Women with Methylenetetrahydrofolate Reductase Gene Polymorphism and the Need for Proper Periconceptional Folate Supplementation

Abstract

Maternal folate supplementation is critical for fetal development. Women with MTHFR (methylenetetrahydrofolate reductase) gene polymorphisms may not be getting the proper folate form to support fetal development. The objectives of this review were to: (1) undertake a comprehensive review on the association of MTHFR polymorphisms with the risk for various congenital diseases and other adverse pregnancy outcomes, (2) assess the efficacy and safety of current folic acid and other supplementations in women with the MTHFR polymorphism, and (3) provide guidance on the appropriate supplementation for women of childbearing potential with the MTHFR gene polymorphism in order to decrease these adverse pregnancy outcomes. Our assessments show that women with MTHFR gene polymorphism cannot efficiently convert folic acid to L-5-methyl-tetrahydofolate, the predominant active form of folic acid, due to reduced MTHFR enzymatic activity. L-5-methyl-tetrahydrofolate is currently commercially available under several brand names. Based on our comprehensive review and knowledge of the biochemistry of the folates, we recommend that L-5-methyltetrahydrofolate be given in combination with folic acid to women with MTHFR polymorphism that are pregnant or planning to become pregnant. Further study is needed to determine the optimal dose.

Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS)

“…Unbalanced folate homeostasis during pregnancy may cause adverse epigenetic mechanisms on the offspring [43], and though maternal folate supplementation reduces congenital malformations [24], indiscriminate fortification may cause a different kind of pediatric cancers [21,24,44,45,46,47,48].…”

“…Polymorphisms in DHFR (dihydrofolate reductase) and MTHFR (methylene-tetrahydrofolate reductase) genes and in other folate-metabolizing genes have been investigated both in children and mother DNA as inherited predispositions to different pediatric pathological conditions [20,21,22,23,24] and as pharmacogenetics factors involved in treatment response and survival both in adult and pediatric patients [11,15,16,17,18,25,26,27]. We previously reported a significant under-representation of DHFR and MTHFR gene variants among adult ALL and non-Hodgkin’s lymphoma in combined double carrier status, deserving increased drug-related toxicity and reduced survival to the polymorphic condition [15,16,17,18].…”