MTHFR and Overmethylation

Genetic variations in the MTHFR gene can lead to impaired function of the MTHFR enzyme, which typically results in vitamin deficiencies caused by undermethylation. 

However, overmethylation is also possible and poses a serious health concern for those affected. Also known as hypermethylation, overmethylation can result from a range of factors and may be linked to MTHFR single nucleotide polymorphisms (SNPs). It can lead to poor concentration, anxiety, panic attacks, sleep disorders, and sensitivities to environmental toxins, among other symptoms.

This article will explain overmethylation, its symptoms, and its differences from undermethylation. We will describe how methylation issues develop and how they can be managed through diet and supplementation.

Methylation is a crucial biochemical process in which one carbon atom and three hydrogen atoms are added to a molecule to create a methyl group. Methyl groups are required for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, protein synthesis, and many more. The methyl group can be delivered via dietary methyl donors, such as methionine, folate, betaine, and choline.

Methyl groups turn on many crucial processes, including the body’s stress response, detoxification, the synthesis of neurotransmitters, and glutathione production. 

Some research suggests that people with a high intake of alcohol and low intake of folate show a higher frequency of methylation-promoting factors involved in colorectal cancer carcinogenesis compared with people with high folate intake/low alcohol intake. Another study found that chronic alcohol intake led to significant changes in CpG methylation and, in particular, increased hypermethylation. 

Recent studies in-vitro and in animal models suggest that long-term exposure to estrogen may lead to epigenetic effects and altered DNA methylation. Exposure to Bisphenol A (BPA), an estrogenic environmental toxin used in plastics, may also have hyper-methylating effects. 

Studies in mice suggest that a maternal diet of additional methyl donors can lead to increased methylation. Feeding the mice extra folic acid, vitamin B(12), choline, and betaine altered the offspring's phenotype, which the researchers suggested may have similar effects in humans. 

People who were homozygous for MTHFR 677TT were found to have an elevated copper-to-zinc ratio and a higher risk of over-methylation. High levels of free copper are also noted in those shown to be over-methylating, which may lead to irregularities in thyroid function, adrenal hormone production, and lower histamine levels. 

The inactive MTHFR 677TT polymorphism results in elevated homocysteine, so the body tries to metabolize the homocysteine via an alternative channel using a flavin cofactor (flavin adenine dinucleotide). Hyper-activation of this pathway results in excessive SAMe production with an attendant risk of low catecholamines and low histamine, leading to adrenal exhaustion.

Low histamine (histapenia) has been linked to overmethylation. Histamine is formed by the decarboxylation of histidine and is metabolized by the enzymes histamine-N methyltransferase and diamine oxidase. 

Methylation status in the body can be determined by measuring whole blood histamine, as histamine and methyl are inversely related. Low blood histamine levels indicate that the individual will be overmethylated; high levels indicate undermethylation.

Symptoms of overmethylation* are said to include:

Anxiety, restlessness

Higher levels of DNA methylation have been found in patients experiencing anxiety, along with  elevated levels of inflammatory cytokines (interleukin-6) and an increased risk for inflammatory diseases.

Depression

A systematic review showed that most studies found BDNF (Brain-derived neurotrophic factor) and SLC6A4 (the serotonin transporter gene) hypermethylation to be associated with MDD or depression in general. 

*Many symptoms associated with overmethylation are similar to undermethylation, which highlights the importance of the methylation cycle. 

Some sources suggest that those with the homozygous MTHFR 677TT variant is related to an elevated copper:zinc ratio, flavin sufficiency, and a risk of over-methylation. Copper supplements or high intake of copper-rich foods (liver, oysters, spirulina) may make symptoms worse. However, zinc supplementation reduces excess free copper and moderates copper effects in relationship to neurotoxicity, oxidative stress, and thyroid damage.

Zinc supplementation also benefits antioxidant capacity and impairs copper bioavailability. 

Higher levels of inflammatory cytokines in the body can be treated with natural anti-inflammatory agents such as Omega-3 fish oil, turmeric, ginger, and green tea extract.

Undermethylation can occur when methyl molecules are insufficient. Characteristics of undermethylation include high levels of oxidative stress, low vitamin B6, D, and folate levels, and low levels of unbound copper. There is also a tendency for higher histamine. 

Those who undermethylate also tend to have low levels of neurotransmitters, which may increase their risk of depression, anxiety, and low energy. 

Undermethylating is associated with MTHFR 677CT  gene variants due to insufficient folate and other B vitamin cofactors required for the methylation cycle. 

Symptoms of undermethylation may include:

Lower levels of methylation have also been associated with more ADHD symptoms in childhood due to increased neurotransmitter release during brain methylation before birth.

Proper methylation is critical for numerous biochemical pathways in the body. 

Overmethylation and undermethylation can lead to complications with daily function, increasing the risk of physical and mental health issues. 

Undermethylation is most commonly treated with supplements that assist with methylation, including methylfolate and vitamin B12. Choosing a high-quality methylfolate supplement such as Methyl-life’s® Methylfolate range and eating a diet high in methylation-supporting nutrients is also recommended.

Treating overmethylation may involve managing your body’s histamine levels to avoid the elevated levels of serotonin, dopamine, and norepinephrine. High levels of copper may be reduced by supplementing with zinc, manganese, Vitamin C, niacinamide, Vitamin B12, and methylfolate.