Birdlady

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

Rich, Aside from being able to stop researching, it also has implications for my family and if I ever have children. I could pass this on to them.... One of my parents had to give me the "A" allele. I'd suspect my dad considering his health problems, but out of his parents I don't know where he got it from, so I'm thinking there has to be more to it than just carrying an A allele. Probably a trigger of some sort to cause even further reduction in NET protein. In recent months, I've suspected my dad has a mild form of POTS and doesn't know it. I think my brother also probably has it too. He's been showing signs of it for the past 2 years, but it is no where near as severe as mine. However he has heat intolerance and is starting to get exercise intolerance too. He said he is having trouble doing a workout video he used to be able to do without any problems. He is 22 years old and that's around the age when I became disabled. I've been getting texts from him suggesting he is in the beginning stages of what I went through. I'd be completely shocked if my sister or mom had it because even though they have their own health problems (my sister had a cancerous brain tumor at 25), it does not act like POTS. Rama, In one study, scientists predict the mutation I have has a 0.43% frequency in the population, so it is rare, but certainly not specific to one family. The other mutation A457P, yes is extremely rare and I probably don't have that one, but won't know unless I have my entire gene sequenced. I just need to find out if this mutation can cause POTS like symptoms. If it can, then I can start looking for specific medications to help this. Do you know of anything medications that increases NET activity or would in the very least counteract this?

I only recommend 23andme if you are ready for a challenge. Interpreting your results takes a lot of research, knowledge and patience on your part. If this isn't something you realistically find yourself doing, then I really don't recommend it at all and would ask your doc to see a geneticist. I'm not trying to be insulting or anything like that! Only you know if you can put the dedication and research necessary to make the results of any use to you. I've had my results since the end of March and I'm still learning every day! You will have to look at the raw data and should know the basics of genetics and/or be willing to learn as you go. I didn't know a single thing when I started! haha I just don't want people to think if they get this test done, it tells you right on the website that you have POTS because of this gene or you are fatigued because of this gene. It is not like that at all. The disease risk health reports from 23andme are very fluffy and may or may not be of any use to you. I originally got tested because I wanted to know my APOE status and I wanted to make sure I didn't have Factor V. I also like knowing my carrier status on certain things. I may have actually found my cause for POTS in my results, so it has been amazing for me but your mileage may vary as they say. Of course I am always willing to help people with their results, but I can't look at your raw data so what I can do is very limited. There are 3rd party tools out there to help you with your results, but it still takes research.

If you can get into a genetics counselor definitely go with that. They will do actual sequences of your genes which is really what you need to have done. 23andme is better than nothing though. I'm just not sure how much they really cover on the ApoB gene. Looks like only 52 snps. Charmed Yes there are mutations that do the exact opposite.

Heat intolerance is my worst symptom above everything else.

I've been looking into my genetics too! Do you know what mutation you have exactly? What test did you have done to find this out? If I had to guess, I'd think low cholesterol would cause a lot of hormonal imbalances because it is the building block where all hormones come from. Check out this image. I also found this in google. Not sure if you've seen it or not. Familial hypobetalipoproteinemia a review http://www.jlr.org/c...t/44/5/878.long

I'm curious what exercise would do to those with NET deficiency? Perhaps that's why some of us do worse and others do better with exercise. Maybe Rama would know the answer to this one. I had to give up on even the tiny amount of exericse I was doing. Just trying to stay out of the hospital during the summer is more than enough "work" for me.... Doing activity ontop of the heat would definitely push me over my limit.

I really have no idea. There is so much trial and error with this illness. That's what makes it exhausting to me. haha!

Vanderbilt University says 1000+. There is no real standard and it honestly just depends on what doctor you see...

Well if I find out it is a gene causing POTS, then I can stop looking for other things. I don't expect them to have gene therapy any time soon. I guess my excitement about finding this is because I spend a lot of my days researching and I'm getting pretty sick of it. I just want some peace in my life away from medical journals, studies and forums...lol I dunno if that's how any of you feel, but I'm getting pretty sick of looking at medical stuff. Realistically though, I just don't think in our lifetimes they will be curing POTS. There are so many other diseases out there that actually kill you they can't cure. Issie, the study Rama is talking about is the one you emailed me about epigenetics. http://atvb.ahajourn...244343.abstract I asked my brother to see if he could get the study and he said it's not available at his university unfortunately. Have to pay for it. $20 could buy food, so that's not happening here. Maybe I can ask my cardiologist if he can get it.

