Over the past decade, "MTHFR" has undoubtedly become a buzz phrase, capturing the attention of many. What is MTHFR, and how is it relevant to you? MTHFR is an acronym for a regulatory enzyme involved in folate metabolism, DNA replication, and DNA and protein methylation. Variations in the gene that codes for this enzymatic protein are common, affecting 30-60% of all people. For some, the downstream effects of these mutations can increase the risk of chronic health disease.  

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What is the MTHFR Gene?

Methylenetetrahydrofolate reductase (MTHFR) is a fundamental regulatory enzyme in folate and homocysteine metabolism. This enzyme catalyzes an essential step in the methylation cycle, a fundamental biochemical process that regulates numerous physiological functions within the human body. The MTHFR gene encodes the MTHFR enzyme, which is a protein responsible for converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF), a crucial step in the metabolism of folate. 

Why is this important? First, folate is required for DNA synthesis. Second, 5-MTHF is a necessary precursor for synthesizing S-adenosylmethionine (SAMe), considered the universal methyl donor. Methylation refers to the biochemical addition of a methyl group (CH3) to a molecule. It is a ubiquitous biochemical process influencing gene expression, protein function, cellular signaling, and detoxification. (5, 34) 

MTHFR gene mutations, to be discussed in more detail below, cause MTHFR to work less efficiently. When there are insufficient levels of activated folate (5-MTHF) in circulation, methylation slows down and impairs the body's ability to synthesize amino acids, antioxidants, neurotransmitters, and other vital molecules. Therefore, MTHFR mutations are associated with alterations in DNA production, neurotransmitter synthesis, hormone metabolism, and detoxification. Dysregulation of the MTHFR gene has been associated with hyperhomocysteinemia, cardiovascular disease, neural tube defects, and impaired cognitive function (17). (22)

MTHFR Gene Mutation: Basics and Symptoms

Gene alleles and mutations are concepts in genetics that help provide insight into the variations within the DNA code of individuals. An allele is one of the alternative forms of a gene occupying a specific location, or locus, on a chromosome. Humans inherit two alleles for each gene, one from each parent. Alleles can be identical (homozygous) or different (heterozygous). The combination of alleles determines an individual's genotype, which influences their observable characteristics. (2) 

Mutations, or polymorphisms, represent alterations in the DNA sequence of a gene. These changes can occur through various mechanisms, including errors during DNA replication, exposure to environmental factors, or as a result of spontaneous genetic events. Mutations can be classified into different types, such as insertions (addition), deletions (removal), or substitutions (replacement) of genetic nucleotides. (12) 

Two primary genetic variations of the MTHFR gene have been identified. MTHFR polymorphisms are associated with altered MTHFR enzyme function and folate metabolism. The first is the C677T mutation, in which a cytosine (C) is replaced by a thymine (T) nucleotide at position 677 of the MTFHR gene, resulting in an amino acid change (alanine replaced by valine) in the MTHFR protein structure. This variation is relatively common; in the United States, 25% of Hispanics and 10-15% of Caucasians have two copies of C677T. Individuals with homozygous mutations (C677TT) exhibit a 30% MTHFR enzyme function, while those with heterozygous mutations (C677CT) demonstrate 65% enzyme activity. (3) 

The second common MTHFR polymorphism is A1298C, in which an adenine (A) is replaced by a cytosine (C) nucleotide at position 1298 of the MTHFR gene, resulting in an amino acid change (glutamate is replaced by alanine) in MTHFR's structure. The MTHFR 1298C polymorphism is present in about 25% of the global population. Heterozygous (A1298AC) and homozygous (A1298CC) carriers have a reduction of MTHFR activity of 15% and 30%, respectively. (3) 

In the context of the methylation cycle, these polymorphisms are associated with elevated levels of homocysteine (hyperhomocysteinemia) and reduced levels of methylated folate and vitamin B12. While it's important to remember that the clinical significance of these mutations is complex, and their impact can vary among individuals, MTHFR polymorphisms have been linked to increased risk of (18):

• Cardiovascular disease
• Type 2 diabetes
• Alzheimer's disease, dementia, and other cognitive decline
• Parkinson's disease
• Migraines
• Mental health and mood disorders, such as schizophrenia and depression
• Reduced fertility and recurrent miscarriage

MTHFR Symptoms in Children

One of folate's primary roles in the body is DNA synthesis. Ensuring adequate levels during pregnancy and childhood is essential for proper embryonic, fetal, and child growth and development. Disrupted folate metabolism due to MTHFR mutations has specific implications for children. In utero, MTHFR polymorphisms have been associated with an increased risk of neural tube defects, where the spinal cord or brain does not form properly during early development. Additionally, studies have explored links between MTHFR mutations and conditions such as scoliosis, behavior disorders like ADHD, and autism spectrum disorders. While the relationship between MTHFR mutations and these health concerns is complex and multifactorial, the impact on folate metabolism and methylation processes may contribute to the observed associations.

The Importance of MTHFR Testing

The MTHFR test is a genetic blood test that examines the MTHFR gene for C677T and A1298C variants. These mutations may impact an individual's susceptibility to certain health conditions and influence responses to dietary folate and B-vitamin intake.

Individuals who may consider getting the MTHFR test include those with a family history of MTHFR-related health concerns, individuals planning or currently pregnant, and those with a personal or family history of cardiovascular disease. Additionally, individuals experiencing symptoms or conditions associated with altered folate metabolism, such as elevated homocysteine levels, may find the test informative. 

