The MTHFR mutation refers to a change in the gene methylenetetrahydrofolate reductase (MTHFR), which is essential for the body’s ability to process folate (vitamin B9) and regulate homocysteine levels. The MTHFR gene plays a critical role in the methylation process, which involves the conversion of homocysteine into methionine, and the conversion of folate into its active form, 5-MTHF (5-methyltetrahydrofolate). Methylation is crucial for DNA synthesis, gene regulation, immune function, neurotransmitter production, and detoxification processes (1).
When a mutation occurs in the MTHFR gene, it can impair the enzyme’s activity, leading to a range of potential health issues. Understanding the implications of this mutation, how it affects the body, and what steps can be taken to mitigate risks is crucial for those who have inherited the mutation. MTHFR acts as a potential cancer biomarker, because the expression of this gene is significantly lower in several tumors (2).
Types of MTHFR Mutations:
The most commonly discussed MTHFR mutation is the 677C→T polymorphism. There are two main genetic variations in this gene:
MTHFR C677T Mutation
Heterozygous (C/T): One copy of the mutation is inherited, leading to a 50% reduction in enzyme activity.
Homozygous (T/T): Both copies of the gene carry the mutation, resulting in about 30% enzyme activity. This form is often associated with the most significant health impacts.
MTHFR A1298C Mutation:
This variant is less studied but can also reduce enzyme activity and may have similar health implications. Some people may inherit both the C677T and A1298C mutations, which could compound the effects on their health.
The 677C→T mutation leads to reduced efficiency in converting folate into 5-MTHF and homocysteine into methionine, leading to the accumulation of homocysteine in the blood, known as hyperhomocysteinemia.
How the MTHFR Mutation Affects Health:
A mutated MTHFR gene can have a wide range of effects on health due to its role in both folate metabolism and homocysteine regulation. Here are the primary implications:
1. Elevated Homocysteine Levels
The MTHFR enzyme is crucial in converting homocysteine into methionine, a process essential for cardiovascular health and proper cellular function. When the MTHFR gene is mutated, the body's ability to process homocysteine is impaired, leading to elevated levels in the blood. High homocysteine levels can have several negative effects:
Cardiovascular Disease: Elevated homocysteine can damage the blood vessels, leading to an increased risk of heart disease, stroke, blood clots, and deep vein thrombosis (DVT).
Neurodegenerative Diseases: High homocysteine levels have been linked to dementia, Alzheimer’s disease, Parkinson's disease, and other neurological issues.
Neurodevelopmental Disorders, including Autism (5,6,7). A significant body of research has established a strong association between the C677T polymorphism and autism.
2. Folate Deficiency
Folate is a vital nutrient for DNA synthesis, cellular repair, and neural tube development during pregnancy. In individuals with an MTHFR mutation, the body has difficulty converting folate into its active form, 5-MTHF, which can lead to:
Birth Defects: In pregnant women, low levels of active folate can increase the risk of neural tube defects in the baby, such as spina bifida.
Depression and Anxiety: Folate deficiency has been linked to mental health issues such as depression, anxiety, and other mood disorders.
Cancer Risk: Impaired methylation due to low folate can increase the risk of developing certain cancers, such as colorectal cancer.
Reduced Detoxification: Folate is essential for proper detoxification. Impaired methylation can hinder the body's ability to detoxify and process environmental toxins.
3. Impaired Methylation
Methylation is crucial for regulating gene expression, maintaining DNA integrity, and controlling inflammation (3). A mutation in the MTHFR gene can hinder these processes, which may lead to:
Increased oxidative stress: Oxidative stress damages cells and tissues and has been implicated in aging, cancer, and other chronic conditions.
Increased risk of autoimmune diseases: Methylation is essential for immune system regulation, and reduced methylation may contribute to autoimmune conditions like rheumatoid arthritis (RA) and multiple sclerosis (MS).
