MTHFR AND GENE VARIANTS

The methylation cycle is a biochemical pathway that is involved in a number of processes, such as: 

• Detoxification
• Supporting DNA (turning genes on and off)
• Energy production
• Reducing inflammation
• Neurotransmitter production
• Amino acid (particularly homocysteine) metabolism 
• Immune functionThe MTHFR gene encodes for the MTHFR enzyme, which stands for methylenetetrahydrofolate reductase. The MTHFR enzyme converts folate, in the presence of cofactors, into the active form, 5-methyltetrahydrofolate, for it to be metabolized and used in various biochemical reactions within the human body. This is essentially taking inactive B9 and turning it into active B9 and is done through a process called methylation, which is a mechanism of activating certain molecules or mechanisms in the body through adding a methyl group to the target molecule that is required to be activated.

WHAT IS METHYLATION

Methylation is the process of adding or removing  methyl groups inside of the body. These unique chemical reactions are very important for a wide variety of  different things in the body. Methylation issues have been linked to Heart disease, mood disorders, neurological disorders, Issues with detoxification. Like most thing, you can have to much methylation or to little. Which means you are under methylation or over methylation.

Like many things in the body, balance is key. You can either be:

• Under-methylated – meaning your body isn’t adding enough methyl groups where needed
   
• Over-methylated – meaning your body is adding too many methyl groups
   

Both states can affect mood, energy, detox, and your overall sense of well-being. For example:

• Under-methylation is often linked to low serotonin, anxiety, depression, high histamine, and poor detox capacity.
   
• Over-methylation may lead to agitation, insomnia, estrogen dominance, and sensitivity to supplements or medications

When methylation is working optimally, your body can:

• Break down and eliminate toxins and excess hormones
   
• Maintain stable mood and mental clarity
   
• Support cardiovascular health
   
• Repair DNA and reduce inflammation
   
• Promote healthy aging and cellular function

Your ability to methylate efficiently depends partly on your genes—especially ones like MTHFR, MTR, COMT, and BHMT. Mutations in these genes can slow down your body’s ability to produce or recycle methyl groups, leading to imbalances that affect every aspect of your health.

For example, an MTHFR mutation can reduce your ability to convert folic acid or folate into its active form, methylfolate (5-MTHF)—which is critical for methylation. 

Your genes hold the key to understanding not only what makes you unique but also why certain health issues may arise. They play a central role in how your body functions—especially in how it produces proteins, including enzymes, which are essential for carrying out countless biochemical and metabolic processes.

When there is a genetic variation or mutation, the production or function of these proteins can be altered. This can lead to an imbalance—whether it's a deficiency, an excess, or a malfunction—that affects your health. For example, some mutations can reduce your ability to produce methylfolate, the active form of folate. This can disrupt important pathways in the body such as methylation, detoxification, hormone balance, and neurotransmitter production.

These disruptions have been linked to a wide range of health conditions, including;

• Chronic fatigue  
• Diabetes  
• Cancer  
• Autism  
• Insomnia  
• Depression  
• Infertility  
• Cardiovascular disease 

There are two main variations in the MTHFR gene. 

The first being the C677T and A1298C. For each of these genetic changes you can either have one or two copies of either variation. So if you have one of these genetic variations it will put you at a reduced function of this enzyme but if you have two genetic variations then the two compound together and the problem becomes worse. 

Depending on the mutation you have the consequences are slightly different. Each  mutation follows a similar trend towards less methylation within the body or less active folate production (5-MTHF). 

If a mutation is present, the enzyme can have a 20% to 70%  loss of function

Heterozygous = 1 copy of the gene from mum or dad  

Homozygous = 2 copies of the gene from mum and dad. 

These mutations cause a DOWN regulation of the enzyme  

MTHFR C677T Heterozygous (1 copy) – 30-40% loss of function  

MTHFR C677T Homozygous (2 copies) - 60-70% loss of function  

MTHFR A1298C Heterozygous – 20-30% loss of function  

MTHFR A1298C Homozygous - 40 loss of function = compound heterozygousction  If you are heterozygous for both i.e.: one copy of each 40-50%  loss of fun

 Methylation is like a master switch for many critical body functions. It’s the process of adding a methyl group (one carbon and three hydrogen atoms — CH₃) to DNA, proteins, enzymes, and other molecules to activate or deactivate them.

Think of methylation as your body’s "on/off switch" for healing, detox, hormone regulation, and mental health

• Methylation is required to make key brain chemicals (neurotransmitters) like:
   
  • Serotonin – mood balance
  • Dopamine – motivation and focus
  • Melatonin – sleep regulation
  • Norepinephrine – energy and stress response
     
• Poor methylation can contribute to anxiety, depression, irritability, brain fog, and even ADHD or mood instability.

