Methylation and MTHFR

Copyright 2015  All rights reserved   •
This site is still
a work in progress. 
Please email
with corrections or comments
Genes vs. DNA
The cells thorughout one's body all have the same DNA, but include many different types of cells that perform very different functions. Cells, tissues and organs differ because they have certain sets of genes that are "turned on" or expressed, as well as other sets that are "turned off" or inhibited. Within cells, there are various systems that can interact with each other to silence genes. DNA methylation is one of those systems.
When the structure of a gene changes resulting in a variant form that may be transmitted to subsequent generations, it is called a mutation. A mutation can occur at any location along the DNA sequence of a gene. Such locations are called single nucleotide polymorphisms (SNPs).
What is methylation
DNA methylation is a chemical process that adds a methyl group to DNA. Methylation is an important component in many cellular processes, including cell differentiation in the embryo, genomic imprinting, X-chromosome inactivation and chromosome stability. Impaired methylation has been shown to negatively impact DNA synthesis and repair, embryonic development, neurotransmitter synthesis and cardiovascular risk factors. Extensive research is being done to understand its role in cancer and other systemic illness.
Where does MTHFR fit in?
Tetrahydrofolate (THF) is the form of folate that can enter the folate cycle to be converted to 5-MTHF. Natural folate in foods is metabolized to THF in the mucosa of the small intestine. Synthetic folic acid, used to fortify processed food products such as bread and the nutrient included in most B vitamin complexes, undergoes initial reduction in the liver. Here conversion to THF requires dihydrofolate reductase (DHFR). Low activity of DHFR, combined with high intake of folic acid, may result in unnatural levels of unmetabolized folic acid entering the systemic circulation.
Individuals with mutations of MTHFR or DHFR have difficulty converting natural folate or folic acid to useful 5-MTHF. This discussion concerns only MTHFR.
An individual can have one copy of one of these mutations (heterozygous for the particular mutation), two copies of one of these mutations (homozygous for the particular mutation), one copy of each mutation (compound heterozygous), or two copies of each mutation (compound homozygous).
One copy of A1298C (heterozygous) appears to have the least amount of consequence, with possibly no health issues created by it. When someone is homozygous for A1298C, it appears to affect the BH4 pathways which rely on methylfolate. When someone is homozygous for C677T, methylation is severely impaired. When someone is compound heterozygous, both pathways may be compromised.
Much of the negative impact of C677T appears to be associated with the increase in homocysteine that occurs. This includes heart disease, stroke, cancer and birth defects. Mutations of A1298C appear to have more effect on neurotransmitter pathways and have been linked to neuropsychiatric/neurologic conditions due to the indirect effects on serotonin, dopamine and norepinephrine. One or both mutations have been associated with such diverse neuropsychiatric/neurologic conditions as insomnia, irritability, forgetfulness, migraine with aura, depression, psychosis, peripheral neuropathy, restless leg syndrome, bipolar disorder, Parkinson’s disease, schizophrenia-like syndromes, Alzheimer’s disease.
The deficits caused by the mutations are addressed by supplementing with methylfolate. However, this is neither simple nor straightforward. For instance, adequate amounts of B12 are needed in order to make best use of methylfolate. Also, someone taking methylfolate may experience side effects from taking too much too soon and may have other issues such as inadequate digestion and inadequate cofactors that need to be addressed first.
Research in the field is relatively new and ongoing, but it will likely be many years before there is consensus among medical professionals and treatment protocols are well known. However, anyone who has assorted symptoms that do not respond to treating thyroid and adrenals, such as those with extreme food and/or chemical sensitivities, may do well to get MTHFR genetic testing.
These are additional resources: