Decreased enzymatic activity of 5,10-methylene tetrahydrofolate reductase affects the development of several diseases

  • Maša Vidmar Univerzitetni klinični center Ljubljana Ginekološka klinika
  • Jasna Grželj KRKA, d.d. Novo mesto Šmarješka 6 Novo mesto
  • Ksenija Gersak Univerza v Ljubjani Medicinska fakulteta in Univerzitetni klinični center Ljubljana Ginekološka klinika
  • Irena Mlinarič-Raščan Univerza v Ljubljani Fakulteta za farmacijo Aškerčeva 7 Ljubljana
Keywords: folic acid, MTHFR polymorphisms, folate metabolism, disease risk, drug interaction


The importance of folates in human physiology is well known, as are various pathologies associated with low folate status. Folate deficiency can occur due to low dietary intake, genetic predisposition or treatment with medicines affecting the folate status. The aim of this paper is to explore the importance of determining genetic polymorphisms which influence the levels of biologically active folate. MTHFR is involved in the transformation of 5,10-methylene-THF to 5-methyl-THF. Polymorphisms of the MTHRF gene are associated with decreased enzymatic activity.

Only 9.3 % of the population in Slovenia displays full activity of the MTHFR enzyme; these subjects are non-mutated homozygotes (wild-type alleles). In contrast, the average enzymatic activity in subjects with mutated alleles is between 50 and 60 %. MTHFR polymorphism is associated with an increased risk of hyperhomocysteinemia and cardiovascular diseases, neurological disorders and various types of cancer. There is also an increased risk for congenital malformations. Folic acid food fortification was introduced in some countries in order to assure an adequate folate status in the population. However, this approach does not address the decreased activity of MTHFR.

Polymorphism in the key enzymes of the folate cycle is common. Determination of the genetic predisposition is therefore plausible in the most vulnerable groups of the population, such as pregnant women and patients receiving medicines influencing the folate cycle in various ways, e.g. 5-fluorouracil, methotrexate and 6-mercaptopurine. Genotyping would allow the identification of patients at high risk for suboptimal folate status.


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Vidmar M, Grželj J, Gersak K, Mlinarič-Raščan I. Decreased enzymatic activity of 5,10-methylene tetrahydrofolate reductase affects the development of several diseases. ZdravVestn [Internet]. 26Jul.2016 [cited 17Sep.2019];85(5-6). Available from:
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