Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of

homocysteine Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In th ...

(

hyperhomocysteinemia Hyperhomocysteinemia is a medical condition characterized by an abnormally high level of homocysteine in the blood, conventionally described as above 15 μmol/L. As a consequence of the biochemical reactions in which homocysteine is involved ...

). It is caused by genetic defects in

MTHFR Methylenetetrahydrofolatereductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the ''MTHFR'' gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahyd ...

, which is an important enzyme in the methyl cycle. Common variants of MTHFR deficiency are asymptomatic and have only minor effects on disease risk. Severe variants (from nonsense mutations) are vanishingly rare.

Symptoms

The common MTHFR deficiencies are usually asymptomatic, although the 677T variant can cause a mildly increased risk of some diseases. For individuals homozygous in the 677T variant, there is a mildly elevated risk of thromboembolism (odds ratio 1.2), and stroke (odds ratio 1.26). There is also an elevated risk of neural tube defects among children of individuals with the C677T polymorphism (odds ratio 1.38). For cardiovascular risk, common MTHFR deficiencies were once thought to be associated but meta-analyses indicate that correlation this was an artifact of publication bias.

Causes

MTHFR is the rate-limiting enzyme in the methyl cycle, which includes the conversion of homocysteine into methionine. Defects in variants of

can therefore lead to

. There are two common variants of

deficiency. In the more significant of the two, the individual is homozygous for the 677T polymorphism. This variant in particular is the most common genetic cause of hyperhomocysteinemia. The resulting enzyme is thermolabile and in homozygotes, enzymatic activity is depressed to 35% of its usual level. The second variant is a milder one, caused by a homologous 1298C polymorphism. This leads to 68% of the control values of enzyme activity, and it normally does not lead to low serum folate.

Diagnosis

MTHFR deficiency is diagnosed by genetic testing.

Management

In common forms of MTHFR deficiency, elevated plasma homocysteine levels have sometimes been treated with

Vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...

and low doses of

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

. Although this treatment significantly decreases the serum levels of homocysteine, this treatment is not thought to improve health outcomes. Due to the ineffectiveness of these treatments, it was no longer considered clinically useful to test for MTHFR in most cases of thrombophilia or recurrent pregnancy loss. A more recent evaluation from a case series recommends testing for

in case of long lasting impaired fertility and repeat miscarriages. Treatment with high doses of

(5 mg/day) are deemed unsuitable for MTHFR isoform carriers, who could alternatively be treated with the metabolically active form,

5-methyltetrahydrofolate Levomefolic acid ( INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprod ...

. 5-MTHF was shown to induce significantly higher plasma folate concentrations compared to folic acid in

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

MTHFR

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

carriers in this case series. A different study corroborates these results and suggests a physiological dose (800 μg) of

can bypass MTHFR C677T and A1298C isoforms in couples with fertility problems. This treatment with

5-MTHF Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprod ...

also avoids un-metabolized folic acid syndrome, which can occur with folic acid intakes of 5 mg per day.

Prognosis

Whether MTHFR deficiency has any effect at all on all-cause mortality is unclear. One Dutch study showed that the MTHFR mutation was more prevalent in younger individuals (36% relative to 30%), and found that elderly men with MTHFR had an elevated mortality rate, attributable to cancer. Among women, however, no difference in life expectancy was seen. More recently, however, a meta-analysis has shown that overall cancer rates are barely increased with an odds ratio of 1.07, which suggests that an impact on mortality from cancer is small or zero.

Epidemiology

The prevalence of 677T homozygosity varies with race. 18-21% of Hispanics and Southern Mediterranean populations have this variant, as do 6-14% of North American Whites and <2% of Blacks living outside of Africa. The prevalence of the 1298C mutation is lower, at 4-12% for most tested populations. A study in 2000 had identified only 24 cases of severe MTHFR deficiency (from nonsense mutations) across the whole world.

References

External links

{{Medical resources , DiseasesDB = 32650 , ICD10 = {{ICD10, E72 , ICD9 = , ICDO = , OMIM = 607093 , OMIM_mult = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = D042965 Mutation Metabolic disorders