Despite significant advances in modern prenatal diagnostics, fetal neural tube defects (NTDs) remain one of the most common congenital malformations. Every year in the United States, 1 case of NTD is registered per 1,000 pregnancies, with 4,000 pregnancies per year being terminated, including spontaneous miscarriages and induced abortions, due to foetal CNS development disorders.
NT, or spina bifida, is a significant factor in disability, although some forms of this pathology can now be corrected surgically.
In most cases, DNT occurs as a result of a failure of the neural tube to close or its reopening. In humans, the neural tube is formed from the ectoderm and closes on the 21st-28th day after conception. If the formation of the neural tube is disrupted, depending on the location of the defect, either anencephaly or spina bifida develops, which clinically manifests as paralysis of the lower limbs, bladder, rectum, etc.
In Denmark, N.M. van der Put et al. identified an increased frequency of the C677T polymorphism of the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR) in family members who had children with DNT. The gene mutation was found in 16% of mothers, 10% of fathers, and 13% of newborns with spina bifida, compared to 5% in the control group. Similar results were obtained in other countries. This study shows that the risk of developing spina bifida increases sevenfold when the mother and foetus have a homozygous mutation. This proves the influence of folate metabolism disorders in the foetus on the development of DNT.
The severity of spina bifida can vary from mild forms to severe defects with spinal clefting combined with myelocystis.
Spina bifida is classified according to severity:
- spinal dermal sinus;
- hidden vertebral arch closure;
- vesicular arch closure;
- spinal cleft combined with myelocystis.
Although DNT has been known to humans since ancient times, the mechanisms of development of this defect are still unclear, although there is no doubt that genetic factors, unbalanced nutrition (deficiency of folates and B vitamins), hyperhomocysteinemia (HHC), and environmental factors (radioactive radiation, etc.) play an important role.
Most studies in recent years demonstrate the influence of disturbances in folate metabolism in the methionine cycle on the pathogenesis of DNT. Since these processes are inextricably linked, deficiencies or defects in any cofactor (B vitamins, folates) and enzymes, which may be either acquired or genetically determined, lead to either GGC or mild or severe forms of folate deficiency.
Many pathological effects of folate deficiency are associated with an increase in the level of HC in the blood plasma. The role of folates in the development of DNT has been known for over 40 years, while the role of vitamins B12 and B6 was established much later.
Intracellular vitamin B12 acts as a factor in the remethylation of HC to methionine with the participation of the enzyme methionine synthase (MS). Vitamin B12 deficiency can therefore cause HC, even though the concentration of folate in the blood may be normal or even elevated. This phenomenon is known as the ‘methylfolate trap.’
It should be emphasised that the combination of GGC and folate deficiency, including a lack of B vitamins, especially vitamin B6, is a powerful risk factor for the development of not only DNT, but also vascular complications: venous and arterial thrombosis, gestosis, premature detachment of a normally located placenta, foeto-placental insufficiency and foetal growth restriction syndrome, antenatal foetal death, early and late miscarriages. Vitamin B6 in the form of pyridoxal-5-phosphate participates in the transsulfation of GCS to cysteine with the help of the enzyme cystathionine beta-synthase (CBS).
