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Methylenetetrahydrofolate Reductase Deficiency.

Authors

Dean L7.

Editors

In: Pratt V1, McLeod H2, Rubinstein W3, Dean L4, Kattman B5, Malheiro A6, editors.

Source

Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-.
2012 Mar 8 [updated 2016 Oct 27].

Author information

1
Director, Pharmacogenomics and Molecular Genetics Laboratories, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Bloomington, IN 47405
2
Medical Director, The DeBartolo Family Personalized Medicine Institute, Senior Member, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL 33612
3
Division Director, Clinical Data Management and Curation, CancerLinQ LLC, Alexandria, VA
4
Senior Medical Writer, Medical Genetics and Human Variation, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health, Bethesda, MD 20894
5
Chief, Medical Genetics and Human Variation, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health, Bethesda, MD 20894
6
Project Lead, Medical Genetics and Human Variation, National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health, Bethesda, MD 20894
7
NCBI

Excerpt

Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). The MTHFR enzyme plays an important role in processing amino acids, specifically, the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene can lead to impaired function or inactivation of this enzyme, which results in mildly elevated levels of homocysteine, especially in individuals who are also deficient in folate (1). In these individuals, a daily supplement of low dose folic acid may reduce and often normalize their homocysteine levels, but this has not been demonstrated to improve health outcomes (2, 3). A common genetic variant in the MTHFR gene is a 677C>T polymorphism (NM_005957.4:c.665C>T, rs1801133). This variant encodes a thermolabile enzyme that is less active at higher temperatures. Individuals who carry two copies of this variant (“TT homozygous”) tend to have higher homocysteine levels and lower serum folate levels compared to controls. More than 25% of Hispanics and around 10-15% of North America Caucasians are estimated to be homozygous for the “thermolabile” variant (TT genotype) (4). The TT genotype is least common in individuals of African descent (6%) (5, 6). Another common MTHFR variant, 1298A>C (NM_005957.4:c.1286A>C, rs1801131), does not cause increased homocysteine levels in heterozygous or homozygous individuals, but combined heterozygosity of 1298A>C and 677C>T results in an outcome similar to TT homozygous individuals (7). Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, and recurrent pregnancy loss (8-11). However, more recent analysis has not found an association between elevated homocysteine levels and the risk of venous thrombosis or the risk of coronary heart disease (12). MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members (4). Rarely, more severe variants in the MTHFR gene can be a cause of an autosomal recessive inborn error or metabolism where extremely high levels of homocysteine accumulate in the urine and plasma. This can cause developmental delay, eye disorders, thrombosis, and osteoporosis. But more commonly, homocystinuria is caused by variants in a different gene (cystathionine beta-synthase, CBS). To read more about homocystinuria caused by CBS deficiency, please see GeneReviews.

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