3745: 3716: 3687: 3652: 3651: 3641: 3609: 3600: 3599: 3571: 3565: 3564: 3557:Clinical Science 3552: 3546: 3545: 3533: 3527: 3526: 3498: 3487: 3486: 3450: 3441: 3440: 3412: 3403: 3402: 3382: 3371: 3360: 3354: 3353: 3325: 3314: 3313: 3301: 3290: 3289: 3261: 3255: 3254: 3244: 3212: 3203: 3202: 3184: 3158: 3149: 3143: 3142: 3132: 3122: 3098: 3087: 3086: 3076: 3036: 3023: 3022: 2986: 2980: 2979: 2951: 2945: 2944: 2933: 2927: 2926: 2897: 2891: 2890: 2882: 2876: 2875: 2865: 2825: 2819: 2818: 2782: 2776: 2775: 2765: 2733: 2724: 2723: 2713: 2704:(47): 36029–35. 2689: 2683: 2682: 2672: 2662: 2638: 2632: 2631: 2621: 2589: 2580: 2579: 2543: 2537: 2536: 2526: 2502: 2487: 2486: 2450: 2444: 2443: 2433: 2423: 2397: 2388: 2387: 2377: 2360:(48): 12566–75. 2345: 2336: 2335: 2325: 2315: 2283: 2272: 2271: 2261: 2237: 2228: 2227: 2217: 2193: 2187: 2186: 2176: 2166: 2134: 2128: 2127: 2091: 2085: 2084: 2048: 2042: 2041: 2029: 2023: 2022: 2010: 1999: 1998: 1988: 1979:(8): 2011–2019. 1964: 1951: 1950: 1914: 1903: 1902: 1874: 1868: 1867: 1855: 1849: 1848: 1836: 1830: 1829: 1817: 1811: 1810: 1798: 1783: 1782: 1762: 1756: 1755: 1735: 1729: 1728: 1708: 1702: 1701: 1665: 1648: 1647: 1641: 1633: 1607: 1601: 1600: 1556: 1550: 1549: 1539: 1487: 1481: 1480: 1462: 1453:(8): 1847–1854. 1438: 1432: 1431: 1421: 1389: 1383: 1382: 1372: 1340: 1329: 1328: 1310: 1286: 1280: 1279: 1269: 1259: 1235: 1123: 1122: 894:fluoroquinolones 537: 526: 484:action potential 394:from Japan, and 303:. Specifically, 34: 22: 21: 5783: 5782: 5778: 5777: 5776: 5774: 5773: 5772: 5748:Channelopathies 5738: 5737: 5736: 5731: 5719: 5692: 5574: 5533: 5466:Thomsen disease 5447:Cystic fibrosis 5422: 5343: 5166: 5107: 5086:Erythromelalgia 4949: 4900: 4784:Calcium channel 4778: 4773: 4743: 4734: 4716: 4642: 4599:Microangiopathy 4594:Macroangiopathy 4573: 4537: 4506:Gastric varices 4492: 4405: 4396: 4365: 4337: 4297: 4229:Aortic aneurysm 4215: 4198: 4184:Erythromelalgia 4162: 4139: 4064:Atherosclerosis 4041: 4005: 3993: 3987: 3957: 3952: 3951: 3928: 3927: 3860: 3846: 3841: 3661: 3659:Further reading 3656: 3655: 3624:(2203): 662–3. 3610: 3603: 3572: 3568: 3553: 3549: 3534: 3530: 3499: 3490: 3451: 3444: 3413: 3406: 3383: 3374: 3364:Erythromelalgia 3361: 3357: 3326: 3317: 3302: 3293: 3262: 3258: 3213: 3206: 3156: 3150: 3146: 3099: 3090: 3037: 3026: 2987: 2983: 2952: 2948: 2935: 2934: 2930: 2898: 2894: 2883: 2879: 2826: 2822: 2783: 2779: 2734: 2727: 2690: 2686: 2653:(10): 1587–90. 2639: 2635: 2590: 2583: 2544: 2540: 2503: 2490: 2451: 2447: 2398: 2391: 2346: 2339: 2298:(21): 8245–50. 