Neural tube defects are defined as
abnormalities in a fetus’ early development of the brain or spinal cord and are
often fatal or severely debilitating. Examples of these defects include Spina
Bifida (when the neural tube fails to close properly) and Anencephaly
(underdeveloped brain and incomplete crania). Neural tube defects, or NTDs,
have an extreme prevalence in India, easily surpassing the average of other
countries-especially in the northern regions. Comparative statistics of the
extreme occurrence included an 11/1000 prevalence in India while in the United
States and Europe the chance is closer to 1/1000 (Godbole, Deshmuka, &
Yajnik, 2009). The etiology of these particular set of diseases includes
several environmental and dietary factors, the foremost being the analysis of
the fetus’ DNA methylation during embryogenesis. In India, inbreed marriages
and dietary restraints also play a large role in the fetus’ chance of
developing an NTD. Occurrence of Neural tube defects has decreased on a global
scale due to increased education of the effects of folate deficiency and
increased abortions from early diagnosis. This trend excludes rural regions
with few hospitals that can detect the defects early enough (Allagh, Shamanna,
Murthy, Ness & Neogi, 2015).

            The
role of folic acid in proper neural tube development in the very early stages
of intrauterine growth, but is no longer likely to be the leading cause of such
defects since the recent increase in awareness of its importance. Folate is in
the polyglutamate family, and is a (Godbole at el., 2009). Folic acid is
required to make homocysteine, a non-protein containing amino acid that serves
as a transporter to make the amino acid methionine (Ansari, Mallack & Luo,
2014). Methionine is then used for DNA methylation, a process in which gene
expression is encoded during embryogenesis, mainly in relation to the nervous
system (Blom & Smulders, 2010). NTDs arise when the incorrect levels of
homocysteine are made from an inadequate level of folates, leading to over or
under expression of genes during the DNA methylation process (Godbole at el.,
2009). In the developed world, you can find folic acid added to many breads and
flours, but in India where processed foods are not common, they get the vitamin
from natural sources such as leafy greens and legumes (Godbole at el., 2009).
Luckily, their diet is heavily reliant on said vegetables-especially for women-
so the chances of NTDs being caused from folic acid deficiency is negligible while
still possible.

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            While
most of the Indian population consumes the necessary folate levels, their
vegetarian diet can cause issues with another cofactor of the methylation process:
B12. Vitamin B12 is crucial for proper nervous system development and
maintenance and is naturally found in meat, poultry, and milk. Indian women’s
mainly plant based diet will often leave holes in their vitamin needs,
especially in B12. B12 is similar to folic acid in that it is required for the
development of methionine and the DNA methylation process (Godbole at el.,
2009). Therefore, we can conclude that while folic acid can be to blame for a
majority of the neural tube defects in the western world, in India B12
deficiency is much more likely to be the cause. While both folic acid and B12
deficiencies are easily detectable and treatable, India does not have adequate
resources to do so or it is discouraged to seek “western” forms of medicine.

Genetic
predisposition also plays a large role in the likelihood of an NCD in all countries,
but India holds a certain risk factor that increases the prevalence by nearly
10 times the normal population: incest (Allagh at el., 2015). Consanguineous
marriages are the main cause of genetic mishaps that would lead to defects and
are extremely common in India, including relationships as close as uncle and
niece marriages. These inbreed relations lead to a pooling of recessive genes,
increasing the chances of receiving several risk alleles that would result in a
defect (Godbole at el., 2009). With the increased risk of mutated DNA from
inbreeding comes the chance of over/under active DNA methylation that can
result in too much or too little production of enzymes and proteins that make
up the neural tube. This mixing of family genes can even begin to disturb mRNA
coding and integrity (Godbole at el., 2009). The rate at which consanguineous
marriages produce neural tube defects is 11.5/1000 to 4.3/1000 in non-consanguineous
relationships (Allagh at el., 2015). While avoiding incest can significantly
decrease the chances of NTDs along with many other birth defects, India has
been inbreeding for over 2000 years so the chances of breeding with someone who
does not have any genetic relation is impossible (Kulkarni, Mathew, &
Reddy, 1989). Male to female discrepancy has been found to not show relevance
in which is more susceptible.

