Nav 1.7 Mutations And Sympathetic Dysfunction

[~elizabeth~]

Just before christmas, I saw another neurologist who specialises in head pain, as my main reason for pursuing diagnosis for my autonomic dysfunction is to try and stop the horrendous flushing and burning in my face.

He diagnosed my problem as facial erythromelalgia (which is what we always thought it was, he thought that previous diagnoses of rosacea and MCAS were 'nonsense') and thinks it's very likely the cause a NaV 1.7 sodium channel polymorphism, especially given that all other forms of pain relief are completely ineffective.

Researching today I came across the following research that links hyperactivity of the NaV 1.7 sodium channel with underactivity of the sympathetic ganglion neurons ( "These data provide an explanation of why primary erythromelalgia presents with pain due to hyperexcitability of nociceptors together with sympathetic dysfunction (flushing/erythema) that is at least in large part due to hypoexcitability of sympathetic ganglion neurons")

I've never come across this as a potential cause of autonomic dysfunction before but the neurologist said that he thinks it's probably greatly underdiagnosed. Disturbingly, none of the neurologist in the autonomic department seem to know of any connection between NaV 1.7 and autonomic dysfunction, and almost dismissed the possibility of the facial flushing problem being a channelopathy. I think it's important, as some people with this disorder may be mistakenly being diagnosed with MCAS.

SCN9A codes for Na_v1.7, a voltage-gated, tetrodotoxin-sensitive (TTX-sensitive) sodium channel with high-level expression in the nociceptors and sympathetic ganglia (16, 17). Analysis of the mutant channels showed a gain-of-function phenotype marked by a hyperpolarizing shift in the activation of the channel, slower deactivation, and an increase in ramp current in response to slow depolarizing ramps (18). The consequence of this gain-of-function phenotype is hyperexcitability of the nociceptors and reduced thresholds for the activation of action potentials, which would contribute to the pain and heat associated with erythermalgia. The etiology of the redness and swelling accompanying pain in erythermalgia is not known but likely involves hypoexcitability of the sympathetic neurons innervating the microvasculature of the affected limbs (19). There are now ten independent mutations inSCN9A linked to varying severity erythermalgia, all of which exhibit a hyperpolarizing shift in activation and slowed inactivation (20). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965577/

...While the expression of PE Na_v1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat sympathetic ganglion neurons indicate that expression of these same PE mutations in sympathetic ganglion neurons, that is, another cell type in which Na_v1.7 is normally expressed, leads to a reduction of excitabilit y in these cells (43). This occurs because Na_v1.8 channels, which are relatively resistant to inactivation by depolarization and are selectively expressed in addition to Na_v1.7 in DRG neurons, are not present within sympathetic ganglion neurons (43). These PE mutations produce membrane depolarization due to an overlap between activation and steady-state inactivation, which inactivates sodium channels other than Na_v1.8 ... But in sympathetic ganglion neurons, which lack Na_v1.8, the inactivation of the sodium channels results in reduced excitability

These data provide an explanation of why PE presents with pain due to hyperexcitability of nociceptors together with sympathetic dysfunction (flushing/erythema) that is at least in large part due to hypoexcitability of sympathetic ganglion neurons

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2096434/?report=reader

[Tachy Phlegming]

That sounds like a very sound type of theory and very much better than some of what's out there.

Here's an article on some sodium channelopathies for those who may be interested. I don't know that it covers exactly NaV 1.7 but it explains how these disorders work (oh, and hey, maybe someone can figure out from this article why this way of thinking about disease is so alien to doctors because I haven't figured that one out).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180550/

[~elizabeth~]

Very interesting, particularly the bit about sodium channels in muscle. I also have severe muscle spasms, along with what looks like central vertigo and severe tinnitus, which are other conditions which appear to have a sodium channel pathology. A lot of people with Ehlers Danlos have the same range of problems, along with the autonomic dysfunction, hyperalgesia and widespread insensitivity to lidocaine, which to me suggests some sort of sodium channel defect. My guess it that you may get a cluster of related sodium channel mutations, as although erythromelalgia is not common among the POTS/EDS community, these related disorders are.

[~elizabeth~]

The L858H erythermalgia mutation results in a single amino acid substitution in the domain II S4–S5 linker within Na_v1.7 (2, 7), a sodium channel that is preferentially expressed in DRG and sympathetic ganglia neurons (8, 9, 16, 25). Our experiments show that L858H produces hyperexcitability (decreased threshold and enhanced repetitive firing) within DRG neurons and hypoexcitability (increased threshold and attenuated repetitive firing) within sympathetic ganglion neurons. The latter observation provides a molecular basis for the sympathetic dysfunction that has been reported (26, 27) in erythermalgia. Moreover, this observation suggests the more general hypothesis that other ion channel mutations may have differing physiological effects in different cell types in which the channel is normally expressed. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472458/?report=reader

This article doesn't seem to rule out other mutations might exist, I think there are thought to be 10 separate mutations on the SNC9A gene causing differing variability of pain, so I guess it's possible to have a variation where the sensory pain is not that severe but the autonomic dysfunction is. EM doesn't just affect the feet, it can spread from the extreme peripheries towards the core of the body. I only noticed signs of blood pooling in my legs (purple discolouration on calves and knees) and pronounced tachycardia at the same time as the facial problems started.

