MTHFR defect (23andme) and chronic infections

[Markus83]

My post has been transferred to the "Introduce Yourself" section, so I post it again here and hope I get some comments:

Hello together,

I have been ill for a long time (20 years, now 34 years old) and maybe have CFS – maybe not. I fullfill most of the criteria for CFS, but not the major criteria of post exertional malaise, which led one of my doctors to the hypothesis of „untypical“ CFS. I’m also in treatment by a infectious disease specialist, who found multiple chronic bacterial infections (Chlamydia pneumoniae, Pseudomonas aeruginosa, Klebsiella oxytoca). So it seems that my body cannot fight off special kinds of bacteria. As far as I know, Chlamydia pneumoniae has been described as a possible cause for CFS. I had extensive diagnostics for immune defects, but all tests came back normal (just very low CD57+ killer cells, which has been described in Lyme disease but is most likely not specific for this disease).

Recently, I got back my results from 23andme, and I’m not sure how they might be related to my illness. Some of the methylation results from Genetic Genie are:

MTHFR C677T rs1801133 AA +/+
MTHFR 03 P39P rs2066470 GG -/-
MTHFR A1298C rs1801131 TT -/-

MTR A2756G rs1805087 AA -/-
MTRR A66G rs1801394 AG +/-
MTRR H595Y rs10380 __ no call
MTRR K350A rs162036 AA -/-
MTRR R415T rs2287780 __ no call
MTRR A664A rs1802059 GG -/-

BHMT-02 rs567754 TT +/+
BHMT-04 rs617219 __ no call
BHMT-08 rs651852 TT +/+

So it seems that I do have a homozygous defect in MTHFR and in BHMT-02 and BHMT-08. I’m not sure what the defect in BHMT has to say. Is it possible that these defects can have an impact on the immune system, so that these could be a case for may chronic infections?

I have tried in the past (without knowing the test results above) 1 mg Methyl-B12 sublingual ones or twice a day. Short time after (30 minutes or so) I got more energy and felt quite better, but after a few hours I developed flulike symptoms with a runny nose and more fatigue which made me stop the supplements after a few days. Thanks for reading my post until here. Thankful about every hint you might give me.

 

[Learner1]

You only mentioned a few genes. You have many more that could be affecting you, and making the situation more complex.

Of those on your list, the most significant find is the MTHFR C677T SNP which pinches your folate pathway. Its extremely likely that you need more folate than most people, and you'll need a version called 5-methyltetrahydrofolate, or 5-MTHF. Not folic acid, which your body may not be able to use.

This SNP has been shown to be more frequent in CFS patients. Folate is used in a larger process called methylation which uses other B vitamins, magnesium, potassium and certain aminos. Methylation is critical to the proper function of your immune system, your endocrine system, neurotransmitter production, detoxification, and DNA replication, among other things, so it could play a factor in your illness. Many people with this SNP have cardiac problems and mental health issues.

Its very treatable...you just need good information. It would be wise to test your levels of methylation nutrients, glutathione, and heavy metals. One test that's especially good is Genova Diagnostics NutrEval, which does all of this. You can see a sample test on their website. RBC folate, a methylmalonic acid B12 test, homocysteine can give you a snapshot on regular lab work, but there's be a lot of guessing.

As you begin to supplement, you may encounter brain symptoms, anxiety, depression, headaches, or increased fatigue. A knowledgeable doctor can help you tweak your supplements to make these symptoms go away. Its likely you have built up toxins due to this problem, and as you start to supplement, you'll start to mobilize toxins, making you feel sick. You can manage this process so you don't feel sick all the time with supplements. Getting rid of toxins is important.

If you look around this site, there's a lot of info on methylation. Ben Lynch has some good videos on YouTube as well to help you learn more.

 

[pcmenten]

MTHFR C677T rs1801133 AA +/+
MTHFR 03 P39P rs2066470 GG -/-
MTHFR A1298C rs1801131 TT -/-

I have tried in the past (without knowing the test results above) 1 mg Methyl-B12 sublingual ones or twice a day. Short time after (30 minutes or so) I got more energy and felt quite better, but after a few hours I developed flulike symptoms with a runny nose and more fatigue which made me stop the supplements after a few days.

Adding to Learner1's good information about Folate - Folic acid has been added to refined flour in an effort to reduce birth defects. But in people with the MTHFR polymorphisms, folic acid clogs the methylation process. You need to avoid Folic acid where possible. In fact, you might consider a one-time dose of Niacin to try to purge the Folic acid. Small dose. Then re-try the 5L-methylcobalabmine. The flu-like symptoms might actually be a sign that your body was adjusting to new levels of B12.

 

[Valentijn]

This SNP has been shown to be more frequent in CFS patients.

No, it hasn't.

