Erythromelalgia: Difference between revisions
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==Classification== | ==Classification== | ||
Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an [[autosomal dominant]] manner. Both of these may be further classified as either juvenile or adult onset. Juvenile onset occurs prior to age 20 and frequently | Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an [[autosomal dominant]] manner. Both of these may be further classified as either juvenile or adult onset. Juvenile onset occurs prior to age 20 and frequently less than 10 years of age. 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 form.<ref name="Novella_2007">{{cite journal |author=Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG |title=A case of inherited erythromelalgia |journal=Nature clinical practice. Neurology |volume=3 |issue=4 |pages=229-34 |year=2007 |pmid=17410110 |doi=10.1038/ncpneuro0425}}</ref> | ||
==Symptoms and signs== | ==Symptoms and signs== | ||
The most prominent symptoms of erythromelalgia are episodes of [[erythema]], [[swelling (medical)|swelling]], and a painful burning sensation primarily in the extremities. These symptoms are usually 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 minutes to hours and occur infrequently to multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and [[ethanol|alcohol]] or [[caffeine]] consumption. In some patients sugar and even melon consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this | The most prominent symptoms of erythromelalgia are episodes of [[erythema]], [[swelling (medical)|swelling]], and a painful burning sensation primarily in the extremities. These symptoms are usually 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 minutes to hours and occur infrequently to multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and [[ethanol|alcohol]] or [[caffeine]] consumption. In some patients sugar and even melon consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat generates and this is known to produce erythromelalgia attacks.<ref name="Novella_2007" /> | ||
==Cause== | ==Cause== | ||
In general, erythromelalgia seems to consist of [[neuropathology|neuropathological]] and [[capillary|microvascular]] 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 [[erythromelalgia#Diagnosis|diagnosis]], below.<ref name="Novella_2007"/> | In general, erythromelalgia seems to consist of [[neuropathology|neuropathological]] and [[capillary|microvascular]] 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 [[erythromelalgia#Diagnosis|diagnosis]], below.<ref name="Novella_2007" /> | ||
Primary erythromelalgia is a better understood [[autosomal dominant]] disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of [[group C nerve fiber|C-fibers]] in the [[dorsal root ganglion]]. Specifically, [[nociceptor]]s (neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily | Primary erythromelalgia is a better understood [[autosomal dominant]] disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of [[group C nerve fiber|C-fibers]] in the [[dorsal root ganglion]]. Specifically, [[nociceptor]]s (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 [[sympathetic nervous system]] controls [[cutaneous]] [[vascular smooth muscle|vascular]] [[muscle tone|tone]] 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 [[sodium channel]] [[Nav1.7|Na<sub>V</sub>1.7]]. These differences in excitability alterations between the [[sympathetic nervous system]] and [[nociceptor]]s is due to different expression of [[sodium channel]]s other than Na<sub>V</sub>1.7 in them.<ref name="Novella_2007" /> | ||
==Pathophysiology== | ==Pathophysiology== | ||
''N.B. This section pertains solely to primary erythromelalgia as the secondary form is too poorly understood.'' | ''N.B. This section pertains solely to primary erythromelalgia as the secondary form is too poorly understood.'' | ||
