Decoding MTHFR Mutations: What You Need to Know

Humans have genetic variations, also known as ‘mutations’, which can affect our functions. A well-studied variation is the MTHFR mutation, with the main superstars being MTHFR C677T and MTHFR A1298C.

The language used in genetics is confusing, so here we explain in as much plain English as possible what the MTHFR C677T and A12198C mutations might mean for you.

What does MTHFR mean?

MTHFR is an enzyme critical for human body functioning. Enzymes are used as in-betweeners for two things.

For example, the enzymes in your clothes-washing detergent break down dirt and grease, allowing them to be dissolved in water and rinsed away. Or, the enzyme in your saliva that breaks down sugars and carbs – if you put a cookie in your mouth and hold it there, it will dissolve, but if you put a piece of chicken (protein) in there, it will not. Protein-degrading enzymes are further down in your digestive system.

The MTHFR enzyme is critical for the process that repairs DNA, turns genes off and on, and other important metabolic functions¹.

The MTHFR enzyme also converts folate and folic acid (forms of vitamin B9) into their biologically active form L-methylfolate (5-MTHF).

The MTHFR gene provides the instructions to the body to produce the MTHFR enzyme. Without the directions from the gene, there is no enzyme. A gene variation – or mutation – can impact the function of the MTHFR enzyme, thus impairing your body’s key functions like making energy or degrading histamine.

Understanding MTHFR C677T and MTHFR A1298C

Variations in the MTHFR gene (polymorphism, defect, mutation) can be inherited from your parents and in fact, are very common. So far there are about 30 different mutations recorded, with C677T and A1298C two of the most well-studied and tested mutations².

The letters may be mixed up in other ways, for example, 677CT or 129AC. If you have raw genetic data, your results may look different, for example, rs1801133, Ala222Val or A222V, or for A1298C, rs1801131, E429A.

Sciencey stuff
The numbers represent the base position while the letters represent the allele. C677C is the 'normal' MTHFR gene (c = cytosine), with the variance being C677T (t = thymine). Carriers of the T allele produce less efficient MTHFR enzymes, which can result in health repercussions³.

Hetero or homo?

Hetero = different
Homo = same
Zygous = degree of similarity

MTHFR mutations are either heterozygous or homozygous.

Heterozygous means one copy of the variation on the MTHFR gene from just one parent.
Homozygous means two copies of the same variation, one from each parent, with more impact on function.
Compound heterozygous is one variation on both the 677 and 1298.

Which MTHFR mutations cause the most problems?

We never assume the MTHFR gene mutation will cause problems – everyone’s different. But, we know that some variants have greater potential for problems than others.

Why should I care about MTHFR mutations?

The MTHFR mutations can impact homocysteine levels in the blood. Homocysteine is an amino acid that is broken down by L-methylfolate – the active form of folate. Less L-methylfolate means higher homocysteine levels.

Researchers have found high homocysteine has a negative impact on health, including high levels being an independent risk factor for heart disease, stroke and cardiovascular disease⁴. This might not bug you when you’re young, but it matters as you age. High or low homocysteine may also have other negative impacts on its own, but when we use it as a marker, it indicates a more serious problem. A perfect homocysteine reading is 7.0-7.5.

It doesn’t matter how much folate you eat, if you are homozygous for C677T (T677T, 677TT), folate levels are always lower than in heterozygous C677T, resulting in higher homocysteine levels⁵. The conversion of folate to L-methylfolate via the MTHFR enzyme is inadequate.

Homozygous C677T and compound heterozygous C677T and A1298C are linked with higher homocysteine concentrations⁶.

Heterozygous MTHFR mutations only have minor influences on the activity of the MTHFR enzyme. Heterozygous A1298C is not thought to be of much consequence, while heterozygous C677T could affect folate metabolism by up to 35 per cent^3,7.

The biggest problem variations in MTHFR are:

Homozygous A1298C (C1298C)
Homozygous C677T (T677T)
Compound heterozygous A1298C + C677T

But while compound heterozygous A1298C and C677T is considered the most severe combination, homozygous mutations can inhibit MTHFR enzymes by up to 70 per cent⁷.

