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Lessons from ME/CFS: Finding Meaning in the Suffering
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Simpler methylation analogy for nonscientists

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by greenshots, Apr 3, 2013.

  1. greenshots

    greenshots Senior Member

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    Wow, I have to say, this is the best simple analogy I have seen yet on methylation and it comes from Dr.Mullan. She may not be as knowledgeable about how to apply this medicine as I hoped and most of us need but she did a decent job breaking it down!

    See a picture of methylation pathway to give a simpler visual (by A. Ward-Hauge)
    http://autismnti.com/images/Methylation_12-11-11.pdf

    More detailed but simpler methylation visual (by A. Ward-Hauge)
    http://autismnti.com/images/Technical_Methylation_12-6-11.pdf


    See her car analogy paragraph #8

    MTHFR+ AND COMT

    written by Dr. Nancy Mullan

    Genetics has generated a giant breakthrough in medical therapeutics. Knowing about genetics is making sense of conditions not formerly understood or thought amenable to treatment. Not only are there genetic mutations, significant abnormalities in the formation of the gene itself, but there are other issues like Single Nucleotide Polymorphisms, or SNPs, that may impact the function of the gene.

    SNPs involve a change in a single chemical base within the structure of a gene. They may or may not have an impact. Depending upon the nature and/or the location of the SNP in the particular gene, the function of the molecule for which the gene encodes can be profoundly impacted.

    Genes encode for proteins. Some important proteins for which genes encode are enzymes. Enzymes move biochemical molecules along their pathways in your body. If a gene has a SNP in an important location, it can make the activity of the enzyme for which it encodes either increase or decrease. Most often, it is a decrease. This is particularly important when the SNP is located in a biochemical pathway that has critical end products. One such biochemical pathway is the Methylation Pathway as described by Dr Amy Yasko, and one such important end product is the methyl group.

    A methyl group is formed from four small atoms, one carbon and three hydrogen atoms. It is similar in size to the water molecule, H2O. Water is a key to life, and methyl groups are critical for health and well being. Methyl groups are symbolized as CH3. C is the symbol for carbon, the same molecule that is in coal or diamonds. H is the symbol for hydrogen, the same as in water.

    Methyl groups are part of a critical regulatory system in your body. Without them, you cannot keep DNA that should not be expressing quiet. Your immune system will not function optimally. You cannot silence viruses, and many physical sequelae can manifest.

    The methylation pathway in figure 1 is the central biochemical pathway in your body for making methyl groups. This pathway is particularly amenable to screening for genetic weakness. Once the precise areas of genetic weakness have been identified, it is possible to target appropriate nutritional supplementation to optimize the functioning of these crucial biochemical processes.

    One consequence of genetic weaknesses (SNPs) in this pathway is increased risk factors for a number of serious health conditions. Defects in the ability to make methyl groups lay the appropriate groundwork for the further assault of environmental and infectious agents resulting in a wide range of conditions including diabetes, cardiovascular disease, thyroid dysfunction, neurological inflammation, chronic viral infection, neurotransmitter imbalances, atherosclerosis, cancer, aging, schizophrenia, decreased repair of tissue damage, improper immune function, neural tube defects, Down’s Syndrome, Multiple Sclerosis, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, and autism.

    Methyl groups are very basic molecules that serve integral functions for body wide genetic performance. They are moved around in the body to turn on or off genes. They serve as your own personal gene mechanic so to speak, helping to repair and direct genetic functions in your body. If you think about your body as being a car, then you have just one car that you need to maintain over the course of your entire life. You maintain it with the help of your own personal gene mechanic. The longer you have that car the more outdated it becomes. Your car-body will accumulate rust and rot, tires will wear out, and the engine may need an overhaul.

    Alternatively, the problems may be simpler, such as the need for more wiper fluid or simply to keep it filled with gas and to change the oil. In any case, your personal gene mechanic ensures that your car keeps running, that it can stay on the road…in this case on the road to health.

    If however your gene mechanic is unable to function, then all of these issues will start to accumulate. The rust may get so bad that car components fall off, like your muffler. The tires may become so worn that it is impossible to navigate a turn without the fear of blowing one. In the absence of your gene mechanic function, you have no way to repair all of the large and small problems that arise with your car, to the point at which your car may no longer function.

