Epigenetics is the study of how genes are expressed and how factors like diet, natural supplements, lifestyle, and environmental changes can influence gene expression, potentially shaping your destiny. Methylation plays a key role in epigenetic processes, determining gene activity without changing their sequence. This process involves adding methyl groups to DNA and histones, which can affect the accessibility of genetic information for RNA transcription and, consequently, protein synthesis. Changes in methylation can lead to long-term alterations in gene function, which are associated with various physiological and pathological conditions, including cancer and neurodegenerative disorders. (1)
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What is MTHFR?
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- The MTHFR gene is one of the 20,000 genes in the human body and provides instructions for producing the MTHFR enzyme.Â
- Genetic mutations or variations in the MTHFR gene, known as SNPs (single nucleotide polymorphisms), represent differences in DNA building blocks.
- Variations in the MTHFR gene can affect detoxification processes. (2)
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MTHFR Facts
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- Approximately 50% of the population has at least one MTHFR SNP.
- Common MTHFR gene variations are C677T and A1298C. You can have none (wild type), one (heterozygous), or two (homozygous) mutations at these sites.
- More mutations mean the MTHFR enzyme is less effective, which can impact health by decreasing methylation ability. (2)
- MTHFR converts 5,10-MethyleneTHF to support methylation. Improper methylation leads to the use of uracil, causing health issues and DNA damage, highlighting the importance of folate. (3)
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Potential Diseases or Conditions Linked to MTHFR Mutations:
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§ Autism
§ ADHD
§ Tongue tie
§ Multiple Sclerosis
§ Miscarriages
§ Pernicious Anemia
§ Depression
§ Schizophrenia
§ Bipolar disorder
§ Chronic Fatigue Syndrome
§ IBS
§ Type 1 Diabetes
§ Epilepsy
§ Alzheimer’s Disease
§ Congenital Heart Disease
§ Blood Clots
§ Heart murmurs
§ Myocarditis
§ Constipation
§ Prostate Cancer
§ Rectal Cancer
§ Bladder Cancer
§ Gastric Cancer
§ Post-Menopausal Breast Cancer
(4-7)
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Histamine
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- Histamine is a neurotransmitter that communicates between the body and the brain.
- It is involved in breaking down food in the stomach and dilating blood vessels to help white blood cells heal the body.
- Excess histamine can cause restlessness, depression, nausea, anxiety, hives, congestion, swelling, itchiness, vertigo, dizziness, and hypertension. (8, 9)Â
- Histamine is broken down or stored by N-methyltransferase (HMT) and Diamine Oxidase (DAO) in the digestive tract.
- Histamine and methylation are closely related.
- Optimal histamine levels in blood are 40–70 ng/ml. (10)Â
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Methylation Functionality
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- Methylation is the process where a carbon and three hydrogens form a methyl group, which attaches to enzymes to perform specific actions.
- It is crucial for DNA synthesis, cell repair, new cell formation, immune cell production, amino acid synthesis, energy production, mitochondrial support, stress response regulation, detoxification, hormone metabolism, neurotransmitter support, histamine reduction, and fertility.
- DNA methylation, where methyl groups attach to DNA bases, can activate or repress gene expression. (11)
- Methylation is vital for clearing estrogens (E1, E2, E3) with the enzyme COMT, which uses methyl groups to break down estrogen metabolites. This prevents the formation of harmful quinones.
- COMT is a methyltransferase enzyme that assists in breaking down neurotransmitters dopamine, norepinephrine, and epinephrine, essential for phase 2 detoxification. Fuentes, N., & Silveyra, P. (2019). (12)
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Overmethylation
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- Blood histamine levels lower than 40 ng/ml. (10)
- Symptoms include high anxiety, panic, depression, paranoia, self-mutilation, sleep disorders, food and chemical sensitivities, estrogen intolerance, rapid speech, low libido, tendency to be overweight, headaches, hives, joint and muscle pain, irritability, nausea, insomnia, and adrenal fatigue.  (4-7)
- Around 45% of people diagnosed with schizophrenia are severely overmethylated. (13)Â
- Be cautious with methyl donor products like SAMe, Folate, Choline, Methionine and Betaine for overmethylators. (14)Â
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Undermethylation
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- Blood histamine levels higher than 70 ng/ml. (10)
- Symptoms include fatigue, IBS, depression, headaches, migraines, moodiness, bipolar disorder, schizophrenia, poor memory and concentration, OCD, ADHD, brain fog, allergies, insomnia, and inner tension. (4-7)
- Undermethylation reduces serotonin and dopamine production, making folate less effective and potentially increasing depression and anxiety. It also interferes with glutathione production and B12 absorption. (15)Â
- SAMe can help, but focus on methionine and B1, B2, B3, B5, B12, and zinc first.  (14)
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Homocysteine
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Changes in DNA methylation due to high homocysteine  involve alterations in key enzymes and compounds critical to the process. This includes methionine adenosyltransferase, DNA methyltransferases, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and methylenetetrahydrofolate reductase (MTHFR). These enzymes and compounds play pivotal roles in regulating DNA methylation patterns. In patients with hypertension, these changes in DNA methylation can impact gene expression. (16)
- High homocysteine can interfere with iron binding and fertility, leading to issues with pregnancy and recurrent miscarriages.
- Choline in the diet is essential as it helps remove homocysteine, forming methionine and SAMe. (16)
- High levels indicate potential B12 depletion and oxidative stress. (16)
- Ideal homocysteine levels are below 9, but not too low.
- Low levels suggest inadequate glutathione production. (17, 18)
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Trimethylglycine (TMG)
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TMG also known as betaine, is a compound derived from the amino acid glycine and is naturally found in foods such as beets, spinach, and whole grains. TMG plays a crucial role in the body’s methylation process, which involves transferring methyl groups to various molecules. This process is vital for many bodily functions, including supporting heart health by reducing homocysteine levels, aiding liver detoxification, enhancing muscle endurance and strength through creatine production, and supporting DNA repair and gene expression. Additionally, TMG helps maintain balanced neurotransmitter levels, potentially improving mood and cognitive function. TMG supplements are often used to support these functions, particularly in individuals with methylation issues or elevated homocysteine levels.
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TMG (trimethyl-glycine) is generally used to support methylation processes in the body. Its effects can vary depending on an individual's specific methylation status:
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- TMG can be beneficial for individuals who are undermethylated, as it donates methyl groups to support various biochemical processes, including the conversion of homocysteine to methionine. (19)Â
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- In cases of over-methylation, TMG might not be as beneficial, and in some cases, it could potentially exacerbate the issue by providing additional methyl groups.  (19)Â
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It's important for individuals to have their methylation status assessed through appropriate testing and to consult with a healthcare provider before starting supplementation with TMG or any other methylation-related nutrients.
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Testing
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- Organic Acids Test (OAT) and Organic Metabolite Test (OMX).
- Serum B12 and serum folate.
- MTHFR blood test or cheek swab.
- Full panel genetic testing.
- Histamine and homocysteine levels.
- Genetic testing for uracil and thymine (high uracil and low thymine indicate methylation issues).
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Diet Guidelines
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- For some, avoidance of dairy and gluten might be beneficial
- Avoid sugary drinks and sweet foods.
- Limit alcohol intake as it depletes B vitamins.
- Avoid processed meats; opt for organic, hormone, and steroid-free meat and chicken.
- Choose wild-caught fish over farmed fish to avoid heavy metals, hormones, and steroids. - - - Eat top-dwelling fish as deep-sea fish have higher heavy metal loads.
- Eat plenty of green leafy vegetables, green salads, and avocado. Avoid overcooking to preserve folate.
- Consume organic seeds and nuts (avoid almonds if oxalate issues are present).
- Drink filtered, fluoride-free, and heavy metal-free water.
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Please consult healthcare professionals first and foremost for any nutrition, life style and medical advice.
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Foods and Substances to Avoid
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- Synthetic folic acid and cyanocobalamin (a form of B12) are toxic to those with MTHFR SNPs.
- Birth control pills as they block folate uptake.
- Fortified foods containing synthetic folic acid.
- Mercury amalgam fillings; have them removed by a trained dentist.
- Heavy metals and toxic exposures.
- Aspirin
- Prenatal vitamins, as they usually contain folic acid.
- Gluten, as it can block the gallbladder and break down the myelin sheath in neurotransmitters.
- Dairy, as it can downregulate folate receptors.
- Processed food, as it is usually packed with sugar and unhealthy ingredients.
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Lifestyle Recommendations
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- Avoid stress.
- Exercise daily, if possible.
- Ensure clean air in a mold-free and smoke-free environment, preferably using a HEPA filter.
- Cook with stainless steel cookware and avoid non-stick pans.
- Choose organic food or refer to the dirty dozen organic list.
- Use saunas at least weekly or every fortnight.
- Use clean body products, including makeup, hair products, and body wash.
- Opt for household cleaning products that are free of chemicals.
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References
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3.        Raghubeer SA-O, Matsha TA-OX. Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. LID - 10.3390/nu13124562 [doi] LID - 4562. (2072-6643 (Electronic)).
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9.        Weinstock LA-O, Nelson RM, Blitshteyn SA-O. Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series. LID - 10.3390/jpm13111562 [doi] LID - 1562. (2075-4426 (Print)).
10.      Brew O, Sullivan MHF. The links between maternal histamine levels and complications of human pregnancy. Journal of Reproductive Immunology. 2006;72(1):94-107.
11.      Jin B, Li Y Fau - Robertson KD, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy? (1947-6027 (Electronic)).
12.      Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. (1876-1631 (Electronic)).
13.      Fryar-Williams S, Tucker G, Strobel J, Huang Y, Clements P. Molecular Mechanism Biomarkers Predict Diagnosis in Schizophrenia and Schizoaffective Psychosis, with Implications for Treatment. International Journal of Molecular Sciences. 2023;24(21):15845.
14.      Bekdash RA. Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection. LID - 10.3390/ijms24032346 [doi] LID - 2346. (1422-0067 (Electronic)).
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16.      Wan C, Zong R-Y, Chen X-S. The new mechanism of cognitive decline induced by hypertension: High homocysteine-mediated aberrant DNA methylation. Frontiers in cardiovascular medicine. 2022;9:928701.
17.      Li D, Zhao Q, Zhang C, Huang X, Godfrey O, Zhang W. Associations of MTRR A66G polymorphism and promoter methylation with ischemic stroke in patients with hyperhomocysteinemia. The Journal of Gene Medicine. 2020;22(5):e3170.
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