BH4 and the Genetics of ME/CFS

[Mimi]

NEW POLL: http://forums.phoenixrising.me/index.php?threads/bh4-gch1-question.35140/

I've been doing a lot of research on BH4 these last few months to see how it fits in with ME/CFS. It's turned out to be a rich vein to mine, and I'm convinced it's an important part of our pathophysiology. I've personally found BH4 supplementation to be incredibly helpful and so have a lot of my friends. I'm now working on getting a grant to do a pilot study on BH4.

GCH1 is the gene that encodes the first rate-limiting step for synthesizing new BH4. If you have a double mutation of GCH1 you make about 80% less BH4 and get a form of PKU. If you have a single mutation you may get dystonia, but you will definitely make less BH4: http://www.ncbi.nlm.nih.gov/pubmed/18598896.

When I started taking BH4 it was a revelation. I found out what it meant to be "normal" instead of insanely moody - and nearly suicidal when I was doing the Cutler protocol. That first dose completely brought me back to good in 30 minutes. Besides depression, BH4 alleviates anxiety, improves concentration and even helps me to prevent crashes. I took BH4 during an exercise stress test and failed to crash. Bad news for my SSDI chances but potentially great news for PWCs.

MTHFR SNPs alter the folate cycle that turns the BH4 salvage pathway. If you have this mutation, and you feel better on L-5MTHF, chances are you are using the additional BH4 to make serotonin and dopamine. That's because BH4 is an essential cofactor for making all of the monoamines. Without enough BH4, you will not only be low in serotonin and dopamine, but also melatonin, norepinephrine and adrenaline.

BH4 also helps you make NO. If you are low in BH4, you will make NO, SOD and ONOO- or nitric oxide, superoxide and peroxynitrite. When you make too much peroxynitrite it oxidizes most of your BH4. That leads to a vicious cycle called NOS uncoupling which makes you chronically ill. Peroxynitrite passes through cell walls and selectively destroys mitochondria. It also overactivates your sympathetic nervous system which causes post-exertional malaise.

When you have both a GCH1 SNP and an MTHFR SNP you get double trouble. You don't make enough BH4 and you don't recycle it efficiently. Add to the mix other methylation defects (the cycles are interlinked), high viral titres, wounds, colds and flus then you really start to feel bad. Fatigue, brain fog, insomnia and depression are just a few of the possibilities.

Add aluminum poisoning to the mix and your life really goes down the tubes. Besides replacing iron in the body, aluminum blocks the recycling of BH4. Aluminum is routinely added to our food, water, hygiene products and medicines. According to a group of toxicologists who just published a report last month, the worst source of aluminum intoxication is vaccines.

Where You Come In

Please look at your 23andme results and let me know if you have the GCH1 SNP. You can also run your raw data through Promethease and search the report. Then, if you would be so kind as to post your results and vote in this poll, I would really appreciate it. If you would also post your MTHFR status that would be doubly great.

Mimi


Instructions for using Promethease to find out if you have a GCH1 mutation:

1) Get your 23andme.com test done. It costs only $99. If you do two people at once there may be a discount.

2) Once you get notified that your results are available, go to www.promethease.com.

3) Read/Check all the boxes that say you agree.

4) Click the button to go to 23andme.com.

5) Login to your 23andme account.

6) Click the green button that says yes, grant access.

7) Click the blue button to Pay with Card. The analysis only costs $5.

8) Save it to your computer somewhere where you can find it. When I did it, it was a web page.

9) Open your Promethease report and click Show Everything in the upper right-hand corner.

10) Type Ctrl+F (hold down the Control key and press “F”). A search box will appear in the very upper right.

11) Type GCH1 into the box. If the page doesn’t scroll down, click the down arrow next to the search field.

If you have any mention of GCH1 in your report, the find function will take you right to it.

Mimi

 

[Hip]

Do you know the particular rsID number of the GCH1 gene mutation that results in lower BH4 production?

Given the rsID number, it would then be possible to just look up your GCH1 mutation on the 23andme.com website: you can see your GCH1 mutations here.

 

[Mimi]

Hip, could you explain how you make that link into my data without having access to my login credentials?

 

[Gingergrrl]

@Mimi I wish I could understand your post which is too scientific for me and my brain! My doctor wanted me to take BH4 but b/c I will be starting some other meds he told me to wait.