    This analogy may show you why the proper functioning of the pathway that makes methyl groups is so important. Methyl groups are critical to the repair and regulation of the function of all the genes in your body, both your own and the genes of other organisms inside you, such as bacterial and viral genes. In addition to the editing of genes, methyl groups also play direct roles in your biochemical function. The addition or removal of a methyl group from another molecule can profoundly change the function of that molecule. Methyl groups are thus critical for your overall health.

    The enzyme called methylene tetrahydrofolate reductase (the MTHFR enzyme) is made by the gene also called methylene tetrahydrofolate reductase (the MTHFR gene). MTHFR is an important enzyme in the methylation pathway. The MTHFR gene has three locations that have an impact on this pathway: MTHFR C677T, MTHFR A1298C and MTHFR 3. While there are several other gene sites in the methylation pathway where blocks can occur as a result of genetic weaknesses, MTHFR C677T is the one we are focusing on now.

    An MTHFR C677T gene that is + or ++ induces a down regulation of the MTHFR enzyme for which it encodes. As a result, the activity of the methylation pathway is impaired. It moves more slowly and makes fewer methyl groups. MTHFR 3+ or ++ acts the same as MTHFR C677T+ or ++, and seems to be the more profound down regulation. MTHFR 3+ or ++ is a more symptomatic SNP than MTHFR C677T+ or ++. Fortunately, it is also more rare.

    MTHFR C677T+/++ is a widely discussed SNP. A large percentage of the population has one or two genes impacted. It turns 5,10 methylene tetrahydrofolate into 5-methyl tetrahydrofolate (5-MTHF). 5-MTHF gives away its methyl group in a critical methylation reaction. It donates the methyl group for the reaction that turns homocysteine back into methionine. Methionine is an important amino acid that starts the whole methylation pathway running. This reaction both bolsters the supply of methionine and supports the continued regeneration of methyl groups.

    Patients with the MTHFR C677T SNP have more physical illnesses than patients without it. It has come somewhat into the mainstream, which is good. Doctors are jumping on the bandwagon, testing for SNPs in the MTHFR gene and treating them when they find them. This is also good. However, if your doctor tests only one gene, the MTHFR gene for example, finds a SNP at MTHFR C677T, and immediately recommends methyl donors like 5-methylTHF and methylB12, this can mean trouble for you. These methyl donors may cause symptoms because they start biochemical pathways moving, and in high doses, they may cause a lot of symptoms.

    At first, it may seem logical to give these because 5-methylTHF is the substrate that the person who is MTHFR+ has trouble making, and methyl B12 supports the regeneration of methyl groups as well as supplies them directly. But there are other genes and conditions that must be taken into consideration. The gene that encodes for catechol-o-methyl transferase, or the COMT gene, must be considered in the decision about what to do for MTHFR+.

    The COMT gene encodes for the COMT enzyme. COMT is the enzyme that inactivates dopamine and nor-epinephrine. COMT inactivates these neurotransmitters by adding a methyl group to them. When you are COMT ++, the enzyme is less active, so it uses fewer methyl groups. When you are COMT --, you inactivate dopamine and nor-epinephrine at a steady, regular rate. As such, you go through methyl groups much faster. This is partly why a COMT -- person can handle methyl B12 better than those who are COMT ++. But dopamine feeds back to inhibit itself. So those who are COMT ++ and don’t inactivate dopamine in a regular, even fashion may have dopamine building up, which then feeds back and inhibits itself. This can cause dopamine swings.

    There are other factors that impact dopamine formation and how many methyl groups you may need, such as the status of the vitamin D receptor gene. When the vitamin D receptor gene is down regulated, you make less dopamine, therefore you have less to deactivate. Other circumstances may be involved also. If your clinician is ordering a test for just one gene, it may be OK if your genetics are reasonable and you do not have any environmental issues or infectious stressors. But if you are chronically ill or autistic, the risk of a downturn is real. You need appropriate methyl donor support for your genetic make-up, not more and not less.

    Chronically ill patients must first get the BHMT pathway moving. This is the pathway that Dr Yasko calls ‘the short cut pathway’, the pathway that goes directly from homocysteine to methionine and bypasses any problems with what she calls ‘the long route’, the route that uses 5-methylTHF, methylB12 and the MTR and MTRR enzymes.