 

[Learner1]

No, it hasn't.

http://mthfrliving.com/health-conditions/chronic-fatigue-syndrome-me-cfs/

 

[alicec]

http://mthfrliving.com/health-conditions/chronic-fatigue-syndrome-me-cfs/

The study you are relying on can't determine anything. Setting aside the absence of any statistical analysis to determine if observed differences have any significance, a group of 88 is far too small to determine any meaningful association of a SNP with a health condition.

Many 1000's are needed along with robust statistical analysis to demonstrate real significance.

Here is a discussion of some of the relevant issues.

 

[Valentijn]

http://mthfrliving.com/health-conditions/chronic-fatigue-syndrome-me-cfs/

That study wasn't published, and for good reason. It has serious methodological problems, mostly involving a lack of description of the methodology. It is never stated how patients were selected (certainly not randomly), and they never say if the testing for MTHFR mutations came before or after selection. There's also a lack of actual controls being tested, which is important since prevalence of the SNPs varies a lot in different ethnic groups. And there's no description of how a statistical analysis was done, if it was done at all. The word "significant" is thrown around a lot, but without "statistical" in front of it, it has no specific mathematical meaning.

I'm also rather wary of the author's apparent lack of understanding regarding what "compound heterozygous" means. Being heterozygous for two mutations on the same gene is not the same thing - typically half of such people will be compound heterozygous, and the other half will not be. The studies he cited for compound heterozygous figures are likely truly compound heterozygous results, so can't be compared to his double heterozygous mutations. This is quite important because having both heterozygous mutations from the same parent, versus one from each parent, has far less impact. Basically it would be exactly the same as being only heterozygous for C677T.

Finally, the document reads more like a promotional advertisement than a real research paper. As a result, I think we simply can't trust any data given.

 

[alicec]

I have tried in the past (without knowing the test results above) 1 mg Methyl-B12 sublingual ones or twice a day. Short time after (30 minutes or so) I got more energy and felt quite better, but after a few hours I developed flulike symptoms with a runny nose and more fatigue which made me stop the supplements after a few days

That sounds very like signs of folate deficiency induced by relatively large doses of B12.

Many people on PR report these or other problems soon after introducing B12.

It has little to do with SNPs though possibly your MTHFR C677T +/+ could be making a contribution since your folate production is slowed.

It is simply that B12 and folate work together and suddenly adding a highish dose of one may increase the demand for the other beyond what your body can supply.

You would be better off starting with a smaller dose of B12 and trying the addition of small doses of methylfolate.

Many other metabolic pathways spin off from the methylation cycle so stimulating the cycle can increase demand for several other nutrients also.

Here is a post about things to consider when introducing these active vitamins. It was written for a very sensitive person - you might not need to be so cautious but even so start low and increase slowly is always a good idea.

 

[Markus83]

Ok, guys, thanks for your replies. If my worsening of symptoms is because my systems start to "work" again, that would be just fine. But I'm afraid that the opposite could be true: that I'm just feeding bugs.

Most bacteria need iron for their metabolism, except Borrelia, which need manganese instead. If there is a long term chronic infection the body might get depleted of iron (it's a strategy to fight of bacteria). If you take iron because of your deficiency, you might "feed on" the bugs. I don't know if this might also be true for B12 and MTHF (I don't know very much about bacterial metabolism).

There is a class of antibiotics which block folic acid synthesis. So I guess at least some bacterias need it for their metabolism. Maybe I feed them on with MTHF, and perhaps with M-B12. What do you think about my hypothesis? I'm just afraid that I do more harm than anything else with the supplements. Years ago, I gave myself shots with hydroxycobalamin, which worsened my situation significantly for months.

 

[Learner1]

Ok, guys, thanks for your replies. If my worsening of symptoms is because my systems start to "work" again, that would be just fine. But I'm afraid that the opposite could be true: that I'm just feeding bugs.

Most bacteria need iron for their metabolism, except Borrelia, which need manganese instead. If there is a long term chronic infection the body might get depleted of iron (it's a strategy to fight of bacteria). If you take iron because of your deficiency, you might "feed on" the bugs. I don't know if this might also be true for B12 and MTHF (I don't know very much about bacterial metabolism).

There is a class of antibiotics which block folic acid synthesis. So I guess at least some bacterias need it for their metabolism. Maybe I feed them on with MTHF, and perhaps with M-B12. What do you think about my hypothesis? I'm just afraid that I do more harm than anything else with the supplements. Years ago, I gave myself shots with hydroxycobalamin, which worsened my situation significantly for months.

