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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by pixel8mbb on July 23, 2020, at 23:12:24
I don't see any posts here on this subject, probably because it's a very rare condition, but also said to be under-diagnosed. There are two genes that can cause it, the one I have is in the GCH1 gene, the SNP known as rs41298442. There are lots of papers being written about it, more all the time, but most doctors dont know much about it. Its most obvious symptoms are muscular dystonic symptoms, but recent studies have shown more about psychiatric symptoms.
Wikipedia explains it thus: the precursor of the neurotransmitter dopamine, L-dopa, is synthesised from tyrosine by the enzyme tyrosine hydroxylase and utilises tetrahydrobiopterin (BH4) as a cofactor. A mutation in the gene GCH1, which encodes the enzyme GTP cyclohydrolase I, disrupts the production of BH4, decreasing dopamine levels Wikipedias BH4 page says its also used in the biosynthesis of serotonin, melatonin, norepinephrine, epinephrine, and is a cofactor for the production of nitric oxide (NO).
Not having enough BH4 results in decrease in neurotransmitters, which results in DRD, and the expression of DRD symptoms varies from subtle to severe. In addition to the GCH1 mutation there is another gene that can have the same effect. Wikipedia does not include much from studies showing psychological symptoms of DRD, which include depression, anxiety, OCD, problems sleeping, and others.
My muscular symptoms are fairly subtle, although my mother asked the family doctor about my muscles when I was a child, and I can look back and identify with dystonic symptoms from an early age. I think my psychological symptoms have been more debilitating, including all the above listed, and Ive tried dozens of psych meds for many years without much improvement or tolerance. Lately Ive been having some improvement with TMS for depression and OCD.
Doctors prescribe levodopa/carbodopa as primary treatment for DRD, but at least one study also recommended medications to increase serotonin.
I didn't put my symptoms together under a "DRD" diagnosis until my 23andMe DNA data showed the gene in my raw data, after I had it analyzed it through Promethease.com. DRD is one of the rare conditions that is caused by a single gene, and with Promethease it came up first as my most significant mutation. Since 23andMe does not guarantee accuracy, I had my DRD gene checked by a professional lab, and it was confirmed.
I'm waiting for a neurology appointment in a couple of months, at UC San Francisco, not my favorite healthcare provider but its nearby. If any dr-bob readers have any information to share or recommendations on healthcare for this condition I would be very grateful and Id be glad to answer any questions Im able to. Caveat: Im not an expert, just a pretty good researcher, but its been hard to be a lone researcher on this. Im now at retirement age, and after struggling through life until now, Im not ready to give up if there could be help, and I would also like to contribute information about this condition and help others if I can.
Since genetics is so new, I guess its understandable that doctors are not yet using it much as a diagnostic tool, but I'm still a bit surprised about that. My DNA report also came up with a gene that explains why I, and my mother (I had her DNA done too) had very bad reactions to anesthesia. We share a mutation that makes one intolerant in a dangerous way to a certain anesthesia, one which doctors can avoid if they know. Im sure there are many genes that would be helpful for doctors to know about.
Thanks to all the great Psychobabble folks whose posts Ive been reading for many years with great interest and sympathy.
Melinda
Posted by linkadge on July 24, 2020, at 19:27:57
In reply to Dopa-responsive Dystonia, posted by pixel8mbb on July 23, 2020, at 23:12:24
Wow.
That's a very interesting story. Many of us like have (different) disruptions in genes which code for a variety of different neurotransmitters, receptors, neuromodulators, ion channels etc. I don't know anything about this disorder specifically. However, doing a little bit of reading:
BH4 is a cofactor in the following processes needed to make neurotransmitters:
https://www.snpedia.com/index.php/Tetrahydrobiopterin
"BH4 is a cofactor in the following processes needed to make neurotransmitters
Conversion of Phenylalanine to Tyrosine by the Phenylalanine Hydroxylase (PAH) Gene
Conversion of Tyrosine and vitamin B6 to L-DOPA by the Tyrosine Hydroxylase (TH) Gene
Conversion of Tryptophan and vitamin B6 to 5-HTP by the Tryptophan Hydroxylase (TPH1) Gene"This would suggest that supplementation of tyrosine, l-dopa, and 5-htp might help offset some of the mood symptoms. Tryptophan probably wouldn't help (5-htp would be needed). As far as the ratios, that could be very tricky, but you could go based on mood response. They also suggest supplementation with folate. I don't know if folate would be better or worse than methylfolate. You might also get tested for the methylfolate gene (this could indicate if methylfolate would work better). Apparently you can buy BH4 directly, but it is not widely available. This might be the best solution. Other supplements may include NADH. However, I know very little about this, so you'd need to seek other information / opinions.
Do keep us informed about what helps. I would be VERY interested.
Linkadge
Posted by linkadge on July 24, 2020, at 19:30:00
In reply to Dopa-responsive Dystonia, posted by pixel8mbb on July 23, 2020, at 23:12:24
Wow.