There are 10 known mutations in the voltage-gated [[sodium channel]] α-subunit Na<sub>V</sub>1.7 encoding gene, ''[[Nav1.7|SCN9A]]''. This channel is expressed primarily in [[nociceptor]]s of the [[dorsal root ganglion]] and the [[sympathetic nervous system|sympathetic]] ganglion neurons. 9 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 Na<sub>V</sub>1.7 channels that activate at more hyperpolarized potentials. Na<sub>V</sub>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 [[resting membrane potential]]. 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 | There are 10 known mutations in the voltage-gated [[sodium channel]] α-subunit Na<sub>V</sub>1.7 encoding gene, ''[[Nav1.7|SCN9A]]''. This channel is expressed primarily in [[nociceptor]]s of the [[dorsal root ganglion]] and the [[sympathetic nervous system|sympathetic]] ganglion neurons. 9 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 Na<sub>V</sub>1.7 channels that activate at more hyperpolarized potentials. Na<sub>V</sub>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 [[resting membrane potential]]. 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 period of time, producing larger and more prolonged changes in [[membrane potential]]. | ||
Some of these mutant channels have been expressed in [[dorsal root ganglion]] (DRG) or [[sympathetic nervous system|sympathetic]] [[neuron]]s. In DRG neurons expressing the F1449V mutation, a lower threshold is required for [[action potential]] creation (93.1 ± 12.0 pA) 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.<ref name="Dib-Hajj_2005">{{cite journal |author=Dib-Hajj SD, Rush AM, Cummins TR, ''et al'' |title=Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons |journal=Brain |volume=128 |issue=Pt 8 |pages=1847-54 |year=2005 |pmid=15958509 |doi=10.1093/brain/awh514}}</ref> 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 mV versus wild-type channel expressing cells.<ref name="Rush_2006">{{cite journal |author=Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG |title=A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=21 |pages=8245-50 |year=2006 |pmid=16702558 |doi=10.1073/pnas.0602813103}}</ref><ref name="Harty_2006">{{cite journal |author=Harty TP, Dib-Hajj SD, Tyrrell L, ''et al'' |title=Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons |journal=J. Neurosci. |volume=26 |issue=48 |pages=12566-75 |year=2006 |pmid=17135418 |doi=10.1523/JNEUROSCI.3424-06.2006}}</ref> 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 | Some of these mutant channels have been expressed in [[dorsal root ganglion]] (DRG) or [[sympathetic nervous system|sympathetic]] [[neuron]]s. In DRG neurons expressing the F1449V mutation, a lower threshold is required for [[action potential]] creation (93.1 ± 12.0 pA) 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.<ref name="Dib-Hajj_2005">{{cite journal |author=Dib-Hajj SD, Rush AM, Cummins TR, ''et al'' |title=Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons |journal=Brain |volume=128 |issue=Pt 8 |pages=1847-54 |year=2005 |pmid=15958509 |doi=10.1093/brain/awh514}}</ref> 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 mV versus wild-type channel expressing cells.<ref name="Rush_2006">{{cite journal |author=Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG |title=A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=21 |pages=8245-50 |year=2006 |pmid=16702558 |doi=10.1073/pnas.0602813103}}</ref><ref name="Harty_2006">{{cite journal |author=Harty TP, Dib-Hajj SD, Tyrrell L, ''et al'' |title=Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons |journal=J. Neurosci. |volume=26 |issue=48 |pages=12566-75 |year=2006 |pmid=17135418 |doi=10.1523/JNEUROSCI.3424-06.2006}}</ref> 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 initially is notably 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<sub>V</sub>1.8 in the former. Consequently, expression of Na<sub>V</sub>1.8 channels in sympathetic neurons also expressing L858H mutant Na<sub>V</sub>1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.<ref name="Rush_2006" /> | ||
