top of page

Methylation Cycle Defects


Information provided by Dr. J Dunn


Genetic Variants and Methylation Dysfunction


The recent advances in genetic research have finally reached a point where we can begin to look at specific genes and what their functions are. With the recent completion of the genome project, research is mounting as studies are being conducted and associations being made as to the relevance of genetic variants to disease causation. One such area of research has lead to a major breakthrough in our understanding of the origins of cancer, heart disease, osteoporosis, autoimmune disease, chronic fatigue syndrome and so much more. This connection between our genetic variants or SNiP’s (Single Nucleotide Polymorphisms) and disease has revealed the importance of a metabolic pathway in the body that is critical to maintaining health, the methylation cycle. The methylation cycle, it turns out, is involved in many regulatory processes and genetic defects there can be particularly damaging. The good news is that we now have ways to bypass these defects with specific targeted nutrients and restore normal functioning to the body.


Methylation is the process of a transfer of a methyl group (one carbon atom and three hydrogen atoms) onto amino acids, proteins, enzymes, and DNA in every cell and tissue of the body to regulate healing, cell energy, genetic expression of DNA, neurological function, liver detoxification, immunity, etc. This process is one of the most essential metabolic functions of the body and is catalyzed by a variety of enzymes. The methylation process is responsive to environmental conditions and degrades with age, a process associated with a large variety of age-related disorders. Thus, with respect to the effect of methylation, it is a continuous struggle in life to adapt to the ever-changing environment. Health and quality of life are highly dependent on the methylation process.


This is such a new and emerging science but one that holds great promise in the natural health care realm. The results that are being seen in the preliminary stages are astounding. Understanding the cycle does take some time and study, but for health care practitioners and patients alike the rewards are tremendous. Prevention of those conditions that we consider “inherited” is well within our grasp.


The Methylation Cycle and the Production of Glutathione


The most important point of the methylation cycle is the production of glutathione (GSH). If GSH production is inhibited as it is with several types of genetic “glitches” then dysfunction and disease result.


Methyl cycle defects (and low glutathione) leave you sensitive to environmental toxins, compromise your defense against microbial infection, and complicate proper reading of your remaining genes. Methyl cycle dysfunction explains why one individual is damaged by environmental toxins, while others living in the same environment are unaffected.


Glutathione is technically a tripeptide, which is a small protein, it is made up of only three amino acids. It is present naturally in every cell of the body, as well as in the blood, the bile and the fluid lining the lungs. The liver is normally the main producer of glutathione which plays many important roles in the body. Probably the best known are its protection against oxidative stress produced by oxidizing free radicals and other reactive oxygen species, its support for the immune system, and its role in removing a variety of toxic substances from the body.

When glutathione becomes somewhat depleted, as it does in many cases of CFS (Chronic Fatigue Syndrome), or ME (Myalgic encephalitis) its normal functions are simply not performed well. Many of the symptoms of CFS as well as observed abnormal results on specialized lab tests can be traced directly to glutathione depletion.


Methylation “Glitches” can lead to Low Glutathione Symptoms:


  • Fatigue due to oxidative stress and mitochondrial dysfunction and low ATP output (Pyruvate cannot run through Krebs cycle).

  • Diastolic dysfunctions in the heart and resultant low cardiac output (heart palpations, fatigue, low heart rate)

  • Buildup of toxins including heavy metals which damage many enzymes and block absorption. Which leads to further depletion of glutathione (vicious cycle).

  • Immune dysfunction (inability to fight infections and autoimmune issues) from Natural Killer cell and CD8 cell cytotoxicity. This leads to chronic fatigue syndrome-reactivation of herpes family viral infections (Including EBV, HSV, etc).

  • Autoimmune disease-Decreased cell mediated immune response and shift to TH2 immune response from TH1. Initially caused by the high cortisol output and later in the decreased HPA function and decreased glutathione in the CD4 T cells. Folate deficiency with low methylation decreases the B and T cell production.

  • Joint pain and inflammation-Increased inflammation from pro-inflammatory cytokines reflects the ongoing activation of the dysfunctional immune response to pathogens and lack of control of inflammation from low cortisol.

  • Digestive issues due to lack of ATP in parietal cells and low production of HCL. Low absorption of nutrients results along with gastric reflux and survival of yeasts and bacteria from food which results in dysbiosis. Lack of conversion of pepsinogen to pepsin (requires ATP). This all results in poor gastric signaling to the pancreas and gallbladder for release of digestive enzymes and bile. This also results in low absorption of B12 and further aggravates the problem. Low GSH leads to low volume of bile from the gallbladder.