That's a very interesting story. Many of us like have (different) disruptions in genes which code for a variety of different neurotransmitters, receptors, neuromodulators, ion channels etc. I don't know anything about this disorder specifically. However, doing a little bit of reading:
BH4 is a cofactor in the following processes needed to make neurotransmitters:
https://www.snpedia.com/index.php/Tetrahydrobiopterin
"BH4 is a cofactor in the following processes needed to make neurotransmitters
Conversion of Phenylalanine to Tyrosine by the Phenylalanine Hydroxylase (PAH) Gene
Conversion of Tyrosine and vitamin B6 to L-DOPA by the Tyrosine Hydroxylase (TH) Gene
Conversion of Tryptophan and vitamin B6 to 5-HTP by the Tryptophan Hydroxylase (TPH1) Gene"This would suggest that supplementation of tyrosine, l-dopa, and 5-htp might help offset some of the mood symptoms. Tryptophan probably wouldn't help (5-htp would be needed). As far as the ratios, that could be very tricky, but you could go based on mood response. They also suggest supplementation with folate. I don't know if folate would be better or worse than methylfolate. You might also get tested for the methylfolate gene (this could indicate if methylfolate would work better). Apparently you can buy BH4 directly, but it is not widely available. This might be the best solution. Other supplements may include NADH. However, I know very little about this, so you'd need to seek other information / opinions.
Do keep us informed about what helps. I would be VERY interested.
Linkadge
Posted by linkadge on July 24, 2020, at 19:30:54
In reply to Re: Dopa-responsive Dystonia, posted by linkadge on July 24, 2020, at 19:30:00
Sorry for the repeat post above. Do you happen to have the exact variant of GCH1 that you have?
Linkadge
Posted by linkadge on July 24, 2020, at 19:44:37
In reply to Dopa-responsive Dystonia, posted by pixel8mbb on July 23, 2020, at 23:12:24
Sorry, you got me REALLY interested. What have been your major symptoms (i.e. psychiatric) over the years. Are you able to describe the core symptoms?
Sadness, low energy, anheonia, anxiety, insomnia, learning / cognitive difficulties ... all of the above?
Linkadge
Posted by pixel8mbb on July 25, 2020, at 14:50:44
In reply to Re: Dopa-responsive Dystonia » pixel8mbb, posted by linkadge on July 24, 2020, at 19:44:37
Thanks for your replies, Linkadge. I noticed several interesting posts of yours here, and sympathize with/can relate to much of what you've written.
I was excited after putting my 23andMe raw data through Promethease to find I have quite a few genes affecting neurotransmitters, but realized very soon how complex they all are. One example, I have a version of the COMT gene which implies I have a somewhat high level of dopamine, one would think it helps to have that COMT version to counteract the DRD gene, and maybe that sort of thing explains the varying degress of expression of the DRD gene. But since dopamine is controlled in different parts of the brain by different genes, I don't pretend to make sense of much.
The DRD mutation I have is in the GCH1 gene, the SNP rs41298442. My 23andMe raw data shows it as (G;G), and the common version is (A;A). If you have only one G allele you can have DRD (i.e. it's autosomal dominant). I had that gene checked by a geneticist who used Invitae, a company which is cheap ($250), compared to another company I found, Prevention Genetics, which charges $640 for a more comprehensive test of that gene. My Invitae results came back as (A;G) instead of (G;G), but they might not test for both alleles since the test is for the DRD condition, requiring only one G. Or, 23andMe may be inaccurate on my second G. Im having my brother send in a 23andMe saliva test, because it might be quite a phenomenon if my whole family is G;G, since it's such a rare condition.
One of the psychiatric conditions associated with DRD is OCD, which I have. My mother once told me it began at age 5, and turns out I have several genes associated with early onset OCD. So those genes might contribute to it, as well as the DRD gene. At the moment, I'm getting deep TMS with the H-7 coil for OCD. I was lucky to find a skilled psychiatrist who administers it correctly, presenting me with psychological provocations tailored to my OCD triggers beforehand. He first used the H-1 coil for my depression, but switched to the H-7 coil, which Brainsway recommends for both depression and OCD. Im about halfway through the series, and feel very encouraged.
In answer to another question from you on this thread, in addition to depression, anxiety, OCD, and trouble sleeping, I believe I've experienced some level of anhedonia, maybe a lessened enjoyment rather than none, my whole life. My head trip sometimes makes me want to theorize that OCD might be related to less enjoyment in a weird way, the brain trying hard to figure out how to be more human, not finding out so it keeps on looping forever. Sorry didn't mean to get on the couch here.
I also have ADD, not recognized in my youth because it just wasn't back then, and not recognized later by a psychiatrist I saw for years who just didn't listen well. It seems ADD must be separate from DRD, and its also implied by genes I have, like the one scientists call novelty seeking. I think that sounds better than easily bored.