All of this is soo confusing, so don't feel bad at all! SNP is short for Single-nucleotide polymorphism... Only 18 are tested for, which is not many at all. I couldn't even begin to guess how many SNP's are on a gene. Lots more than that... If you got the gene sequenced, then that is far better than just a mere 18 SNPs! Genotyping is the cheap man's method of genetic testing. It is the full sequences that will be what's next to come and as Rich said in the next few years they are saying under a $1000. The problem though is going to be interpretation....HA! There was an exome pilot on 23andme for $1k and it is insanely confusely what these people are getting as results. I wouldn't even know where to begin. It took me 3 months to figure out I had this stupid SNP sitting in my data and this is just a genotyping! Exome data is like a zipped 16 GB's! Compare that to a tiny 24MB txt file!! hahah Lots of people are getting into the methylation, MTHFR stuff right now. I think for some this could be helpful if you have a homozygous mutation or are what they call compound heterozygous for the two common MTHFR mutations (C677T and A1298C). I know people who are homozygous for these mutations and aren't sick and I know people who don't have MTHFR mutations and are sick, so it's defiinitely not as clear cut as some of these sites try to suggest. I have seen this website linked a few places and the info is very interesting and food for thought. These mutations on MTHFR gene are quite common though. Homozygous C677T and A1298C mutations are seen in ~11% of the population. I think it is probably far higher than that though and as genetic testing becomes cheaper and cheaper, I think we will see it is extremely common in the general public. A few years ago I had tried supplementing with the different B vitamins and it just made me feel worse off, but that's me and I react strangely to things all the time...HAH!!

This was a Christmas gift from my mom, so that's the only way I could afford it... hah! THey also raised the price a month of 2 ago, so that kind of stinks. I looked up the AIRE gene and there are only 18 SNP's tested. Have you ever had your genetics tested with all of the docs you've seen? You'd think they would have considered this optino by now.

I think you are missing the point of my thread. I have something going on with the gene and you keep saying that the gene is normal. lol Also I looked up the study again and I was wrong. The two twins were highly affected by POTS. Some of the other family members who carried the mutation had some symptoms of POTS, but not the full blown disease. http://www.nejm.org/...le&t=articleTop "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." You can have the mutation and not have POTS (good for any siblings who might carry a mutation) and I can't rule out the possibility that my mom could be the carrier as well. Correct. The proband had lower standing blood pressure than her twin and worse symptoms of orthostatic intolerance. Its hard to say why this was the case. I know that when my blood pressure is higher I feel better for what ever reason. Net could be the result of POTS rather than a cause as well.

Yes this is very interesting and I read your thread. I wonder though is everyone with a mutation on the SLC6A2 gene, symptomatic with POTS? I think in the twin studies only one of them was highly symptomatic, right? Correct me if I am wrong there. If it was the mutation alone that was causing POTS, then they both should have had it. So I wonder if the mutation and another mechanism suppressing NET would explain the difference in phenotype. Epigenetics are an amazing concept that science is just not even close to understanding. We are at least 10-15 years out from it IMO....

I was shocked to see most people don't take naps... I am confused by this because many consider fatigue their worst symptom. Am I missing something? I probably take 1-3 naps a week. If I get overheated, it is almost guaranteed I'll be napping at some point. Even if it's just for 15 minutes. The heat really takes it out of me. Also my sleep schedule continuously rotates. haha

Rama I have seen this. Thanks for posting. You figure if I have a mutation on this gene that decreases function AND something else triggered this chromatin modifying event, then this very well could be the cause of my POTS.

With the ones tested by 23andme, then it looks like you are good. There are 8 or 9 not tested by 23andme, so we don't know about those ones. Can't completely rule it out.

If you match mine in the 2nd post and you are GG on the first one, then you are good. I'm going to edit my post above to make it more clear. I don't have any of the other missenses. There are lots 23andme doesn't test for though, so I'd have to get my gene sequenced. Good reason to reinstate my insurance! lol Sue, As Issie said, we did 23andme direct to consumer genetic testing. I've been going through my results for the past 3 months when I finally came across this. This seems huge...This is the biggest discovery I have found thus far, but I still don't know what it all means. hahah!

