MTHFR+ and COMT

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.

Methylation_Pathway1

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.

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About Nancy Mullan, MD

Some people call Dr. Nancy Mullan the MTHFR genetic medicine expert. Dr. Mullan works with people who are struggling with chronic disease or other significant illness, who are willing to use diet and genetics-based nutritional supplementation, and who want to increase wellbeing and energy, enhance immunity, lift mood, fine-tune genetic function, and get their lives back. Dr. Mullan has studied at a number of exceptional institutions: the University of Pennsylvania, Tufts University School of Medicine, and the University of Chicago Hospitals and Clinics. She excels at integrating the results of biochemical and genetic testing into sustained clinical improvement for you. She has succeeded with patients who confounded the specialists at Massachusetts General Hospital, the Mayo Clinic, the Cleveland Clinic, Stanford, and many well-known integrative medical doctors. When recommending her, her patients say, “This is the woman you need to talk to. She really knows how to handle tough clinical problems.” Dr. Mullan's specialty areas are MTHFR+, methylation genetics, and genetics-based nutritional supplementation. Within this context, she most often works with Chronic Fatigue Syndrome, Lyme Disease, Psychiatric Disorders, Autism Spectrum Disorders, Women’s Health Issues, Thyroid Disorder, Gastrointestinal Disorder, and Heavy Metal Toxicity.
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