Methylenetetrahydrofolate reductase deficiency is the most common genetic cause of elevated serum levels of homocysteine. It is caused by genetic defects in MTHFR, 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 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, and stroke. There is also an elevated risk of neural tube defects among children of individuals with the C677T polymorphism. 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 MTHFR can therefore lead to hyperhomocysteinemia. There are two common variants of MTHFR deficiency. In the more significant of the two, the individual is homologous 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.
In common forms of MTHFR deficiency, elevated plasma homocysteine levels have sometimes been treated with Vitamin B12 and low doses of folic acid. 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 is no longer considered clinically useful to test for MTHFR in most cases of thrombophilia or recurrent pregnancy loss.
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, 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 homozygozity 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 across the whole world.