An | An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels in unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16ºC the activation V<sub>½</sub> of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35ºC. 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 cooling is unlikely to affect neuronal cell bodies, [[axon]]s and termini express Na<sub>V</sub>1.7 and are present in the skin.<ref name="Han_2007">{{cite journal |author=Han C, Lampert A, Rush AM, ''et al'' |title=Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7 |journal=Molecular pain |volume=3 |issue= |pages=3 |year=2007 |pmid=17239250 |doi=10.1186/1744-8069-3-3}}</ref> | ||
{| class="wikitable" style="text-align:center" | {| class="wikitable" style="text-align:center" | ||
|+'''Table 1.''' Summary of mutations Na<sub>V</sub>1.7 associated with primary erythromelalgia | |+'''Table 1.''' Summary of mutations Na<sub>V</sub>1.7 associated with primary erythromelalgia | ||
|- valign="bottom" | |- valign="bottom" | ||
! Mutation | !Mutation | ||
! Region | !Region | ||
! Shift of activation V<sub>½</sub> | !Shift of activation V<sub>½</sub> | ||
! Shift of inactivation (fast and/or slow) V<sub>½</sub> | !Shift of inactivation (fast and/or slow) V<sub>½</sub> | ||
! Other effects | !Other effects | ||
! References | !References | ||
|- | |- | ||
! I136V | !I136V | ||
| D1S1 | |D1S1 | ||
| | | | ||
| | | | ||
| | | | ||
| <ref name="Lee_2007">{{cite journal |author=Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC |title=Characterization of a familial case with primary erythromelalgia from Taiwan |journal=J. Neurol. |volume=254 |issue=2 |pages=210-4 |year=2007 |pmid=17294067 |doi=10.1007/s00415-006-0328-3}}</ref> | |<ref name="Lee_2007">{{cite journal |author=Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC |title=Characterization of a familial case with primary erythromelalgia from Taiwan |journal=J. Neurol. |volume=254 |issue=2 |pages=210-4 |year=2007 |pmid=17294067 |doi=10.1007/s00415-006-0328-3}}</ref> | ||
|- | |- | ||
! F216S | !F216S | ||
| D1S4 | |D1S4 | ||
| Hyperpolarized | |Hyperpolarized | ||
| Hyperpolarized | |Hyperpolarized | ||
| Faster entry into fast-inactivation | |Faster entry into fast-inactivation | ||
| <ref name="Drenth_2005">{{cite journal |author=Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB |title=SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels |journal=J. Invest. Dermatol. |volume=124 |issue=6 |pages=1333-8 |year=2005 |pmid=15955112 |doi=10.1111/j.0022-202X.2005.23737.x}}</ref>, <ref name="Choi_2006">{{cite journal |author=Choi JS, Dib-Hajj SD, Waxman SG |title=Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy |journal=Neurology |volume=67 |issue=9 |pages=1563-7 |year=2006 |pmid=16988069 |doi=10.1212/01.wnl.0000231514.33603.1e}}</ref>, <ref name="Sheets_2007">{{cite journal |author=Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR |title=A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity |journal=J. Physiol. (Lond.) |volume=581 |issue=Pt 3 |pages=1019-31 |year=2007 |pmid=17430993 |doi=10.1113/jphysiol.2006.127027}}</ref> | |<ref name="Drenth_2005">{{cite journal |author=Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB |title=SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels |journal=J. Invest. Dermatol. |volume=124 |issue=6 |pages=1333-8 |year=2005 |pmid=15955112 |doi=10.1111/j.0022-202X.2005.23737.x}}</ref>, <ref name="Choi_2006">{{cite journal |author=Choi JS, Dib-Hajj SD, Waxman SG |title=Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy |journal=Neurology |volume=67 |issue=9 |pages=1563-7 |year=2006 |pmid=16988069 |doi=10.1212/01.wnl.0000231514.33603.1e}}</ref>, <ref name="Sheets_2007">{{cite journal |author=Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR |title=A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity |journal=J. Physiol. (Lond.) |volume=581 |issue=Pt 3 |pages=1019-31 |year=2007 |pmid=17430993 |doi=10.1113/jphysiol.2006.127027}}</ref> | ||
|- | |- | ||
! S241T | !S241T | ||
| D1S4-5 | |D1S4-5 | ||
| Hyperpolarized | |Hyperpolarized | ||
| Hyperpolarized | |Hyperpolarized | ||
| | | | ||
