Pots Breakthrough! The cause of Beta-adrenagic pots

[ramakentesh]

I have just been notified by my doctor that they have made some dramatic discoveries regarding the mechanisms that cause POTS in the majority of patients and with this discovery, the possibility of a potential cure to the disorder.

The study and its discoveries are currently open for debate in a medical journal and are yet to be published - therefore has informed me that it would be inappropriate to comment on them - but that It was OK for me to give a layman's rundown of what they have discovered.

Basically much of the study of POTS in patients other than those with connective tissue disorders and other primary causes has focused on the NET or Noradrenaline transporter. Basically it appeared that this transporter was not working properly in the majority of POTS patients and noradrenaline was not clearing effectively, causing excessive autonomic overactivity and the dilation of arteries throughout the body.

Professor Esler and his team at the Baker Institute apparently found that in POTS patients there could be a reduction in blood flow to the brain of up to 40% - and as a response to excessive sympathetic overactivity, a narrowing of the carotid arteries which compounded the problem.

Most study around the world had aimed to try and find out what was wrong with NET in POTS patients. They examined the gene that is responsible for NET and the amounts in the body and expected to find a mutation of some sort. Despite lengthy studies, no mutation was found.

The team at the Baker Institute decided that rather than looking for a mutation in the gene itself, they should look at the gene promoter - the part of the gene that activates the gene or deactivates it so to speak.

What they found was that in POTS patients this area of the gene was covered in some kind of particle attachments (excuse my wording here - Im no genetic bioliogist) The attachment is called metho-something with the chemical name CH3.

They found that in normal people the gene promoter lacked these CH3s whereas in the POTS patients studied (including me apparently ) the promoter was covered with these attachments to a degree that turned the gene 'off' 100%. So the gene that regulates the NET in POTS patients is effectively completely off.

To confirm this finding they examined the levels of the chemical transcription factor of this attachment in the blood of normal and POTS patients and found that in normal people it was almost absent, whereas in POTS patients it was extraordinairely high.

This firstly means that in the future their may be a type of gene test that could easily diagnose POTS without a lengthy tilt table test.

But the bigger news is that medical journals have already demonstrated that some chemicals - when introduced to the human body - can cause these CH3s to attach to gene promoters. And that some medicines can actually detach these particles from the cell promoter. Currently they are only aware of hazardess drugs that do this - but there is the possibility that they may find a medicine that can do this - effectively turning the gene back 'on' and curing POTS in patients.

Edited February 22, 2012 by ramakentesh

[corina]

Ramakentesh,

thank you so much for sharing this (and maybe you can thank your doctor as well!). I really got excited about this. Let's keep our hopes high!!!!

Corina

[cnm1]

Ramakentesh,

Thank you for posting this. Rachel was on accutane just before she got sick!!!! Where is Dr Murray Esler located?

Louise

[DSM3KIDZ]

I'm not up to date on the terms does Beta-adrenagic something that has to do with all pots patients or is it just a type of pots? (I'm experiencing major brain-fog this morning)

Thanks for forwarding that information. Any hope is hope!

Dayna

[michiganjan]

I just googled Murray Esler and read about him. He sounds like a brilliant researcher.

I read about his research on panic attacks. I get panic attacks. I am sure I have a genetic predisposition to them.

I wish all these brilliant minds would hurry up and get us the right medicine. I am getting old while I wait.

Please do post whenever the information is published. I am sure many on this list would like to take it to their doctors.

[futurehope]

Ramakentesh,

Sounds way cool. I'm going to print out what you wrote and show it to my neurologist.

Thanks for the info.

Here's hopin'!

[biatecki]

Thanks so much for sharing this information. It sounds very exciting and hopeful. If you find out when and where this research is going to be published could you also share that?

Margaret.

[MomtoGiuliana]

Sounds interesting--look forward to seeing some published articles on this! thanks for sharing, Katherine

[nantynannie]

I was on Accutane years ago...hmmm.

