Why am I so interested in folate methylation? It’s because it is now known that approximately 50 percent of us have trouble metabolizing folate and B vitamins from the foods we eat and we don’t even know it.
I am referring to the MTHFR (Methyl-Tetra-Hydro-Folate-Reductase) gene abnormality known to be associated with many chronic health conditions. In these next two articles let me explain why it is so important to understand folate metabolism and what to do if you are found to have the MTHFR gene polymorphism.
A case study of abnormal folate methylation
Ryan is a 24 year-old man who has suffered with fibromyalgia for several years. He recently came to see me in the office as a new patient. I discovered he is well-studied on folate methylation and its effects on health. That’s because a few years ago he accidently discovered that when he eats foods known to be high in folate, his fibromyalgia pains worsened immensely. He explained to me that his folate methylation pathway is unusual and that the antibiotic Septra (a sulfa drug) stops his fibromyalgia symptoms! Oddly enough, even though we know that sulfa antibiotics kill bacteria by blocking their folate synthesis, for Ryan, Septra affected his folate methylation so that he could have energy and get out of pain. He was relieved when I agreed to prescribe it for him on an ongoing basis.
Then he reminded me of the famous MTHFR gene abnormality that I’ll explain below. And because of Ryan, today I am learning more about this topic and writing this article.
What is folate and why is methylation so crucial?
Folate is an important vitamin of the B complex group of vitamins. We get it from our diet every day. It is required to make DNA (genetic code) and it also drives methylation reactions in all your cells. Methylation is a term in biochemistry that refers to the donation of a methyl group (carbon atom with 3 hydrogen atoms attached, or “CH3”) to important enzymes in your body. This biochemical step is so crucial that without it you’ll have difficulty repairing DNA, detoxifying your blood, manufacturing neurotransmitters, and recycling vital molecules such as methionine (SAMe) [1] [2] as with what happens with a malfunctioning MTHFR enzyme. It turns out that insufficient methylation contributes to a host of illnesses from cognitive impairment and disorders of mood and behavior [3] to immune system dysfunction, cervical cancer and lymphoma, [4] heart disease and much more. [5]
Now consider your own genetic code. You have 23 pairs of chromosomes, each comprised of tightly wound strands of DNA (deoxyribonucleic acid) found within the nuclei of your body’s cells. Genetic variants in your chromosomes cause you to experience disease. Let me explain more about a common and important genetic variant in the MTHFR gene that controls key enzymes and folate metabolism.
The MTHFR gene SNP
Genetic variation (abnormality) of just one amino acid in the gene sequence of amino acids is known as a “single nucleotide polymorphism” (SNP). If you inherit SNP from your father or your mother then you are heterozygous for that gene SNP. And if you get the gene SNP from both of your parents, you are homozygous for that gene SNP
In the case of the very common MTHFR gene SNP, key important enzymes stop working. That’s because this gene controls the activity of the enzyme, methylenetetrahydrofolate reductase (MTHFR), which is a vital enzyme that activates and regulates other enzymes such as glutathione, your body’s chief antioxidant and detoxifier. It also controls folate metabolism and creates elevated homocysteine concentrations when it is not working.
Now you may be wondering, how common is the MTHFR gene SNP (abnormality) and what does all this mean for you?
The most extensively studied MTHFR gene SNP is the “C677T” variant. It is estimated that 50% of us are heterozygous (inherited one copy) while up to 25% of us are homozygous (inherited two copies) of C677T. The prevalence of having one copy (heterozygous) of the MTHFR gene SNP in Italians, Hispanics, and Asians is up to 20% greater than in Caucasians and Africans.
If you have two copies of C677T then you will have at least a 50-60% reduced MTHFR activity. For comparison, 0-20% MTHFR enzyme activity is considered severe, and can cause early developmental delay, muscle strength and walking dysfunction, seizures, and schizophrenia. [6]
The MTHFR gene SNP contributes to these illnesses
Here are the predominant conditions associated with the MTHFR gene SNP.
- Cancer (cervical cancer, lymphoma)
- Heart disease, stroke and vascular health [7] [8]
- Cognitive function (dementia) and mood disorders (depression)
- Low sperm count in men [9]
- Schizophrenia and bipolar disorder [10]
- Attention deficit hyperactivity disorder, autism spectrum disorder [11]
- Birth defects (neural tube defects), miscarriage [12]
Moreover, the MTHFR gene SNP contributes to a wider range of chronic disease that has not yet been scientifically studied, based on what we know about its ill effects on folate methylation. Consider that the MTHFR gene SNP is known cause the following (which may give you symptoms but no “diagnosis”):
- Can’t break down toxins or heavy metals well, leading to elevated iron (hemochromatosis), copper, lead, or mercury
- Reduced glutathione, the chief antioxidant and detoxifier of your cells.
- Less SAMe (amino acid nutrient) production increases depression risk
- Chemical sensitivity
- Irritable bowel symptoms
- Migraines
- High levels of inactive folate/B12 levels in your blood because you cannot convert inactive to active forms. These inactive forms block the metabolically active forms.
- Many symptoms not listed here have been correlated with MTHFR gene SNP but may not yet be found in the scientific literature: http://mthfr.net/mthfr-mutations-and-the-conditions-they-cause/2011/09/07/
The good news is that the Human Genome Project has given birth to all this science called “nutrigenomics”—how nutrients and nutritional status affect the genetic expression (health or diseases).
In my next article I’ll discuss how nutritional status, environment, genotype, and race/ethnicity affect the expression of this gene SNP. I’ll also share with you how to test for it and the best ways to treat it if you are found to have it.
To feeling good and staying on top of your health,
Michael Cutler, M.D.
Easy Health Options
[1] Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):862-77. Review. PMID: 10791559.
[2] Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20. Review. PMID: 24091066.
[3] Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26. Review. PMID: 18950248.
[4] Zhu XL, Liu ZZ, et al. Association between the MTHFR A1298C polymorphism and risk of cancer: evidence from 265 case-control studies. Mol Genet Genomics. 2015 Jul 9.
[5] Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20.
[6] Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002 Apr;75(4):616-58. Review. PMID: 11916749.
[7] Reilly R, McNulty H, Pentieva K, et al. MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins? Proc Nutr Soc. 2014 Feb;73(1):47-56. PMID: 24131523
[8] Sánchez-Marín B, Grasa JM. [Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in ischemic vascular disease]. Rev Neurol. 2006 Nov 16-30;43(10):630-6. Review. Spanish. PMID: 17099857.
[9] http://www.ncbi.nlm.nih.gov/pubmed/26196053
[10] Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20. PMID: 24091066
[11] Neggers YH. Increasing prevalence, changes in diagnostic criteria, and nutritional risk factors for autism spectrum disorders. ISRN Nutr. 2014 Feb 13;2014:514026. PMID: 24967269
[12] Reilly R, McNulty H, Pentieva K, et al. MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins? Proc Nutr Soc. 2014 Feb;73(1):47-56. PMID: 24131523
