Interesting Genetic Test Result

[Sarah4444]

Just another piece of the puzzle. In August a geneticist up here in Canada ran a test for dopamine beta-hydroxylase deficiency. When I looked it up at the time I read that only 18 or so people have been identified with it so far, so I assumed my test would come back normal - I mean really, what were the odds...? They seem to think it is an autosomal recessive condition, so I would need two abnormal genes to have the condition.

So, the test results came in last week and apparently one of my DBH genes is normal, and the other has a sequence variation of unknown clinical significance. So if the condition is recessive, that would mean I don't have it and am at most a carrier of something. But DBH deficiency causes severe orthostatic hypotension due to autonomic failure. Although my bp didn't drop during my TTT (of course), it does all the time when I stand up, and this summer was dropping all the time even while I was supine. So now I'm thinking what are the odds that I have an abnormal DBH gene but have orthostatic hypotension caused by something else, and this is just a coincidence? As I read further about DBH, it seems that the mode of inheritance is not totally finalized either, with one study from the Netherlands stating it is an autosomal dominant condition. DBH is the enzyme that converts dopamine to norepinephrine, so people without the enzyme have no norepinephrine (or epinephrine/adrenaline?) and seem to use dopamine in its place. I don't have my catecholamine results from the TTT yet, but I have a lot in common with the hyperPOTS people on this site - Friedbrain provided a great explanation last week as to how this could be even if I have low levels of NE (thanks!).

So now I am confused. I also have many things in common with the DBH deficiency people - this orthostatic intolerance has been creeping up on me as long I can remember, my mother has a history of pregancy loss, I have a high palate, some hyperflexible joints, a history of anemia, insomnia, polyuria, postprandial hypotension, some evidence of hypoglycemia and increased creatinine... but I don't have the two abnormal genes. I have an appointment with a new geneticist this week (the one who originally ran the test is not coming back to my local genetics clinic as far as I know). Am I crazy to want to see if there might be a significance to my genetic result? What if I have a partial, but not total deficit of DBH and could still be helped by L-DOPS (Droxidopa?), the medication they use to treat orthostatic hypotension caused by this condition?

I am very worried that they may have stumbled upon the cause of my POTS and yet not know it because not enough is known about the DBH variations. The internet tells me that they only test for this at three centers in North America - Toronto, Atlanta and Dallas I think. This means that few people are getting tested, and there are probably others out there with at least some degree of DBH deficiency who will not get tested - if few doctors know about POTS, and fewer seem to try to identify causes, how many would know to test for DBH deficiency?

Does anyone have any knowledge of this condition, and/or advice regarding how I should approach the upcoming appointment? Much of my life has been slowly stolen from me over the years by OI, and I'm desperate not to let that happen to my kids.

The genetic counselor at Dr. Francomano's office in Baltimore suggested I email Drs. Robertson and Garland at Vanderbilt and outline my situation, and ask if they know of any instances of carriers being symptomatic or of variations which might have clinical significance. Should I do this before or after seeing my local geneticist? Should I do it at all?

Any input is so welcome. Here's a link if anyone is interested:

http://www.ncbi.nlm.nih.gov/books/NBK1474/

[sue1234]

I don't know anything about it, but was just reading about in on the Dysautonomia Research website with Vanderbilt. It apparently is one of the areas they have been researching.

[Noreen]

Sarah-

I think you should e-mail the docs at Vanderbilt as suggested by Dr. F's office. Your explanation is cogent and concise. Opinions from researchers/experts in the field should at the least be helpful when you see the new geneticist.

wishing you the best,

noreen

[juliegee]

Sarah-

I finally had time to read the article form the NIH and I think MANY of us should have this genetic testing done. My son & I don't meet allof the diagnostic criteria all of the time.....but what if one who is a carrier CAN exhibit lesser symptoms? I know you are wondering the same thing.

I think that the researchers at Vanderbilt would be DELIGHTED to hear from you.

Do a search on this site of Droxidopa. I know others here have done trials with that med- can't remember their results.

I do NOT think this genetic abnormality is a coincidence. I DO believe that you are displaying some of the characteristics of this disease. I suspect it is underDXed as physicians and patients alike don't know about it.

This is fascinating stuff. I plan to research more. Keep us posted on what you learn.

Julie

[Sarah4444]

Another thing that I forgot - from what I have read about most forms of Pure Autonomic Failure, they expect that the fall in blood pressure on standing would not be accompanied by a rise in heart rate. I believe that DBH deficiency is a form of PAF, but in this case the OH is accompanied by the compensatory tachycardia. I wonder if some POTS diagnoses may arise from this effect.

[iheartcats]

I had 23andMe done because I find genetics intriguing. (they have a sale for $99...it's usually $400!)

I went and looked up my SNP for this: http://www.snpedia.com/index.php/Rs1611115 and I'm CC so it looks like I don't have that specific abnormality.

I understand the dominant versus recessive, but I agree that we don't understand enough to know can one carrier gene cause slight issues? Look at Sickle Cell Anemia. Double recessive means you are very ill. One recessive gene protects you from malaria!

Good luck finding out more, I'm glad others are interested in genetics.

[Crow]

I had 23andMe done because I find genetics intriguing. (they have a sale for $99...it's usually $400!)

I went and looked up my SNP for this: http://www.snpedia.com/index.php/Rs1611115 and I'm CC so it looks like I don't have that specific abnormality.

I understand the dominant versus recessive, but I agree that we don't understand enough to know can one carrier gene cause slight issues? Look at Sickle Cell Anemia. Double recessive means you are very ill. One recessive gene protects you from malaria!

Good luck finding out more, I'm glad others are interested in genetics.

Thanks for posting about the sale, cat lady!!!

I got my results back. I'm CC for that SNP as well.

But I have a Rs17602729 AA which is an AMPD1 deficiency

http://www.snpedia.com/index.php/Rs17602729%28A;A%29

http://ghr.nlm.nih.gov/condition/adenosine-monophosphate-deaminase-deficiency

[Sarah4444]

What do cc and snp mean? Also, how is the test you guys had done, and what do they look for?

[Crow]

What do cc and snp mean? Also, how is the test you guys had done, and what do they look for?

the CC in my post is a genotype

SNP ("snip") is a Single Nucleotide Polymorphism

http://www.ncbi.nlm.nih.gov/About/primer/snps.html

it's the changes in your DNA that can tell you about disease or how you process certain drugs etc.

What I did was get that $99 23andme test - they send you a vial and you spit in it and send it back. Then after a while you get your results and there are reports they give you that tell you if you are susceptible to any diseases or carriers for any, (that they test for). There's also some genealogy stuff.

Anyway, you can download your raw data from 23andme. I did that and ran the data through a free program called Promethease

http://www.snpedia.com/index.php/Promethease

That tells you more about your SNPs.

[Sarah4444]

Thanks, Crow. I feel like I'm trying to learn about so many things at once, it's a bit overwhelming.

Does this test look at collagen defects? Or metabolic disorders like the glycogen storage disorder mentioned on a recent post?