Methylenetetrahydrofolate reductase deficiency

Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism.

MTHFR deficiencies cause hyperhomocysteinemia with homocystinuria, or mild hyperhomocysteinemia.

MTHFR is a key enzyme in the folate pathway and is responsible for the metabolism of homocysteine.

Two common variant of the MTHFR gene exist: C677T and A1298C.

Predisposition to hyperhomocystinemia, particularly when deficient in folate.

Presently a total of 34 rare but deleterious mutations in MTHFR exist.

A total of 9 common variants (polymorphisms) have also been reported.

The 677C→T (A222V) variant is the most common genetic cause of hyperhomocysteinemia.

Methylenetetrahydrofolate reductase plays a central role in folate and homocysteine metabolism by catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.

5-methyltetrahydrofolate is the primary circulatory form of folate which is utilized in homocysteine remethylation to methionine.

Homocystinuria is due to a severe deficiency of the enzyme, and while being the most common inborn error of folate metabolism, is still rare.

About 8 to 20% of white north Americans are homozygous, and 40 to 50% or heterozygous for mutations in the MTHFR gene, which confers decreased enzymatic activity.

Patients with decreased MTHFR activity or expected to have decreased response to folic acid.

A milder deficiency, which is more common, results in a mild to moderate elevation of plasma total homocysteine, an emerging risk factor for cardiovascular disease.

Symptoms displayed by MTHFR-deficient patients include developmental delay, and neurological and vascular problems, such as seizures, thromboses and vascular lesions.

MTHFR polymorphism, a common mutation, that results in mild hyperhomocysteinemia, reflects milder versions of the fulminant biochemical lesions present with severe MTHFR deficiency.

Homocystinuric patients often have 3 or 4 mutations in the MTHFR gene.

The association of the homozygous mutant genotype (677TT) with mild hyperhomocysteinemia is present only in individuals with low folate status.

Folate supplementation is effective in treating hyperhomocysteinemia in individuals with the mutation.

The MTHFR variant is reported to be the first genetic risk factor for neural tube defects.

The prevalence of the variant 677C→T polymorphisms is relatively high in the general population, with homozygosity (TT) of 6-14% in several White populations.

The 677T allele is less common in Blacks, with homozygosity frequencies of less than 2%.

The 677T allele appears to be very common among Hispanics, at about 20%.

A point mutation in exon 7 (1298A→C) results in a glutamate to alanine substitution.

The activity of the encoded enzyme is decreased to 68% of the wild type enzyme, but not as much as that for the 677T.

Homozygotes represent approximately 8% of individuals in the tested populations, largely European and ranges is from 4% to 12% for most tested populations, and do not appear to have higher serum homocysteine levels than controls.

Homozygosity of 677TT associated with a 20-25% increase in homocysteine level compared with wild type 677CC.

Studies have failed to show an association between MTHFR 677TT and risk of VTE and MTHFR 677TT in populations with high folate intake, and should not be part of a thrombophilia workup.

Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies.

It is suggested that elevated total plasma homocysteine levels are associated with the risk of venous thrombosis.

MTHFR 677TT genotype and the risk of venous thrombosis by conducting a meta-analysis of all relevant studies.

A meta-analysis of 24 retrospective (n = 3289 cases) and three prospective studies (n = 476 cases) was carried out to examine the association of homocysteine with venous thrombosis.

A meta-analysis of 53 studies (n = 8364 cases) of the MTHFR 677TT genotype that increases homocysteine was carried out to assess if this association is causal.

A 5 micromol L(-1) higher measured homocysteine level was associated with a 27% higher risk of venous thrombosis in prospective studies and a 60% higher risk in retrospective studies.

The 677TT genotype was associated with a 20% higher risk of venous thrombosis compared with the 677CC genotype.

This meta-analysis of prospective and retrospective studies demonstrates a modest association of homocysteine with venous thrombosis.

A third variant, R594Q, results from the change 1793G→A.49 It is less common than the 677C→T or 1298A→C polymorphism.

R594Q has an allele frequencies of 6.9% among Caucasians, 5.8% among Hispanics and 3.1% among African-Americans. and homozygosity only in Caucasians.

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