In very basic terms, is BH4 for high ammonia or something else?

 

[halcyon]

I agree the rsID would be helpful. It doesn't appear in my Promethease report which I assume means I don't have the mutation you're talking about but it would be nice to double check it on 23andme.

 

[Mimi]

On Promethease, mine showed up as gs223. It reads thusly:

gs223
Magnitude: 2.1
Repute: Bad
You have one copy of GCH1 variant associated with lower levels of tetrahydrobiopterin. Those with two copies of this haplotype will likely have somewhat reduced levels of tetrahydrobiopterin GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. The haplotype rs10483639(C)-rs3783641(A)-rs8007267(T) is associated with lower levels of tetrahydrobiopterin. Additional resources *23andMe discussion *Yahoo group

 

[Mimi]

Gingergrrl, from what I can see, low BH4 accounts for most, if not all of the symptoms of ME/CFS. BH4 does clear ammonia. It also scavenges peroxynitrite, which is a very nasty oxidant.

The main thing I take BH4 for is mood followed by cognitive function. My energy varies according to how hard I have to work and what else is going on in my life, but I have more chi with BH4.

Note: I may be wrong about BH4 clearing ammonia. See discussion below.

 

[halcyon]

I am:

rs10483639 GG
rs3783641 TT
rs8007267 CC

So I don't appear to have any of these mutations.

 

[Gingergrrl]

@Mimi from your research, what dose would someone take of BH4 for ME/CFS vs. Mood? Is there a certain brand that you recommend? Also, from your research does BH4 do anything for autonomic dysfunction?

 

[Mimi]

@Gingergrrl, I like to start low and go slow. I started with a single 2.5 mg capsule of the Ecological Formulas BH4. It's now called Pteridan-4 and it's available on www.spectrum-supplements.com for $75 for a bottle of 60 capsules. You can also buy it on Nutrimedical.com. Last time I checked it was $10 more. Shipping tends to be expensive since it's best to ship rapidly and keep it cold. My current dose is 25 mg. which is a quarter tablet of the prescription version, Kuvan. That seems to keep the demons at bay, and I augment that with flavins, antioxidants, resveratrol, estradiol and L-5MTHF.

I use resveratrol and estradiol to stimulate the estrogen receptors. This induces the synthesis of new BH4. When estrogen levels drop in middle aged women, BH4 levels also appear to drop. This may account for the gender and age bias in ME/CFS. In other words, a lot of middle aged women get sick, even though anyone else can, too.

Low BH4 leads to sympathetic nervous system overactivation. The SNS is part of the autonomic nervous system. The other part is the parasympathetic nervous system. If the SNS is overactivated then your body will spend more time in "fight or flight" and less time in "rest and digest." I would call this an imbalance of the autonomic nervous system. Taking BH4 may well help you, but there is too little research in that area for me to answer that question definitively.

 

[Mimi]

There are actually 6 genes that are involved in BH4 synthesis and 2 that we know of that are involved in BH4 salvage. I'll look them up tomorrow and post them here. But even if you don't have any mutations of these, you can still have low BH4 from MTHFR or other SNPs, aluminum poisoning, infection, poor diet and maybe even lead or mercury toxicity.

 

[nandixon]

@Mimi
You only have one copy (=gs223) of the CAT haplotype, i.e., you're only heterozygous for that haplotype (in a "cis" fashion, meaning all three "bad" SNPs are on the same DNA strand).

It requires two copies (=gs224) to potentially have any impact at all, i.e., you would need to be homozygous for the CAT haplotype (and thus both strands would be affected).

Even individuals who are gs224 often have perfectly normal BH4 levels.

(Just FYI, I have an oddball situation where I have 5 out of 6 of the bad nucleotides, which perhaps means there was a relatively recent mutation in my ancestry because normally it's a well preserved haplotype, I think. That's why I put "~gs224" in my signature.)

Also, some of the information that you're presenting that arose from Amy Yasko isn't correct, we've found:

BH4 isn't used up with respect to ammonia elimination (she didn't understand that BH4 was a catalyst and not actually consumed in a particular reaction).

MTHFR (A1298C) has not been shown to be involved in BH4 recycling (she got this idea from some in vitro work she misinterpreted and misconstrued).