[Guest Finrussak]

[basically much of the study of POTS in patients other than those with connective tissue disorders and other primary causes has focused on the NET or Noradrenaline transporter.]

Does this mean that this whole area of research will NOT apply to those of us with EDS(connective tissue) orother primary causes??? Perhaps if they perfect the methylation test (CH3 is a methy group and if its attached its called methylation...sometimes the agent that makes it detach is called a demthylating agent)

that test can at the very least tell which of us will be helped..I wonder what implications for those of us with mixed dysauto's...interesting and exciting!!!

BTW Prof Esler is based in Australia . or was as recently as '04.

[ramakentesh]

The study is currently printed in the New England Journal of Medicine.

The initially focused on denervation in the legs and kidneys of POTS patients and found no evidence of either in any of the POTS patients tested.

Therefore that would suggest that there is really only one type of POTS - that which in the past has been labelled Hyperadrenagenic or beta adrenagenic - caused by impaired uptake of noradrenalin. The second variety of denervation suggest in studies by Streeton hasnt really been confirmed.

They secondly discuss the fact that a mutation of the NET gene was suggested but in many studies by the Vanderbilt Institute only two people were found to have this.

Im not sure how this impacts on people with POTS because of EDS but in my discussion I think I got the feeling that he thought that most or the majority of patients would be in the boat discussed in the study.

The basic contention is that hyper-methylation of the NET gene promoter is a major cause of POTS.

The study examined 14 POTS patients and 14 normal individuals and found firstly that the promoter in all POTS patients and none of the normal patients were hypermethylated. Hypermethylation of the promoter has the basic effect of silencing the gene - or its transcription.

Ive done some research and apparently methylation is quite common in genes as CH is a weaker bond than CH3 - but in this case the methylation is unusual.

To check their results they tested the methyl gene transciptor MeCP2 and found that it did not bind at all NET gene DNA in normal patients and bound highly to NET gene DNA in POTS patients - demonstrating their contention.

Now they are looking for the cause of this hypermethylation.

Prof.Esler is based in Melbourne, Australia and I must say that there are a number of other doctors and professors involved in this study.

Professor Esler is by far one of the best doctors/medical professionals I have ever had the pleasure of meeting. His open to new ideas, treats you like a human and you can tell he cares. I consider myself very lucky that he is based in Melbourne considering his expertise and his wealth of knowledge.

Apparently they can test for agents that hypermethylise in the lab and hopefully test for anti-methylising agents there as well - fingers crossed!

[Eli6596]

Hi Ramakentesh,

Thank you for this fascinating information! I am so grateful to researchers like him. Unfortunately, the time that it takes to develop a new drug is several years. I have seen some drugs in neurology take more than 10 years to be tested, and then approved by the FDA. I don't mean to be a party pooper, but I just want to make sure that no-one thinks that a new drug would be available quickly. Thanks again for the info.

Karyn

[Poohbear]

"The study currently under debate in the New England Journal of Medicine printed by Professor Murray Esler, et al. from the Baker Institute in Australia has done extensive testing on the catecholamine levels in POTS patients, there spill-over (which is undetectable by conventional catecholamine urine tests), peripheral autonomic neuropathy (as suggested as a casual factor by Streeton, et.al) and NET deficiniency and found that in ALL patients there as no evidence of peripheral denervation."

Can you provide more info or a link? I've tried to find this article you mention in NEJM and can't find it.

Thanks!

[michiganjan]

I'm going to really muddy the waters now.

Where does mestinon fit in to all this? Does it make sense that it might help POTS patients with the methylation would be helped by mestinon? How?

Yipes!

