blood analysis

MTHFR mutation of G.Bertelli


The MTHFR mutation is a genetic defect affecting the methylen-tetrahydrofolate reductase enzyme. This aberration is related to hyperhomocysteinemia (elevated levels of homocysteine ​​in the plasma) and affects the metabolism of folates .

The MTHFR gene mutation is transmitted in an autosomal recessive manner and is responsible for a reduction in the activity of the enzyme for which it encodes. This phenomenon has been identified as a risk factor for the development of thrombosis, coronary heart disease, spontaneous abortions and neural tube defects .

MTHFR mutation analysis is performed from a blood sample.

What's this

The MTHFR mutation is a genetic defect that causes the reduction or loss of activity of the methylen-tetrahydrofolate reductase enzyme. The consequence of this phenomenon is the increase in the values ​​of homocysteine in the blood and, at the same time, the reduction of plasma levels of folic acid .

Gene MTHFR: what is it?

The MTHFR gene encodes an enzyme called methylen-tetrahydrofolate reductase . The latter is involved in the conversion of 5, 10-methylen-tetrahydrofolate to 5-methyl-tetrahydrofolate, a molecule that allows the remethylation of homocysteine ​​into methionine, through the intervention of vitamin B12 as a cofactor.

The transformation of homocysteine ​​into methionine is a very important metabolic stage. High levels of this substance in the blood (hyperhomocysteinemia) are related to the increase in cardiovascular risk and other related diseases.

Transmission mode

The MTHFR gene can be subject to mutations that are transmitted in a recessive manner . This means that the disease can express itself when the genotype is homozygous, ie it has both mutated alleles of the gene (note: if the genotype is heterozygous, the condition of a healthy carrier is defined instead).

At the European level, the MTHFR mutation occurs in 3.5% of the total population; heterozygosity affects about 43-45% of people (healthy carriers), while homozygosity - that is the state that involves the manifestation of the disease - is present in 8-15% of cases.

In homozygous subjects, the activity of the MTHFR enzyme is reduced by 50-70% . This results in an increase in homocysteine ​​in the blood (hyperhomocysteinemia), therefore a greater risk of developing a cardiovascular disease .

Furthermore, in pregnant women with folic acid deficiency, the presence of the MTHFR mutation is also a risk factor for neural tube defects .

What is the enzyme MTHFR for?

  • Methylen-tetrahydrofolate reductase ( MTHFR ) is an enzyme involved in the transformation of 5-10-methylene-tetrahydrofolate (THF) into 5-methyl THF, which is the most abundant circulating form of folic acid.
  • Folic acid serves as a methyl donor (or methyl group) in the remethylation of homocysteine (an amino acid normally present in very small amounts in the body's cells) to methionine (an essential amino acid that the body can only derive from nutrition). Vitamin B12 is required for this reaction, catalyzed by methionine synthase. In practice, the MTHFR enzyme reduces the concentration of homocysteine, transforming it into methionine.
  • The mutation determines the production of a mutated MTHFR with a reduced enzymatic activity of about 50% : as a consequence there is an increase in homocysteine ​​in the blood, therefore an increased risk of vascular disease. In the dietary deficiency of folic acid, the presence of the mutated enzyme also represents a risk factor for neural tube defects in pregnant women.

What is homocysteine?

  • The MTHFR mutation is one of the most common genetic alterations involved in the metabolism of homocysteine .
  • Homocysteine ​​is a sulfur amino acid (ie containing a sulfur atom), whose metabolism is regulated thanks to the fundamental intervention of enzymes and vitamins. Once produced inside the cells, this substance is quickly converted into other products.
  • The control of homocysteine ​​values ​​in the blood ( homocysteinemia ) allows to diagnose a deficiency of folic acid or vitamin B12.
  • Increased levels of homocysteine ​​in the blood are considered cardiovascular risk factors, predisposing to the development of atherosclerosis, coronary artery disease, stroke and diseases of the peripheral vessels due to lipid deposits.

What is the MTHFR C677T mutation?