MTHFR C677T heterozygous – 30-40 per cent loss of function
MTHFR C677T homozygous – 60-70 per cent loss of function
MTHFR A1298C heterozygous – 20-30 per cent loss of function
MTHFR A1298C homozygous – 40 per cent loss of function
Heterozygous for both – 40-50 per cent loss of function

Why we need healthy methylation

Turns genes on and off
Repairs and rebuilds DNA and RNA
Reduces the ageing process by protecting telomeres
Detoxifies chemicals and heavy metals
Processes hormones
Builds immune cells
Provides energy
Modulate stress response (turn on and off)
Reduces histamine
Repairs cell membranes
Myelinates nerves
Supports neurotransmitters and mental health, working to prevent depression, anxiety, insomnia
Supports healthy brain function

There are MTHFR gene variation associations with polycystic ovarian syndrome (PCOS), low ferritin no matter what you eat, depression, anxiety, hormonal disruptions (relative oestrogen excess, high cortisol, low progesterone, for example) and high histamine.

MTHFR, methylation and histamine

L-methylfolate is a key nutrient in methylation. If you’re not methylating effectively, several other enzymes that break down important body products like histamine do not work effectively, resulting in a build-up of problems.

MTHFR and histamine are closely linked, with histamine overload being a major cause of vaginal symptoms and dysbiosis.

Methylation actives the HNMT and MAO enzymes, which move intracellular histamine out of the body. The DAO enzyme moves extracellular histamine out of the body. Poor methylation results in histamine building up in the body.

Getting tested

DNA testing

It is recommended you find a methylation-specialist practitioner who can guide you through testing and treatment. You can muddle through on your own if you feel equipped, just prepare yourself for a lot of complex information and trial and error.

Do not leap into high doses of any nutrient – it is not appropriate for everyone and you can cause some very uncomfortable problems. Go slow, learn about the different forms of folate and B12, and what else needs support along the way. Read books, do courses, get help. You will need it. There is a lot to learn.

You can get a genetic test for one or both of the main MTHFR genes, though this can be pricey for what you get – two specific genes. If that’s all you need, great, but it could be worth having a panel run. It can be less expensive and more interesting to get a DNA panel run from Ancestry.com or other ancestral DNA providers, and have the raw data run to get your MTHFR and other mutations. You do NOT need the health information test, just the regular test is fine and has everything you need.

If you have an ancestry DNA test (ancestry.com, 23andme, etc.), the information on genetic mutations lies within the raw text file. You will need to request the raw data to find the genetic information relating to MTHFR and related genes.

Your practitioner can decipher this, or if you’re keen, do it yourself. Keep in mind there are several important gene variations that could be contributing to your symptom picture, all related to methylation, so solving one problem might create another and MTHFR gene variations may only be a part of the puzzle.

Important blood tests

Always do blood tests in a fasting state, as results will vary if in a fed state.

Homocysteine
Red cell folate
Serum B12
Full blood count
Urea, electrolytes and creatinine (UEC)
Serum zinc
Serum copper
Thyroid panel (free T3, free T4, TSH, and all three antibodies)
Iron panel (iron, ferritin, transferrin)
A hormone panel on a specific day of the menstrual cycle (ask your practitioner – usually Day 2-3 of bleeding or Day 21, aiming for 7 days after ovulation)
Cortisol

You can get these tests run privately or by your practitioner as needed. It is useful to have a practitioner to decipher your results. Not all tests will need to be run for you all, so ask your practitioner for advice.

References

1.
Nazki FH, Sameer AS, Ganaie BA. Folate: Metabolism, genes, polymorphisms and the associated diseases. Gene. Published online January 2014:11-20. doi:10.1016/j.gene.2013.09.063
2.
Sibani S, Leclerc D, Weisberg IS, et al. Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation. Hum Mutat. Published online May 2003:509-520. doi:10.1002/humu.10193
3.
Yamada K, Chen Z, Rozen R, Matthews RG. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proceedings of the National Academy of Sciences. Published online December 11, 2001:14853-14858. doi:10.1073/pnas.261469998
4.
Boushey CJ. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. JAMA. Published online October 4, 1995:1049. doi:10.1001/jama.1995.03530130055028
5.
de Bree A, Verschuren WM, Bjørke-Monsen A-L, et al. Effect of the methylenetetrahydrofolate reductase 677C→T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample. The American Journal of Clinical Nutrition. Published online March 1, 2003:687-693. doi:10.1093/ajcn/77.3.687
6.
Ghazouani L, Abboud N, Mtiraoui N, et al. Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease. J Thromb Thrombolysis. Published online January 19, 2008:191-197. doi:10.1007/s11239-008-0194-1
7.
Bezold G, Lange M, Peter RU. Homozygous Methylenetetrahydrofolate Reductase C677T Mutation and Male Infertility. N Engl J Med. Published online April 12, 2001:1172-1173. doi:10.1056/nejm200104123441517