• Methylation controls how your genes are expressed—turning them on or off without changing the DNA itself. 
• This means it affects how your body responds to stress, toxins, infections, and more.

• Methylation is crucial for Phase II liver detox, especially in removing:
  • Estrogen 
  • Heavy metals 
  • Environmental toxins 
  • Histamines
     
• If methylation is impaired, you may detox slowly, leading to symptoms like headaches, fatigue, hormone imbalances, and skin issues.

• Methylation breaks down homocysteine, a potentially toxic amino acid.
• High homocysteine is linked to heart disease, stroke, blood clots, and pregnancy loss
• MTHFR mutations can raise homocysteine levels if methylation isn't supported.
   

• Methylation helps clear used-up estrogen from the body. 
• Impaired methylation can contribute to estrogen dominance, which is linked to PMS, endometriosis, fibroids, and menopausal symptoms.

• Supports proper immune cell regulation. 
• Helps keep autoimmune reactions and chronic inflammation in check. 
• Plays a role in protecting the body against infections and even cancer.
   

• Methylation helps maintain DNA integrity and supports cell renewal and repair.
• This process is essential for anti-aging, fertility, and cancer prevention.

Symptoms may include:

• Fatigue and low energy
• Mood swings, anxiety, depression
• Trouble sleeping 
• Hormone imbalances 
• Histamine intolerance (sneezing, rashes, allergies)
• Poor detox or sensitivity to chemicals
• Brain fog or memory issues
• High homocysteine levels

Why and how you develop methylation issues are due to genetic and environmental. Both of these things play are role. We all have genetic variations that can give us advantages or disadvantages and over the years they have found many genes that are linked to methylation. This includes genes such as the MTHFR, MTRR, MTR, COMT, FUT2, TCN2, SHMT1 and more..... The MTHFR gene is the one most talked about as it is very common in the general population. It is important to know what is in your supplements because a lot of B vitamins will give you the inactive form and for people who don't have this genetic variation they can convert it but people with the MTHFR they cannot convert it into its active form.

THINGS THAT AFFECT METHYLATION

• Environmental toxins
• Mental and physical stress
• Medications eg. antacids & methotrexate
• Heavy metals lead and mercury
• Alcohol
• Diet

1. Elevated Homocysteine Levels (Hyperhomocysteinemia)

• Mechanism: Impaired methylation slows the conversion of homocysteine to methionine.
• Risks: Increases risk of cardiovascular disease, stroke, and blood clots.

2. Cardiovascular Disease

• Connection: High homocysteine levels damage blood vessels and contribute to plaque build up (atherosclerosis).

3. Recurrent Miscarriages & Infertility

• In Women: Poor folate and methylation status affects egg quality, implantation, and early embryo development.
• In Men: DNA methylation affects sperm health.

4. Neural Tube Defects

• Examples: Spina bifida, anencephaly.
• Risk: Especially high in mothers with untreated MTHFR mutations who take folic acid instead of methyl folate.

5. Pregnancy Complications

• Includes:
  • Preeclampsia
  • Placental abruption
  • IUGR (intrauterine growth restriction)

6. Mental Health Disorders

• Conditions:
  • Depression
  • Anxiety
  • Bipolar disorder
  • Schizophrenia
• Why: Poor methylation disrupts neurotransmitter  production (e.g., serotonin, dopamine).

7. Chronic Fatigue

• Methylation is essential for energy production, mitochondrial function, and detoxification.

8. Fibromyalgia and Chronic Pain Syndromes

• Linked through mitochondrial dysfunction  and poor detoxification of inflammatory by-products.

9. Autism Spectrum Disorders (ASD)

• Higher prevalence of MTHFR mutations in children with ASD; affects detoxification and brain development.

10. ADHD & Learning Difficulties

• Linked through impaired neurotransmitter  synthesis and brain methylation.

11. Migraines

• Especially with aura—linked to vascular issues and high homocysteine.

12. Thyroid Dysfunction

• Methylation supports thyroid hormone  conversion (T4 → T3) and autoimmune regulation.

13. Histamine Intolerance

• MTHFR mutations can impair DAO enzyme activity and histamine breakdown.

14. Autoimmune Disorders

• Including lupus, Hashimoto’s thyroiditis, rheumatoid arthritis—due to impaired immune regulation and  detoxification.

15. Cancer Risk

• Improper methylation may affect DNA  repair and tumour suppressor gene expression (e.g., breast, colon, prostate cancers).

