[Methylene tetrahydrofolate reductase mutations as genetic risk factors for neural tube defects (NTF)]

Folic acid supplementation before conception and during the first trimester of pregnancy prevents about 70% of all neural tube defects (NTD). Folic acid is a cofactor in the homocysteine metabolism. Its product--S-adenosylmethionine is a major methyl donor for reactions taking place in a cell. The 677 C-->T mutation in the methylene tetrahydrofolate reductase gene leads to thermolability and decreased activity of the enzyme. In the individuals homozygous for that mutation hyperhomocystynemia and lowered plasma folate level are observed. Presence of the MTHFR 677 C-->T mutation increases the requirements for folic acid, especially at the time of rapid foetal growth. Studies showed higher rate of TT homozygotes in people with NTD and their parents compared with the control group. Hyperhomocystynemia has been associated with higher risk of recurrent miscarriages in women. It was also proved that stillbirths are a risk factor associated with NTDs. TT homozygosity varies among different country populations, from 6% to 16%. An additional risk factor for NTD is MTHFR 1298 A-->C mutation. Combined heterozygosity for the 1298 A-->C and 677 C-->T mutations is associated with increased homocysteine and lowered plasma folate levels. This genotype is more frequent in NTD patients compared with controls. Further investigations in the field of genetic aspects of NTD in Poland will be very important for the primary prevention of NTD.