MTHFR gene mutation. What you need to know!

The MTHFR gene is responsible for the production of an enzyme called methylenetetrahydrofolate reductase that plays role in processing amino acids, the building blocks of proteins. This enzyme is very important for a chemical reaction involving forms of the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a molecule called 5,10-methylenetetrahydrofolate to a molecule called 5-methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.

Homocysteine is an aminoacid containing a thiol group and formed by intracellular demethylation of methionine. Homocysteine is what scientists refer to as a non-protein amino acid. In other words, we cannot build protein from homocysteine. It is a substance found in the blood that can be accurately measured with a simple blood test. Homocysteine is not obtained from the diet but is biosynthesized inside our bodies from the amino acid methionine by the removal of a methyl group.

The level of plasma homocysteine varies according to its two metabolic pathways.

1. remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction);

2. transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase.

Figure 1. Simplified folate metabolism pathways involved in methionine recycling, DNA synthesis, purine synthesis and methylation reactions

The blood homocysteine level is inversely proportional to the plasma levels of folate, vitamin B12 , pyridoxal 5-phosphate and implicitly with the exogenous intake of these vitamins.

Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture.

There are two main MTHFR mutations that researchers focus on most often: MTHFR C677T and MTHFR A1298C. Mutations can occur on different locations of these genes and be inherited from only one or both parents. Having one mutated allele is associated with increased risk of certain health problems, but having two increases the risk much more.

The autosomal recessive bp 677 C --> T mutation in the MTHFR gene leads to the substitution of valine for alanine. Individuals who are homozygous for this C677T mutation exhibit a decreased specific activity and increased thermolability of this enzyme. This leads to increased plasma levels of homocysteine. Hyperhomocysteinaemia elevates the risk of mild cognitive impairment and dementia of the Alzheimer's type.  However, some studies have reported that an increase in plasma homocysteine may be an independent risk factor for the development of AD.

the MTHFR T/T genotype and the T allele are significantly associated with severity of AD. The plasmatic homocysteine level are directly correlated with cognitive decline in old people.

Action plan. Test your MTHFR and CBS genes and test your homocysteine level.

The normal value for plasmatic homocysteine: 5-12μmol/L

In case of high homocysteine level, here the basic pro-methylation protocol:

TMG(betaine) 250 mg

400 mcg folate( 5-MTHF)

Vitamin B12 5mcg

Vitamin B6 3 mg

Vitamin B2 2.4 mg

Zinc 12.5 mg

And have  more folate in your diet means you’re better able to create the active form of 5-MTHF. Some of the best high folate food include:

• Beans and lentils
• Leafy green vegetables like raw spinach
• Asparagus
• Romaine
• Broccoli
• Avocado
• Bright-colored fruits, such as oranges and mangoes

References

Brustolin S, Giugliani R, Félix TM (2010). Genetics of homocysteine metabolism and associated disorders. Braz J Med Biol Res.43(1):1-7. PMID:19967264

Den Heijer M, Lewington S, Clarke R (2005). Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost. 3(2):292-9. PMID:15670035

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 10(1):111-3. PMID:7647779

Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group (2002). MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 288(16):2023-31. PMID:12387655

Van der Put NM, Gabre?ls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998). A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 62(5):1044-51. PMID:9545395