BH4 and the Genetics of ME/CFS

[jepps]

"The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).
....
Functions
Tetrahydrobiopterin has the following responsibilities as a cofactor:

• Tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP)

Candida also blocks the tryptophan metabolism by this way.
No need to take BH4, before Candida is addressed.

 

[Mimi]

It says C.albicans causes tryptophan to be converted less to kynurenines and more to 5HTP. That actually seems favorable to me.

 

[Mimi]

To simplify things, I have posted a simple yes/no poll on GCH1 at http://forums.phoenixrising.me/index.php?threads/bh4-gch1-question.35140/. Even if you posted your more detailed results here, please vote so I can see a simple total.

 

[kel88]

Hihi ok good to know Mimi!! I will send you a PM for me its not a problem to share. I hope that you find the same as at youre account

 

[Mimi]

Hi August59,

I think I figured it out. They only report on those same 3 GCH1 SNPs because they are representative. If you go and look at your 23andme raw data it will tell you the particulars. I had 38 SNPs on GCH1. Can you see what you have?

 

[Mimi]

@Hip, getting back to your question, I don't know if there is a particular rsID that impairs BH4. Would there have to be a particular one or could it be an aggregate number?

Actually, it may not matter in my case. According to this, there are 42 known variants in the GCH1 gene, of which 13 are common and 29 are rare. Having 38 SNPs would cover all but 4 of those.

 

[silverseas2014]

Hello. I am interested in this conversation. I also have 38 SNPs on the GCH1 gene. I have some of the Ecological Forumlas Pteridin-4 supplement. I have not tried it yet as I am working with other supplements right now.

Mimi--could you elaborate: How long does a dose of Pteridin-4 last in your system? And can you go over the dose(s) you take every day? I know you said you take 25 mg. but that is 10 capsules of the 2.5 mg./capsule---Is that correct? You take 10 capsules of Pteridin-4 a day? (It's just that this supplement is quite expensive and I want to make sure of the dose(s) you are experimenting with before trialling it myself).

Cheers,
Silverseas2014

 

[Mimi]

Someone just told me a SNP is not necessarily bad. So I need to look into that and find out what is relevant. In any case, I am now taking Kuvan which is cheaper than buying EF Pteridan-4 at that quantity. I got a prescription and a friend paid for it. Very nice friend. Without it, I'm extremely depressed in part because I am grieving some major losses. In better times, my mood is up and down. But when I'm up, have a lot of optimism, and that comes back when I'm on BH4.

My thinking is clearer and I can organize more. I have a good basic sense of energy now if I get enough sleep. BH4 helps me sleep, along with s-acetyl glutathione, passion flower extract, and 5HTP or tryptophan. Otherwise, I have intense early morning insomnia, sleeping for just 4-5 hours and then full awake. Also, since October when I started taking BH4 at higher doses, my blood pressure has improved from 90/60 (a longterm score) to 124/70 as of the last reading.

 

[Sea]

I looked at the raw data on 23andme and it says I have 38 SNPs. That's 38 out of 42. I read somewhere that single CAT GCH1 mutations lead to 30-70% reductions in BH4 levels. So I think it's safe to assume that I'm at least 30% impaired.

The 38 snps that show in your results are the snps on that gene that 23andme has tested. Everyone tested will have the same number (except that recently 23andme changed the number of snps they test so the person who said they have 29 is probably the new number of snps tested on that gene). You don't know if you actually have a mutation or not without looking at dbsnp or other research

Also, the fact that there are 42 known pathogenic variants doesn't mean that you can assume the 38 23andme test for are a subset of that 42. There are 3068 snps on GCH1 that appear in the Variation Viewer
http://www.ncbi.nlm.nih.gov/variation/view/?q=GCH1&filters=source:dbsnp&assm=GCF_000001405.25

 

[Mimi]

Got it. I've been looking at the research and not getting very far. Will try dbsnp tomorrow.

 

[Sea]

Just to confuse you a little more, 23andme lists some of the snps with an i (an internal identifier) instead of an rs. You have to find these based on the position on the chromosome instead. Variation Viewer will help you there.

 

[August59]

Just to confuse you a little more, 23andme lists some of the snps with an i (an internal identifier) instead of an rs. You have to find these based on the position on the chromosome instead. Variation Viewer will help you there.

Several of mine SNP's have the "I" associated with them

Someone on the forum ordered Tetrahydrobiopterin as part of a "group" purchase and was able to get it substantially cheaper and it was in powder form.

Addittion: It was your post Mimi about Schircks Laboratories!

 

[nandixon]

Thanks for your comment, nandixon. I particularly appreciate the correction on the ammonia elimination and have edited my posts accordingly.

I looked at the raw data on 23andme and it says I have 38 SNPs. That's 38 out of 42. I read somewhere that single CAT GCH1 mutations lead to 30-70% reductions in BH4 levels. So I think it's safe to assume that I'm at least 30% impaired.

I think you understand now that everyone who tested with 23andMe on the v3 platform will have 38 SNPs listed. What relevance each has depends on whether a particular SNP has any effect at all (many don't) on either the function of the enzyme or transcription of the gene (among other possibilities), and on whether you are heterozygous or homozygous for the SNP.

Note that, by definition, a SNP does not cause disease, because these are simply variations, albeit some of them pretty rare. Some SNPs can definitely predispose to disease (or to good health), but other factors will be required for the disease to manifest itself (e.g., combinations with other SNPs and/or environmental exposures and/or epigenetic effects, etc.).

On the other hand, a true mutation might very well cause disease. 23andMe mostly does not test for these. For example, on the GCH1 gene (which contains over 60,000 base pairs, I think), there are well over a hundred actual disease-causing mutations.

