Spina bifida у детей от многоплодной беременности: полиморфизм генов фолатного цикла и реализация действия экзогенных факторов риска

Abstract

Introduction. Congenital malformations of the central nervous system account for about 25% of all defects and cause psychomotor retardation and pronounced neurological deficits in children. The etiology of congenital neural tube defects remains unexplored until the end. The key role of folic acid in the genesis of neural tube defects is proved. Objective. To study the molecular genetic markers of violation of folate cycle and exogenous risk factors in children with spina bifida from multiple pregnancies and their siblings. Materials and methods. A clinical and laboratory analysis of two cases of the open form of spina bifida in children of multiple births was carried out at the Odessa Regional Children’s Hospital. To identify the etiology of the disease, clarify the mechanism of inheritance and determine the cause of discordance of the twins used genealogical, genetic, molecular and twin methods. Polymorphisms of MTHFR were investigated. To determine the metabolic disorders biochemical method (for the definition of folate levels and homocysteine in the blood) and clinical examination methods were used in children with spina bifida, as well as their mothers and siblings. Results. Presented clinical cases confirmed NTD belonging to the group of polygenic inherited disease with the alleged maternal inheritance mechanism. In both cases, the impact of environmental factors related to the proven risk factors for the various types of NTD of the fetus is realized: weighed down gynecological and obstetric history of mothers (cases of spontaneous abortions taking oral contraceptives, unbalanced diet and lack of vitamins, especially folic acid and В12), SARS, hyperthermia in the first trimester of pregnancy, smoking during pregnancy, tumors of the female reproductive system and breast cancer. Multiple pregnancy can be identified as an individual risk factor for NTD. In the first case study of polymorphisms C677T and A1298C gene MTHFR did not reveal the presence of a mutation in the gene neither in the proband nor in his mother and siblings. However, in this case could not be stated that there is no genetic conditions of impaired folate metabolism. Mutations of other genes encoding enzymes of folate cycle, such as methionine synthase reductase (MTRR) gene and MTR, encoding the amino acid sequence of the enzyme methionine synthase, are possible. In second case, maternal and siblings heterozygous form of MTHFR polymorphism was detected, which resulted in thermolability and, accordingly, decrease the activity of the enzyme. This was a genetic basis and compounded the effects of the risk factors that led to the formation of congenital malformations in both siblings of twins. Conclusions. Taking into account the percentage of concordance for dizygotic twins with NTD and a large number of hidden forms of malformation in-depth examination and supervision of all siblings (especially twins) of children with open forms of spina bifida is needed. Identification of the closed form of spinal malformation in siblings at early age will determine the timely provision of necessary medical aid and would hinder the development of neurological and urological complications.