The MTHFR mutation is a genetic defect that hinders the conversion of homocysteine ​​into methionine, resulting in an increase in homocysteinemia, especially in subjects whose dietary intake of folic acid is not optimal. This alteration also determines a decrease in circulating folate levels.

Currently, about 40 different genetic aberrations against MTHFR are known.

  • The most common defect is represented by the replacement of a cytosine (C) in thymine (T) at the nucleotide at position 677 of the MTHFR gene ( mutation MTHFR C677T or 677C> T ). This corresponds to the presence of an Alanina with a Valine in the amino acid chain of the enzyme variant compared to the normal form. In subjects homozygous for the MTHFR C677T mutation, enzyme activity is reduced by 50%. The MTHFR C677T mutation is associated with cardiovascular problems, hyperhomocysteinemia, migraine and neural tube defects in the first trimester of pregnancy.
  • Another mutation associated with decreased activity of MTHFR is the replacement of an adenine (A) with a cytosine (C) at position 1298 (genetic variant A1298C). In particular, homozygous carriers maintain an enzyme activity of 60%. The MTHFR A1298C mutation is associated with irritable bowel, fibromyalgia, chronic pain and mood-related disorders.

The double heterozygosity, or copresence of the MTHFR C677T and A1298C mutations, preserves an enzymatic activity equal to 50-60%.

Why do you measure

Evaluation of the MTHFR mutation is indicated in cases where genetic causes are suspected to cause the increase in homocysteine.

The MTHFR mutation is analyzed as it is considered a risk factor for various diseases, especially in the presence of the concomitant folic acid or vitamin B12 deficiency (cofactors of the enzyme methylen-tetrahydrofolate reductase). These include heart disease, stroke, high blood pressure (hypertension), preeclampsia (increased blood pressure in pregnancy), psychiatric disorders and some particular forms of cancer.

When is the analysis prescribed?

The doctor may indicate the evaluation of the MTHFR C677T and A1298C mutations, when the patient presents:

  • Familiarity with cardiovascular diseases;
  • Venous thromboembolism (venous thrombosis or pulmonary embolism);
  • Cardiovascular diseases with premature onset;
  • Repeated natural abortions (poliabortività).

The test can also be recommended before using oral contraceptives.

The evaluation can be indicated by the doctor as part of prenatal screening (on amniotic fluid or chorionic villi) and neonatal.

Related Exams

The MTHFR mutation can be suspected after plasma or urinary homocysteine ​​dosing. Other exams associated with the MTHFR mutation search include:

  • Folate dosage (cofactor in the homocysteine ​​remethylation; without this, the homocysteine ​​levels in the plasma increase);
  • Search for mutations of factor V or factor II of coagulation, which may predispose to thrombotic phenomena.

Normal values

As a rule, the MTHFR mutation is absent .

Associated pathologies

MTHFR mutation is responsible for a number of pathological conditions, which can occur during fetal development (eg neural tube defects) or during adult life. The consequences of this anomaly are various and include delays in psycho-motor development, neural tube defects during fetal development (eg spina bifida), thrombotic phenomena, stroke, infarction, placental detachment and fertility disorders in general.


The MTHFR mutation is one of the causes that can determine hyperhomocysteinemia (increase in the plasma level of homocysteine). In fact, people who are affected are unable to transform homocysteine ​​into methionine.

The consequence of hyperhomocysteinemia is the increased risk of developing thrombotic episodes, stroke, atherosclerosis and myocardial infarction.

The mechanism by which the excess of homocysteine, following a MTHFR mutation, is associated with this increased predisposition to manifest cardiovascular disorders is not yet completely clear, but seems to be due to alterations in coagulation and damage to the endothelial wall of the vessels sanguinei.

Hyperhomocysteinemia can be associated with initially subtle and non-specific symptoms and signs, such as:

  • Diarrhea;
  • Dizziness;
  • Sense of fatigue and weakness;
  • Loss of appetite;
  • Pallor;
  • Accelerated heart beat;
  • Shortness of breath;
  • Pain in the mouth and tongue;
  • Tingling, numbness and / or burning on feet, hands, arms and legs.

