{"paper_id":"f6fc84f6-0753-4666-a839-1cf8a7a0f6a9","body_text":"Open Access, Volume 2 \n5-MTHF: A mandatory support for infertile \nT677T MTHFR mutation carriers\nCase Report\nwww.jcimcr.org\nJournal of\nClinical Images and Medical Case Reports\nReceived: Sep 16, 2021\nAccepted: Oct 21, 2021\nPublished: Oct 28, 2021\nArchived: www.jcimcr.org\nCopyright: © Menezo YJR (2021).\n*Corresponding Author: Yves JR Menezo\nLaboratoire CLEMENT, Paris, France. \nEmail: Yves.menezo@gmail.com\nISSN 2766-7820\nKristy L Martin1,2,3; Edouard J Servy1; Yves JR Menezo2*\n1University of Medicine and Health Sciences, New York, NY, USA.  \n2Servy institute of Reproductive endocrinology, Augusta, Ga, USA.\n3Laboratoire CLEMENT, Paris, France.\nIntroduction\nMTHFR, (methylenetetrahydrofolate reductase) is an en -\nzyme involved in the folic acid cycle connected to the 1-carbon \ncycle (1-CC). MTHFR, located on the short arm of chromosome \n1, catalyses the reduction of 5,10 methylenetetrahydrofolate to \n5-methytetrahydrofolate, and is used for cellular methylation \nprocesses including epigenetic and imprinting regulation via \nDNA and histone methyl tagging. These two cycles play a ma -\njor role in DNA repair, but also in gametogenesis, early embryo \ndevelopment, embryo implantation, and pregnancy mainte -\nnance [1,10]. Two common MTHFR polymorphisms, C677T and \nAbstract\nMethylation is an ineluctable biochemical process in reproduc -\ntion, that is a necessary step for proper gametogenesis and embryo \ndevelopment, through the conversion of folic acid to 5 methyltetra -\nhydrofolic acid. This case report describes a 39-year-old female with \nknown history of stage II endometriosis and premature ovarian in -\nsufficiency, who suffered from a biochemical pregnancy, followed by \nfailed ART attempts such as intrauterine inseminations (IUI) and in-vi-\ntro-fertilization (IVF) while being treated with high doses of folic acid. \nAfter discovering the patient was affected with a homozygous methy-\nlenetetrahydrofolate reductase (MTHFR) mutation (SNP 677TT), she \nwas subsequently treated with 5-methyltetrahydrofolate. After three \nmonths of treatment, she spontaneously conceived and delivered at \nterm, by c-section, a healthy 48.26 cm (19 inches), 3 kg (6 pounds \n9 ounces) girl. Infertility management of patients with MTHFR de -\nficiency should focus on replacement of 5-methyltetrahydrofolate. \nThereby, minimizing the risk of pregnancy loss, decreasing fetal ab -\nnormalities, and improving chances of conception. This observation \nemphasizes the need to include methylenetetrahydrofolate reduc -\ntase deficiency in the differential diagnosis in patients with recurrent \npregnancy loss, failed assisted reproductive therapy and unexplained \ninfertility.\nKeywords: MTHFR 677TT SNP; endometriosis; ART failures; prema -\nture ovarian insufficiency; 5MTHF.\nA1298C, reduces MTHFR activity, causing hyperhomocystein -\nemia, homocystinuria, and hypomethioninemia [2,3,9] increas-\ning first trimester miscarriages, failed assisted reproductive \ntechnology,  endometriosis, and premature ovarian insufficien-\ncy [5,6,7,8,11]. High doses of folic acid is not a solution for the \naforementioned problems, as synthetic folic acid has a poor ca-\npacity to enter the folate cycle to form tetrahydrofolate (THF).  \nThis can lead to unmetabolized folic acid syndrome (UFAS). This \nreport reviews the case of a female patient who had a history \nof stage II endometriosis with premature ovarian insufficiency, \none biochemical pregnancy, and failed ART attempts. After dis-\n\nwww.jcimcr.org                Page 2\nCitation: Martin KL, Servy EJ, Menezo YJR. 5-methyltetrahydrofolate: A mandatory support for T677T MTHFR SNP women \nsuffering from premature ovarian insufficiency, endometriosis and/or multiple ART failures. J Clin Images Med Case Rep. \n2021; 2(5): 1386.\ncovering the homozygous mutation for MTHFR C677T SNP , the \npatient was successfully treated with 5-MTHF.