Methylenetetrahydrofolate Reductase (MTHFR) deficiency is a genetic condition that impacts how the body processes folate (vitamin B9). This condition is rooted in a variation of the MTHFR gene, which provides the instructions for creating a specific enzyme. When the enzyme is less efficient, it disrupts a crucial chemical process necessary for maintaining overall health.
The Enzyme’s Role in Folate Metabolism
The MTHFR enzyme drives a single, irreversible step in the body’s one-carbon cycle, a network of reactions central to cellular function. Its primary job is to convert inactive forms of folate—such as dietary folate or synthetic folic acid—into 5-methyltetrahydrofolate (5-MTHF). This 5-MTHF is the biologically active form of the vitamin that the body can readily use.
The 5-MTHF is responsible for managing levels of the amino acid homocysteine. It donates a methyl group to convert homocysteine back into methionine, a necessary building block for proteins. When the MTHFR enzyme is impaired, this recycling process slows down, causing homocysteine levels to accumulate in the bloodstream, a condition known as hyperhomocysteinemia.
Understanding MTHFR Genetic Variants
The rare, severe MTHFR deficiency is a metabolic disorder that can cause serious neurological symptoms in infants and children. This must be distinguished from the much more common genetic variations, or polymorphisms, that most people refer to. The common variants are widespread genetic differences that result in reduced, but not absent, enzyme function, and are not typically classified as a disease.
The two most frequently discussed polymorphisms are C677T and A1298C, with the letters and numbers indicating the precise location of the change on the gene. Everyone inherits two copies of the MTHFR gene, one from each parent. A person is heterozygous if they have one normal copy and one variant copy, while a person with two variant copies is called homozygous.
The C677T variant is the most impactful on enzyme efficiency. Individuals homozygous for this variant (TT genotype) typically see their MTHFR enzyme activity reduced to about 30% of normal function. The A1298C variant is generally milder, reducing enzyme activity to approximately 60% of normal in homozygous individuals. Individuals can also be “compound heterozygous,” possessing one copy of C677T and one copy of A1298C, which often results in an activity level similar to the homozygous A1298C variant.
Health Implications of Impaired MTHFR Function
The main health concern associated with impaired MTHFR function is the elevation of homocysteine in the blood (hyperhomocysteinemia). This buildup contributes to irritation and damage to the inner lining of blood vessels. While MTHFR variants are not considered a direct cause of disease, the resulting high homocysteine levels are an acknowledged risk factor for certain health outcomes.
Elevated homocysteine has been linked to an increased risk of cardiovascular issues, including hardening of the arteries and the formation of blood clots. However, for the majority of people with common MTHFR variants, this risk remains low, particularly where food is routinely fortified with folic acid.
The common variants are also associated with a slightly higher risk of having a child with a neural tube defect (NTD), such as spina bifida. This occurs because the active form of folate is necessary for proper development of the fetal spine and brain early in pregnancy. For individuals with reduced MTHFR capacity, insufficient folate intake can exacerbate the problem, leading to elevated homocysteine and a higher NTD risk. Research also suggests links between reduced MTHFR function and some neurological issues, as the methylation cycle supports neurotransmitter production and nerve health.
Testing and Treatment Approaches
Testing for MTHFR variants is typically performed using a genetic test (blood sample or cheek swab) to identify the common C677T and A1298C variants. However, medical experts often prioritize a simpler blood test to measure homocysteine levels, since elevated levels are the clinical concern, regardless of the cause.
The primary goal of managing reduced MTHFR function is to bypass the enzyme’s inefficiency. For those with high homocysteine levels, treatment involves targeted nutritional supplementation. Standard folic acid, which must be converted by the MTHFR enzyme, may not be effectively processed. Therefore, healthcare providers recommend L-methylfolate (5-MTHF), which is the pre-converted, active form of folate the body can use immediately.
Complementary supplementation with vitamin B12, often in the form of methylcobalamin, is also frequently recommended. B12 acts as a necessary cofactor in the process that uses 5-MTHF to convert homocysteine to methionine. Dietary changes focus on ensuring adequate intake of natural folates found in leafy green vegetables, as well as B vitamins, to support the entire metabolic pathway. The effectiveness of this approach often eliminates the clinical consequence of the genetic variant.