[Guest Finrussak]

Michelle just posted the Fall 05 newsletter and within research articles there are 2 articles by the same author ( one I believe is JAMA) regarding research and how reliable (or not) it can be, What is germaine to this discussion is that while Dr Essler is widely regarded in his field, nonetheless if indeed he only studied a scant 14 subjects then that IN MY OPINION, as a credentialed researcher myself, is too small a sample size to generalize on anything. It is a GREAT start to further look at this topic. For example assuming that most of our over 600 members are afflicted, this isnt even 3%. Then factor in that we dont know how many of us have the various types described ( percentages)...and how that compares with dysauto in general, and even how many are still going undiagnosed. While this MAY end up as a miracle treatment for those with methylation issues; are there accurate tests to point out who those are?? and how it will affect the others??

To hope that it's the "only" cause, or that this is the only "true" POTS is a bit premature at best.

[Michelle Sawicki]

The information regarding false research findings was in no way meant to reflect my thoughts on Dr. Esler's study. I am waiting to read the published article before I draw any conclusions as to who it might help. I too looked for information on this study in JAMA and was not able to locate it there or on Medline.

Michelle

[Guest Finrussak]

The only thing I attributed to Michelle , was the posting of the newsletter!!! I dont think my post is that confusing. I simply availed myself of the timeliness of those articles. I am sure that no one assumes that the research articles in the newsletter refers specifically to anyone or anyone's post!!

[Michelle Sawicki]

I knew that is not what you meant, but as someone was bound to ask I posted my thoughts on the study.

Michelle

[ramakentesh]

Professor Esler explained that the study was under 'review - New England Journal of Medicine' and that the study is published once it has been reviewed and discussed by other medical researchers in the field. I dont actually know if this means that its been printed there for review or how it works.

I cant really debate the content of the study too much because it goes into detail that was beyond even a friend of mine doing genetic biology at University.

What was apparent was that although the POTS patients involved only number 14, these were the only POTS patients available in Australia - and hypermethylation of the NET gene promoter was found in all 14 while denervation of the legs was not readily found in any.

That doesnt automatically mean that every POTS patients will have a similar finding - but the law of averages would suggest that it may apply for a fair number unless people in Australia develop a different kind of POTS to elsewhere. If it were a majority maybe it could be variable, but for all 14 to be in this basic looks pretty positive. Time will tell.

Perhaps if Michelle reviewed the study she might have more experience on how to interpret these developments.

As for medicines aimed at fixing the problem if it is found that this applies to the majority of POTS patients no time frame was given and in the study it says that 'no tests are imminent' but I was told that they were already aware of some medications that could resolve hypermethylation but that these were quite toxic. He was very positive about finding other chemicals that were less harmful in the future. It could be ten years or more - or in a much quicker timeframe I guess, but atleast they know what they are looking for.

[lthomas521]

When you submit an paper to a peer-reviewed medical journal, they send it out to other experts, who review the article for scientific merit. In journals I have worked for, the reviewers supposedly didn't know who the authors were, and vice versa. That's difficult to achieve in real life, because people generally have a good idea of who is doing what in their field. After the reviewers have had their say, the editors of the journal have to decide whether to accept the article, ask for revisions, or reject the article. Once the article has been accepted for publication, there can still be a wait of several months before the paper appears in the printed journal. Some journals make accepted articles available electronically through their Web site as soon as the article is accepted. Others make you wait.

As for the sample size of the study: Even if you have only 14 cases and 14 controls in a study, if all 14 of the cases and none of the controls have a particular finding, that is very compelling. I could ask one of my statistician friends to figure out the odds of that happening purely by chance, but I can tell you offhand that it is somewhere between slim and nil. I mean, the odds of tossing a coin and getting "heads" 14 times in a row is 1 out of 2 to the 14th power, which is 1/16384, I think.

Of course, a case-control study can only establish a statistical correlation. It doesn't prove a cause-and-effect relationship (i.e., causality). But it is encouraging, because if there is no correlation there probably is no causality. When you do find correlation that is too extreme for you to accept that it has happened by chance, there are three basic possibilities. Factor A may cause factor B, or B may cause A. Or they both might be the results of some other factor. Did the switched-off gene cause the POTS, or did POTS cause the gene to switch off? Or did the switching off and the POTS both result from a third factor? I think that the smart money is on option number 1.