Note that taking BH4 in any quantity is not going to be a good idea for most people (although perhaps it's good for you), because it can be easily oxidized to BH2, and the ratio of BH4 to BH2 is just as important as the absolute amount of BH4 (with respect to recycling by DHFR, if I remember correctly).

The best thing, for most people, is probably to preserve the BH4 they already have (e.g., by making sure they have enough methylfolate to scavenge peroxynitrite, by avoiding inhibitors of DHFR like green tea and folic acid, and so forth).

That's interesting that you've found that BH4 helps you. But gs223 is almost certainly not a source of trouble for you. Perhaps you have some other bad SNP(s) in GCH1, or in PTS or QDPR, etc.(?)

 

[August59]

On Promethease, mine showed up as gs223. It reads thusly:

gs223
Magnitude: 2.1
Repute: Bad
You have one copy of GCH1 variant associated with lower levels of tetrahydrobiopterin. Those with two copies of this haplotype will likely have somewhat reduced levels of tetrahydrobiopterin GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. The haplotype rs10483639(C)-rs3783641(A)-rs8007267(T) is associated with lower levels of tetrahydrobiopterin. Additional resources *23andMe discussion *Yahoo group

My Promethease Report is listed identical to yours. When I follow the directons from Hip's post to 23andme it returns 29 SNP's for GCH1.

Of the ones listed in my Promethease report compared to the ones that appears in my 23andme is:
rs3783641 AT

My 23andme report is from Feb 10th, 2014 (Build date: 11/02/13)

I don't have a clue?????

 

[Mimi]

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.

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:

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.

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.

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 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.

 

[Hip]

Hip, could you explain how you make that link into my data without having access to my login credentials?

The web address for the GCH1 gene (or any gene for that matter) is the same for everyone with a 23andme account.

Because each 23andme user goes through the 23andme login page, that's how they know who you are, and will then serve you up your gene data, and not someone else's. So we all use the same web address, but each of us sees our own personal gene details.

Same as online banking, which gives the same bank web address for everyone, but when you go to that address they serve you up your own particular bank balance, based on your login credentials.

So if you post up any 23andme weblink on this forum, each person will see their own gene details when they login to 23andme and look at that link.

 

[Hip]

By the way, the reason tetrahydrobiopterin (BH4) is so expensive, and without prescription is only available in small dose tablets, is because BH4 was given orphan drug status in 2002, and this gives specific companies the exclusive right to sell BH4. Biomarin and Merck Serono has this right, and they sell their BH4 (trade name Kuvan) in 100 mg tablets.

But all the other sources of BH4, such as Pteridin-4 from Ecological Formulas, are at low doses (eg 2.5 mg), sold as "homeopathic" formulations.

However, this BH4 orphan drug status is due to expire in June 2015, ending the exclusivity, so thereafter we can expect the price of BH4 to drop, and the general availability and dosage amounts of BH4 to increase.

 

[kel88]

Good to know hip!! Thanks for that info about the BH4 price!

Mimi interesting! For me its very hard to understand but ive got i believe almost the same mutstions as u got ( u have CBS also right ? And a MTHFR?) if i give you my username and password for 23andme, can you look than for me? Greet that you are studing this! Very very good!

*sorry for my bad Englisch!

 

[Gondwanaland]

such as Pteridin-4 from Ecological Formulas

"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)
• Phenylalanine hydroxylase (PAH) for conversion of L-phenylalanine (PHE) to L-tyrosine (TYR)
• Tyrosine hydroxylase (TH) for the conversion of L-tyrosine to L-DOPA (DOPA)
• Nitric oxide synthase (NOS) for conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO)
• Alkylglycerol monooxygenase (AGMO) for the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol "

AHA! That is why I feel the worse on Phenylalanine even though I'm low in it

 

[Gondwanaland]

is due to expire in June 2015

 

[Mimi]

Thanks, Hip! Nice explanation. And thanks for the news about the orphan status. I will pass that on.

Thanks, kel88. I am glad, too! It seems more promising with every new study that gets published. There is obviously a lot of excitement right now.

Yes, I think that is correct - a single CBS. If you feel comfortable sharing your info, send me a PM. It will be interesting to compare notes. Also, I have no problem with your English which is way better than my fragments of German, French or Spanish.