2284: 2275: 2238: 2231: 2194: 2190: 2135: 2131: 2092: 2088: 2049: 2045: 2034:Bot Gaz (Tokyo) 2030: 2026: 2011: 2002: 1965: 1954: 1915: 1906: 1875: 1871: 1856: 1852: 1837: 1833: 1818: 1814: 1799: 1786: 1763: 1759: 1736: 1732: 1709: 1705: 1666: 1651: 1635: 1634: 1622: 1608: 1604: 1573:10.1038/nrn3404 1557: 1553: 1488: 1484: 1439: 1435: 1390: 1386: 1341: 1332: 1287: 1283: 1236: 1232: 1227: 1199: 1187: 1134:Erythromelalgia 1072: 1063: 1047: 996: 920: 868:Fabry's disease 828: 822: 744:Hyperpolarized 725:Hyperpolarized 706:Hyperpolarized 688:Hyperpolarized 675: 666:Hyperpolarized 648:Hyperpolarized 625:Hyperpolarized 610:Hyperpolarized 607:Hyperpolarized 591:Hyperpolarized 588:Hyperpolarized 555: 549: 534: 523: 514: 506: 502: 498: 459: 455: 432: 423: 421:Pathophysiology 406: 386: 358: 347: 342:sodium channels 329: 257: 219: 202: 187: 175: 170: 162: 136:α-subunit gene 58:Erythromelalgia 25:Erythromelalgia 20: 17: 12: 11: 5: 5781: 5771: 5770: 5765: 5760: 5755: 5750: 5733: 5732: 5724: 5721: 5720: 5718: 5717: 5716: 5715: 5702: 5700: 5694: 5693: 5691: 5690: 5689: 5688: 5676: 5675: 5674: 5669: 5653: 5652: 5651: 5645: 5640: 5635: 5623: 5622: 5621: 5609: 5608: 5607: 5602: 5597: 5584: 5582: 5576: 5575: 5573: 5572: 5571: 5570: 5558: 5557: 5556: 5543: 5541: 5535: 5534: 5532: 5531: 5530: 5529: 5517: 5516: 5515: 5503: 5502: 5501: 5489: 5488: 5487: 5485:Dent's disease 5475: 5474: 5473: 5468: 5456: 5455: 5454: 5449: 5436: 5434: 5428: 5427: 5424: 5423: 5421: 5420: 5419: 5418: 5406: 5405: 5404: 5392: 5391: 5390: 5385: 5380: 5368: 5367: 5366: 5353: 5351: 5345: 5344: 5342: 5341: 5340: 5339: 5327: 5326: 5325: 5320: 5315: 5310: 5305: 5293: 5292: 5291: 5279: 5278: 5277: 5265: 5264: 5263: 5251: 5250: 5249: 5244: 5232: 5231: 5230: 5218: 5217: 5216: 5204: 5203: 5202: 5189: 5187: 5178: 5172: 5171: 5168: 5167: 5165: 5164: 5163: 5162: 5138: 5137: 5136: 5117: 5115: 5109: 5108: 5106: 5105: 5104: 5103: 5098: 5093: 5088: 5076: 5075: 5074: 5069: 5057: 5056: 5055: 5043: 5042: 5041: 5036: 5031: 5026: 5014: 5013: 5012: 5007: 4995: 4994: 4993: 4988: 4983: 4970: 4968: 4961: 4959:Sodium channel 4955: 4954: 4951: 4950: 4948: 4947: 4946: 4945: 4940: 4928: 4927: 4926: 4921: 4908: 4906: 4902: 4901: 4899: 4898: 4897: 4896: 4884: 4883: 4882: 4877: 4865: 4864: 4863: 4858: 4846: 4845: 4844: 4839: 4834: 4822: 4821: 4820: 4815: 4810: 4797: 4795: 4786: 4780: 4779: 4772: 4771: 4764: 4757: 4749: 4740: 4739: 4736: 4735: 4733: 4732: 4726: 4724: 4718: 4717: 4715: 4714: 4709: 4704: 4699: 4694: 4693: 4692: 4682: 4677: 4672: 4667: 4661: 4659: 4650: 4648:Blood pressure 4644: 4643: 4641: 4640: 4635: 4630: 4625: 4624: 4623: 4618: 4613: 4603: 4602: 4601: 4596: 4585: 4583: 4579: 4578: 4575: 4574: 4572: 4571: 4566: 4561: 4556: 4551: 4545: 4543: 4539: 4538: 4536: 4535: 4530: 4529: 4528: 4523: 4518: 4508: 4502: 4500: 4498:Varicose veins 4494: 4493: 4491: 4490: 4485: 4484: 4483: 4473: 4472: 4471: 4466: 4456: 4455: 4454: 4449: 4444: 4439: 4434: 4424: 4423: 4422: 4411: 4409: 4398: 4397: 4395: 4394: 4388: 4386: 4377: 4371: 4370: 4367: 4366: 4364: 4363: 4361:Spider angioma 4358: 4353: 4347: 4345: 4343:Vascular nevus 4339: 4338: 4336: 4335: 