Genetic polymorphisms in the key enzyme MTHFR (methylenetetrahydrofolate reductase) can lead to a L-methylfolate deficiency which is not detected by
standard folate blood tests. MTHFR polymorphisms, and thus lowered Lmethylfolate levels is associated with symptoms and conditions such as mental
health disorders, cardiovascular disease, obesity and birth defects. Genetic testing can ascertain whether an individual has one of the common polymorphisms which leads to methylfolate deficiency, and can verify when supplementation of this special form of folate is warranted.

Folate: An essential vitamin

Folate is a water soluble B vitamin (B9), which humans cannot synthesize and is thus a dietary requirement. The primary function of folate is the transfer of methyl and formyl groups. It is essential for cell growth and reproduction, the formation of certain amino acids (methionine, serine, glycine,
and histidine), the breakdown of proteins (e.g. homocysteine), the formation of DNA and RNA, red blood cell maturation, and serotonin, noradrenaline (norepinephrine) and dopamine formation.

Active and Inactive Forms of Folate

Dihydrofolate (DHF) is the dietary form of folate, whilst folic acid is the synthetic form of folate used in supplements and to fortify the food supply. These forms of folate are not biologically active; they must undergo enzymatic transformation to methylfolate in order to be used by cells. Methylfolate,
unlike the other folates, is able to cross the blood-brain barrier for use in the CNS.

The conversion of dihydrofolate (DHF) and folic acid to methylfolate, occurs through a process. i.e. Folic acid is converted to DHF by the dihydrofolate reductase enzyme (DHFR) –> DHF converted to tetrahydrofolate (THF) –> THF converted to 5,10-methyleneTHF –> 5,10-methyleneTHF converted to methylfolate by the methyltetrahydrofolate reductase enzyme (MTHFR).

L-MethylFolate Deficiencies

For many people, their DHF from the diet leads to adequate methylfolate levels, however, malabsorption, digestive and liver disease, as well as certain genetic enzyme polymorphisms, can result in an impaired ability to activate folic acid. This methylfolate deficiency results in symptoms and conditions including mental health disorders, cardiovascular disease, increased adiposity, reduced lean body mass, birth defects, and an increased risk for certain cancers.

  • Alcohol withdrawal seizure
  • Hypertension
  • Autism
  • Increased breast cancer risk (women >55 years)
  • Cardiovascular disease: thromboembolism, atherosclerosis, and myocardial infarction Neural tube and other birth defects
  • Colorectal neoplasias
  • Peripheral neuropathy
  • Dementia and memory loss
  • Reduced lean body mass and increased body fat
  • Depression and irritability
  • Schizophrenia
  • Elevated homocysteine
  • Stroke
MTHFR Polymorphisms C677T & A1298C Alleles

The C677T allele is characterised by a point mutation at position 677 of the MTHFR gene that converts a cytosine (C) into a thymine (T); this mutation results in an amino acid substitution (alanine to valine) in the enzyme. This genetic change leads to a defective MTHFR enzyme that maintains only 50% of the normal activity. The wild-type genotype (677CC) exists in 75%, while heterozygosity (677CT) exists in 10% of the general white population from northern European descent. Homozygosity for the valine variant (677TT) is present in about 15% of the general population and these individuals tend to have increased blood homocysteine levels. Those heterozygous (677CT) have intermediate homocysteine levels. The effect of the MTHFR genotype on homocysteine concentrations is most significant among those with low folate status.

Another common polymorphism, the A1298C allele, is characterised by a point mutation at position 1298 of the MTHFR gene that converts an alanine (A) into cytosine (C); this mutation results in an amino acid substitution (glutamate to alanine) in the enzyme. People who are heterozygous for both
the A1298C and C677T alleles tend to have increased serum homocysteine levels, a biochemical profile similar to that seen among C677T homozygotes.

MTHFR Polymorphisms and Obesity

Research has indicated that the C677T MTHFR allele is associated with obesity. A study found that those with the homozygote mutation (677TT) had lower lean body mass. Healthy postmenopausal women who have the 667TT allele also have higher androgen hormone levels, body mass index (BMI),
and waist to hip ratios. It was hypothesised that the reduced methylfolate caused impaired homocysteine breakdown, endothelial dysfunction and insulin resistance.


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