Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

MTHFR Deficiency [E72.1]

OMIM numbers: 236250 (MTHFR deficiency), 603174 (homocysteinemia), 607093 (MTHFR)

Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

MTHFR (Methylenetetrahydrofolate reductase) deficiency is a rare, autosomal recessive disorder of the folic acid metabolism and leads to variable neurological signs and symptoms such as muscle weakness, paresthesia, lack of coordination and poor memory. The enzyme methylenetetrahydrofolate reductase (MTHFR) is vital for the metabolism of homocysteine. MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (THF), which is an important methyl group donor. Due to the enzyme deficiency, less 5-methyl THF is available for remethylation of homocysteine to the essential amino acid methionine. The remaining activity of MTHFR is usually < 10%. The consequence is homocystinuria, hyperhomocysteinemia (homcysteine level > 100 µmol/l) and reduced methionine plasma concentration. The disorder is caused by mutations in the MTHFR gene, which is located on the long arm of chromosome 1.

The mild form of the MTHFR deficiency is a lot more common. It is caused by a thermolabile variant of the enzyme with limited function. This mild form is characterized by increased levels of homocysteine (hyperhomocysteinemia); in contrast to the classic form there are no neurological signs and symptoms. In most cases, molecular genetic analysis shows the common C677T polymorphism (rs1801133) in exon 5 of the MTHFR gene. Homozygosity for this polymorphism has been associated with increased homocysteine levels. A weak positive association with multifactorial disorders such as thrombophilia or neural tube defects (spina bifida) has been described only in homozygous carriers and only in combination with other risk factors. A sufficient intake of folic acid, vitamin B6 and B12 is recommended for carriers of the T/T genotype. Another polymorphism in the MTHFR gene, A1298C (rs1801131) in combined heterozygosity with the C677T polymorphism, has been associated with reduced enzyme activity and elevated homocysteine levels in the blood as well. Homozygosity for the C/C genotype, however, has no effect on the folate-dependent homocysteine metabolism.

Determination of the MTHFR genotype is currently recommended only for patients with a plasma homocysteine concentration (tHyc) of >50 µmol/L. In the case of thrombophilia, the analysis is currently not covered by German national health insurances.