Correspondence

Homozygous Methylenetetrahydrofolate Reductase C677T Mutation and Male Infertility

N Engl J Med 2001; 344:1172-1173April 12, 2001

Article

To the Editor:

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The C677T in the gene that encodes MTHFR decreases the activity of the enzyme by 35 percent in persons who are heterozygous for the mutation and by 70 percent in those who are homozygous.1 The prevalence of the homozygous form is estimated to be between 5 percent and 10 percent. One study showed an increase in sperm count and motility after three months of treatment with folinic acid.2 By determining the frequency of the MTHFR C677T mutation, it may be possible to identify patients who have a tendency toward an altered folic acid metabolism and might benefit from folic acid supplementation.

Using the polymerase chain reaction (PCR) and restriction digestion with HinfI and internal restriction control,1 we assessed the prevalence of the MTHFR C677T mutation in male patients seeking fertility evaluation (Figure 1Figure 1Products of Internally Controlled Restriction Digestion of DNA from Fertile and Infertile Men.). DNA samples from 255 randomly selected men seeking fertility evaluation and from 200 controls were analyzed. Of the men in the infertility group, 44.7 percent were normal and 36.5 percent were heterozygous for the mutation, as compared with 46.0 percent and 44.5 percent, respectively, in the control group. The prevalence of the homozygous mutation was 18.8 percent in the infertility group as compared with 9.5 percent in the control group (P=0.008 by chi-square analysis). Hence, MTHFR products may have a role in the pathogenesis of male infertility. In about 50 percent of cases of infertility or subfertility among couples, a male factor can be identified,3 so among fertile partners of subfertile women, one would expect the prevalence of the homozygous MTHFR C677T mutation to be about 10 percent, which means that the prevalence should be considerably greater among subfertile men. Homozygosity for the MTHFR C677T mutation decreases folate levels in the blood4 and increases homocysteine levels.1,4 The association between homozygosity for the MTHFR C677T mutation and male infertility cannot explain whether the decrease in methyltetrahydrofolate, the main constituent of plasma folate, or the increase in homocysteine is directly responsible for impaired fertility. However, there may be beneficial effects of folic acid supplementation in selected patients with infertility who can easily be identified with the use of PCR. Supplementation with folic acid, which is currently being widely discussed, will both increase folate levels in the blood and reduce homocysteine levels.5 Folic acid supplementation is known to mask anemia that is due to vitamin B₁₂ deficiency, allowing irreversible neurologic damage to occur. Therefore, in trials in which subfertile men who are homozygous for MTHFR C677T receive folic acid supplementation, vitamin B₁₂ levels should be monitored.

Guntram Bezold, M.D.
Monika Lange, M.D.
Ralf Uwe Peter, M.D.
University of Ulm, 89081 Ulm, Germany

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Citing Articles (31)

Citing Articles

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   Meng Yin, Lingyan Dong, Jinghao Zheng, Haibo Zhang, Jinfen Liu, Zhiwei Xu. (2012) Meta Analysis of the Association between MTHFR C677T Polymorphism and the Risk of Congenital Heart Defects. Annals of Human Genetics 76:1, 9-16
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   Annelien Massart, Willy Lissens, Herman Tournaye, Katrien Stouffs. (2012) Genetic causes of spermatogenic failure. Asian Journal of Andrology 14:1, 40-48
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   Laura Pickell, Qing Wu, Xiao-Ling Wang, Daniel Leclerc, Hana Friedman, Alan C. Peterson, Rima Rozen. (2011) Targeted insertion of two Mthfr promoters in mice reveals temporal- and tissue-specific regulation. Mammalian Genome
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   Işıl Özer, Mustafa Özçetin, Hatice Karaer, Semiha G. Kurt, Şemsettin Şahin. (2011) Retrospective Approach to Methylenetetrahydrofolate Reductase Mutations in Children. Pediatric Neurology 45:1, 34-38
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   G. T. Vani, N. Mukesh, P. Rama Devi, P. Usha Rani, P. P. Reddy. (2011) Methylenetetrahydrofolate reductase C677T polymorphism is not associated with male infertility in a South Indian population. Andrologiano-no
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   W. Wu, O. Shen, Y. Qin, J. Lu, X. Niu, Z. Zhou, C. Lu, Y. Xia, S. Wang, X. Wang. (2011) Methylenetetrahydrofolate reductase C677T polymorphism and the risk of male infertility: a meta-analysis. International Journal of Andrologyno-no
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   Debbie Montjean, Moncef Benkhalifa, Lionel Dessolle, Paul Cohen-Bacrie, Stéphanie Belloc, Jean-Pierre Siffroi, Célia Ravel, Anu Bashamboo, Kenneth McElreavey. (2011) Polymorphisms in MTHFR and MTRR genes associated with blood plasma homocysteine concentration and sperm counts. Fertility and Sterility 95:2, 635-640
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    Jung Hoon Park, Han Chul Lee, Yu-Mi Jeong, Tae-Gyu Chung, Hyun-Joo Kim, Nam Keun Kim, Sook-Hwan Lee, Suman Lee. (2005) MTHFR C677T polymorphism associates with unexplained infertile male factors. Journal of Assisted Reproduction and Genetics 22:9-10, 361-368
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    KIRAN SINGH, S. K. SINGH, R. SAH, INDU SINGH, RAJIVA RAMAN. (2005) Mutation C677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population1. International Journal of Andrology 28:2, 115-119
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    Bernd Schwahn, Rima Rozen. (2001) Polymorphisms in the Methylenetetrahydrofolate Reductase Gene. American Journal of PharmacoGenomics 1:3, 189-201
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