4334: 4333: 4328: 4321:Telangiectasia 4318: 4313: 4307: 4305: 4299: 4298: 4296: 4295: 4294: 4293: 4288: 4283: 4278: 4273: 4263: 4258: 4256:Aortic rupture 4253: 4248: 4247: 4246: 4241: 4236: 4221: 4219: 4217:pseudoaneurysm 4204: 4203: 4200: 4199: 4197: 4196: 4191: 4186: 4181: 4176: 4170: 4168: 4164: 4163: 4161: 4160: 4155: 4149: 4147: 4141: 4140: 4138: 4137: 4136: 4135: 4130: 4128:Oxycholesterol 4125: 4120: 4115: 4110: 4100: 4094: 4093: 4092: 4091: 4086: 4081: 4076: 4071: 4060: 4058: 4049: 4043: 4042: 4040: 4039: 4034: 4033: 4032: 4021: 4019: 4010: 3995: 3994: 3986: 3985: 3978: 3971: 3963: 3954: 3953: 3950: 3949: 3947:article/200071 3937: 3936: 3934: 3930: 3929: 3926: 3925: 3914: 3903: 3892: 3877: 3861: 3856: 3855: 3853: 3852:Classification 3845: 3844:External links 3842: 3840: 3839: 3821:(5): 477–482. 3810: 3790:(11): e15860. 3775: 3757:(1): 136–149. 3751:Mayo Clin Proc 3746: 3728:(3): 465–474. 3717: 3699:(3): 453–462. 3688: 3662: 3660: 3657: 3654: 3653: 3601: 3566: 3547: 3528: 3488: 3442: 3404: 3372: 3355: 3315: 3291: 3256: 3204: 3144: 3088: 3024: 2981: 2946: 2928: 2892: 2877: 2820: 2777: 2748:(38): 8232–6. 2725: 2684: 2633: 2581: 2538: 2488: 2445: 2407:Molecular Pain 2389: 2337: 2273: 2229: 2208:(8): 535–536. 2188: 2129: 2086: 2043: 2024: 2000: 1952: 1904: 1869: 1850: 1831: 1812: 1784: 1757: 1730: 1719:(5): 291–294. 1703: 1649: 1620: 1602: 1551: 1482: 1433: 1384: 1330: 1281: 1229: 1228: 1226: 1223: 1217:as following: 1198: 1195: 1186: 1183: 1180: 1179: 1176: 1172: 1171: 1168: 1164: 1163: 1157: 1153: 1152: 1146: 1142: 1141: 1135: 1131: 1130: 1127: 1126:Suggested name 1071: 1068: 1062: 1059: 1046: 1043: 1037:) and Lyrica ( 995: 992: 919: 916: 915: 914: 913: 912: 890: 885: 880: 875: 870: 865: 860: 855: 850: 821: 818: 815: 814: 754: 753: 751: 748: 745: 742: 739: 733: 732: 730: 728: 726: 723: 720: 716: 715: 713: 710: 707: 704: 701: 697: 696: 694: 691: 689: 686: 683: 679: 678: 676: 673: 670: 667: 664: 661: 657: 656: 654: 651: 649: 646: 643: 639: 638: 636: 629: 626: 623: 620: 616: 615: 613: 611: 608: 605: 602: 598: 597: 595: 592: 589: 586: 583: 579: 578: 576: 574: 572: 570: 567: 563: 562: 559: 558:Other effects 556: 553: 550: 547: 544: 541: 532: 521: 512: 504: 500: 496: 457: 453: 430: 427:sodium channel 422: 419: 405: 402: 385: 382: 357: 354: 345: 327: 323:sodium channel 256: 253: 218: 215: 201: 200:Classification 198: 190:Stephen Waxman 185: 173: 168: 160: 134:sodium channel 108:of any cause, 90:sensory nerves 53: 52: 47: 41: 40: 36: 35: 27: 26: 18: 15: 9: 6: 4: 3: 2: 5780: 5769: 5768:Rare diseases 5766: 5764: 5761: 5759: 5756: 5754: 5751: 5749: 5746: 5745: 5743: 5730: 5729: 5722: 5714: 5711: 5710: 5709: 5708: 5704: 5703: 5701: 5699: 5695: 5687: 5684: 5683: 5682: 5681: 5677: 5673: 5670: 5668: 5665: 5664: 5663: 5662: 5658: 5654: 5649: 5646: 5644: 5641: 5639: 5636: 5634: 5631: 5630: 5629: 