Molecular and Structural Biology Division
Central Drug Research Institute, Lucknow - 226001, India

Neural tube defects (NTDs) are common congenital problem of central nervous system. Even though the epidemiologic link between maternal folate deficiency and fetal NTDs and preventive role of folate supplementation on oc currence and recurrence of these defects is establis hed, the causal mechanism at cellular and molecular level remains undefined. However, an elevated level of homocysteine is an independent risk factor for NTDs due to mutations in MTHFR gene which inhibits the production of this enzyme. Supplementation of folic acid 0.4µg per day may reduce the risk of this fetal disease. Hence public awareness program by the government should be built up in India as the occurrence of this fetal disease in North India as high as 4-9 per 1000 births.

Methylenetetrahydr ofolate reductase ( MTHFR ) is the name of a gene which is located on chromosome 1 at p 36.3 . The cDNA sequence is 2.2 kb long and appears to consist of 11 exons. There are two MTHFR variants found commonly. The C667T and the A1298C are common in many populations and have been studied in relation to birth defects mainly spina bifida and anenceaphaly. The C667T allele is a single base pair mutation, in which cytosine is converted to thymine at base pair 677 resulting in an amino acid substitution (alanine to valine) in the enzyme. Functionally, the encoded protein has a reduced enzymatic activity at 37 0 C and higher, so that the C677T mutation is often termed as “thermolabile” 1 . However, in A1298C allele, a point mutation in exon 7 results in the coding of a glutamate instead of an alanine residue 2 . This gene produces an enzyme called as methylenetetrahydrofolate re ductase in normal course. If a person carries the genetic mutation or variations in MTHFR activity associated with above discussed variants that inhibits production of this enzyme, it can result in hyperhomocystenemia, which is an elevated level of an enzyme called homocysteine. In healthy, well nourished human being, homocysteine metabolism is well regulated and the concentration of plasma total homocysteine ranges between 5-12µM. Deficiencies of the enzymes or the cofactors involved in the metabolism of homocysteine can lead to its incontinence occur. The seve rity depends on the site and the type of the type of the defect.

? Caucasians with English/Irish ancestry ? People who do not eat well balanced diet ? Couples who have already had other NTD affected pregnancies ? Women who have low folic acid levels before they become pregnant and during the earliest weeks of pregnancy
Tests for neural tube defects include ultrasound examination and measurement of Maternal Serum Alfa-Fetoprotein (MSAFP). Alpha Feto Protein (AFP) is a chemical made by fetus that enters the mother’s blood. A large amount of AFP may mean the fetus had NTD 4 . An elevated level MSAFP measured at 16-18 weeks gestation is a good predictor of neural tube defects.