For many years I worked with a meds doctor who prescribed almost any med I suggested, without anything helping much, and I've decided not to try anything now without talking to a neurologist. Levodopa with carbodopa are the default treatment for DRD, and levodopa is available in supplements but I don't want to try it without carbodopa, which must be prescribed. I had some very good serotinergic effects from 5-HTP in the past, also good effects from stimulants, taken at separate times, and wonder if a balance of the right two things might work for me. I take a little melotonin now, which helps my sleep a bit.
Tried to keep this brief but there's a lot to it. Googling can come up with a lot of interesting studies.
Posted by pixel8mbb on July 25, 2020, at 15:24:55
In reply to Re: Dopa-responsive Dystonia » pixel8mbb, posted by linkadge on July 24, 2020, at 19:44:37
Hi again, forgot to include the dystonic muscular symptoms, since you might want to know those too. These vary among people and there are other symptoms, some more severe, these are mine.
As a child odd gait, that's what doctors call it. I had a hard time walking in a straight line, sometimes compensated with a springy walk, amusing my classmates. Later, walking gingerly, toe-walking.
Couldnt walk on a balance bar or do a pullup. Very sore muscles after exercises, even missed school once. Throughout life frequent falls, stumble easily, drop things. I got used to people laughing at me for these, or sort of!
Severe muscle cramps in feet, toes become distorted and hard to get back to normal. Also leg cramps, and writer's cramp in the days when we used to write a lot. Toes curling, a known symptom, when sitting. Also leg bouncing, not sure if this is a symptom or just me.
Dystonia can affect the muscles in the neck, including the vocal chords, and Ive always had an extremely soft speaking voice, sent to speech therapist age 6. Also frequent choking, when eating or just swallowing wrong. Can become very short of breath when talking while walking, talking becomes too effortful. Have esophageal reflux/spastic esophagus.
Since I was young, pain when twisting torso. Hula hoop was popular but had to give it up. Could not tolerate pain from doing the Twist. Took exercise classes involving abdominal twisting and afterwards experienced abdominal muscle popping out painfully, thought it must be a hernia but was not.
I believe these are pretty much all things considered benign enough by doctors not to worry about. If a lot of people have symptoms like these, and especially if they have psychiatric symptoms as well, it's my opinion, especially since there are treatments, that they are worth looking into. I'm not sure the neurologists I have access to feel that way but fingers crossed.
Posted by pixel8mbb on July 25, 2020, at 15:45:58
In reply to Re: Dopa-responsive Dystonia, posted by linkadge on July 24, 2020, at 19:30:54
I think you posted about effexor, one of the few meds I've seen articles about in regards to DRD. Btw, Segawa Syndrome is not used much as a name for DRD so googling can be difficult, but they included it in this Cleveland Clinic study: Caution Using Venlafaxine and Other Serotonin-norepinephrine Reuptake Inhibitors in Patients with Dopa-Responsive Dystonia (Segawa Syndrome)
https://www.eventscribe.com/2017/APM/ajaxcalls/PosterInfo.asp?efp=RFhNSVhVR0I0MjAw&PosterID=112157&rnd=0.4579715
Posted by linkadge on July 25, 2020, at 17:47:31
In reply to Re: Dopa-responsive Dystonia, posted by pixel8mbb on July 25, 2020, at 14:50:44
Interesting. I'll try and read a bit more on this issue to be better informed. The reason I am intrigued is that often psychiatric disorders just get chalked up to personality. Its nice to have something on paper that says "no - my brain does, in fact work differently, fundamentally"
Yes, having a low acting version of COMT would prolong the effects of dopamine. Given that you have reduced BH4, this might offset the dopamine deficit to some degree. COMT inhibitors can be used to prolong the effects of dopa. As far as novelty seeking, was this in the dopamine D4 gene that was analyzed? Interestingly, rTMS does have a pretty significant effect on dopamine.
Have you ever tried marijuanna? I remember reading that low COMT was associated with more adverse reactions, but this may be offset (in your case) by lower dopamine synthesis.
>depression, anxiety, OCD, and trouble sleeping
Sounds like me (of course, I have taken no tests to guide me). Tack on the ADD issues and we have similar symptoms. I have not really responded well to many psych meds. I'm currently on venlafaxine, mirtazapine, atomoxetine and lithium, but I relapse frequently. I also take medical marihuana, as needed.
Keep us informed about what / if is helping.
Linkadge
Posted by linkadge on July 25, 2020, at 17:52:31
In reply to Re: Dopa-responsive Dystonia - Meds » linkadge, posted by pixel8mbb on July 25, 2020, at 15:45:58
Thank for describing more of your symptoms. It's very interesting that you have uncovered a mechanism for this.
>Caution Using Venlafaxine and Other Serotonin->norepinephrine Reuptake Inhibitors in Patients with >Dopa-Responsive Dystonia (Segawa Syndrome)
Yes. I read this study. I wasn't sure of the mechanism. Venlafaxine is fairly weak acting on norepinephrine. However, perhaps in combination with dopa, levels of norepinephrine become too elevated (dopa can increase norepinephrine as well).
Linkadge
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