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MTHFR gene mutation symptoms in Men: Understanding the Impact of Gene Variations

MTHFR gene mutation symptoms in Men: Understanding the Impact of Gene Variations 

MTHFR gene mutation symptoms in Men: Understanding the Impact of Gene Variations 

The interplay between genetics and health has been the subject of much research for the past few decades. One gene that is still under investigation is the methylenetetrahydrofolate reductase (MTHFR) gene. The MTHFR gene plays a key role in regulating the enzyme activity required for numerous bodily processes. The presence of specific variations in the MTHFR gene can lead to impaired enzyme function, potentially causing certain health conditions. 

In this article, we will discuss how MTHFR gene variations can impact men's health and the specific conditions that can result. Understanding MTHFR can help those affected by genetic variants to manage their health and, if necessary, seek MTHFR gene mutation treatment to prevent further complications. 

Cardiovascular health

Heart disease is the leading cause of death in men in the US, including most racial and ethnic groups. Statistics from 2021 show that 384,886 men died from heart problems, accounting for one in four male deaths. [1]

What Does it Mean to be the “Best” Methylfolate

Men with MTHFR gene mutations may be at an even higher risk of cardiovascular issues. 

The MTHFR gene is required for the proper metabolism of homocysteine, an essential amino acid produced during the metabolism of methionine. The decreased enzymatic activity that results from the gene mutations can lead to an increase in homocysteine concentrations.

When homocysteine levels increase, oxidative stress increases, leading to inflammation of the vascular cells and thrombosis due to endothelial cell dysfunction. [2]

Chest pain and shortness of breath have also been linked to future heart attack, atrial fibrillation (irregular heartbeat) and heart failure. [3]

Although stroke is the condition least associated with chest symptoms, men with MTHFR are also at a higher risk of stroke and blood clots. One study found that patients with a C677T mutation and nonvalvular atrial fibrillation have a greater risk of hypertension, heart failure, dyslipidemia, type II diabetes mellitus, and increased inflammation. 

It has also been reported that C677T is linked to increased risk of hypertension and poorer blood pressure control. [4]

Similarly, the A1298C MTHFR gene mutation has been associated with a higher incidence of previous stroke and stroke recurrence. Dyslipidemia is the main cardiovascular issue for those with A1298C. [5]

The C677T variant is also strongly linked to vitamin B12 deficiency.  [6] Vitamin B12 plays a key role in homocysteine metabolism and is shown to be a factor in cardiovascular disease. [7]

The B vitamins folate, B6, and B12 are required for the metabolism of homocysteine. Supplementing with vitamin B12 in the form of hydroxocobalamin may support healthy homocysteine levels. Hydroxocobalamin is a precursor of methylcobalamin and adenosylcobalamin, the active forms of vitamin B12. [8] It is often used to restore B12 deficiency in the form of intravenous injection. 

A more convenient option is Methyl-Life’s® Hydroxocobalamin, a sublingual tablet that provides maximum B12 absorption through the mucous membranes in the mouth. 

Mental Health:

Elevated homocysteine is also harmful to neurons and blood vessels, including the cerebral microvasculature. Damage to these areas can increase the risk of mood disorders, depression, and cognitive decline later in life. [9]

In addition, reduction of MTHFR enzyme activity can affect the DNA methylation process, which is shown to have significant impacts in various psychiatric diseases. MTHFR gene mutations have been reported as increasing susceptibility to schizophrenia due to compromising the methylation of catechol -O- methyltransferase (COMT). COMT are genes responsible for catabolizing catecholamines such as dopamine. Deficits of COMT methylation have been widely reported to play roles in the pathogenesis of schizophrenia. [10]

The C677T form of MTHFR also has an influence on symptoms of schizophrenia, with studies showing that the T allele load is linked to the increased severity of negative symptoms in schizophrenia. It is also suggested that this effect could be further enhanced by folate deficiency. [11] Dysfunctional serotonin signaling has also been linked to mood disorders and schizophrenia.