The clinical significance of MTHFR mutations is still an area of active research, and it must be recognized that these mutations' presence doesn't guarantee the development of health issues. Genetic testing is often done in consultation with healthcare professionals or genetic counselors who can interpret the results in the context of an individual's overall health and family history. Test results may provide valuable genetic information to guide personalized healthcare strategies, including tailored interventions such as specific vitamin supplementation to support folate metabolism.

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MTHFR, Folate, and Pregnancy

Folate is vital during pregnancy as an essential vitamin in supporting healthy fetal development. Necessary for DNA synthesis and cell division, folate is particularly critical in the early stages of pregnancy, where it aids in forming the neural tube – the precursor to the baby's brain and spinal cord. Adequate folate levels are associated with a reduced risk of neural tube defects and other birth defects by supporting proper fetal growth and minimizing the risk of complications, such as preterm birth and low birth weight. Folate is equally important for maternal health, helping prevent anemia by supporting red blood cell production. This is why the CDC recommends that all women of reproductive age get 400 mcg of folic acid daily. (11, 23) 

While "folic acid" and "folate" are commonly used interchangeably, there are differences between the two. Folic acid is the synthetic form of the vitamin used in fortified foods and many dietary supplements. After folic acid is consumed, but before it enters the bloodstream, an enzyme called dihydrofolate reductase converts folic acid to tetrahydrofolate (THF). THF must then be methylated into the activated form of folate, 5-MTHF. Due to the slowed methylation pathway in individuals with MTHFR polymorphisms, it is advised to avoid folic acid and opt for methylated folate supplements instead. (10, 18) 

Dietary Considerations: The MTHFR Diet

You've been diagnosed with an MTHFR genetic variation – what's next? Some may suggest that you follow a "MTHFR diet;" however, no specific diet has been shown to be specifically beneficial for those with MTHFR gene variations.

Nevertheless, recognizing that these variations diminish the body's inherent capacity for methylation, there are dietary elements that can alleviate this effect. Methyl donors other than folate include methionine, betaine, and choline. Incorporating foods that are rich in these nutrients can support methylation pathways. Foods rich in methionine include eggs, cod, chicken, beef, pork, milk, and rice. The most common dietary sources of betaine include beets, spinach, and whole grains. Choline-rich foods include liver, shellfish, poultry, eggs, leafy greens, cauliflower, lentils, soybeans, and flax seeds. 

Additionally, as mentioned above, patients with MTHFR variants want to avoid folic acid in fortified foods and dietary supplements. Focus on eating naturally folate-rich foods, which include beef liver, legumes, vegetables (especially dark leafy greens), eggs, dairy products, and grains (34). 

Supplementation Strategies

Dietary supplements also have a role in managing MTHFR mutations, aiming to support folate metabolism and methylation pathways. One key consideration is utilizing specific forms of folate supplements, given that MTHFR mutations can compromise the conversion of folic acid to 5-MTHF. Dietary supplements containing 5-MTHF are available and are the preferred supplemental form of folate for patients with MTHFR gene variations. 

In addition to folate supplementation, other supportive nutrients can contribute to overall methylation support. Vitamin B12 (cobalamin), for instance, is closely linked to folate metabolism and can enhance the effectiveness of folate supplements. Moreover, vitamins B2 (riboflavin) and B6 (pyridoxine) are essential cofactors in the methylation process and may be included in a comprehensive supplementation strategy. (8) 

Omega-3 fatty acids have also shown promise in supporting MTHFR-related concerns. These fatty acids play a protective role in neurodevelopment and cardiovascular health, and their inclusion in a supplement regimen may offer preventive benefits for those at higher risk of cardiovascular disease and neurodegeneration due to elevated homocysteine. (26) 

Beyond MTHFR: Comprehensive Methylation Support

Beyond genetic considerations, lifestyle and environmental factors must be appreciated for their roles in supporting overall methylation processes. Adopting a holistic approach can contribute to optimizing methylation and promoting general well-being.

Regular exercise has been linked to altered methylation patterns, impacting the epigenetic regulation of gene expression and disease risk. Epigenetics, modifications in gene activity that don't involve changes to the underlying DNA sequence, can influence how genes are activated or silenced. The relationship between exercise and DNA methylation is intricate, involving multiple mechanisms. These exercise-induced epigenetic modifications contribute to tissue adaptability, influencing various physiological processes such as muscle function, metabolism, and cardiovascular health. (25, 27) 

Smoking reduces DNA methylation and negatively impacts gene expression in fat tissue, increasing the risk of diabetes and cancer. Research shows these epigenetic changes can be reversed within two years after quitting smoking.

Poor sleep is implicated in DNA methylation changes and increased risk of cardiometabolic and psychiatric diseases (16, 30). Establishing good sleep hygiene is the first step in prioritizing an adequate amount of sound sleep.

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MTHFR Genetic Variations, Testing, & Support Key Takeaways

MTHFR gene mutations can impact folate metabolism, influencing diverse physiological processes related to the methylation cycle. Part of a personalized, preventive healthcare strategy may include identifying and managing MTHFR mutations effectively. To do this, individuals are encouraged to consult healthcare professionals regarding MTHFR genetic testing. Treatment approaches to address MTHFR polymorphisms may include targeted supplementation and lifestyle modifications that provide comprehensive methylation support.