Jump to content

Possible Cause For Pots? Mutation On Net Gene


Recommended Posts

Rich,

Since they found those twins, they have done a lot more research on this gene. No one else has the exact same mutation these twins had and you are right, some of the other family members of these twins who carried the A457P mutation had symptoms of POTS, but did not the have full-blown disease. However, I still think the NET deficiency theory is a good one especially for those people who have already been at this for years and fit the profile.

I'll be honest, I never looked much into it before I found this gene because I did not understand enough about genetics. I also thought by now I would have cured my POTS with other various treatments/ supplements and that hasn't happened yet. So for me, I am just going down the natural progression of research. I've been at this for a long time, so genetic testing for some on here is probably not appropriate yet because they haven't ruled out other simple things.

I was fairly certain NET deficiency is listed on the dinet set as a possible cause. :)

The studies that really caught my eye were these two. There are drugs which inhibit NET and when they do this in healthy people, they essentially get POTS. That's pretty significant IMO.

Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance

http://circ.ahajourn.../105/3/347.full

Here they tested mice. The significant part of this study for me at least is that they were normal while resting. I am pretty much normal when I sit.

Norepinephrine Transporter–Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity

http://circ.ahajourn...10/10/1191.full

Link to comment
Share on other sites

  • Replies 88
  • Created
  • Last Reply

Top Posters In This Topic

Rich,

Since they found those twins, they have done a lot more research on this gene. No one else has the exact same mutation these twins had and you are right, some of the other family members of these twins who carried the A457P mutation had symptoms of POTS, but did not the have full-blown disease. However, I still think the NET deficiency theory is a good one especially for those people who have already been at this for years and fit the profile.

I'll be honest, I never looked much into it before I found this gene because I did not understand enough about genetics. I also thought by now I would have cured my POTS with other various treatments/ supplements and that hasn't happened yet. So for me, I am just going down the natural progression of research. I've been at this for a long time, so genetic testing for some on here is probably not appropriate yet because they haven't ruled out other simple things.

I was fairly certain NET deficiency is listed on the dinet set as a possible cause. :)

The studies that really caught my eye were these two. There are drugs which inhibit NET and when they do this in healthy people, they essentially get POTS. That's pretty significant IMO.

Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance

http://circ.ahajourn.../105/3/347.full

Here they tested mice. The significant part of this study for me at least is that they were normal while resting. I am pretty much normal when I sit.

Norepinephrine Transporter–Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity

http://circ.ahajourn...10/10/1191.full

The first study is pretty definitive that NET deficiency and/or mutated NET proteins is the cause of POTS.

Link to comment
Share on other sites

Interesting articles Dana. Thanks for posting them. I can attest to the fact that clonidine makes for more dizziness and fatigue feelings. It does lower the bp and hr however. But, creates the other problem. I've been off of it for about a week now and I'm being able to think more clearly and have less fatigue. But, now the hr and tacky is worse. So. . . .which evil do we want to deal with????

I found it interesting about the connection to phenalynamine - this is a glutamate and there appears to be a number of us with sensitivities to glutamate. I'm better off not having them. But, I don't have the mutation in my gene for phenalyanamine to be a problem - but, it is. So, figure that!

I found several things of interest in my case.

Ohhhh, the complexities. We are all so alike, yet so very different.

Issie

Link to comment
Share on other sites

Issie, the information I was looking for with the SNP's is actually in the supplemental data for the study found here at this link!

"Association ρ-values of all SNPs with POTS diagnosis are presented in Table IV. Compared with healthy subjects, the rs5564 T genotype was found to be significantly associated with the diagnosis of POTS (ρ=0.0014) following adjustment for multiple testing. The rs5564 polymorphism is located in the splice site consensus sequence of exon 5. Whether the rs5564 genotype has a functional affect on mRNA processing remains to be established." I really question this to be honest. I am AA which would be TT. However, AA is the most common result. HapMap puts the CEU population as having 91.1% frequency for AA.

Rama,

There are currently 16 known missenses in the SLCA2 gene (NET). You can see them listed here at this website. One was found just in 2009 (T283M) and it was shown to cause a POTS like syndrome in a woman. Her standing HR increased by 26 bpm and her standing NE was 595. The decrease in NET with T283M is very similiar to those with V245I. I think this alone suggests you can have POTS with other NET mutations besides the one the twins had.