5628: 5624: 5620: 5617: 5616: 5615: 5614: 5610: 5606: 5603: 5601: 5598: 5596: 5593: 5592: 5591: 5590: 5586: 5585: 5583: 5581: 5577: 5569: 5566: 5565: 5564: 5563: 5559: 5555: 5552: 5551: 5550: 5549: 5545: 5544: 5542: 5540: 5536: 5528: 5525: 5524: 5523: 5522: 5518: 5514: 5511: 5510: 5509: 5508: 5504: 5500: 5497: 5496: 5495: 5494: 5490: 5486: 5483: 5482: 5481: 5480: 5476: 5472: 5469: 5467: 5464: 5463: 5462: 5461: 5457: 5453: 5450: 5448: 5445: 5444: 5443: 5442: 5438: 5437: 5435: 5433: 5429: 5417: 5414: 5413: 5412: 5411: 5407: 5403: 5400: 5399: 5398: 5397: 5393: 5389: 5386: 5384: 5381: 5379: 5376: 5375: 5374: 5373: 5369: 5365: 5362: 5361: 5360: 5359: 5355: 5354: 5352: 5350: 5346: 5338: 5335: 5334: 5333: 5332: 5328: 5324: 5321: 5319: 5316: 5314: 5311: 5309: 5306: 5304: 5301: 5300: 5299: 5298: 5294: 5290: 5287: 5286: 5285: 5284: 5280: 5276: 5273: 5272: 5271: 5270: 5266: 5262: 5259: 5258: 5257: 5256: 5252: 5248: 5245: 5243: 5240: 5239: 5238: 5237: 5233: 5229: 5226: 5225: 5224: 5223: 5219: 5215: 5212: 5211: 5210: 5209: 5205: 5201: 5198: 5197: 5196: 5195: 5191: 5190: 5188: 5186: 5185:Voltage-gated 5182: 5179: 5177: 5173: 5161: 5158: 5157: 5156: 5155: 5150: 5149: 5144: 5143: 5139: 5135: 5132: 5131: 5130: 5129: 5124: 5123: 5119: 5118: 5116: 5114: 5110: 5102: 5099: 5097: 5094: 5092: 5089: 5087: 5084: 5083: 5082: 5081: 5077: 5073: 5070: 5068: 5065: 5064: 5063: 5062: 5058: 5054: 5051: 5050: 5049: 5048: 5044: 5040: 5037: 5035: 5032: 5030: 5027: 5025: 5022: 5021: 5020: 5019: 5015: 5011: 5008: 5006: 5003: 5002: 5001: 5000: 4996: 4992: 4989: 4987: 4984: 4982: 4979: 4978: 4977: 4976: 4972: 4971: 4969: 4967:Voltage-gated 4965: 4962: 4960: 4956: 4944: 4941: 4939: 4936: 4935: 4934: 4933: 4929: 4925: 4922: 4920: 4917: 4916: 4915: 4914: 4910: 4909: 4907: 4903: 4895: 4892: 4891: 4890: 4889: 4885: 4881: 4878: 4876: 4873: 4872: 4871: 4870: 4866: 4862: 4859: 4857: 4854: 4853: 4852: 4851: 4847: 4843: 4840: 4838: 4835: 4833: 4830: 4829: 4828: 4827: 4823: 4819: 4816: 4814: 4811: 4809: 4806: 4805: 4804: 4803: 4799: 4798: 4796: 4794: 4793:Voltage-gated 4790: 4787: 4785: 4781: 4777: 4770: 4765: 4763: 4758: 4756: 4751: 4750: 4747: 4731: 4728: 4727: 4725: 4723: 4719: 4713: 4710: 4708: 4705: 4703: 4700: 4698: 4695: 4691: 4688: 4687: 4686: 4683: 4681: 4678: 4676: 4673: 4671: 4668: 4666: 4663: 4662: 4660: 4658: 4654: 4651: 4649: 4645: 4639: 4636: 4634: 4631: 4629: 4626: 4622: 4619: 4617: 4614: 4612: 4609: 4608: 4607: 4604: 4600: 4597: 4595: 4592: 4591: 4590: 4587: 4586: 4584: 4580: 4570: 4567: 4565: 4562: 4560: 4557: 4555: 4552: 4550: 4547: 4546: 4544: 4540: 4534: 4531: 4527: 4524: 4522: 4519: 4517: 4516:Caput medusae 4514: 4513: 4512: 4509: 4507: 4504: 4503: 4501: 4499: 4495: 4489: 4486: 4482: 4479: 4478: 4477: 4474: 4470: 4467: 4465: 4462: 4461: 4460: 4457: 4453: 4450: 4448: 4445: 4443: 4440: 4438: 4435: 4433: 4430: 4429: 