What is MTHFR?

MTHFR is the name for both a gene and the enzyme it encodes. Certain mutations of the gene can affect the function of the enzyme, leading to symptoms such as neurological disorders, birth defects, and cardiovascular issues.


Signs and symptoms

Though MTHFR deficiency can manifest itself in a variety of ways, anyone with one or more of the following symptoms should consider further testing.

  • Having a child with a birth defect, especially spina bifida, cleft palate, or neural tube defects.
  • Elevated homocysteine levels.
  • Mental dysfunction (depression, anxiety, mood swings, schizophrenia, bipolar disorder, and others)
  • IBS, fibromyalgia, Down Syndrome, or Chronic Fatigue
  • Neurological disorders
  • Cancer (also a family history of cancer)
  • Infertility
  • Cardiovascular issues, either personal or by family relation

Who is predisposed?

Environmental and lifestyle factors do not play major roles in MTHFR mutations, as it is largely genetic.

1 Ethnically, Caucasians and Hispanics are the most susceptible. Roughly 40% of the western population are carriers, but only 10-15% actually have the condition, and in these it is generally mild.

2 Nonetheless, the effects of even mild MTHFR can be detrimental.

Why to test

MTHFR mutations are prevalent in the general population, and may play a significant role in cancer, birth defects, cardiovascular disease, fibromyalgia, and other health issues. Fortunately, it requires only a simple blood test to diagnose. If you are experiencing any of the above symptoms, consider testing for MTHFR mutations.

Clinical Complications

Though MTHFR deficiency can directly cause the above signs and symptoms, it can also worsen the impact of other conditions, including:

  • Various forms of cancer, including breast, rectal, gastric, and prostate
  • Dementia
  • Neurological disorders
  • Congenital heart defects
  • Diabetes
  • Glaucoma

Different types of polymorphism

Nine polymorphisms, or common variants, of the MTHFR gene have been identified. Of note are the following two:

  • The 677C→T variant, which leads to one of the most common symptoms: disruption of homocysteine metabolism. This polymorphism is thought to be the most potentially detrimental, as it has been directly linked to a variety of issues.
  • The 1298A→C variant, which has also been confirmed to affect enzymatic activity, and can lead to or worsen neurological, cardiovascular, and psychological conditions.

Since, we all get one copy of the MTHFR gene from each parent, a person could have any one of the following combinations as well as the problems that go with it:

AA1298 / CC677 Normal for the two common variants, or mutations, 677 and 1298
AA1298 / C677T Single 677 mutation – More susceptible to environmental damage, depression, central nervous system issues, etc. (referred to as Heterozygous)
A1298C / CC677 Single 1298 mutation – More susceptible to environmental damage, depression, central nervous system issues, etc. (referred to as Heterozygous)
1298CC / CC677 Double 1298 mutation – Much worse for the above problems (referred to as Homozygous)
AA1298 / 677TT Double 677 mutation – Similar to 1298CC plus heart disease, blood clots, and more (referred to as Homozygous)
C677T / A1298C Single 1298 + Single 677 – Susceptible to all of the above and worse for strokes, heart disease, blood clots, etc. (referred to as Compound Heterozygous)


Interpreting 23andme results

MTHFR AA1298 (rs1801131) or TT is normal (no gene mutation)  
MTHFR A1298C (rs1801131) or GT is heterozygous (single gene mutation)  
MTHFR 1298CC (rs1801131) or GG is homozygous (a double gene mutation)  
MTHFR CC677 (rs1801133) or GG is normal (no gene mutation)  
MTHFR C677T (rs1801133) or AG is heterozygous (single gene mutation)  
MTHFR 677TT (rs1801133) or AA is homozygous (a double gene mutation)  
MTHFR A1298C (rs1801131) or GT + MTHFR C677T (rs1801133) or AG is referred to as “compound heterozygous” (a single gene mutation of each type)  

And it’s very rare, but some folks can even have 3 mutations (a double mutation in one gene and a single mutation on the other) or conceivably 4 mutations (though I’ve not heard of any specific case of this in real life) if they have:

MTHFR 1298CC (rs1801131) or GG    +    MTHFR C677T (rs1801133) or AG   –   (a triple mutation)  
MTHFR A1298C (rs1801131) or GT    +    MTHFR 677TT (rs1801133) or AA   –   (a triple mutation)  
MTHFR 1298CC (rs1801131) or GG    +    MTHFR 677TT (rs1801133) or AA   –   (a quadruple mutation)


Most cases of MTHFR deficiency are treated with folate supplementation (specifically methylfolate, the most active form of folate in the body), methyl-B12 supplementation, P5P supplementation, and dietary changes. Generally, this will restore natural enzyme function. Severe deficiency may lead to more radical treatments.




MTHFR C677T gene mutation as a risk factor for arterial stroke - NCBI

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer

Effects of the C677T and A1298C polymorphisms of the MTHFR gene

A Common Mutation in the Methylenetetrahydrofolate Reductase

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Analysis of the MTHFR C677T variant with migraine phenotypes

C677T and A1298C Polymorphisms of the Methylenetetrahydrofolate

Homozygous Methylenetetrahydrofolate Reductase C677T Mutation

Methylenetetrahydrofolate Reductase C677T Polymorphism

Interactions of Methylenetetrahydrofolate Reductase C677T

C677T polymorphism of the MTHFR gene and variant hemoglobins

Methylenetetrahydrofolate reductase polymorphism (C677T)

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism

MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders

The methylenetetrahydrofolate reductase C677T gene polymorphism

Associations between Two Common Variants C677T and A1298C

Colorectal cancer and polymorphism of methylenetetrahydrofolate

The C677T Mutation in the Methylenetetrahydrofolate Reductase

The Association of the MTHFR Gene Polymorphisms C677T