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Update on Baker Institute Studies


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Here is another post to update on the progress towards publishing of a study of POTS patients conducted by the Baker Institute in Melbourne at the Alfred Hospital.

They are attempting to get a this work published in the New England Journal of Medicine, but if they are unable to do this, will try another journal.

As quick background, they found that all POTS patients tested had hypermethylated gene promoters in their NET gene - the NET gene controls how much norepinephrine is taken out of the blood stream by the NET transporter protein. When it is hypermethylated it is turned off. If this happens their hypothesis is that norepinephrine reuptake is reduced or non-existent and symptoms of sympathetic overactivity occur.

They tested this first by giving normal patients a substance that effected their norepinephrine reuptake and created symptoms in these individuals identical to POTS.

They then test their hypothesis they examined the reuptake of norepinephrine in the heart of normal and POTS patients and found that it was greatly reduced under MIBG scan in POTS patients - which could proide a new diagnostic test.

The latest update is that they have taken a vein biospy in POTS patients and normal peopel and compared the amount of Norepinephrine transporter protein found. THis was important to see whether impaired reuptake occured because of resistance to the transporter protein or because of diminished protein which would prove the hypermethylation theory.

They found that in POTS patients there was nearly no Transporter protein - again demonstrating that POTS was caused in all patients tested by hypermethylation of the NET gene promoter.

This will have huge implications in future treatment protocols and the understanding of teh disorder.

They have also found that the levels of methylation wax and wane as our symptoms waxed and wained - but they dont know why

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Very interesting. In my overly active inquisitive mind, I can't help but wonder why the gene promoter gets methylated?

Many of us were functioning and okay up to a point. I mean, we did not have symptoms of POTS (or at least not noticeable) up to a certain age.

So, I wonder what caused this gene promoter to become hypermethylated and thus cause symptoms?

Obviously, something happened or we would have had this from birth.

I don't expect you have an answer. I'm just being overly inquisitive as usual.

I do thank you for relaying the latest.

Take care.

I wanted to add: Praise God for doctors doing this study of our condition. I can't appreciate them enough for their efforts on our behalf.

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I'm guessing that if you have antibodies to ACH receptors, then the receptors are being rendered unusable by the antibodies.

Ramakentesh was talking about a gene promoter being rendered inactive by hypermethylation. If the gene promoter is rendered inactive, she said, we cannot "reuptake" the norepinephrine and we wind up having too much NE circulating.

Seems like there is a bit of a difference between inactivating receptors via an antibody and inactivating a gene promoter that reuptakes NE.

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Fascinating. Thanks for the update. I have heard of hypermethylation in relationship to an unrelated problem, so I just performed a quickie search. I am sure the Baker Institute will offer a lot of insight, but while waiting, maybe we are allowed to guess....

First of all, methylation of genes is a normal process. It is one way the body keeps the genes ready to work, but not working until needed. If we injure ourselves, we want genes of inflammation turned on, but once the healing is done, we want them turned off. So the important thing is the location of the methyl groups and the timing of methylating and demethylating.

One person can have some areas of hypo and other areas of hypermethylation at the same time, neither of which would be proper. Free radical insults and foreign objects may mess with methylation. Maybe some people are genetic hypermethylators.

Folic acid deficiencies are another source of methylation problems. Many people do not use folic acid normally -- have a gene variation which requires a different form of folic acid -- and so their needs are higher than other people. I know I have had a folic acid deficiency. When I first had symptoms, I was surprised to discover that my homocysteine levels were high. This is a cheap test, relatively speaking.

There are other tests, too, but let's wait and see if any recommendations are made.

Thanks again.

OLL

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Yoru right - hypermethylation of DNA is quite different to antibodie tests and fom what I understand the people at Baker institute are the first to tst for this rather than just testing for faults in the gene itself which were never found.

They have just received 5 years worth of funding to study POTS based on the success they have had so far. They have found that this NET gene promoter is very susecptable to hypermethylation. In the patients tested including myself methylation of the gene promoter was found to be 100% which means its completely turned off!

I think they have found some causes for this hypermethylation - certain medications that some patients say they were on right before getting POTS - but they are also investigating viruses and whether they cause this state simply because most POTS patients report a viral infection before onset of POTS or find that catching colds generally makes their symptoms worse for a while.

They are unsure why the methylation levels and the symptoms fluctuate and I suggested to the Professor that it might be an autoimmune thing but he didnt want to confirm that until further studies indicated this.

But the vein biopsies were conclusive - in the POTS patients tested there was a profound difference in NET protein and normal patients - from a bright black mark for normal patients to nothing at all in the results from POTS patients so they are very excited about their findings and feel that this is a huge development in the understanding of the disorder.

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Actually the simple way for anyone to test if this applies to them would be to ask for a tilti table test where the norepinephrine levels are tested supine and at each stage of tilt along with norepinephrine's neural metabolite 3,4-dihydroxyphenylglycol (DHPG) at each stage of tilt.

Any doctor should be able to see whats going on from that.

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Ramakentesh,

Thank you so much for keeping us up to date with this research. Your updates have really boosted my spirits and given me hope. The information about the vein biopsy results really cheered me up, because it sounds so definitive. The information about the folate was particularly intriguing, because I have been doing much better since I started extra folate supplementation. The most important thing that I have done is to take high doses of thiamine. Maybe the researchers from Baker will figure out why that has been beneficial!

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