4428: 4425: 4421: 4418: 4417: 4416: 4413: 4412: 4410: 4408: 4403: 4399: 4393: 4390: 4389: 4387: 4385: 4381: 4378: 4376: 4372: 4362: 4359: 4357: 4354: 4352: 4349: 4348: 4346: 4344: 4340: 4332: 4329: 4327: 4324: 4323: 4322: 4319: 4317: 4314: 4312: 4309: 4308: 4306: 4304: 4300: 4292: 4289: 4287: 4284: 4282: 4279: 4277: 4274: 4272: 4269: 4268: 4267: 4264: 4262: 4259: 4257: 4254: 4252: 4249: 4245: 4242: 4240: 4237: 4235: 4232: 4231: 4230: 4226: 4223: 4222: 4220: 4218: 4213: 4209: 4205: 4195: 4192: 4190: 4187: 4185: 4182: 4180: 4179:Degos disease 4177: 4175: 4172: 4171: 4169: 4165: 4159: 4156: 4154: 4151: 4150: 4148: 4146: 4142: 4134: 4131: 4129: 4126: 4124: 4121: 4119: 4116: 4114: 4111: 4109: 4106: 4105: 4104: 4101: 4099: 4096: 4095: 4090: 4087: 4085: 4082: 4080: 4077: 4075: 4072: 4070: 4067: 4066: 4065: 4062: 4061: 4059: 4057: 4053: 4050: 4048: 4044: 4038: 4035: 4031: 4028: 4027: 4026: 4023: 4022: 4020: 4018: 4014: 4011: 4009: 4004: 4000: 3996: 3991: 3984: 3979: 3977: 3972: 3970: 3965: 3964: 3961: 3948: 3944: 3943: 3939: 3938: 3935: 3931: 3924: 3920: 3919: 3915: 3913: 3909: 3908: 3904: 3902: 3898: 3897: 3893: 3891: 3887: 3886: 3882: 3878: 3876: 3872: 3871: 3867: 3863: 3862: 3859: 3854: 3850: 3836: 3832: 3828: 3824: 3820: 3816: 3811: 3807: 3803: 3798: 3793: 3789: 3785: 3784:Dermatol Ther 3781: 3776: 3772: 3768: 3764: 3760: 3756: 3752: 3747: 3743: 3739: 3735: 3731: 3727: 3723: 3718: 3714: 3710: 3706: 3702: 3698: 3694: 3689: 3685: 3681: 3677: 3673: 3669: 3664: 3663: 3649: 3645: 3640: 3635: 3631: 3627: 3623: 3619: 3615: 3608: 3606: 3597: 3593: 3589: 3585: 3581: 3577: 3570: 3562: 3558: 3551: 3543: 3539: 3532: 3524: 3520: 3516: 3512: 3509:(3): 238–41. 3508: 3504: 3497: 3495: 3493: 3484: 3480: 3476: 3472: 3468: 3464: 3461:(2): 97–100. 3460: 3456: 3449: 3447: 3438: 3434: 3430: 3426: 3422: 3418: 3411: 3409: 3400: 3396: 3392: 3388: 3381: 3379: 3377: 3370: 3366: 3365: 3359: 3351: 3347: 3343: 3339: 3336:(1): 107–11. 3335: 3331: 3324: 3322: 3320: 3311: 3307: 3300: 3298: 3296: 3287: 3283: 3279: 3275: 3271: 3267: 3260: 3252: 3248: 3243: 3238: 3234: 3230: 3226: 3222: 3218: 3211: 3209: 3200: 3196: 3192: 3188: 3183: 3178: 3174: 3170: 3166: 3162: 3155: 3148: 3140: 3136: 3131: 3126: 3121: 3116: 3112: 3108: 3104: 3097: 3095: 3093: 3084: 3080: 3075: 3070: 3066: 3062: 3058: 3054: 3050: 3046: 3042: 3035: 3033: 3031: 3029: 3020: 3016: 3012: 3008: 3004: 3000: 2996: 2992: 2985: 2977: 2973: 2969: 2965: 2961: 2957: 2956:Arch Dermatol 2950: 2942: 2938: 2932: 2924: 2920: 2916: 2912: 2909:(3): 519–22. 2908: 2904: 2896: 2888: 2881: 2873: 2869: 2864: 2859: 2855: 2851: 2847: 2843: 2839: 2835: 2831: 2824: 2816: 2812: 2808: 2804: 2800: 2796: 2792: 2788: 2781: 2773: 2769: 2764: 2759: 2755: 2751: 2747: 2743: 2739: 2732: 2730: 2721: 2717: 2712: 2707: 2703: 2699: 2698:J. Biol. 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