My guess is that the cases in the study were carefully chosen to represent hyperadrenergic POTS with no other apparent cause. If so, then it provides some very encouraging news for those of us with primary hyperadrenergic POTS. Of course, it would provide no useful information for people with other forms of POTS. Okay, so it can provide some general encouragement that scientists are starting to take us seriously, which is good.

I must say that the suggestion of this breakthrough is the most encouraging news I have heard in quite some time.

[Guest Julia59]

It's great to see that Professor Esler has the guts to go forward with this research. It sounds pretty hopeful, and i'm sure one day he will find a way to help those afflicted with this type of POTS.

It takes a lot of courage for someone to forge ahead with medical research. It can takes years away from their life----I feel so greatful that this man takes it upon himself to help find the answers for this rare disorder. Most Docs don't even believe it exists and will not even take the time to treat the symptoms that can be so crippling. It's time we start seeing Doctors who will stop admitting people with a 200+ heart rates to the psychiatric ward claiming that "anxiety" is the cause.

I have come very close to losing my faith in the medical community, but hearing about this Professor and his research has given me a little hope that just maybe someone out there has a clue other then the handful of doctors who continue to work beside him in their hunt for the demon behind this ANS mess.

Thanks for posting about this little light at the end of the tunnel.

Julie :0)

[StandUpSitDown]

As for medicines aimed at fixing the problem if it is found that this applies to the majority of POTS patients no time frame was given and in the study it says that 'no tests are imminent' but I was told that they were already aware of some medications that could resolve hypermethylation but that these were quite toxic. He was very positive about finding other chemicals that were less harmful in the future. It could be ten years or more - or in a much quicker timeframe I guess, but atleast they know what they are looking for.

I tell you this.

I would trade 5 years of my life to live the remaining years of my life without this disease.

There are probably many people on this forum who feel the same way.

There are some medicines that do help hypermethylation in cancerous cells.

Bluntly: If it turns out THIS is the cause for the majority of POTS, well, it's good and bad news. Good, because it is KNOWN. And this bizzare claim of "Oh - you just started losing nerve endings in your legs" - well, that always seemed od. But, a drug to fix this is not easy. However, even if it is not fixable, it may be that treatments, acknowledging (if true) THIS problem as the problem in POTS, maybe some treatments could create a maintenance lifestyle better than the "squeeze the blood vessels and fill em with fluid" hacks we have today.

[Evie]

Does Prof Esler need more paitients to test on?

I have been diagnosed with POTS and am in australia. I am recovering with bed tilt, florinef and knowing what to avoid. A dr is also helping me calm down my nervous system so im not quite so sensitive to sound/stress/touch etc.

I sometimes get confused as other people have stated about the 'different' types of POTS. Since i assume that Prof Esler seems to take it that we are all similar (or mostly) at least that brings some hope of a universal treatment.

My drs didnt want me to go on the other medications unless i truely had to as they said they can have some not so nice side effects. I didnt realise the medications were toxic though? I suppose a lot of things in life are yet we still eat/drink them for pleasure.

Thankyou for this information ramakentesh! Its lovely to bring hope into this field. Sometimes i seriously consider becomming a dr myself just so i can try to treat the ignored paitients. Shame about the reality of the medicical field and the extreme stress you have to go through to graduate. I think i may be more of a liability than a help heh.

[ramakentesh]

n

[ramakentesh]

sorry Finnurik - the study doesnt suggest that all POTS patients have this as the cause - just all the patients in the study. I would find it hard to believe that it could be found in all patients tested who happened to live in Melbourne Australia and that it wasnt atleast somewhat representative of otehr POTS patients.

Im sure once you read the study you may feel less sceptical.

Since this is probably one of the first studies of POTS that has provided a significant causal factor that has been confirmed using two seperate tests, I think in a year's time the studies significance will be demonstrated.