Yes, you may be feeding the bugs. But your body still needs folate and B12 to do its job.
They are used in a biochemical pathway that supports:

• Cellular respiration
  
• Energy production, making ATP
  
• Cellular detoxification
• Immune function
• Maintaining and replicating DNA
• Neurotransmitter production
• Controlling inflammation
• Sustaining the negative voltage of a cell

Not having enough folate and B12 can contribute to many conditions, including:

• Cardiovascular disease
• Cancer
  
• Diabetes
• Neurological conditions
• Autism and related disorders
• Chronic Fatigue Syndrome
  
• Alzheimer’s
  
• Miscarriages, infertility, and other problems in pregnancy
• Allergies, immune system, and digestive problems
• Mood and psychiatric disorders

You may need to take more of these nutrients to make sure you get enough for your body.

And you may find certain forms of B12 work better for you than others. I take adenosyl and methyl B12 orally and do injections of methylB12 3x a week, and hydrixoB12 every 10 days, along with a B complex and extra folate. You need to make sure you're getting all the cofactors, Be, B6, magnesium, some B3 and maybe potassium, plus B1, molybdenum, and taurine support the transsulfuration pathway, which is the next biochemical step.

Good lab testing is helpful in sorting this out.

 

[Learner1]

I'm also rather wary of the author's apparent lack of understanding regarding what "compound heterozygous" means. Being heterozygous for two mutations on the same gene is not the same thing - typically half of such people will be compound heterozygous, and the other half will not be. The studies he cited for compound heterozygous figures are likely truly compound heterozygous results, so can't be compared to his double heterozygous mutations. This is quite important because having both heterozygous mutations from the same parent, versus one from each parent, has far less impact. Basically it would be exactly the same as being only heterozygous for C677T.

It would be really nice if the government of (where is it you live and how much are they investing in solving ME/CFS?) would invest in the proper studies with the proper number of test subjects with all the proper controls and it was all tied up with a nice bow in a top peer reviewed journal. Maybe if all if these topics were investigated and published to that degree, we'd all be well. Seriously, that's not likely to happen for decades, if ever.

As for the definition of compound heterozygous, he seems to be using it in the same way as here, which is one of many peer-reviewed journal articles on the HFE gene,
"Compound heterozygous C282Y/Q283P and Q283P/H63D mutations in haemochromatosis":

http://onlinelibrary.wiley.com/doi/10.1111/bjh.13417/full

 

[Valentijn]

It would be really nice if the government of (where is it you live and how much are they investing in solving ME/CFS?) would invest in the proper studies with the proper number of test subjects with all the proper controls and it was all tied up with a nice bow in a top peer reviewed journal.

I'm American, thanks for asking. And where I live is not a valid basis to imply that I don't have the status necessary to disagree with crap studies being conducted elsewhere.

As for the definition of compound heterozygous, he seems to be using it in the same way as here ...

He's not using it in the appropriate way, which is evidenced by his failure to subgroup the people with two heterozygous mutations as either compound heterozygous or not.

 

[Mary]

@Markus83 - in addition to folate (not folic acid) as others have suggested, you may very likely need more potassium as well. A major symptom of low potassium is fatigue. Starting B12 and/or folate can induce a potassium deficiency because they cause cells to divide more rapidly, increasing the need for potassium, thus inducing a deficiency. I experienced severe fatigue a few days after starting methylfolate; fortunately I had read about the potassium issue and was able to resolve it (and keep taking the folate - I'd already been taking methylB12 for years, with little results) by titrating up to 1000 mg of potassium, in divided doses, over a couple of days

A simple way to find out if you are dealing with low potassium is to drink low-sodium V8 or tomato juice, which is high in potassium; I'd drink a couple of glasses and see if there is any improvement. And if there is, you can decide whether to add a potassium supplement, after reading about it. Many on this board have to take extra potassium because it's been difficult if not impossible to get enough in food alone. A banana or two just doesn't cut it for most of us. People with ME/CFS tend to have trouble with low intracellular potassium, despite adequate blood levels: http://forums.phoenixrising.me/inde...ded-in-methylation-treatmt.18670/#post-291422

I'd also suggest reading some of Freddd's posts about methylation: http://forums.phoenixrising.me/index.php?threads/b-12-the-hidden-story.142/

 

[alicec]

As for the definition of compound heterozygous, he seems to be using it in the same way as here, which is one of many peer-reviewed journal articles on the HFE gene,
"Compound heterozygous C282Y/Q283P and Q283P/H63D mutations in haemochromatosis":

http://onlinelibrary.wiley.com/doi/10.1111/bjh.13417/full

If you look a bit further in that article you will see that the authors are not using compound heterozygous to mean any combination of two heterozygous SNPs, which the authors of the folate study appear to be doing.

Our results indicate the association between the C282Y/Q283P compound heterozygous genotype in trans and the development of iron overload. A C282Y/Q283P compound heterozygous mutation in cis will not result in haemochromatosis, because a wild-type HFE gene can still be expressed.