16. Alzheimer’s Disease & Cognitive Decline

• MTHFR mutations contribute to elevated  homocysteine and poor methylation of brain-protective genes.

17. Detoxification Issues

• Reduced methylation capacity can impair liver Phase II detox (particularly Glucuronidation and Sulfation).

It is important that we understand that these supplements are specifically for people for undermethylation and  If used appropriately they can create a lot of side affects. If you use them well they can make a huge impact on your health. These are not the only supplements used in a methylation protocol but they are the ones that are used most often.

1. Methylfolate (L-5-MTHF) B9

Why: This is the active form of folate that bypasses the MTHFR enzyme, which can be sluggish in people with MTHFR mutations.

• Best Form: L-5-Methyltetrahydrofolate 
• Avoid: Folic acid (synthetic and not well      metabolized with MTHFR) 
• Dosage: Start low (e.g., 200–400 mcg daily),      and titrate based on tolerance and bloodwork.

2. Methylcobalamin or Adenosylcobalamin (B12)

Why: Supports methylation and reduces homocysteine. Methylcobalamin works synergistically with methylfolate.

• Best Forms:
  • Methylcobalamin – supports methylation
  • Adenosylcobalamin – supports mitochondrial function
• Avoid: Cyanocobalamin (poorly converted)
• Dosage: 500–1500 mcg daily (sublingual or      lozenge preferred)

3. Vitamin B6 (as P5P – Pyridoxal 5-Phosphate)

Why: Helps convert homocysteine into cysteine through the transsulfuration pathway.

• Best Form: P5P (activated B6)
• Dosage: 20–50 mg daily

4. Trimethylglycine (TMG or Betaine)

Why: Supports an alternate methylation pathway (BHMT), helping lower homocysteine without overloading the folate cycle.

• Best Form: TMG powder or capsule
• Dosage: 500–1000 mg 1–2x daily

Optional But Helpful

• Magnesium – cofactor for methylation enzymes
• Riboflavin (B2) – needed for proper MTHFR function
• Zinc & B3 (niacin) – also support methylation

FOLATE (Natural Form) B9

• Source: Found naturally in foods like leafy greens,      lentils, liver, and avocados.
• Body Use: Easily used in the body if your      genes (MTHFR) are functioning well.
• Best Form in Supplements:
  ✅ Methylfolate (e.g., 5-MTHF) – this is      the active form that bypasses MTHFR issues.
  ✅ Calcium folinate – a gentle form also      used when methylation needs to be supported more gently (especially with      COMT mutations or anxiety)

The Problem with Folic Acid:

1. Synthetic & Inactive Form

Folic acid is the man-made version of folate used in fortified foods and cheap supplements.
It is not biologically active and must be converted by multiple steps in the body — the final step involving the MTHFR enzyme.

If someone has a MTHFR mutation, like C677T or A1298C, their ability to convert folic acid into active 5-MTHF is reduced by up to 70% or more. That means folic acid builds up in the bloodstream as unmetabolized folic acid (UMFA).

How Folic Acid Disrupts Methylation Pathways:

2. Blocks Receptors

Unmetabolized folic acid competes with natural folate for binding sites on cells and enzymes (like DHFR and folate receptors), essentially “clogging” the system.

➡This means even if you’re eating folate-rich foods or taking 5-MTHF, the body may not absorb or use it properly.

3. Raises Homocysteine

When folic acid isn't converted properly, the methylation cycle becomes stalled, leading to:

• Elevated homocysteine (a toxic      amino acid linked to cardiovascular disease, inflammation, miscarriage,      and poor detox)
• Impaired neurotransmitter production      (low serotonin, dopamine, etc.)
• Estrogen dominance (since methylation is      needed to detox excess estrogen)

4. Associated with Disease Risk

Studies have linked high levels of unmetabolized folic acid with:

• Increased cancer risk (breast, prostate,      colorectal)
• Immune dysfunction
• Cognitive decline (Alzheimer’s)
• Fertility and miscarriage issues
• Autism spectrum disorders (when taken      during pregnancy without the proper active form)  
   

What is 5-MTHF?