| <ref name="Michiels_2005">{{cite journal |author=Michiels JJ, te Morsche RH, Jansen JB, Drenth JP |title=Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7 |journal=Arch. Neurol. |volume=62 |issue=10 |pages=1587-90 |year=2005 |pmid=16216943 |doi=10.1001/archneur.62.10.1587}}</ref>, <ref name="Lampert_2006">{{cite journal |author=Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG |title=Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating |journal=J. Biol. Chem. |volume=281 |issue=47 |pages=36029-35 |year=2006 |pmid=17008310 |doi=10.1074/jbc.M607637200}}</ref> | |<ref name="Michiels_2005">{{cite journal |author=Michiels JJ, te Morsche RH, Jansen JB, Drenth JP |title=Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7 |journal=Arch. Neurol. |volume=62 |issue=10 |pages=1587-90 |year=2005 |pmid=16216943 |doi=10.1001/archneur.62.10.1587}}</ref>, <ref name="Lampert_2006">{{cite journal |author=Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG |title=Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating |journal=J. Biol. Chem. |volume=281 |issue=47 |pages=36029-35 |year=2006 |pmid=17008310 |doi=10.1074/jbc.M607637200}}</ref> | ||
|- | |- | ||
! N395K | !N395K | ||
| D1S6 | |D1S6 | ||
| Hyperpolarized | |Hyperpolarized | ||
| Depolarized | |Depolarized | ||
| Creation of a large window current, decreased [[lidocaine]] sensitivity | |Creation of a large window current, decreased [[lidocaine]] sensitivity | ||
| <ref name="Drenth_2005"/>, <ref name="Sheets_2007"/> | |<ref name="Drenth_2005" />, <ref name="Sheets_2007" /> | ||
|- | |- | ||
! I848T | !I848T | ||
| D2S4-5 | |D2S4-5 | ||
| Hyperpolarized | |Hyperpolarized | ||
| | | | ||
| Slowed deactivation and inactivation | |Slowed deactivation and inactivation | ||
| <ref name="Drenth_2005"/>, <ref name="Yang_2004">{{cite journal |author=Yang Y, Wang Y, Li S, ''et al'' |title=Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia |journal=J. Med. Genet. |volume=41 |issue=3 |pages=171-4 |year=2004 |pmid=14985375 |doi=}}</ref>, <ref name="Cummins_2004">{{cite journal |author=Cummins TR, Dib-Hajj SD, Waxman SG |title=Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy |journal=J. Neurosci. |volume=24 |issue=38 |pages=8232-6 |year=2004 |pmid=15385606 |doi=10.1523/JNEUROSCI.2695-04.2004}}</ref> | |<ref name="Drenth_2005" />, <ref name="Yang_2004">{{cite journal |author=Yang Y, Wang Y, Li S, ''et al'' |title=Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia |journal=J. Med. Genet. |volume=41 |issue=3 |pages=171-4 |year=2004 |pmid=14985375 |doi=}}</ref>, <ref name="Cummins_2004">{{cite journal |author=Cummins TR, Dib-Hajj SD, Waxman SG |title=Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy |journal=J. Neurosci. |volume=24 |issue=38 |pages=8232-6 |year=2004 |pmid=15385606 |doi=10.1523/JNEUROSCI.2695-04.2004}}</ref> | ||
|- | |- | ||
! L858F | !L858F | ||
| D2S4-5 | |D2S4-5 | ||
| Hyperpolarized | |Hyperpolarized | ||
| Depolarized | |Depolarized | ||
| Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V<sub>½</sub> | |Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V<sub>½</sub> | ||
| <ref name="Drenth_2005"/>, <ref name="Han_2006">{{cite journal |author=Han C, Rush AM, Dib-Hajj SD, ''et al'' |title=Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7 |journal=Ann. Neurol. |volume=59 |issue=3 |pages=553-8 |year=2006 |pmid=16392115 |doi=10.1002/ana.20776}}</ref>, <ref name="Han_2007"/> | |<ref name="Drenth_2005" />, <ref name="Han_2006">{{cite journal |author=Han C, Rush AM, Dib-Hajj SD, ''et al'' |title=Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7 |journal=Ann. Neurol. |volume=59 |issue=3 |pages=553-8 |year=2006 |pmid=16392115 |doi=10.1002/ana.20776}}</ref>, <ref name="Han_2007" /> | ||
|- | |- | ||
! L858H | !L858H | ||
| D2S4-5 | |D2S4-5 | ||
| Hyperpolarized | |Hyperpolarized | ||
| | | | ||
| Slowed deactivation, enhanced slow inactivation, | |Slowed deactivation, enhanced slow inactivation, | ||
| <ref name="Rush_2006"/>, <ref name="Drenth_2005"/>, <ref name="Yang_2004"/>, <ref name="Cummins_2004"/> | |<ref name="Rush_2006" />, <ref name="Drenth_2005" />, <ref name="Yang_2004" />, <ref name="Cummins_2004" /> | ||
|- | |- | ||
! A863P | !A863P | ||
| D2S5 | |D2S5 | ||
| Hyperpolarized | |Hyperpolarized | ||