4. Pregnancy Complications
Women with an MTHFR mutation, particularly the homozygous C677T variant, may be at higher risk for pregnancy complications due to impaired folate metabolism and elevated homocysteine levels (4). These complications can include:
Miscarriage
Pre-eclampsia
Placental abruption
Premature birth
Managing MTHFR Mutation:
While MTHFR mutations cannot be "cured," their effects can be managed effectively through targeted dietary changes, supplementation, and lifestyle modifications. Here are some strategies to manage the mutation:
1. Folate Supplementation
People with the MTHFR mutation should avoid synthetic folic acid, which requires the MTHFR enzyme for activation. Instead, they should take methylated folate (5-MTHF), the bioavailable form of folate that bypasses the need for MTHFR enzyme activation. This ensures the body can use folate efficiently.
2. B Vitamins
Vitamin B12 (especially methylcobalamin) and Vitamin B6 are essential for proper methylation and can help lower homocysteine levels.
B-complex vitamins: These vitamins work synergistically to support the methylation process and overall metabolic health.
3. Dietary Adjustments
Leafy greens and other folate-rich foods (e.g., spinach, kale, broccoli, legumes) are important sources of natural folate.
Foods high in B12 such as meat, fish, eggs, and dairy can help support overall methylation.
4. Lowering Homocysteine
In addition to folate and B vitamins, lifestyle changes such as avoiding smoking, reducing alcohol consumption, and increasing physical activity can help reduce elevated homocysteine levels.
5. Detoxification Support
People with the MTHFR mutation may benefit from supporting their detoxification systems with adequate hydration, high-fiber foods, and possibly supplements like glutathione or N-acetylcysteine (NAC), which help neutralize oxidative stress and support detox.
Testing for MTHFR Mutation:
Testing for MTHFR mutation can provide valuable information, especially to a child with NDD or suspected Autism diagnosis. A test uses a blood sample from a vein in the arm to look for two very common changes in a MTHFR gene. This genetic test can determine whether one has the 677C→T mutation, the 1298A→C mutation, or both. If you have a family history of cardiovascular issues, neural tube defects, or other conditions related to impaired methylation, including neurodegenerative and neurodevelopmental conditions, testing may be especially beneficial.
This test typically doesn't require a prescription and can often be done directly at the lab.
References:
Moll, S., & Varga, E. Homocysteine and MTHFR mutations. (2015) Circulation, 132(1). https://doi.org/10.1161/circulationaha.114.013311
Peng, J., & Wu, Z. MTHFR act as a potential cancer biomarker in immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration. (2023) Discover. Oncology, 14(1), 112. https://doi.org/10.1007/s12672-023-00716-0
Clément, A., Amar, E., Brami, C., Clément, P., Alvarez, S., Jacquesson-Fournols, L., Davy, C., Lalau-Keraly, M., & Menezo, Y. (2022). MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients. Biomolecules, 12(8), 1086. https://doi.org/10.3390/biom12081086
Ota, K. Takahashi, T., Han, A., Damvaeba, S. et al. Effect of MTHFR C677T polymorphism on vitamin D, homocysteine and natural killer cell cytotoxicity in women with recurrent pregnancy losses, Human Reproduction, Volume 35, Issue 6, June 2020, Pages 1276–1287, https://doi.org/10.1093/humrep/deaa095
Anand, S. et al. Role of MTHFRGene With Down Syndrome. (2024) World Journal of Pharmaceutical Research. 13. 44-57. 10.20959/wjpr202420-33985. Retrieved from https://www.researchgate.net/profile/Shubham-Anand-28/publication/384966678_ROLE_ASSOCIATION_OF_MTHFR_GENE_WITH_DOWNS_SYNDROME/links/670fa5e124a01038d0f03e18/ROLE-ASSOCIATION-OF-MTHFR-GENE-WITH-DOWNS-SYNDROME.pdf
Vidmar Golja, M., Šmid, A., Karas Kuželički, N., Trontelj, J., Geršak, K., & Mlinarič-Raščan, I. Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate. (2020) Journal of Clinical Medicine, 9(9), 2836. https://doi.org/10.3390/jcm9092836
Maltsev, D., Kurchenko, A., Marushko, Y.i & Yuriev, S. Biochemical profile of children with autism spectrum disorders associated with genetic deficiency of the folate cycle. (2023) Biochimica Clinica. 47. 132-140. 10.19186/BC_2022.082.