• 5-MTHF = 5-methyltetrahydrofolate
• It is the active form of folate      your body uses directly for methylation, DNA repair, detox,      neurotransmitter production, and pregnancy health.
• It's the form your body is supposed      to make from folate — but if you have an MTHFR mutation, this process is impaired

You order a test kit through a naturopath who specialises in genetics or Functional doctor. It is a buccal swab (which means you collect DNA from the inside of the mouth).  It's quick and easy. You send it back to the lab and your results are sent to you via email. Or you can order through a Naturopath or functional doctor. These tests should always be interpreted through a doctor who specializes in Genetics. For more information on referrals please contact me via email jodie@back2basicshealthcoach.com.a

1. Avoid folic acid containing foods – supplements, bread /  baked goods (ALWAYS READ LABELS)  

2. Increase natural folate containing foods – leafy greens &  legumes  

3. Avoid inflammatory and allergenic foods e.g. processed foods,  refined carbohydrates/sugar, additives, gluten, dairy, soy  

4. Reduce exposure to toxins & chemicals – instead use natural  house hold cleaning products, natural make-up / skin care &  eat organic where possible. 

5. Eat more Colourful vegetables - antioxidant & detoxification  support  

6. Stress management 

7.  Avoid smoking/ passive smoking & reduce or eliminate  alcohol 

• Avoid birth control pills as they are known to reduce folate levels. 
• Avoid acid-lowering medication which may block essential Vitamin B12 absorption. 
• Avoid chemicals as much as possible. 
• Have homocysteine levels measured. 
• If elevated this may indicate a problem with methylation or a deficiency of B12 or folate and the intake of methionine-rich foods should be limited. 
• Avoid eating processed foods, many of which have synthetic folic acid. 
• Eat whole foods with no added chemicals or preservatives. 
• Eat leafy greens daily – full of natural folate which is more easily processed. 
• Eat hormone-free, grass fed meat, organic eggs & dairy. 
• Nutrients such as methyl-B12, methyl-folate, curcumin, fish oil, Vitamins C, D, E and probiotics may be beneficial. 
• Gentle detox – e.g.: dry skin brushing, Epsom salt baths, infra-red saunas, regular exercise or sweating.

5-MTHF (L-methylfolate) is a more natural form of folate and this is the  preferred supplemented form. If tolerated well methyl folate can have a  very positive effect on mood (2). An anti-depressant using high dose  methyl folate is now available in Australia and studies continually  support its importance in mood. However, like all supplements,  methylfolate may not be tolerated well by everyone. There can be  several reasons for side effects with 5-MTHF, these include:  Genetics – COMT+/+ - with these genetics you need to tread carefully  with 5-MTHF. Superoxide Dismutase (SOD +/+)(3). If you have SOD  snps and are also low in zinc, copper and/or manganese.  B12 deficiency  Gut issues – particularly yeast  Glutathione deficiency  Low in electrolytes. 

Methyl folate, with the help of Vitamin B12 goes on to make SAMe (S adensoyl methionine). SAMe distributes methyl’s to wherever they are needed and most notably are utilised by neurotransmitters. SAMe & Mood S-adenosyl-L-methionine (SAM-e) is found naturally in the body and studies have found that lowered SAM-e levels are associated with depressive symptoms. Like 5-MTHF, SAM-e isn’t right for everyone but if tolerated we see some extremely positive results. SAM-e can offer a safer alternative to people suffering from depression and wanting to avoid medication. A little more about SAM-e: SAM-e is the amino acid methionine bound to an ATP molecule; this molecule circulates in the blood naturally and acts as a 'methyl donor'. Studies show that the transmethylation pathway boosts levels of the neurotransmitters serotonin, dopamine and norepinephrine. This process is how Sam-e has its antidepressant action. SAM-e is vital to the production of our most important antioxidant, glutathione, as well as the secondary antioxidants, cysteine and taurine. SAM-e works with vitamin B12 and folate. Being deficient in either vitamin B12 or folate may reduce levels of SAM-e in your body. SAM-e increases the synthesis of neurotransmitters that are crucial to normal mood, behaviour, and emotion. Although normally abundant, SAM e levels decline with age and drop dramatically during bouts of depression. A noticeable drop in SAM-e levels is also associated with neurological disorders such as Alzheimer's disease, Parkinson's disease, and dementia. Double-blind studies showed SAM-e (between 800 milligrams to 1600 milligrams) as effective as antidepressants, and produced relatively fewer adverse effects. SAM-e also improved the response to antidepressant medication.

Anxiety and depression can feel overwhelming and completely take over your life. When you're in the thick of anxiety, even simple daily tasks—like leaving the house, speaking to others, or just getting through the day—can feel impossible. But please know this: there is always a reason, and there is always hope. Never accept that there's nothing you can do.

Depression is often the result of a combination of chronic stress, environmental triggers, and an underlying genetic predisposition. If you've tried antidepressants, worked with multiple doctors or practitioners, and still haven’t found relief, exploring your genetic blueprint can be a game-changing step.

Understanding your genetic makeup—particularly how it affects neurotransmitters, methylation, detox, and inflammation—can help uncover the root cause of your symptoms.