According to SNPedia, gs224 reduces median plasma BH4 levels by approximately 80%. If that's what you have, I would expect BH4 to be very helpful for you. Here is why:

The study cited measured BH4 only in patients suffering from coronary artery disease (CAD). Healthy controls were used for alleleic frequency determinations only.

The 80% reduction doesn't appear to apply to either healthy people or to people suffering from ME/CFS. A number of us with the "gs224" haplotype had our biopterin levels measured and they were perfectly normal. We also tried BH4 supplementation and it wasn't helpful (e.g., I tried 2.5mg to 25mg with no effect). It might be helpful for someone else though, of course.

(I think the person who wrote the SNPedia blurb may be the moderator of the Yahoo gs224 group, so I'll ask her to place a big caveat with the 80% citation.)

Recent research shows that BH2 can be rescued by DHFR as well as by DHFRL1. So even if all of your supplemental BH4 was oxidized, your body has at least two pathways to salvage it.

The problem is that the higher the amount of BH2 becomes - relative to BH4 - the more that decoupling of eNOS occurs, which in turn causes more oxidation of BH4 to BH2, and a vicious cycle ensues. (This is from the 2009 and subsequent work of Crabtree.)

Regarding those ratios, if taking Kuvan did not raise BH4, then Kuvan wouldn't work for PKU. You need BH4 to break down phenylalanine. Without it, you die.

If I remember correctly, it actually tends to be very hit or miss in its effectiveness here, surprisingly.

My MTHFR mutation is C677T and I usually take a large L-5MTHF supplement. However, L-5MTHF doesn't give me nearly the boost that BH4 does. There are experiments that incorporated both BH4 and L-5MTHF that had excellent results. The challenge is scavenging peroxynitrite - taking Kuvan doesn't seem to lower peroxynitrite levels on its own. I suspect you need agmatine, arginine or other antioxidants to really make a dent. I personally take s-acetyl glutathione, Vitamin C, Gamma E tocopherals and inosine which have all be shown to do so.

I'm pretty sure that the most effective peroxynitrite scavenger, specifically with respect to maintaining BH4 levels, is methylfolate.

I heard from the owner that BH4 sales have been very strong for Spectrum Supplements, far beyond expectations. I don't think the parents of ASD kids would keep spending the money if BH4 wasn't helping. Recent studies show great promise for mental illnesses without all the nasty side effects. I look forward to seeing BH4 treat a host of neurological diseases as well as metabolic disorders, cardiovascular disease, and with luck, ME/CFS.

A lot of those parents are desperate for anything that helps, but it'll be interesting to see how BH4 plays out in autism.

 

[Mimi]

Thanks for your detailed answers, nandixon. I know you are sick so it's good of you to write. From what I've read on autismweb, a lot of parents are seeing behavior changes that really make a difference.

I'm sorry to hear BH4 didn't make a difference for you. We all have different biochemistry. Among my CFS friends, the first thing they notice is a boost in mood. Many of us are depressed or anxious and not all of us wish to take antidepressants. Within that group, the ones who have MCS are getting relief from their sensitivity. This is a big deal since having severe MCS makes you a prisoner. Finally, two friends found that they had to lie down afterwards. As I'm sure you know, NO is a vasodilator and BH4 boosts NO. They are waiting to see the results of our experiment before trying it again. Blood pressure drops are the pits.

I, too, have had very low blood pressure but I'm not so unstable. Taking BH4 at 15 mg or more for several months resulted in gradually increasing BP until I hit 130/70. Then it settled down to 124/70. I'm not sure if this is because of increased RBC production or better heart health due to less mitochondrial destruction by peroxynitrite or some other factor completely. There's so much we don't know about BH4, including how best to use it and for what. I am just glad for the cognitive and mood gains, and the improvement in blood pressure. If it's helping my energy, that too, but that's harder to say. However, I'm glad I found BH4 and for what it's doing so far.

 

[Mimi]

Sea, thank you so much for your kind directions. I will look up that Viewer - it sounds like a big help.

August59, yes, we had it all set up - an order for 5 grams and ten participants in a pilot study. Then Schircks pulled the plug. Apparently they are not allowed to sell BH4 for human trials. So we are proceeding with a Kuvan trial, but it will take more time since it's not a patient trial and so is subject to FDA regulations and overhead. Hence the grant application.

 

[Mimi]

nandixon, do you have a link to any research or recommendations on using methylfolate to scavenge peroxynitrite? or anything that compares it against other supplements or drugs?

 

[kel88]

Mini i hope that the trial gives good results that it will be able to buy BH4 for
Someone with CFS/ME or with out MTHFR mutation! You take kuvan 25mg a day right?

And how can i send you a PM? Than you can look if i got the same mutation if you want...

 

[Mimi]

Yes, I was just checking my inbox! Please do. But I am in the dark about the mutation - I'm finding it's harder to figure out than I thought. However, I will continue to dig in and share what I find out. It just might take me awhile.

 

[nandixon]

nandixon, do you have a link to any research or recommendations on using methylfolate to scavenge peroxynitrite? or anything that compares it against other supplements or drugs?

I think this is the original work:

5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling

These changes were not explained by direct superoxide scavenging by 5-MTHF in vitro or by changes in plasma total homocysteine in vivo. Rather, 5-MTHF was a strong peroxynitrite scavenger and increased vascular BH4 and the BH4/total biopterin ratio. Furthermore, 5-MTHF reversed eNOS uncoupling...

http://circ.ahajournals.org/content/114/11/1193.long

 

[kel88]

Mimi i dont know hoe to send a PM ... In a newby at this site so dont know how to do it ... Haha...

But if you dont know how to look at it than thats not a problem, than you dont have to look! Only if you know where to look for i am happy to share my results with you!