MTHFR: a key enzyme in homocysteine metabolism

Homocysteine is an amino acid produced from the metabolism of methionine, an amino acid that is crucial for protein synthesis and whose metabolism depends on cofactors such as vitamins B12, B6 and folic acid that are naturally consumed in the diet (Moll, Varga, 2015).
The enzyme methylenetetrahydrofolate reductase (MTHFR) plays an essential role in the conversion of homocysteine to methionine and thus in the regulation of homocysteine levels in the blood. Proper functioning of the MTHFR enzyme, in fact, is crucial for maintaining proper homocysteine levels, which, if accumulated, leads to increased risk of cardiovascular disease (Ganguly, et al., 2015).
Normally, homocysteine levels in the blood are low (approx. <15 µmol/L), but 5% to 7% of the general population are known to have slightly higher homocysteine levels (approx. 13-30µmol/L) . Homocystinuria, characterised by blood levels of homocysteine >100 µmol/L, is rarer.
Several factors contribute to elevated homocysteine levels in the blood, such as lack of dietary intake of folic acid, vitamin B6 and B12, mutations in the MTHFR gene, diseases such as hypothyroidism, renal dysfunction, chronic diseases such as diabetes and hypertension, and medication (Moll, Varga, 2015).

MTHFR gene mutations

Inherited mutations in the gene that produces the enzyme MTHFR lead to dysregulation of enzyme activity and consequently to excessively high physiological homocysteine levels, which are often associated with an increased risk of developing cardiovascular events (Ganguly, et al., 2015).
The most common mutations in the MTHFR gene are the point mutations C677T and A1298C, loss-of-function mutations that lead to a reduction in the efficiency of the enzyme and, consequently, cause homocysteine accumulation (Boˇskovi ́c et al., 2023).
The former, C677T, is extremely common in certain ethnic and geographical populations. In the United States, for example, 20% to 40% of white and Hispanic individuals are heterozygous for MTHFR C677T. The second, A1298C, on the other hand, is present in a smaller percentage: 7% to 12% of North American, European and Australian populations (Moll, Varga, 2015).

So what are the consequences of the presence of an MTHFR mutation?

As mentioned above, these mutations are associated with increased levels of homocysteine in the blood and consequently an increased risk of developing cardiovascular diseases, such as DVT and PE, but also complications in pregnancy, such as Down Syndrome and defects in neural tube development. (Moll, Varga, 2015).
Furthermore, mutations in the MTHFR gene can influence the response to chemotherapeutic drugs.
Indeed, as the MTHFR enzyme is involved in the metabolism of folate, its reduced functionality may increase the cytotoxicity of drugs such as fluorpyrimidines (e.g. 5-fluorouracil) commonly used for the treatment of colorectal, breast and head and neck cancer. Reduced activity of the enzyme, in fact, increases the formation and intracellular accumulation of 5,10-MTHF, an intermediate of 5-fluorouracil metabolism that is toxic to cells (Perrone, 2013).

Diagnosis and prevention of thrombotic events

Mutation diagnosis in the MTHFR gene is nowadays performed by genetic testing from a drop of blood or saliva. The Eurospital Eu-Gen MTHFR Dual-Type kit is able to detect both C677T and A1298C mutations in a single reaction tube, offering a valuable aid in identifying individuals carrying these mutations.
Subjects with mutations in the MTHFR gene are not treated specifically. However, in order to compensate for the reduced MTHFR activity and prevent the consequences, a diet rich in folic acid and vitamins B12 and B6 is recommended, which support the folate cycle and help maintain low homocysteine levels in the blood (Boˇskovi ́c et al., 2023).

Visit https://emb.eurospital.com/en/diagnostic-tests to find out more about this kit and the other products of the EGT – Eurospital Genetic Testing Product Line.

References:
1 Ganguly, P., Alam, S.F. Role of homocysteine in the development of cardiovascular disease. Nutr J 14, 6 (2015). https://doi.org/10.1186/1475-2891-14-6
2 Circulation Volume 132, Issue 1Jul 2015, “Homocysteine and MTHFR Mutations” Stephan Moll and Elizabeth A. Varga (doi: 10.1161/CIRCULATIONAHA.114.013311)
3 Bošković A, Ćuk A, Mandrapa V, Dugandžić Šimić A, Cvetković I, Orlović Vlaho M, Krešić T, Tomić T, Tomić V. Association of MTHFR polymorphism, folic acid and vitamin B12 with serum homocysteine levels in pregnant women. Biomol Biomed. 2024 Jan 3;24(1):138-143. doi: 10.17305/bb.2023.9260. PMID: 37622180; PMCID: PMC10787622.
4 Tesi Perrone Gabriele, 2013 “Identificazione di MTHFR 1298>C come marcatore predittivo di sopravvivenza in due coorti di pazienti con carcinoma colon-rettale (stadio II e III) trattati con terapia adiuvante a base di fluorpirimidine con o senza oxaliplatino”.

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