| Depolarized | |Depolarized | ||
| Creation of a window current, slowed deactivation | |Creation of a window current, slowed deactivation | ||
| <ref name="Harty_2006"/> | |<ref name="Harty_2006" /> | ||
|- | |- | ||
! F1449V | !F1449V | ||
| D3-4 | |D3-4 | ||
| Hyperpolarized | |Hyperpolarized | ||
| | | | ||
| | | | ||
| <ref name="Dib-Hajj_2005"/> | |<ref name="Dib-Hajj_2005" /> | ||
|- | |- | ||
| colspan="6" | Region nomenclature: D'''A'''-'''B''', linker between domains '''A''' and '''B'''; D'''A'''S'''B''', transmembrane segment '''B''' in domain '''A'''; and D'''A'''S'''B'''-'''C''', the linker between transmembrane segments '''B''' and '''C''' in domain '''A'''. | | colspan="6" |Region nomenclature: D'''A'''-'''B''', linker between domains '''A''' and '''B'''; D'''A'''S'''B''', transmembrane segment '''B''' in domain '''A'''; and D'''A'''S'''B'''-'''C''', the linker between transmembrane segments '''B''' and '''C''' in domain '''A'''. | ||
|} | |} | ||
| Line 121: | Line 121: | ||
Some diseases present with symptoms similar to erythromelalgia. [[Complex regional pain syndrome]] (CPRS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CPRS. | Some diseases present with symptoms similar to erythromelalgia. [[Complex regional pain syndrome]] (CPRS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CPRS. | ||
Erythromelalgia is often a secondary condition for other disorders that must be ruled out for a diagnosis of primary erythromelalgia. A partial list of diseases known to precipitate erythromelalgia is below.<ref name="Novella_2007"/> | Erythromelalgia is often a secondary condition for other disorders that must be ruled out for a diagnosis of primary erythromelalgia. A partial list of diseases known to precipitate erythromelalgia is below.<ref name="Novella_2007" /> | ||
:*[[Myeloproliferative disease]] | :*[[Myeloproliferative disease]] | ||
:*[[Hypercholesterolemia]] | :*[[Hypercholesterolemia]] | ||
| Line 135: | Line 136: | ||
For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment, though [[aspirin]] may reduce symptoms of erythromelalgia. | For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment, though [[aspirin]] may reduce symptoms of erythromelalgia. | ||
The primary method of primary erythromelalgia | The primary method of management of primary erythromelalgia is the avoidance of trigger attacks, such as heat, over-exertion and alcohol consumption. While a cool environment is helpful in guarding against symptoms, the use of cold water baths is discouraged as such use may cause skin [[necrosis]]. One clinical study has demonstrated the efficacy of [[intravenous therapy|IV]] [[lidocaine]] or oral [[mexilitine]], though it should be noted that differences between the primary and secondary forms was not studied. Another trial has shown promise for [[misoprostol]], while other have shown that [[gabapentin]], [[venlafaxine]], and oral [[magnesium]] may also be effective.<ref name="Novella_2007" /> | ||
==External Links== | ==External Links== | ||
* [http://www.erythromelalgia.org/ | |||
* [http://health.groups.yahoo.com/group/emsupport Erythromelalgia Support Group] | *[http://www.erythromelalgia.org/ The Erythromelalgia Association] | ||
*[http://health.groups.yahoo.com/group/emsupport Erythromelalgia Support Group] | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
[[Category:Channelopathy]] | [[Category:Channelopathy]] | ||
Latest revision as of 15:05, 9 June 2021
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Erythromelalgia, also known as Mitchell's disease (after Silas Weir Mitchell), red neuralgia, or erythermalgia, is a rare disorder in which blood vessels, usually in the lower extremities, are episodically blocked and inflamed. There is severe burning pain and skin redness associated with this blood vessel blockage. The attacks are periodic and are commonly triggered by heat, alcohol consumption, or exertion. Erythromelalgia can 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 small fiber peripheral neuropathy of any cause, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene SCN9A.