\nMTHFR SNPs may decrease, the formation of 5MTHF, neces-\nsary for Homocysteine recycling, as it impairs the methylation \ncapacity (especially DNA). The blockade can lead to accumula -\ntion of unmetabolized folic acid, and to an increase of circulat -\ning homocyteine.\nFigure 1: Folic acid and 1 carbon cycle.\nCase description  \nSA Gravida 0, Para 0, Abortus 0, presented at 39 years of \nage in October 2019 with a past medical history of hypermen -\norrhea, secondary dysmenorrhea and pelvic adhesive disease \nwith stage II endometriosis discovered at the time of a laparos-\ncopy performed in October 2018. Her menarche occurred at the \nage of 13. She had regular 28–30-day cycles with heavy periods \nlasting 5 to 7 days. At this time the couple had been trying to \nconceive for over 2 years while taking nature-made prenatal vi-\ntamins and the wife was given 9 rounds of clomid treatments \n(6 – 50 mg, 3- 100 mg).  \nNormal physical examination with an AMH value of 0.877 \nng/mL was noted. Patient was asked to return in November \n2019 for an ultrasound. Pelvic ultrasound revealed normal size \nuterus with bilateral hypo-trophic ovaries. Right ovary had a \nvolume of 1.71 mL, with 1 or 2 antral follicles. Left ovary had a \nvolume of 1.83 mL, with 2 antral follicles noted.  At this time the \npatient was diagnosed with premature ovarian insufficiency. Pa-\ntient was advised to take DHEA 25 mg 3 times per day. The male \nfactor was considered as sub-normal with a concentration of \n20 million sperm cells per ml, a 10% progressive motility and a \n4% normal morphology (Kruger criteria). The couple was coun-\nselled on intrauterine insemination (IUI), in-vitro-fertilization \n(IVF) and continuation of commercial routine prenatal vitamins.  \nPatient was then started on an IUI cycle with stimulation using \n50 mg of clomid on cycle days (CD) 3-7 and 100 IU of rFSH CD \n6-10. Patient returned on November 20,2019, CD 10, where a \nfollicle measuring 20 mm was noted on the left ovary and en -\ndometrium 8 mm with a triple layer, estradiol level of 519 pg/\nmL and LH level of 5.2 mIU/mL. Following an injection of 10,000 \nunits hCG on Nov 20, IUI was completed on November 22, when \novulation was noted. No conception was noted on December \n9, 2019. \nPatient returned, January 3, 2020, for a saline infusion sono-\nhysterogram (SIS). Normal uterine size endometrial cavity, no \ndefect and good expansion noted. Right ovary had a volume of \n10 mL, with a 30 mm functional ovarian cyst noted. Left ovary \nhad a volume of 1.51 mL and 2 antral follicles.  Patient had a \nbiochemical pregnancy on July 6, 2020 following a spontaneous \nconception.\nOn July 31,2020, the patient returned for IVF. Her ovaries \nwere stimulated with 9 days of 200 IU of rFSH with 150 IU of \nFSH/LH, and 4 days of .25mg GnRH antagonist on cycle days \n7 through 10. Ten oocytes were retrieved. Seven fertilized af -\nter intracytoplasmic sperm injection (ICSI). On day 3, four 7-8 \ncell embryos and three 4-6 cell embryos were noted.). Further \ngrowth arrested and no embryo transfer completed. \nThe patient and her spouse were both advised to discontin -\nue any vitamins containing folic acid and start vitamins with a \ndaily dose of 1,000 mcg of 5-MTHF (folate) with chelated zinc \nand a vitamin B complex. On December 3, 2020 spontaneous \nconception occurred and the patient was followed through the \nfirst trimester of gestation, then transferred for obstetrical care.  \nOn July 27, 2021, a healthy 48.26 cm (19 inches), 3 kg (6 pounds \n9 ounces) girl was delivered by c-section.\nDiscussion and conclusion\nThis case report is in line with the association between long \nlasting infertility, miscarriages, failed ART attempts and MTHFR \nSingle Nucleotide Polymorphism (SNP). Moderate endome -\ntriosis surgically treated, recurrent failed clomid stimulations, \nfailed IUI, biochemical pregnancy and failed ART could not be \novercome before treatment with 5-MTHF, the compound lo -\ncated downstream the MTHFR blockade. MTHFR SNP may lead, \nsooner or later to embryo developmental arrests [1,4,8,14]. \nThis means that patients with endometriosis [11,12], a history \nof recurrent pregnancy losses, multiple failed IUIs or failed ART \nshould be tested for MTHFR mutations. Homocysteine levels \nwere not obtained in this patient, although it is a weaker marker \nespecially in women, more protected than the men against an \nincrease in homocysteine.