Commentary: One-carbon metabolism has major implications for fetal growth and development beyond neural tube defects

Nutrition and epigenetic changes is the emerging topic of interest in the present scenario to understand the effects of increased supplementation of micronutrients like Folic Acid (FA). The study is taken up in the public health interest, to evaluate the importance of balancing the different micronutrients in the diet to avoid unbalanced nutritional disorders and other health complications later in life. It has been hypothesized that disease risks after birth or later in life can be determined by paternal or maternal diet. This raised an interest to study in-utero effects of environmental exposures like air pollution, toxins, nutrition, etc. It had been assumed that during embryonic period most of the dividing tissues get exposed to the environmental insults and that change results in predisposition of cancer or other health outcomes. There could be the possibility of maternal exposures like nutrition may alter the intrauterine one-carbon metabolism or the precursor milieu and may be involved in the disruption of one-carbon metabolism in developing offspring. Modification in methyl me of offspring with subsequent changes in phenotypes has been noted in the preliminary studies with increased folic acid (FA) supplementation during pregnancy. Maternal folate deficiency has been implicated as a cause of prematurity and both folate deficiency and cobalamin deficiency have been implicated in recurrent fetal loss and neural tube defects. Folic acid supplementation at the time of conception and in the first 12 weeks of pregnancy is expected to reduce by 70% the incidence of neural tube defects (NTDs) (meningomyelocele, encephalocele and spina bifida) in the fetus. Most of the protective effect can be achieved by taking folic acid, 0.4 mg daily at the time of conception. However there is no clear relationship between maternal folatestatus and the fetal abnormalities. It has been observed that, the lower the maternal folate, the greater the risk to the fetus. On the other hand maternal cobalamin status is a strong predictor of vitamin B12 in breastfed infants up to at least 6 months of age. Because of the transfer from mother to offspring during pregnancy and lactation, maternal requirements during this period are increased and deficiency may occur. The influence of low vitamin B12 during pregnancy may have cognitive ability of children later in life. Hypothyroidism is caused by insufficient production of thyroid hormones by the thyroid gland. In females, hypothyroidism is associated mainly with oligomenorrhea.

Download Full-text

The role of folate and one-carbon metabolism in brain development and hydrocephalus: a literature review

Manchester Medical Journal ◽

10.7227/mmj.0018 ◽

2017 ◽

Vol 2 (1) ◽

pp. 1

Author(s):

Z. Shehata

Keyword(s):

Cerebrospinal Fluid ◽

Neural Tube ◽

Neural Tube Defects ◽

Carbon Metabolism ◽

Treatment Options ◽

Methyl Donors ◽

Novel Treatment ◽

One Carbon Metabolism ◽

Insight Into

Folate metabolism has been known to influence the development of the nervous system, as found in the case of neural tube defects. Folates are a group of compounds involved in one-carbon metabolism, which is necessary for the formation of purine and thymidine nucleotides, as well as methionine and methyl donors. In addition to the well-documented role of folates within the pathogenesis of neural tube defects, current literature provides evidence that folate imbalances may play a significant role in the development and effects of hydrocephalus. This review considers the possibility that folate imbalances in hydrocephalic cerebrospinal fluid may be responsible for the neurological deficit seen in patients with this condition. Understanding the details of this potential imbalance may provide further insight into novel treatment options for hydrocephalus in the future.

Download Full-text

Analysis of polymorphisms of genes associated with folate-mediated one-carbon metabolism and neural tube defects in Chinese Han Population

Birth Defects Research Part A Clinical and Molecular Teratology ◽

10.1002/bdra.23478 ◽

2016 ◽

Vol 106 (4) ◽

pp. 232-239 ◽

Cited By ~ 6

Author(s):

Wei Piao ◽

Jin Guo ◽

Yihua Bao ◽

Fang Wang ◽

Ting Zhang ◽

...

Keyword(s):

Neural Tube ◽

Neural Tube Defects ◽

Carbon Metabolism ◽

Chinese Han Population ◽

Chinese Han ◽

Han Population ◽

One Carbon Metabolism

Download Full-text

Folate-mediated one-carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

Birth Defects Research Part C Embryo Today Reviews ◽

10.1002/bdrc.20100 ◽

2007 ◽

Vol 81 (3) ◽

pp. 183-203 ◽

Cited By ~ 90

Author(s):

Anna E. Beaudin ◽

Patrick J. Stover

Keyword(s):

Gene Expression ◽

Neural Tube ◽

Neural Tube Defects ◽

Carbon Metabolism ◽

One Carbon Metabolism

Download Full-text

MTRR gene variant rs1801394 found in Malaysian patients with neural tube defects

Neuroscience Research Notes ◽

10.31117/neuroscirn.v3i1.41 ◽

2020 ◽

Vol 3 (1) ◽

pp. 24-31

Author(s):

Amelia Cheng Wei Tan ◽

Siti Waheeda Mohd-Zin ◽

Nur'Awatif Ishak ◽

Meow-Keong Thong ◽

Azlina Ahmad-Annuar ◽

...

Keyword(s):

Neural Tube ◽

Neural Tube Defects ◽

Carbon Metabolism ◽

Protein Function ◽

Molecular Mechanisms ◽

Protein Function Prediction ◽

Neural Tube Closure ◽

Nucleotide Polymorphisms ◽

One Carbon Metabolism ◽

The One

Neural tube defects (NTDs) are congenital anomalies resulting from the failure of neural tube closure during embryogenesis. The precise molecular mechanisms underlying this multifactorial disease is poorly understood, although single nucleotide polymorphisms in genes involved in the one-carbon metabolism cycle are believed to contribute towards NTD development. Among them is 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Protein function prediction algorithms (PolyPhen-2, PROVEAN, SIFT, SMART-Ensembl) were employed to evaluate its pathogenicity potential caused by the replacement of isoleucine with methionine. Seven NTD patients and 12 of their parents were recruited for this study. DNA samples were collected through blood or saliva whereby the extracted DNAs were then sent for whole exome sequencing (WES). Zygosity of the variant was confirmed from WES data of each subject and further validated through polymerase chain reaction (PCR) and Sanger sequencing. The results revealed that 57% of patients and 83% of parents carried rs1801394 mutation in their MTRR gene, based on either homozygous (G/G) or heterozygous (A/G) genotypes. Bioinformatics analysis of this missense mutation predicted that this change is damaging to MTRR protein function by 2 of the 3 predictor algorithms and that the change from isoleucine to methionine amino acid affects flavodoxin domain of the protein. This impacts enzyme activity within the one-carbon metabolism pathway, which is linked to the aetiology of NTDs. From population databases, this variant was considered common with a MAF >0.3, however, it was not found in the Singapore Genome Variation Project (SGVP), whose population is a closer representation of the Malaysian subjects investigated here. Hence, we explored the prevalence of this variant in other studies and found that its association with NTDs differed across populations worldwide. Finally, we conclude that rs1801394 may be an NTD risk factor in the Malaysian population and should be further investigated as a potential prenatal screening tool.

Download Full-text