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MTHFR Gene Spotlight

MTHFR and MTHFR Variant

What are MTHFR enzymes?

The methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for catalyzing the conversion of folic acid to the biologically active form, methylfolate.

Methylfolate is the only metabolite of folate that can cross the blood-brain barrier, and plays a key role in cell metabolism, protein methylation, and the synthesis of the monoamine neurotransmitters. Methylfolate is required in the activation of tetrahydrobiopterin (i.e., BH4), which is a necessary co‐factor for both tryptophan hydroxylase and tyrosine hydroxylase, enzymes required in the synthesis of serotonin and norepinephrine/dopamine, respectively (Figure 1).4

decision tree diagram of folate metabolism simplified

Figure 1. Simplified Folate Metabolism7

MTHFR is a gene that provides instructions needed to make the MTHFR enzyme, and is located on the short (p) arm of chromosome 1 at position 36.3 (Figure 2).

MTHFR gene location on chromosome 1


Figure 2. Depiction of the location of MTHFR1

A single nucleotide polymorphism (SNP) in the MTHFR gene (known as the C677T variant) involves the replacement of a cytosine (C) by a thymine (T); this reduces the enzymatic activity of MTHFR by approximately 35% per T allele, resulting in inefficient production of methylfolate (Figures 3 and 4).

Another common SNP in the MTHFR gene, known as A1298C, involves the replacement of an adenine (A) with a cytosine (C); this reduces the enzymatic activity of MTHFR by approximately 20% per C allele.2 The decrease in enzymatic activity is additive across these polymorphisms.2

MTHFR and MTHFR Variant

Figure 3. Depicts normal MTHFR activity; Figure 4. Depicts MTHFR variant activity

For example, an individual who is heterozygous at both C677T (C/T) and A1298C (A/C), known as a compound heterozygote, is expected to exhibit a 55% decrease in MTHFR enzymatic activity (‐35% activity due to the presence of one T allele at C677T and ‐20% activity due to the presence of one C allele at A1298C = ‐55%). Additionally, compound heterozygosity is associated with elevated plasma homocysteine, similar to what is observed among those homozygous for the “T” allele at C677T.2

MTHFR Enzyme Activity %
















The association between MTHFR genetic variations and psychiatric disease

Studies have shown a link between folate deficiency and neuropsychiatric illnesses8. Given the impact of MTHFR polymorphisms on methylfolate production, nuclear methylation, and the production of monoamines, there has been considerable research examining the association between MTHFR genetic variations and psychiatric disease states including unipolar depression, bipolar depression, schizophrenia, and more.3

How does MTHFR function affect methylfolate conversion?

As we discussed earlier, MTHFR function is essential for catalyzing the conversion of folic acid to the biologically active form, methylfolate. L‐methylfolate can be taken orally as a supplement, therefore bypassing a dysfunctional MTHFR enzyme. Antidepressant effects may result from a downstream increase in monoamine synthesis.

Randomized controlled trials have indicated that L‐methylfolate supplements can be an effective antidepressant augmentation strategy. For example, Papokastas and colleagues5 found that treatment of major depressive disorder (MDD) with 15mg of L‐methylfolate in conjunction with an SSRI showed significantly greater efficacy compared to SSRI therapy alone regarding response rate and degree of change in depression symptom scores.

Preliminary data suggests that biomarkers related to methylfolate synthesis and/or metabolism may identify patients who would benefit from supplementation with L-methylfolate.

Is L‐methylfolate supplementation effective?

One pharmacogenetic study has been conducted6 examining the efficacy of L‐methylfolate in patients with MDD and at least one risk variant at C677T or A1298C. The data demonstrated that patients treated with the combination product of reduced B vitamins and micronutrients (including 7mg of L‐ methylfolate) Enlyte® had a significantly greater decrease in depression scores and homocysteine levels relative to the placebo group, and 42% of patients treated with Enlyte® remitted after 8 weeks (Figure 5).

Figure 5. Enlyte Treatment of Depression in MTHFR C677T and A1298C88Figure 5. Enlyte Treatment of Depression in MTHFR C677T and A1298C88

L-methylfolate is available both as a prescription as well as over-the-counter (OTC). Prescription options:

  • Deplin® [L-methylfolate from Metafolin®] (7.5 and 15mg)
  • Generic L-methylfolate (7.5 and 15mg)
  • EnLyte® with DeltaFolate™ [A combination of L-methylfolate, folinic acid, and folic acid]
  • Many OTC options: Considerations include the amount of methylfolate, the ratio of stereoisomers, and the type of folate salt as this will impact the bioavailability of the product.

How Genomind’s Pharmacogenetic Test applies to MTHFR variants

An example of the utility of the MTHFR gene when using the Genomind pharmacogenetic (PGx) test is summarized in the following case.

A clinician performed the Assay on his 67‐year old male patient, an attorney, with a long history of mild persistent depression and generalized anxiety disorder, as well as cognitive issues and sleep disturbance. At the time of testing, the patient was prescribed fluoxetine, 20mg/day and folic acid, 1mg/day. While on this regimen, the patient’s PHQ‐9 score was an 8 (mild depression). Genetic results showed that this patient was homozygous at the C677T polymorphism, which is associated with a 70% reduction in MTHFR activity. Following the test results, the clinician discontinued the folic acid regimen and prescribed 15mg of L‐methylfolate. The patient was also prescribed trazodone for sleep. At 8 week follow up, the patient’s PHQ‐9 score was 0, and he reported improved sleep, concentration, and reduced anxiety. He also indicated, “I am finally enjoying my job again.”

In Conclusion

The MTHFR gene is essential in providing the body with the instructions needed to make the MTHFR enzyme. It is responsible for converting folic acid to the biologically active form, methylfolate. Insight into your patients’ genetics and drug metabolism profile, specifically MTHFR, can allow for personalized treatment plans and medication choices.

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  1. U.S. National Library of Medicine. Genetics Home Reference, <> (2016).
  2. Van der Put, N. M. et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural‐tube defects? American journal of human genetics 62, 1044‐1051, doi:10.1086/301825 (1998).
  3. Zintzaras, E. C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta‐analysis of genetic association studies. Psychiatric genetics 16, 105‐115, doi:10.1097/01.ypg.0000199444.77291.e2 (2006).
  4. Stahl, S. M. Novel therapeutics for depression: L‐methylfolate as a trimonoamine modulator and antidepressant‐ augmenting agent. CNS spectrums 12, 739‐744 (2007).
  5. Papakostas, G. I. et al. Effect of adjunctive L‐methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. The Journal of clinical psychiatry 75, 855‐863, doi:10.4088/JCP.13m08947 (2014).
  6. Mech, A. W. & Farah, A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double‐blind, placebo‐controlled study. The Journal of clinical psychiatry 77, 668‐671, doi:10.4088/JCP.15m10166 (2016).
  7. Wan, L., Li, Y., Zhang, Z. et al. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry 8, 242,  Methylenetetrahydrofolate reductase and psychiatric diseases | Translational Psychiatry ( (2018).
  8. Shelton, R. C., Sloan Manning, J., Barrentine, L. W., & Tipa, E. V. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. The primary care companion for CNS disorders15(4), PCC.13m01520.
  9. Liew, S.C. and E.D. Gupta, Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet, 58(1): p. 1-10 (2015).

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