Classification
Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Both of these may be further classified as either juvenile or adult onset. Juvenile onset occurs prior to age 20 and frequently less than 10 years of age. 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 form.[1]
Symptoms and signs
The most prominent symptoms of erythromelalgia are episodes of erythema, swelling, and a painful burning sensation primarily in the extremities. These symptoms are usually 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 minutes to hours and occur infrequently to multiple times daily. Common triggers for these episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption. In some patients sugar and even melon consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat generates and this is known to produce erythromelalgia attacks.[1]
Cause
In general, erythromelalgia seems to consist of neuropathological and microvascular 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 diagnosis, below.[1]
Primary erythromelalgia is a better understood autosomal dominant disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of C-fibers in the dorsal root ganglion. Specifically, nociceptors (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 sympathetic nervous system controls cutaneous vascular tone 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 sodium channel NaV1.7. These differences in excitability alterations between the sympathetic nervous system and nociceptors is due to different expression of sodium channels other than NaV1.7 in them.[1]
Pathophysiology
N.B. This section pertains solely to primary erythromelalgia as the secondary form is too poorly understood.
There are 10 known mutations in the voltage-gated sodium channel α-subunit NaV1.7 encoding gene, SCN9A. This channel is expressed primarily in nociceptors of the dorsal root ganglion and the sympathetic ganglion neurons. 9 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 NaV1.7 channels that activate at more hyperpolarized potentials. NaV1.7 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 resting membrane potential. 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 period of time, producing larger and more prolonged changes in membrane potential.
Some of these mutant channels have been expressed in dorsal root ganglion (DRG) or sympathetic neurons. In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential creation (93.1 ± 12.0 pA) 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.[2] 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 mV versus wild-type channel expressing cells.[3][4] 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 initially is notably 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 NaV1.8 in the former. Consequently, expression of NaV1.8 channels in sympathetic neurons also expressing L858H mutant NaV1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.[3]
An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels in unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16ºC the activation V½ of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35ºC. 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 cooling is unlikely to affect neuronal cell bodies, axons and termini express NaV1.7 and are present in the skin.[5]
| Mutation | Region | Shift of activation V½ | Shift of inactivation (fast and/or slow) V½ | Other effects | References |
|---|---|---|---|---|---|
| I136V | D1S1 | [6] | |||
| F216S | D1S4 | Hyperpolarized | Hyperpolarized | Faster entry into fast-inactivation | [7], [8], [9] |
| S241T | D1S4-5 | Hyperpolarized | Hyperpolarized | [10], [11] | |
| N395K | D1S6 | Hyperpolarized | Depolarized | Creation of a large window current, decreased lidocaine sensitivity | [7], [9] |
| I848T | D2S4-5 | Hyperpolarized | Slowed deactivation and inactivation | [7], [12], [13] | |
| L858F | D2S4-5 | Hyperpolarized | Depolarized | Slowed deactivation, faster recovery from inactivation, cooling depolarizes activation and hyperpolarizes inactivation V½ | [7], [14], [5] |
| L858H | D2S4-5 | Hyperpolarized | Slowed deactivation, enhanced slow inactivation, | [3], [7], [12], [13] | |
| A863P | D2S5 | Hyperpolarized | Depolarized | Creation of a window current, slowed deactivation | [4] |
| F1449V | D3-4 | Hyperpolarized | [2] | ||
| Region nomenclature: DA-B, linker between domains A and B; DASB, transmembrane segment B in domain A; and DASB-C, the linker between transmembrane segments B and C in domain A. | |||||
Diagnosis
Some diseases present with symptoms similar to erythromelalgia. Complex regional pain syndrome (CPRS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CPRS.