The epigenetic supplemental data PDF is more interesting to me than the actual study....Those who did in fact carry rare alleles on V245I (the one I have) and V69I (23andme doesn't test this one), were all healthy subjects. The researchers for this study say that V245I in vitro did not alter NET function. But they took a study from 2005 and disregarded a newer one from 2009 where they actually tested people and there was in fact a 30-40% decreased NET function and a significant decrease in DAT function. I checked out both studies and they are from the same researcher I emailed and have yet to hear back from. I dunno what to make of this conflicting information.

It sounds like the epigenetic study was done many years ago because it said they used the latest dbSNP build, 124. Meanwhile, they are on build 137 now. 124 was new back in 2005. I'm kind of hoping the dbSNP build was a typo because a lot has happened in 7 years and their conclusions that the minor alleles found in the healthy subjects were meaningless seems...irresponsible. But if they had to admit they were meaningful, then their entire study would have crumbled.

After more research and time to think about all of this, I believe it takes a combination of things to occur in order to have POTS from low NET function. The one genetic mutation the twins had caused a 98% decrease in function...That's huge. But perhaps other mutations in NET with smaller decreases like 30-60% may not affect everyone unless you also have an epigenetic change too.

I am aware a lot of these SNP's are being tested for ADHD. I definitely don't have ADHD. If anything I have an insane amount of focus, concentration and I can become obsessive with things very easily/quickly. That's the exact opposite of ADHD. I have an usual ability to recall images too. It's like I have a constant radar on looking out for anything out of place or not the way it was when I last saw it or left it. My husband is amazed by it. lol

I'm not sure about that. In the study, they demonstrated the POTS patients had NET decreases of 34% compared to controls.

Link to comment
Share on other sites

Found an interesting article on Tramadol. This is some partial quotes from the study. " Appears to suppress symathetic activity through inhibitory mechanisms related with nicotinic AChRs in the adrenal chromaffin cells. Nicotinic AChRs modulate the release of various neurotransmitters such as norepinephrine, dopamine, GABA, glutamate, serotonin, and ACh itself, tramadol could modulate the neurotransmitter release in the CNS through the inhibitory mechanism via nicotinic AChRs revealed in the present study. Tramadol inhibits catecholamine secretion at least partly by inhibiting nicotinic AChR functions at clinically relevant concentrations in a manner independent of opiod receptors."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573343/

Issie

Link to comment
Share on other sites

You have to remember that not all of the family members in that first study even had POTS yet they were carriers for A457P. I don't think it was definitive. Even the researchers said there must have been other things to account for the phenotype. If A457P really does cause >98% decrease in NET function, then why aren't all of the family members affected by POTS? It certainly raised a lot of questions and they started doing more research. I think the studies where they take healthy people and induce POTS is more definitive so that's why I posted them for Rich to take a look at. No need to be condescending here. We are all learning and desperate for answers.

""Furthermore, in the current study, family members who had the mutation also had some of the physiologic and biochemical abnormalities detected in the proband and her twin sister, but none had the full-blown syndrome. Thus, other genetic or environmental factors must have contributed to the phenotype in the two affected women.""

The first study is pretty definitive that NET deficiency and/or mutated NET proteins is the cause of POTS.

Link to comment
Share on other sites

I don't think we're talking about the same thing. Sorry. I'm not talking at all about the genetic mutations because I don't know about that. I'm talking only about the study showing that blocking NET in healthy volunteers produced POTS OI and the study demonstrating that POTS patients had 34% reduction of NET expression.

Now why that is is a completely different thought which I apologize because I take it that was the point of this thread.

Did the first study test the NET expression of the healthy members with the mutation? Maybe it was reduced but not on the order of 34% reduced.

Link to comment
Share on other sites

It's ok jangle. My bad too. It was just a misunderstanding on both of our parts. I want this thread to be a happy place where people can ask questions because this stuff is soo darn confusing. lol

I'm talking only about the study showing that blocking NET in healthy volunteers produced POTS OI and the study demonstrating that POTS patients had 34% reduction of NET expression.

Yes I agree with you too. This study really seals the deal for me! Do you remember which study said that POTS patients had 34% reduced expression of NET? I might have missed that one.

I'm not really sure if they tested NET expression in the healthy family members with the mutations. That's a good question! I'd have to look over it again.

Link to comment
Share on other sites

It's ok jangle. My bad too. It was just a misunderstanding on both of our parts. I want this thread to be a happy place where people can ask questions because this stuff is soo darn confusing. lol

I'm talking only about the study showing that blocking NET in healthy volunteers produced POTS OI and the study demonstrating that POTS patients had 34% reduction of NET expression.