In other words, iron overload arises only when the SNPs are on opposite strands.

Unlike with 23andme which doesn't report which SNP comes from which strand, when you are genetically tested for haemachromatosis and are reported to be compound heterozygous, you actually are.

 

[Learner1]

If you look a bit further in that article you will see that the authors are not using compound heterozygous to mean any combination of two heterozygous SNPs, which the authors of the folate study appear to be doing.



In other words, iron overload arises only when the SNPs are on opposite strands.

Unlike with 23andme which doesn't report which SNP comes from which strand, when you are genetically tested for haemachromatosis and are reported to be compound heterozygous, you actually are.

Compound heterozygosity in medical genetics is the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state. That is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations)

 

[Valentijn]

Compound heterozygosity in medical genetics is the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state. That is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations)

They have to be on opposite strands. This is how recessive diseases turn up in the children of healthy parents who each have a different heterozygous mutation. If both mutations were from the same parent, but still caused disease somehow, the recessive disease would actually be dominant, and would just need one of the mutations from one parent.

Many genes will function pretty normally if only one strand carries pathogenic mutations. So you can have 50 pathogenic heterozygous mutations for a recessive disease on the same strand, and it will be no worse than having only the single worst of those mutations, because either way the healthy strand can carry on doing all of the work with no problems. When it's compound heterozygous, however, both strands are largely or completely dysfunctional, and little or no functional gene product is made.

This is basic genetics.

 

[Learner1]

https://www.healthrising.org/blog/2014/08/12/folic-acid-controversy-mthfr-chronic-fatigue-syndrome/

 

[Valentijn]

https://www.healthrising.org/blog/2014/08/12/folic-acid-controversy-mthfr-chronic-fatigue-syndrome/

Does it say something you think is relevant?

 

[Learner1]

@Valentijn we have crossed paths on methylation genetics before and you seem to be devoted to proving that it's utter nonsense.

I first learned about methyl genetics here on Phoenix Rising 9 years ago, when dealing with a family members serious mental illness which numerous MDs were unable to help.

What I learned from richvank, fredd and others led me to do the 23andme test on my family, which was an excellent investment.

Following the theories of the genes, we and our doctors have been able to tackle a number of health problems and vastly improve them. The family member with the mental illness is well and earning a PhD in molecular and biochemical nutuition thanks to the success of these strategies. I've also attended Ben Lynch's conferences and learned a great deal from the case studies shared by doctors using knowledge of methylation genetics to help/cure their patients.

Martin Pall has written extensively on folate, B12, and vitamin C and peroxynitrites. Maes and Morris have published several papers on oxidative and nitrosative stress, some of which is due to peroxynitrites, in CFS.

Peroxynitrites are related to a lack of folate, and people with MTHFR and other SNPs are more likely to have this situation.

There is also a great deal of research on methylation and the one carbon metabolism which is essential for many, many essential functions in our body, including the immune system.

Ideally, if one knows which SNPs one has, it gives one an idea of what one's biochemistry is prone to. Of course, environmental factors and the expression of other genes may cause the system to work differently.

This is why taking supplements based solely on SNPs is a bad idea. A Genova Diagnostics NutrEval FMV with Amino Acids is the best test out there to sort out what's going on and supplement accordingly, as properly working methylation is essential to health.

Responding to one or more MTHFR SNPs with folate won't necessarily cure CFS, but not having enough folate is a barrier to getting well as folate drives so many things in our bodies.

In fact, in my Sigma Aldrich biochemical pathways chart I have on my wall, folate is a large brown bubble - the only single large item represented in such a fashion due to its importance, with more arrows relating to it than anything else on the very complex chart. It was clear to me that not having adequate folate would be disastrous.

Drs. Craig and Anderson seem to think folate is important in CFS, too.

We are trying to get well here and exchange information to help us cure our ME/CFS, which is complex, with many contributing factors in most cases.

With your revelation about your primary mitochondrial disease, maybe helping those of us with ME/CFS isn't your goal anymore.

All I want to do is get well and exchange info with people that share that goal. The topic on this thread is "MTHFR defect and the immune system" so maybe that's what we should be discussing, eh?

 

[Valentijn]

With your revelation about your primary mitochondrial disease, maybe helping those of us with ME/CFS isn't your goal anymore.

All I want to do is get well and exchange info with people that share that goal.

You've been given some basic information from several people regarding how SNPs and genetics work. This is relevant regarding the impact of those SNPs, in this case specifically the common MTHFR mutations. And whatever my diagnosis might ultimately be, it won't change these basic tenets of genetics.

I'm not sure why you are objecting to this information. And I have every intention of correcting misinformation that you or others attempt to spread.