Recent studies have shown that women who take the B vitamin, folic acid before pregnancy and during the first two months of pregnancy can reduce the risk of serious birth defects of the brain and spinal cord. By taking a safe and readily available multivitamin pill with folic acid (400-500µg) every
aberrant intracellular processing, thereby elevating its level. This increased level shows a spectrum of clinical symptom. Older children have been identified with mental retardation, acute psychosis, muscle weakness and ataxia. Adults have presented with gait disturbance. Young infants have been identified with more severe symptoms of hypotonia, failure to thrive, failure of neurological developments and severe apena. Most infants died at less than one year of age. During the last decade, homocysteine has received increasing attention as elevated levels of this have been implicated as an in dependent risk factor for neural tube defects. In addition to the genetic factors, environmental factors, including diet also influence the level of homocysteine 3 .
NEURAL TUBE DEFECTS (NTDs) Neural tube defects are the defects of central nervous system, which include brain and spinal cord. These defects occurs very early usually in the first month of pregnancy. During the first four weeks of pregnancy, the neural tube is open and then closes to form the spinal cord and brain. Worldwide incidence of NTDs is 1.4-2 per 1000 births. Recurrence risk after one affected child is 30-40 per births and after two affected child is 100 per thousand live births. Ninety percent of babies with NTDs are born into families where this has never happened before 3 . Examples of NTDs are Anencephaly, Encephalocele and Spind bifida. Anencephaly : This disorder occurs when most of the head, brain and possibly the spinal cord do not develop normally. New born children with this severe disorder usually die shortly after birth, as this condition is incompatible with life.
Encephalocele : This disorder results in a hole in the skull through which brain tissue protrudes. Although most babies with this disorder do not live or severe retarded. A few children have survived because of surgery early after birth to correct this defect.
Spina bifida : This disorder also known as cleft or open spine is a defect of the spinal column. Normal development of the spina bifida child is possibly with little physically handicap. Often, however, paralysis of the lower limbs repeated urinary tract infections, hydrocephalus and day there is a 70 percent or greater chance of preventing NTDs 5
Folic acid is a group of chemical compounds occurring in nature as polyglutamates. These are hydrolyzed by intestinal enzymes into respective monoglutamate forms before being absorbed preferentially in the jejunum. In the enterocyte it is successively reduced to a dihydro form and finally to tetrahydro folic acid/folate (THFA/THF) by an NADPH dependent reductase enzyme. This THFA/THF is the actual metabolically active folate. It undergoes methylation to generate N5 methyl- THFA which is transported in blood bound to plasma proteins. The key function of folate in humans is carriage of single carbon moieties derived from amino acid metabolism (Fig.1). These one carbon groups participate in diverse biochemical pathways including nucleic acid synthesis 6 . What is pertinent to present paper is the recognition of several defects in the genes and enzymes involved in these reactions which have a putative role in pathogenesis of NTDs. It is an over simplistic but at least a partly true that folate supplementation overcomes these metabolic blocks and prevents the occurrence and recurrence of NTDs.
Fig. 1. Role of folate in aminoacid metabolism
38 Manthan , International e - Journal, Vol. 11, June, 2010, ISSN No. 0974 - 6331
Folic acid is essential for the production of methionine, which is co-factor in RNA and DNA synthesis and is required for methylation of proteins, lipids and myelin. Folic acid is essential for growth, differentiation and repair, hence it is essential for fetal development during pregnancy. This vitamin is now considered as an important factor in reducing chances of NTDs, Megaloblastic anaemia of pregnancy and some other complications like spontaneous abortions, Intra Uterine Growth Retardation (IUGR) of baby. Folic acid is a vitamin B also known as folate or folacin. Folic acid is needed to make new cells in the body and it can be found in most multivitamin pills and also in certain foods (peas, corn, dried beans, leafy vegetables, beef lever, banana, orange juice and fortified cereals breakfast). Women whose diets follow the United States Dietary Associa tions (USDA) food guide pyramid are more likely to eat 0.4 mg of folate daily. It is recommended that all women able to have a baby take a multivitamin pill with folic acid in addition to eating foods high in folate because over cooking can destroy folate in food and the amount of absorbed from food varies. In 2004, Wald estimated that folic acid supplementation (5 mg/day) preconception and continuing till 12 weeks after getting pregnancy reduce the risk of NTDs by 85%. In the women with the previous baby affected by NTDs periconceptional use of folic acid decreases the recurrence by 70%. However, the bigger problem to prevent occurrence of NTDs is that about 50% of all pregnancies are unplanned even in developed countries.
Several scientific research based on clinical trial have reinforced the observation that risk of delivering a child with NTDs significantly decreases with ingestion of periconceptional folic acid. US Public Health Service made a strong recommendation that all women of childbearing age, who are capable of becoming pregnant should consume 0.4mg of folic
acid per day. An individual should develop a plan with her doctor to check homocysteine levels periodically and adjust tr eatment accordingly. The MTHFR mutations appear to be medically irrelevant, so as long as an individual’s homocysteine level is normal. Hence public awareness “to plan before you conceive and to take folic acid if you plan a pregnancy”, should be built up in India also as the occurrence of this fetal disease in North India as high as 4-9 per 1000 births.
The authors are thankful to Dr. Sarita Agarwal, Associate Professor and Dr. Mandakini Pradhan, Assistant Professor, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow for providing the chance to work with them as a research trainee. Authors are also thankful to Mr. Ujjawal and Subodh for their kind help.
1. Kang, S. S., Wong, P. W., Susmano, A., Sora, J., Norusis, M. and Ruggie, N. (1999). Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am. J. Hum. Genet. 48: 536-545. 2. Viel, A., Dall’Agnese, L. and Simone, P. (1997). Loss of heterozygosity at the 5,10- methyltetrahydrofolate reductase locus in human ovarian carcinomas. Br. J. Cancer. 75: 1105-1110. 3. Pradhan, M., Behari, S., Kalra, S. K., Ojha, P., Agarwal, S. and Jain, V. K. (2007). Association of methylenetetrahydrofolate reductase genetic polymorphisms with atlantoaxial dislocation. J. Neurosurg. Spine . 7: 623-630. 4. Federal Register. (1993). Folic acid: proposed rules. 53254-53317pp. 5. Centers for Disease Control and Prevention. (1983- 1991). Use of folic acid for prevention of spina bifida and other neural tube defects. MMWR . 40: 513-516. 6. Arya, R. and Vyas, A. (2006). Folic acid and neural tube defects: a re view of the mechanism of pathogenesis. Journal of Neonatology . 20: 316-324

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