What I really want to know is if the intense vasodilation in EM is caused by the hyperactive sensory nerves churning out neuroirritants, or by the lack of constriction due to the hypoactive sympathetic nerves. My hunch is that it's due to the former, as blood pooling by itself isn't usually painful. My reason for wanting to know is that I'm considering Botox injections, as my pain is refractory to other treatment. If the paroxysmal flushing is due to neuroinflammation, then there's a chance botox will help, as it there's increasing evidence that it blocks these substances in trials for neuropathic pain. If, however, it's due to blood pooling, then lowering sympathetic tone further will make things worse. My neurologist is willing to try botox, but on the understanding he has absolutely no way of predicting what will happen as it's never been used before for primary EM.

As I understand it, sensory C fibres detect noxious changes in blood chemistry, as well as heat/cold/mechanical stimulus in the skin, so I feel the fact that I have high plasma norepinephrine levels which rise significantly on standing, might be one of the triggers for the sensory nerve misfiring (I think I'm right in saying that C fibres have alpha receptors, which is why norepinephrine has an important relation ship with pain; midodrine also made the pain much worse, so clearly it's not a simple issue of lack of constriction). Equally the sensory nerves might be reacting to hypoxia due to blood stagnation from pooling. I did actually find the flushing improved a lot when I started pyridostigmine, and all the hyperadrenergic symptoms (tachycardia, anxiety, sweating, shivering, flushing on posture change) more or less went away, but the onset of cold weather and starting lamotrigine seem to have sent it back into the pain stratosphere again.

[HopeSprings]

I have SFN, POTS and possible EDS. I had read that SCN9A mutation may be an important cause of idiopathic small fiber neuropathy. My Doctor agreed. Unfortunately (or fortunately depending on how you look at it) I had the testing done and was found to be negative. I think there is a lot more work to be done in this area though and they're definitely onto something. You could always have the testing which is currently available done.

[Kris4444]

Elizabeth,

I have always found that my symptoms are nearly identical to yours. I have had doctors suggest erythermalgia but none have offered treatment. What did your doctor prescribe or recommended?

I am weaning off the clonidine that Mayo put me on for flushing. I DO feel that it was helping and may end up going back on it but I'm trying to reduce and/or eliminate as many drugs as possible however, I will soon be starting Humira in an effort ti see if it helps with the systemic inflammation I am experiencing.

I'm going to look into your diagnosis as it is very interesting to me. Thanks for sharing!

Kris

[~elizabeth~]

Nothing very helpful Kris. He thought that only 5 days of continuous lidocaine infusion, followed up by oral mexiletine would actually be much help, which I can't afford as I don't have private insurance (this is rather similar to the regime they now use for CRPS). He said he'd come to this conclusion about lidocaine after treating someone else with a very similar presentation of extreme facial flushing and burning, and found this protocol helped after every other option had failed miserably (as it has done for me). He left me with a prescriptions for the sodium channel blocker lamotrigine, though clearly with little faith that it would help much.Because of that, he thinks it's pretty likely to be due to a sodium channel problem, as other forms of EM do tend to respond at least partially to tricyclics, duloxetine or pregabalin, albeit usually at high doses.

I actually felt much better when I came off clonidine, although stopping it did corresponded with when the weather warmed up a bit. The rebound effects were awful, very high BPs and at it's worst it triggered EM symptoms in my ear canals, nose, throat in addition to my face, ears and lips (that was with careful tapering). From that, I think being hyperadrenergic must be a factor in irritating sensory nerves (they finally confirmed high plasma NE during upright TTT in September).

It can be due to immune-mediated connective tissue diseases as well, usually scleroderma. For this type they seem to favour medications that alter endothelial/platelet function like iloprost, if you've got a dx of arthritis, then you might have this variation, rather than the purely neurological kind.

[Kris4444]

Elizabeth,

I've been reading about erythermalgia and it really seems to fit. I hope you don't mind if I ask you a few questions? I wonder if any of the following happen to you:

Severe attacks after coming in from the cold- I get extremely red all over and very warm. Sometimes I can't stay awake.

If I take a warm shower, when I get out I feel like I'm being attacked by fire ants. Headache after warm shower or bath.

Problems with my ears. I can constantly hear myself talk, breathe, chew. I was told I have patulous eustachian tubes.

Alcohol brings on attacks but mostly to my face and chest.

My temp seems to fluctuate to extremes. There is no happy medium. Once I start to warm I overheat.

Livedo reticularis

Raynaud's

Flushing with exercise. Vertigo when I stop exercise and extreme sweating that goes on for hours.

I did test positive for cryoglobulins at Johns Hopkins but when tested again at Mayo it was negative.

Although I get very red, I don't experience the pain they speak about with erythermalgia. Do you have pain?

Thanks for any answers you may provide.

-Kris

[Kris4444]

Sorry for the misspelling of the condition.

[~elizabeth~]

Just found this article, which is very interesting. A recent study found sodium channel SCN9A mutations in a significant percentage of people with idiopathic small fibre dysfunction with severe autonomic involvement.

Despite the debilitating nature of autonomic symptoms in small fibre neuropathy, the molecular basis for autonomic dysfunction in small fibre neuropathy is not well understood. Most patients with Na_v1.7 channelopathy-associated small fibre neuropathy experience profound autonomic dysfunction in addition to neuropathic pain (Faber et al., 2012).

http://brain.oxfordjournals.org/content/135/9/2613.long