    This is just not simple…. You need to get lithium in balance before attempting to push the long route with 5-methylTHF and methylB12, or, to quote Dr Yasko, “…you really risk having people crash in a big way.” Our attention was called to this by having really chronically ill MTHFR+ adults come to us whose clinicians were trying to push detox and fill in the substrates in the long route way too much, way too soon.

    Doctors are used to the paradigm in which one gene is responsible for a disease. This is the way genetics has been used historically. Dr Yasko has given us the first genetic test to examine a whole biochemical pathway that impacts on a particular function, the methylation function. So I give her the last word here:

    Single mutations, or ‘biomarkers’ as they are called, are generally perceived to be indicators for specific health issues. A single genetic mutation has been found to be responsible for sickle cell anemia, for example. And cystic fibrosis has also been traced to one gene. However, for a number of health conditions, it may be necessary to consider an entire interconnected biochemical pathway as the biomarker for underlying genetic susceptibility. This requires expanding the view of a biomarker beyond the restriction of a single mutation or a single gene to all of those mutations or SNPs that impact these multiple pathways of interconnected function
    Gestalt, kurt, ninauae and 1 other person like this.
  2. RosieBee

    RosieBee

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    Thanks for posting this Angela. Nice and straightforward. Does she have anything to say about CBS snps?
  3. greenshots

    greenshots Senior Member

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    RosieBee and ninauae like this.
  4. Lotus97

    Lotus97 Senior Member

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    What do you mean by "get lithium in balance"? Do you need to get your lithium levels tested?
  5. greenshots

    greenshots Senior Member

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    It means if you have the following defects you will need to use lithium orotate as caps, lithia water, and if you are really sick and have excitotoxic signs her calming spray works for both. My doc tested my blood lithium thru ins. But not all will pay so hair metals or UTM/UTEE test at DDI.

    MTR A2756G (i went by memory here so it could be off. Its the first MTR on yasko MTR/MTRR panel.
    MTRR 11
    COMT ++ or COMT +\-

    The theory is that if you don't have what you need to transport, dumping more B12 into the system will possibly make you sicker cuz you can't use it. I wonder if this was behind alotta the functional B12 deficiencies Rich saw.
  6. Lynn_M

    Lynn_M Senior Member

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    Angela,
    Are you saying a person needs lithium if they have any of the three defects you list? One is sufficient, you don't need to have all three?

    I haven't seen MTRR 11 on the list of SNPs that Dr. Yasko tests for. Does it go by a different name? Do you have the rs number for it?

    Lynn
  7. Lotus97

    Lotus97 Senior Member

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    If COMT ++ or COMT +\- have problems with too much methyl donors, why do they need more B12? Or does just "dumping more B12 into the system" still increase methylation and the problem is that B12 is not going to the right places? Also, what about the people who say they have B12 deficiency symptoms such as neuropathy? Could their problem also be due to B12 transport issues?
  8. greenshots

    greenshots Senior Member

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    The COMT mention above was in regards to lithium loss specifically rather then B12 need. The COMT region also impacts lithium production thru thioredoxin.

    I think transport issues have alott of impact. My B12 levels used to be very high but I apparently wasn't using it. When I got my methylation going along with lithium orotate, my B12 levels normalized.
    Crux, Philla and Lotus97 like this.
  9. sweetlily

    sweetlily

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    Did you have detox or other symptoms when you started using the lithium? how much did you start with? i have the mtr A 2756G +/+ and two COMT +/-, and have been finding it hard to increase my low b12 (via mma in urine), high b12 in serum. Seems like I get strange rushing headaches and can't pinpoint cause yet... could it be the lithium that was suggested to me? I was taking between 5 and 10 mg a day.
  10. greenshots

    greenshots Senior Member

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    I did the thing you shouldn't do and started several things at once so I really didn't know if lithium was the problem or the methyl b12 and other stuff was causing problems. I've heard some people say that because lithium helps get b12 where it needs to go that it could cause detox but I'm not sure in my case.
  11. sweetlily

    sweetlily

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    Well, I have been saying that very thing all week.... why did i do a whole bunch of things at once? Learned that lesson the hard way! I hear ya... well i went off lithium today, so i've been "walking down" off things one by one in reverse. Next time I'll do it the smart way. I am most curious about the lithium though, please do report what you find out re the lithium. Thanks, I will too.

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