\nTreatment with exogenous 5-MTHF vs synthetic folic acid, \nallows the mutated MTHFR SNP problems to be bypassed. It \navoids uncertainties due to treatments with high doses of syn -\nthetic folic acid, such as Unmetabolized Folic Acid (UMFA) and \npseudo-MTHFR syndrome, while possibly improving ovarian \nquality, and pregnancy outcome [3]. High doses of folic acid \ncan also increase homocysteine via a pseudo MTHFR effect [13] \nand lead to an adverse competition between natural folate (5-\nMTHF) and unmetabolized folic acid, for cellular transport and \nmetabolism. Testing patients for an MTHFR mutation prior to \nIUIs, expensive ART procedure, or pre-implantation genetic \nscreening could possibly help avoid unexplained lack of implan-\ntation or recurrent pregnancy losses. \nReferences\n1. Menezo Y , Clement P , Clement A and Elder K.  Methylation: An \nIneluctable Biochemical and Physiological Process Essential to \nthe Transmission of Life. Int J Mol Sci. 2020; 21: 9311.\n2. Frost P , Bloom H., Milos R, et al. A candidate genetic risk factor \nfor vascular disease: A common mutation in methylenetetrahy-\ndrofolate reductase. Nature genetics. 1995; 10: 111-113.\n\nwww.jcimcr.org                Page 3\n3. Weisberg I, Tran P , Christensen B, Sibani S, Rozen R. A Second \nGenetic Polymorphism in Methylenetetrahydrofolate Reductase \n(MTHFR) Associated with Decreased Enzyme Activity. Molecular \ngenetics and metabolism. 1998; 64: 169-172.\n4. Silvestris E, Cohen M, Cornet D, et al. Supporting the One-Car -\nbon Cycle Restores Ovarian Reserve in Subfertile Women: Ab -\nsence of Correlation with Urinary Bisphenol A Concentration. \nBioResearch open access. 2017; 6: 14-109.\n5. Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR \nisoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic \nacid: A key to pregnancy outcome: a case series. Journal of as -\nsisted reproduction and genetics. 2018; 35: 1431-1435.\n6. Hague WM. Homocysteine and pregnancy. Best practice & re -\nsearch Clinical obstetrics & gynaecology. 2003; 17: 459-469.\n7. A.B.C. Coumans, P .C. Huijgens, C. Jakobs, R. Schats, J.I.P . de Vr-\nies, M.G. van Pampus, G.A. Dekker, Haemostatic and metabolic \nabnormalities in women with unexplained recurrent abortion, \nHuman Reprod., 2019; 14: 211–214.\n8. D’Uva M, Di Micco P , Strina I, et al. Hyperhomocysteinemia in \nwomen with unexplained sterility or recurrent early pregnancy \nloss from Southern Italy: A preliminary report. Thrombosis jour-\nnal.  2007; 5: 10-10.\n9. Steven W Bailey, June E Ayling. The extremely slow and variable \nactivity of dihydrofolate reductase in human liver and its impli -\ncations for high folic acid intake. PNAS. 2009; 106: 15424-15429. \n10. D’Elia P , dos Santos A, Bianco B, Barbosa C, Christofolini D, Aoki \nT. MTHFR polymorphisms C677T and A1298C and associations \nwith IVF outcomes in Brazilian women. Reproductive biomedi -\ncine online. 2014; 28: 733-738.\n11. Clement A, Cornet N, Alvarez, Brami C, Clement P and Menezo Y , \nEndometriosis pathogenesis: role played by the oxidative stress \ndue to MTHFR mutations. Fertility and Sterility. 2018; 110: E394-\nE395.\n12. Koukoura O, Sifakis S, Spandidos D. DNA methylation in endo -\nmetriosis (Review)  DNA methylation in endometriosis, Molecu-\nlar Medicine Reports. 2016; 13: 2939-2948.  \n13. Cornet D, Clement A, Clement P , Menezo Y . High doses of fo -\nlic acid induce a pseudo-methylenetetrahydrofolate syndrome \nSAGE Open Med Case Reports. 2019; 7: 2050313X19850435.\n14. Enciso M, Sarasa J, Xanthopoulou L, Bristow S, Bowles, et al. \nPolymorphisms in the MTHFR gene influence embryo viability \nand the incidence of aneuploidy. Hum. Genet. May. 2016; 135: \n555-568.","source_license":"CC0","license_restricted":false}