  • Food sensitivities and leaky gut: From low folate to repair the enterocytes that line the intestines and repair the damaged cells. Abnormal cortisol also decreases the secretory IgA levels which normally protect the gut lining. Increased levels of histamine lead to the release of zonulin which increases gaps in the cells of the intestines. The resultant food sensitivities result in further immune dysregulation.

  • Thyroid problems (hypothyroidism, increased reverse T3, Hashimoto’s Thyroiditis) Glutathione normally protects the thyroid from damage due to hydrogen peroxide produced in the production of thyroid hormones. The immune system mounts an attack on these foreign proteins and creates the autoimmune response of Hashimoto’s. (GSH helps convert H2O2 to H2O along with Catalase)

  • Low secretion and dysregulation of ACTH (adrenocorticotrophic hormone) This leads to low cortisol in the long run. The initial high stress period starts with high cortisol secretion then eventual exhaustion and low cortisol levels.

  • Blunting of the HPA axis (pituitary-adrenal issues) due to continued high cortisol initially.

  • Decreased ADH (Antidiuretic hormone) which leads to Diabetes Insipidis. Signs and symptoms include constant thirst and high urine volume. Eventually leading to low blood volume and increased fatigue.

  • Excitotoxicity-glutamate cannot be broken down correctly into GABA. This results in neurological damage. (Symptoms include anxiety, nervousness, insomnia, diabetes)

  • Low Dopamine-this can lead to depression, apathy, ADD, ADHD and addictive behavior.

  • Disrepair of myelin-slow brain processing and possible MS, ALS. This also increases sensitivity to EMF’s. Myelin basic protein, phosphatidyl choline and choline plasmogen require methylation for repair. Lack of effective insulation causes the increased susceptibility to electromagnetic radiation damage.

  • Neurotransmitter depletion-Resulting in depression, anxiety, bipolar disorder.


The Importance of Methyl Donors in the Body


The methylation cycle performs many vital roles in the body. First, by means of SAMe, it supplies methyl (CH3) groups to many different biochemical reactions. Some of them produce substances such as coenzyme Q-10 and carnitine, which have been found to be depleted in many chronic fatigue patients. Methylation also plays an important role in “silencing” certain DNA to prevent its expression, and in producing myelin for the brain and nervous system. Some key areas that methylation plays a role in are:

  • Nervous System Function: When the methylation cycle is interrupted, as it is during vitamin B12 deficiency, the clinical consequence is the demyelination of nerve cells resulting in a neuropathy which may lead to loss of control of bodily functions, paralysis, and, if untreated, ultimately death. Not only can nerves not myelinate without proper methylation, but they also cannot re-myelinate after any environmental damage or viral infection. Regeneration of nerves is also disrupted due to the lack of methylation of the myelin sheath.

  • Hormone Balance: Methylation regulates hormone function such as estrogen and testosterone. When one considers that high estrogen levels may lead to breast cancer whereas low testosterone levels may lead to prostate cancer, this turns out to be a critical pathway to balance rather than simply useful for mood stability.

  • Allergies: Methylation also regulates histamine levels, a critical hormone often over-expressed in allergic reactions as well as in those with seasonal allergies, eczema, asthma, hives and/or anaphylactic reactions. Outcomes may range from mild symptoms of sneezing and congestion from animal dander or pollen to life-threatening and even fatal reactions from bee stings or eating simple foods such as peanuts or shellfish.

  • Emotional and Mental Health: In the methylation pathway, one crucial component for neurotransmitter balance is the component, S-adenosyl methionine, or SAMe (pronounced “sammy”). SAMe is the most active methyl donor in your body, bringing methyl groups to numerous chemical compounds in your body. It also acts upon the neurotransmitters by changing them into other needed compounds. If we don’t have sufficient SAMe—or if SAMe can’t be recycled due to weaknesses in the methylation cycle, this can result in imbalances in our neurotransmitters, which in turn can impact mood, focus, sleep patterns, and a range of behaviors.

  • Pain and Inflammation: DNA methylation is also involved in chronic pain. Specifically, DNA methylation of the SPARC promoter is increased with age and intervertebral disc degeneration, resulting in the silencing of a gene that is protective against accelerated disc degeneration. This can lead to chronic low back pain and inflammation. The SPARC gene is likely to be just one example of many pain-relevant genes that are similarly regulated by DNA methylation in both peripheral tissues and in the central nervous system.


How We Use SAMe


  • To convert serotonin to melatonin, which supports the ability to sleep

  • For glutathione synthesis, which is critical to the body’s ability to detoxify

  • In the formation of many proteins, including myelin, the nerve sheaths that are so important to proper nerve firing

  • In the creation of CoQ10, creatine, and carnitine, compounds essential to the work of the mitochondria, the energy factories of our cells

  • To convert the neurotransmitter norepinephrine into epinephrine, (also known as adrenaline)

bottom of page