Hyperhomocysteinemia is related to various other consequences, such as predisposition to develop bone fragility, neurodegenerative pathologies (such as senile dementia and Alzheimer's disease) and preeclampsia during pregnancy.

In the presence of the MTHFR mutation, homocysteine ​​can also be found in urine resulting in a condition known as homocysteine . In fact, homocysteine ​​is eliminated from the body through the urine, in the form of cystine.

It should be noted that the MTHFR C677T and A1298C mutations represent a cardiovascular risk factor especially in subjects with low plasma folate levels (or vitamin B9). This underlines the importance, therefore, both in the prevention and in the therapy of the nutritional intake of folic acid.

Neural tube defects

Some variants of the MTHFR mutation (gene polymorphisms) have been associated with an increased risk of neural tube defects . These consist of a series of congenital malformations secondary to the non-closure of the neural tube, in the period of development of the central nervous system (17th-30th day from ovulation).

The neural tube is a structure present in the embryo, which develops giving rise to the brain and spinal cord. Initially, this looks like a small ribbon of fabric that slowly folds inwards. If this process does not occur correctly, the formation of the spinal cord and brain is irreversibly compromised.

Depending on the type of MTHFR mutation and the presence of other concomitant factors, different pathologies can develop that range from the most severe forms - incompatible with post-natal life (such as anencephaly) - to milder ones, which can be corrected surgically (such as the small meningoceles).

ANENCEPHALIA is one of the most common disorders that occurs in the case of a MTHFR mutation. This very serious congenital malformation is characterized by the lack of development of the brain and skull bones. This condition is not, unfortunately, compatible with life: the children who are affected are destined to die prematurely or survive only for a few hours.

Another neural tube defect caused by a MTHFR mutation is the SPINA BIFIDA . This malformation of the central nervous system, present since birth, is due to the incomplete closure of one or more vertebrae, during skeletal development. This defect consists, in particular, in the lack of fusion on the median line of the two nuclei of ossification of the neural arch. The result is that a part of the spinal cord can protrude through an opening in the spine, with permanent damage to the nerve endings. The spina bifida can also occur in the presence of nutritional folate deficiency, which is why women who are planning a pregnancy and for the following months are strongly advised to take folic acid as a food supplement.

Other disorders

Various scientific studies have indicated the MTHFR mutation as a potential risk factor for several other diseases, including:

  • Cleft lip (birth defect in which there is a crack in the upper lip and an opening in the roof of the mouth);
  • High blood pressure (hypertension);
  • Preeclampsia or gestosis (increase in blood pressure during pregnancy);
  • Psychiatric disorders;
  • Some special forms of cancer.

How to measure it

The presence of the MTHFR mutation is performed on a venous blood sample.

The traditional diagnosis involves biochemical tests to identify the level of homocysteine ​​in the blood . Alternatively, the analysis and typing of mutations in the human MTHFR gene is possible with molecular biology techniques .


No special preparation is required before blood collection is useful for MTHFR mutation analysis.

Interpretation of Results

The results of the examination indicate whether the patient is a carrier of alterations in the gene that codes for the enzyme MTHFR.

The MTHFR mutation is associated with elevated homocysteine ​​levels and reduced plasma folate levels.

The excess of homocysteine ​​in the blood is considered a risk factor for cardiovascular diseases and venous thromboembolism. In the presence of low plasma folate levels, the MTHFR mutation further increases the predisposition to develop these pathological conditions. This underlines the importance, therefore, both in the prevention and in the therapy of the nutritional intake of folic acid.

Dietary deficiency of this element is also a risk factor for neural tube defects in pregnant women.

To know

To reduce the risk of neural tube defects, such as spina bifida, a pregnancy supplement of 4 mg / day of folic acid is recommended for women planning a pregnancy, starting from the pre-conception period (at least 1 month before conception). ), to be continued until the third month of gestation. A low contribution of this element during gestation could contribute, in fact, to the manifestation of a malformation to which the MTHFR mutation contributes.