Erythromelalgia is often a secondary condition for other disorders that must be ruled out for a diagnosis of primary erythromelalgia. A partial list of diseases known to precipitate erythromelalgia is below.[1]
Treatment/Management
For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment, though aspirin may reduce symptoms of erythromelalgia.
The primary method of management of primary erythromelalgia is the avoidance of trigger attacks, such as heat, over-exertion and alcohol consumption. While a cool environment is helpful in guarding against symptoms, the use of cold water baths is discouraged as such use may cause skin necrosis. One clinical study has demonstrated the efficacy of IV lidocaine or oral mexilitine, though it should be noted that differences between the primary and secondary forms was not studied. Another trial has shown promise for misoprostol, while other have shown that gabapentin, venlafaxine, and oral magnesium may also be effective.[1]
External Links
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Novella SP, Hisama FM, Dib-Hajj SD, Waxman SG (2007). "A case of inherited erythromelalgia". Nature clinical practice. Neurology. 3 (4): 229–34. doi:10.1038/ncpneuro0425. PMID 17410110.
- ↑ 2.0 2.1 Dib-Hajj SD, Rush AM, Cummins TR; et al. (2005). "Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons". Brain. 128 (Pt 8): 1847–54. doi:10.1093/brain/awh514. PMID 15958509.
- ↑ 3.0 3.1 3.2 Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG (2006). "A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons". Proc. Natl. Acad. Sci. U.S.A. 103 (21): 8245–50. doi:10.1073/pnas.0602813103. PMID 16702558.
- ↑ 4.0 4.1 Harty TP, Dib-Hajj SD, Tyrrell L; et al. (2006). "Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons". J. Neurosci. 26 (48): 12566–75. doi:10.1523/JNEUROSCI.3424-06.2006. PMID 17135418.
- ↑ 5.0 5.1 Han C, Lampert A, Rush AM; et al. (2007). "Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7". Molecular pain. 3: 3. doi:10.1186/1744-8069-3-3. PMID 17239250.
- ↑ Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC (2007). "Characterization of a familial case with primary erythromelalgia from Taiwan". J. Neurol. 254 (2): 210–4. doi:10.1007/s00415-006-0328-3. PMID 17294067.
- ↑ 7.0 7.1 7.2 7.3 7.4 Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB (2005). "SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels". J. Invest. Dermatol. 124 (6): 1333–8. doi:10.1111/j.0022-202X.2005.23737.x. PMID 15955112.
- ↑ Choi JS, Dib-Hajj SD, Waxman SG (2006). "Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy". Neurology. 67 (9): 1563–7. doi:10.1212/01.wnl.0000231514.33603.1e. PMID 16988069.
- ↑ 9.0 9.1 Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR (2007). "A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity". J. Physiol. (Lond.). 581 (Pt 3): 1019–31. doi:10.1113/jphysiol.2006.127027. PMID 17430993.
- ↑ Michiels JJ, te Morsche RH, Jansen JB, Drenth JP (2005). "Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7". Arch. Neurol. 62 (10): 1587–90. doi:10.1001/archneur.62.10.1587. PMID 16216943.
- ↑ Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG (2006). "Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating". J. Biol. Chem. 281 (47): 36029–35. doi:10.1074/jbc.M607637200. PMID 17008310.
- ↑ 12.0 12.1 Yang Y, Wang Y, Li S; et al. (2004). "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia". J. Med. Genet. 41 (3): 171–4. PMID 14985375.
- ↑ 13.0 13.1 Cummins TR, Dib-Hajj SD, Waxman SG (2004). "Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy". J. Neurosci. 24 (38): 8232–6. doi:10.1523/JNEUROSCI.2695-04.2004. PMID 15385606.
- ↑ Han C, Rush AM, Dib-Hajj SD; et al. (2006). "Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7". Ann. Neurol. 59 (3): 553–8. doi:10.1002/ana.20776. PMID 16392115.