Yes I agree with you too. This study really seals the deal for me! Do you remember which study said that POTS patients had 34% reduced expression of NET? I might have missed that one.

I'm not really sure if they tested NET expression in the healthy family members with the mutations. That's a good question! I'd have to look over it again.

It was in the epigenetic POTS study. They posted a picture where they calculated the NET concentration for the control and POTS patients and found POTS patients in their study had about a 34% reduction of NET protein.

Link to comment
Share on other sites

Ok thanks! I have been looking at so many different studies I can't keep them straight anymore. :lol:

If it only takes a 34% reduction in NET protein, then I think V245I is very close to that. Now what doesn't make sense is how would those with A457P which is >98% reduction in NET protein, not have full blown POTS. Hmmm :huh:

It was in the epigenetic POTS study. They posted a picture where they calculated the NET concentration for the control and POTS patients and found POTS patients in their study had about a 34% reduction of NET protein.

Link to comment
Share on other sites

Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance

http://circ.ahajourn.../105/3/347.full

Just curious if this means that SNRIs would help then?

My understanding would be no, SNRIS would make it worse.

SNRI would inhibit reuptake, but POTS already has low reuptake. We need to augment reuptake so we need the opposite of a SNRI.

Link to comment
Share on other sites

Ok thanks! I have been looking at so many different studies I can't keep them straight anymore. :lol:

If it only takes a 34% reduction in NET protein, then I think V245I is very close to that. Now what doesn't make sense is how would those with A457P which is >98% reduction in NET protein, not have full blown POTS. Hmmm :huh:

It was in the epigenetic POTS study. They posted a picture where they calculated the NET concentration for the control and POTS patients and found POTS patients in their study had about a 34% reduction of NET protein.

It might be possible that even with A457P one could have normal NET expression. What I mean is, maybe the mutation only achieves 98% reduction in NET protein if an environmental cue also triggers it. Now if a person had that mutation and they measured their NET protein to be 98% reduced and they still did not have POTS then that would be confusing.

But really the study where they blocked people's NET protein and it produced POTS pretty much sealed the deal for me already. There's no mistaking that.

Link to comment
Share on other sites

Just a hard lesson learned on my part in regard to SNRI's. Before my POTS DX they thought I had Parkinson's. I had really bad tremors and severe weakness. Sinemet didn't work and so they tried SNRI - Wellbutrin and SSRI Lexapro - to balance. I got progressively worse - so bad the doc then thought I had Multiple System Atrophy. That's when I went to Mayo and got the POTS DX. Everything was explained by the POTS DX and getting off the SSRI and SNRI things got better. So, whether or not that helps or not. In my case adding more dopamine was a complete diaster. Because the SNRI increase the reuptake - so you hold onto it and it recirculates. (That was my understanding of what happened.) Correct me if I'm wrong in how I understood it.

Issie

Link to comment
Share on other sites

Jangle-- what would be the opposite?

Issie-- sorta, SSRIs and SNRIs inhibit the reuptake so there is more floating around extracellularly-- in the synaptic cleft, So the post-synaptic neuron has an increased binding capacity.

SO if this is the case, NET defiency, wouldn't people who use SNRIs have pots symptoms?

Link to comment
Share on other sites

Well, something made me a WHOLE LOT WORSE. Better off it. I think them trying to increase my dopamine levels nearly killed me and I'm not exaggerating. But, we all know - I'm not the typical POTS person either. I have high NE and high blood pressures and numerous other things that can cause or contribute to POTS. So, I think not all people will react the same and in fact know some who do feel that SNRI's have helped them. At first, I thought the meds were helping me too - but with time things got worse.

Issie

Link to comment
Share on other sites

It might be possible that even with A457P one could have normal NET expression. What I mean is, maybe the mutation only achieves 98% reduction in NET protein if an environmental cue also triggers it. Now if a person had that mutation and they measured their NET protein to be 98% reduced and they still did not have POTS then that would be confusing.

But really the study where they blocked people's NET protein and it produced POTS pretty much sealed the deal for me already. There's no mistaking that.

Yep you are right that the normal ones probably did not have decreased NET.... I'm going to have to take a look at the original A457P study again and see what was tested.

SO if this is the case, NET defiency, wouldn't people who use SNRIs have pots symptoms?

In the study that's essentially what happened, yes. They gave them the SNRI reboxetine and it caused a POTS like syndrome. I have no idea how much 8mg of reboxetine is in comparison to a normal dosing someone would take on a daily basis.