Issie, Well while you are at it here's the RS Id's for the other missenses they check for. I don't have any of these ones, so if your result differs from mine, you might want to talk to your doc. If you get SNPtips and use firefox it would take you about 10 seconds to check if you have these... No brain power needed! rs5563 aka N292T AA is Normal rs5566 aka A369P GG is Normal rs5567 aka N375S/A375S AA is Normal rs5570 aka K463R/L463A AA is Normal rs5558 aka F528C/P528C TT is Normal rs5559 aka Y548H/T548H TT is Normal rs3743788 aka I549T TT is Normal If you match these results above, then you do not have any mutations on those! I'm still wondering if anyone here has had the NET gene sequenced by Mayo, Vanderbilt or Cleveland Clinic? Surely if it's talked about as a potential cause, at least some of us have had this ruled out. Every study I've seen says people don't have mutations, so if I do, then I think that's significant. Any thoughts? Edited: To make it more clear what is normal.

I know there's been a lot of discussion about NET on the forums. I have searched through the old posts and I read through some of it! My question is have any of you ever been tested for mutations on the NET gene? This was never even brought up with me. A few months ago I got 23andme tested and I've been going through looking for anything that might give me some clues. Well somehow I overlooked the NET gene (also called SLC6A2). I realized last night I have a missense mutation on this gene. I'm looking at this wondering if this could be the cause of my POTS. Maybe I am jumping the gun here? I dunno, but if it's not specifically causing POTS certainly it must be doing something with norepinephrine. I'm calling my doctor tomorrow and letting him know of my discovery. For those who are into the technical stuff. I have the missense on V245I or rs1805066. My result is AG, where the A changes the protein sequence from a Valine to an Isoleucine. The specific mutation that was found in the family studied here is different than what I have found in my data. A457P [dbSNP:rs121918126) So of course it's not entirely clear cut or a sure thing. Unfortunately 23andme didn't test for the one in the study, so I can't compare. Who knows if this will turn out to be anything, but I really wish docs would do more testing to find the underlying causes...

Ugh I hate it when people say things like you are "lucky" ... I think they are trying to be nice about it, but it really doesn't make me feel all that good. The doctor I originally went to for POTS had no idea what to do with me either. He tried the few basics and really was just shocked I didn't do well on Midodrine and was completely confused by my TTT results. My BP actually went up much higher during that one. I hit 140/80 which is unheard of for me in my normal day activities. Then again I'm not taking my BP every minute while I'm doing stuff either... 23andme has health reports you can read, but as far as finding things that might be causing POTS, yes it can be hard to decipher. If you are doing your own research, which I really recommend, you will have to take a crash course in genetics. If more people are getting testing through there, maybe we can start a thread on things to look at? I dunno if that would be ok or not. Definitely run your data through Promethease. It can pull stuff from your data that 23andme doesn't tell you about, so otherwise you would not have known about it. If you need help, feel free to PM!!

I think in time this designation will get changed. They say Hyper is rare, but it seems like a lot of us have it here. Perhaps there's a larger concentration of Hyper Potsies on forums because the treatments haven't been successful. Those with PD POTS take florinef, salt and water and actually get better so they don't feel the need to reach out? Just makes me wonder really. I'm not trying to diminish anyone's symptoms at all. It is abnormal for your BP go up upon standing even just slightly? I was under the impression a slight increase in BP upon standing was normal.

No my heart rate has never been under control. Even on a beta blocker, I was hitting 150+ so I decided to just stop it. I couldn't see the point in taking it. haha

Aww thanks Issie for posting this! I've had others tell me to try out on one of those shows, but unfortunately it would be too much for me. In order to even try out, you have to camp outside for a week outside of the building where auditions take place. lol That alone makes it nearly impossible. Then the traveling, stress, stand up time... phew. I get tired just thinking about it all. hahaha! I'm blushing over here! Thanks for all the wonderful comments. Means a lot to me!! Singing is one of the few things that keeps me going.... It's not easy to sing at times. Some days impossible with how tachy I get from it, but I keep practicing. Not sure what I'll end up doing with it, if anything, but at least I can share it with people on Youtube.

I definitely meet this criteria for HyperPOTS then. Resting BP was 101/61 and it went as high as 127/81 with a HR of 150. NE levels were 613pg/ml In my normal day life, my BP doesn't go up like this though.