DNA Methylation’s Role in Developing Neural
Tube Defects

            DNA methylation is
the process in which a methyl group is added to a strand of DNA where two
methyl groups would lie diagonally to each other on opposite strands. Other
strands then replicate the strand before it, whether it is correct or not. While
the exact purpose of methylation in gene expression is still unknown we do know
it is integral for proper early growth and development, especially in the
chromatin (Robertson, 2015). As discussed before varying levels in the sulfur
containing amino acid homocysteine can be caused by vitamin deficiency and/or
an elevated load of risk alleles. High levels of homocysteine have been shown
to have a toxic effect, having adverse effects on DNA methylation. Misfunctioning
imprinting mechanisms mostly occur in the X chromosome and in turn cause most
DNA strands after it to copy the same incorrect transcription, leading to
abnormal growth of tissues (Robertson, 2015).

Conclusions

            The
etiology of neural tube is often a combination of several different factors
where environment, maternal health, and genetics play a role during
embryogenesis. Besides avoiding general teratogens, the main push to reducing
NTDs has been increasing awareness and supplementing of folic acid in the
general public, but these efforts do not reach India. The extreme
supplementation of folic acid without addressing B12 levels has also been shown
to lead to neural tube defects suggesting that the imbalance of the two
vitamins is just as dangerous as a deficiency in one of them. Therefore,
addition of folic acid to general foods in India as many countries to now would
be ill advised. The National Family Health Survey of India showed that only
about 56% of women seek continuous prenatal care, so chances of fixing existing
vitamin deficiencies are slim (Godbole at el., 2009). If dietary imbalance is
not the cause the extreme and prolonged cultural encouragement of incest can
also lead to the same defects. Genetic markers exist for congenital defects is
not uncommon, but the overload of the same gene pool makes it substantially
more likely that two of these recessive markers will be combined. In some cases
maternal disease such as diabetes can result in the same abnormal DNA
expression as the other two risk factors discussed, but this is not the
prevalent cause in India.

            Improvements
can be made to decrease the prevalence of neural tube defects in India but
there is no guaranteed way in any country or demographic to completely
eradicate it currently. More emphasis on the importance of eating a balanced
diet that will include all essential nutrients will help the rampant B12
deficiency. Education of the issues connected to inbreed marriages may
discourage some regions but as it is mostly a cultural norm the chances of
making a significant chance is not large. Most importantly, increasing the
amount of facilities and resources such as hospitals and clinics, making them
convenient and affordable, will encourage women to seek prenatal care
throughout their entire pregnancy which will improve the prognosis of both the
mother and fetus.

 

Resources

Allagh,
KP., Shamanna, BR., Murthy, GVS., Ness, AR., Doyle, P., Neogi, SB., etal.
(2015) Birth           Prevalence of
Neural Tube Defects and Orofacial Clefts in India: A Systematic Review and   Meta-Analysis. PLOSONE 10(3): e0118961. doi:10.1371/ journal.pone.0118961

Ansari,
R., Mahta, A., Mallack, E., & Luo, J. J. (2014). Hyperhomocysteinemia and
Neurologic Disorders: a Review. Journal of Clinical Neurology, 10(4),
281. doi:10.3988/jcn.2014.10.4.281

Blom,
H. J., & Smulders, Y. (2010). Overview of homocysteine and folate
metabolism. With   special references to
cardiovascular disease and neural tube defects. Journal of Inherited
Metabolic Disease, 34(1), 75-81. doi:10.1007/s10545-010-9177-4

Godbole,
K., Deshmuka, U., & Yajnik, C. (2009). Nutri-genetic Determinants of Neural
Tube Defects in India. Indian Pediatrics, 46(6),
467-475. Retrieved November 25, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/19556657.

Kulkarni,
M. L., Mathew, M. A., & Reddy, V. (1989). The range of neural tube defects
in southern India. Archives of Disease in Childhood, 64,
201-203. doi:10.1136/adc.64.2.201

Robertson,
B. S. (2015, September 17). What is DNA Methylation? Retrieved December 06,
2017, from https://www.news-medical.net/life-sciences/What-is-DNA-Methylation.aspx

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