We have to remember that not all POTS is NET deficiency though. I don't think PD POTS would fit in this category, but someone correct me if I am wrong.

Link to comment
Share on other sites

I'm thinking there has to be something in addition to NET deficiency. For instance, one would expect everyone who takes SNRI's to get POTS if NET alone was the causal mechanism. EDIT: Actually this may not be true, reboxetine used in the study is actually a very unique NET in that it binds only NET. The other SNRI's bind other parts of the ANS that might balance out NET inhibition and not cause POTS. Actually reboxetine is having difficulty getting approval in the USA because of its uncertain therapeutic benefit and potential side effects, (which probably includes drug induced POTS).

I believe there is also autoantibodies involved. 15-20% of POTS patients have ACHR antibodies. There's probably other antibodies as well.

Link to comment
Share on other sites

No word from any of the researchers/docs. I'm thinking they aren't going to get back to me on this. Where should I go from here?

There has to be more to it. I re-read the one study where some of the family members with A457P did not have POTS and it did not test their NET function. It just tested their supine NE, BP, HR and compared it to standing NE, BP, HR....

I started looking up some of the other people who share this rare allele with me on GEDmatch.com and according to some of these people's FB pages, they look very healthy. Now I look healthy too, so this is not a good way to screen. But one guy was in the military. There is no way a POTSy could be in the military.

I've never had any of the "POTSy" antibodies checked. I've had others done for thyroid, adrenals, lupus, Sjogrens and they are normal. So many pieces to this puzzle and not enough experts out there understand it...

I'm thinking there has to be something in addition to NET deficiency. For instance, one would expect everyone who takes SNRI's to get POTS if NET alone was the causal mechanism. EDIT: Actually this may not be true, reboxetine used in the study is actually a very unique NET in that it binds only NET. The other SNRI's bind other parts of the ANS that might balance out NET inhibition and not cause POTS. Actually reboxetine is having difficulty getting approval in the USA because of its uncertain therapeutic benefit and potential side effects, (which probably includes drug induced POTS).

I believe there is also autoantibodies involved. 15-20% of POTS patients have ACHR antibodies. There's probably other antibodies as well.

Link to comment
Share on other sites

No word from any of the researchers/docs. I'm thinking they aren't going to get back to me on this. Where should I go from here?

There has to be more to it. I re-read the one study where some of the family members with A457P did not have POTS and it did not test their NET function. It just tested their supine NE, BP, HR and compared it to standing NE, BP, HR....

I started looking up some of the other people who share this rare allele with me on GEDmatch.com and according to some of these people's FB pages, they look very healthy. Now I look healthy too, so this is not a good way to screen. But one guy was in the military. There is no way a POTSy could be in the military.

Dana I jus wanted to comment on you saying "there is no way a potsy could be in the military" . I just wanted to direct you to this study

http://www.ncbi.nlm.nih.gov/m/pubmed/15699447/

I'm a military dependent and my Cardiologist is Active duty, he said he would put me back to work now. Generally he would have me out for 6 months to try and stabilize me, and now that I'm stable he said if I were AD I would be back to regular duties. He was NOT impressed with POtS. He said he was pretty familiar it.

Sorry totally random

Link to comment
Share on other sites

I just saw that one study. I wish they had tested the whole NET gene though because we now know that mutation is only unique to that one family.

The reason why I said there is no way a POTSy could be in the military is from my own experience with symptoms. I cannot carry heavy objects. Carrying even a small sized pack on my back is impossble for me. I also cannot crouch down and get up real quick. I can't be in stressful situations at all... Essentially there is no way I could even make it past basic training and the strict schedule and constant stress would kill me.

When I'm experiencing really high HR's (165+) my thinking and decision making abilities go right out the window. I become jumpy, jittery begin to tremble, and I have terrible shortness of breath. I can't do any fine movements without being very clumsy and I trip over my own feet. I drop stuff. I look like I'm on drugs. I also know I'm not feeling well when I'm rambling on, talking a mile a minute. None of these things are good in the military, so I'm just looking at this from my perspective.

Perhaps I should say, there is no way I could be in the military.

Link to comment
Share on other sites

Join the conversation

You can post now and register later. If you have an account, sign in now to post with your account.

Guest
Reply to this topic...

×   Pasted as rich text.   Paste as plain text instead

  Only 75 emoji are allowed.

×   Your link has been automatically embedded.   Display as a link instead

×   Your previous content has been restored.   Clear editor

×   You cannot paste images directly. Upload or insert images from URL.


×
×
  • Create New...