Symptoms of depression according to the DSM-IV include: [12]

1. Depressed mood most of the day, nearly every day; feeling sad or empty

2. Markedly diminished interest or pleasure in activities

3. Significant weight loss or weight gain

4. Insomnia

5. Restlessness and anxiety

6. Fatigue or loss of energy

7. Feelings of worthlessness or guilt

8. Struggling to think or concentrate, make decisions,

9. Recurrent thoughts of death, suicidal ideation

Supporting the body’s methylation cycle is essential for healthy mood. The proper function of the folate cycle is essential for producing mood-supporting neurotransmitters: serotonin, melatonin, dopamine, noradrenaline, and adrenaline. [13] More than a third of psychiatric admissions have been found to be deficient in folate or vitamin B12. [14]

A study comparing the physiologic and clinical effects of L-methylfolate supplementation in schizophrenia patients found that taking methylfolate resulted in beneficial physiologic changes and selective symptomatic improvement. [15] Clinical studies have also shown that patients with treatment-resistant depression show improvement after taking L-methylfolate 15mg. [16]

Methyl-Life's Enhance Mood contains L-Methylfolate 15+ mg plus active B12 and inositol to support healthy mood and neurotransmitter production. Another mood-supporting product is Methyl-Life’s® Hydroxocobalamin, the precursor for active vitamin B12 form, methylcobalamin. Vitamin B12 works alongside methylfolate in supporting methylation and proper neurotransmitter function. 

Reproductive issues

Male fertility and reproductive health may be affected by MTHFR gene mutations. A meta-analysis involving 26 studies found that MTHFR polymorphisms are linked to an increased risk of male infertility. [17] It has been suggested that the MTHFR might play an important role in spermatogenesis because of its higher activity in testes than in other major organs. [18]

Folate is an important mediator of one-carbon transfers for DNA methylation and for the synthesis and repair of DNA itself. It's also crucial for the maintenance of genome integrity. Folate deficiency is common, and the related hyperhomocysteinemia is considered as a risk factor for various diseases, including infertility. [19]

Folate deficiency is shown to result in homocysteine overproduction with subsequent excessive oxidative stress, chaotic methylation reactions, protein synthesis, and spermatogenesis deficiency.  [20] However, previous studies have shown that administration of low doses of folic acid (5 or 10 mg per day) for a duration shorter than one cycle has no impact on spermatogenesis. [21]

As the active form of folic acid, methylfolate is able to entirely bypass a MTHFR mutation for immediate absorption into the bloodstream. 

Fatigue and chronic conditions

Men with MTHFR gene mutations may experience persistent muscle fatigue, weakness, and reduced stamina due to excess homocysteine. Homocysteine reduces the bioavailability of nitric oxide, which regulates the blood flow to muscle cells. High homocysteine also increases free radical production, which can lead to fatigue, ischemia and reduced physical endurance. [22]


MTHFR variants may also affect bone health. The MTHFR C677T polymorphisms are associated with osteoporosis, which research shows that people with the T allele (mutated presentation) have an increased risk of developing osteoporosis. [23]

Yet another study found that C677T polymorphism could be a risk factor for thyroid problems such as hypothyroidism, possibly through hyperhomocysteinemia. MTHFR C677T polymorphism is also shown to be a genetic risk factor for migraine with aura in Caucasians, while the MTHFR 1298CC (double mutation presentation) may contribute to migraine without aura. [25]

Immune system

Folate plays vital roles in cell growth and proliferation, energy Adenosine triphosphate (ATP) production, methylation reactions, and the production of immunomodulatory molecules. These molecules are required for immune signaling and cytotoxicity. 

Deficiency can adversely impact multiple bodily systems by slowing cellular metabolic function and allowing harmful byproducts to build up. It is hypothesized that this could result in immune dysfunction leading to viral reactivation and improper antigen presentation and cytokine production. This can then increase the risk of developing autoimmune diseases. [26]

In addition, insufficient levels of both B12 and folate can affect the body’s immune response by impairing production of nucleic acid, protein synthesis, inhibiting immune cell function, and disrupting metabolic processes such as methylation. Impaired methylation can then lead to hyperhomocysteinemia, followed by increased inflammation and a higher risk of chronic diseases. [27]

Folate deficiency has also been associated with increased levels of alanine transaminase (ALT), which can lead to liver malfunction and damage. [28] Folic acid supplementation is shown to reduce ALT levels in people with liver damage. However, folate supplementation with methylfolate is more efficient than supplementation with folic acid as methylfolate can enter the folate cycle directly, without the need for enzymatic modification, which means it can overcome metabolic defects such as MTHFR mutations. [29]


Recognizing MTHFR symptoms can play an important part in preventative health care, especially for men. MTHFR genetic mutations are common, and can predispose the individual to serious health conditions affecting the cardiovascular system, mood, immune function, and more. 

Consulting a healthcare professional who specializes in MTHFR-related conditions should be the first step in receiving an accurate diagnosis and effective management strategies. 

Remember, this information is not a substitute for professional medical advice, and individuals should consult qualified healthcare providers for personalized guidance.








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    Written By,
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