Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited disorder of the folic acid metabolism that can lead to a variety of neurological symptoms such as muscle weakness, paresthesias, lack of coordination, and impaired memory. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays an essential role in homocysteine metabolism. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate (THF), which is an important methyl group donor.
Due to enzyme deficiency, decreased amounts of 5-methyl-THF are available for the remethylation of homocysteine to methionine, an essential amino acid. The residual activity of MTHFR is usually <10%, resulting in homocystinuria, hyperhomocysteinemia (homocysteine levels >100µmol/l), and reduced plasma methionine concentrations. Pathogenic variants in the MTHFR gene, which is located on the long arm of chromosome 1, are causative.
Significantly more common is a mild form of MTHFR deficiency caused by a thermolabile variant of the enzyme with impaired function. This mild form is characterized by elevated homocysteine levels (hyperhomocysteinemia), but unlike the classic form, there are no neurological symptoms. Molecular genetic analysis can usually detect the common C677T variant (rs1801133) in exon 5 of the MTHFR gene. Homozygosity of this variant is associated with elevated homocysteine levels. Additionally, a weak positive association with multifactorial diseases such as thrombophilia or neural tube defects (spina bifida) has been described for homozygous carriers only and solely in combination with other risk factors. An adequate supply of folic acid, vitamin B6, and B12 are recommended for carriers of the T/T genotype. Combined heterozygosity of another variant in the MTHFR gene, A1298C (rs1801131), with the C677T variant is also associated with reduced enzyme activity and increased homocysteine concentrations in the blood. However, homozygosity for the C/C genotype has no effect on folate-dependent homocysteine metabolism.
Determination of the MTHFR genotype is currently only recommended for patients with a plasma homocysteine concentration (tHyc) of >50µmol/L. In connection with thrombophilia, the examination is currently not part of standard medical care.
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