OUTLINE
 INTRODUCTION
 MEANING OF NEURAL TUBE DEFECTS (NTDs)
 Neurulation
 TYPES OF NEURAL TUBE DEFECTS
 FEATURES OF NEURAL TUBE DEVELOPEMENT AND NTDs
 INCIDENCES AND PREVALENCE OF NTDs
 CAUSES OF NTDs
 VARIATIONS IN THE MTHFR GENE; RELATIONSHIP WITH NTDs
 METABOLIC ROLE OF FOLATE AND ELEVATED HOMOCYSTEINE
 MAIN FOLATE METABOLIC PATHWAY
 ROLES OF FOLIC ACID IN NTDs
 ROLES OF RIBOFLAVIN AND COBALAMIN
 DETECTION OF NTDs
 PREVENTION/TREATMENT OF NTDs
 CONCLUSION

INTRODUCTION
 Neural tube defects (NTDs) are complex congenital
malfunctions of the central nervous system (including the
spinal cord, skull, and brain) of newborns. NTDs foetal
loss and considerable disabilities in surviving infants
 These defects occur as a result of non closure or
incomplete closure of the neural tube caused by genetic,
environmental and nutritional factors.
 Biochemical, genetic and epidemiological observations
have led to the methylation hypothesis, which suggests
that folic acid helps in preventing neural tube defects.
 Increased intake of folic acid before getting and during
pregnancy has been found to reduce the incidence of
NTDs by 50 – 85 %.

MEANING OF NEURAL TUBE DEFECTS (NTDs)
 The neural tube is the embryonic structure that develops into the brain and spinal
cord. It starts out as a tiny ribbon of tissue and normally folds inward to form a
closed tube by the 28th day after conception (Helmi and co., 2011).
 This formation and closure of the neural tube that happens around 4 weeks of
gestation is an important landmark in the development of the nervous system.
 NTDs are very complex birth defects that involve the interactions of multiple
systems such as the central nervous system, the urological system and the
musculoskeletal system (Scaria and Thomas, 2005).
 NTDs are serious congenital defects of the CNS, including the spinal cord, skull, and
brain, that result from failure of the embryonic neural tube to completely close
during the first 28 – 30 days of foetal development.

 Neurulation is a fundamental embryonic process that leads to the
development of the neural tube, which is the precursor of the brain and
spinal cord.
 Neurulation occurs through two distinct phases:
 Primary neurulation (weeks 3-4): – leads to the formation of
the brain and most of the spinal cord till the upper sacral level.
 Secondary neurulation (weeks 5-6): – creates the lowest
portion of the spinal cord including most of the sacral and all
the coccygeal regions
NEURULATION

TYPES OF NEURAL TUBE DEFECTS
 CLOSED: These have very rare incidence.
Examples:
 Lipomyelomeningocele
 Lipomeningocele
 Tethered cord.
 OPEN: Open NTDs occur when the brain and/or spinal cord are exposed at
birth through a defect in the skull or vertebrae (back bones).
Examples:
 Anencephaly
 Spina bifida
 Encephaloceles
 Hydranencephaly
 Iniencephaly
 Schizencephaly

Anencephaly
CraniorachischisiOpen spina bifida
Encephalocele
Closed spina bifidaIniencephaly
Somite
Caudal
Neuropore
Neural
Groove
Neural Fold
Cranial
Neuropore
Somite
Neural Crest
Neural Fold
Neural
Groove
Notochord
Neural Tube
Neural Crest
Surface
Ectoderm
Mesoderm
Yolk Sac
Figure: Features of Neural Tube Development and Neural-Tube Defects

a. Female child with Anencephaly
b. Female child with Encephalocele
c. A male child with Spina bifida
Fig: Cases of NTDs
(Image source: Aminu Kano Teaching Hospital,
Kano, Nnadi, D. C., 2016

SPINA BIFIDA
Spina bifida is a condition in which the bones of the spinal column do not
close completely around the developing nerves of the spinal cord during the
first few weeks of embryonic development. As a result, part of the spinal cord
may stick out through an opening in the spine, leading to permanent nerve
damage.

INCIDENCES AND PREVALENCE OF NTDs
 GLOBAL INCIDENCE: Over 350,000 births each year (1-5/1000 live-
births)
 IN THE U.S: 1.44 per 1000 livebirths
 IN NIGERIA: The true incidence = Still unknown.
 However, it was quoted at 7 per 1000 live births in Middle Belt by Airede K. I (1992) and
0.95 per 1000 live birth in Southern Nigeria by Ugwu R. O and co (2007).
 A total of 286 patients were managed for NTDs from January 2003 and December 2011
from the North-Western parts of Nigeria and also the neighbouring Niger Republic.
 Another study of all live-born neonates in three selected hospitals in the Kano metropolis
between April 2013 and December 2013 indicated an incidence of 2.75/1000 live births.
(Anyanwu and co., 2015)
 In a recent study carried out in Department of Obstetrics and Gynaecology, Usmanu
Danfodiyo University Teaching Hospital, Sokoto, the prevalence of NTDs was 2.2/1000
deliveries (Nnadi and co., 2016).
 A retrospective study of babies with NTDs admitted into Special Care Baby Unit (SCBU) of
the University of Port Harcourt Teaching Hospital from 1st May 2002 to 30th April 2005
showed that there were 7,388 total deliveries of which 7 were neonates with NTDs

CAUSES OF NTDs
 The exact cause is still unknown.
 The most studied and likely causes involve interaction between:
 Nutrition
 Environmental factors and
 Genetic factors
 NUTRITIONAL FACTORS: Deficiency of folate and Vitamin B12 which are required
for:
 Production and maintenance of new cells
 DNA synthesis and
 RNA synthesis.
This leads to defects in folate-methionine metabolic pathways.
 ENVIRONMENTAL FACTORS: Examples;
 Use of certain anticonvulsants, maternal diabetes, maternal use of some
antiepileptic drugs such as valproic acid, fever, maternal obesity, maternal age over
35 years, fetal alcohol syndrome, maternal diabetes, multiple pregnancy, maternal
under-nutrition and stressful life events.
 GENETIC FACTORS: This has to do with variations in some genes especially the
Methylene tetraydrofolate reductase (MTHFR) gene.

VARIATIONS IN THE MTHFR GENE;
RELATIONSHIP WITH NTDs
 Variations (polymorphisms) in the Methylene tetrahydrofolate
reductase (MTHFR) gene which is related to differences in the
ability of MTHFR to process folate. This defect changes a single
DNA building block (nucleotide) in the MTHFR gene (Leclerc
and co., 2013).
 Specifically, it replaces the nucleotide cytosine with the
nucleotide thymine at position 677 (C677T) resulting in a
thermolabile variant of MTHFR enzyme with reduced activity.
This ultimately leads to elevated plasma homocysteine
concentration (hyperhomocysteinemia) (Leclerc and co., 2013).
 Another mutation, the A1298C in the MTHFR gene is also
associated with decreased enzymatic activity (Van Der Put and
co., 1997).

 MTHFR is the enzyme, which irreversibly converts N5, N10
methylene THF to N5-methyl THF, which in turn is the methyl
group donor in conversion of homocysteine to methionine
(Mark and Thomas, 2003).
 Therefore, a defective MTHFR will result in decreased
conversion of homocysteine to methionine and thereby
elevated homocysteine levels and also decreased levels of
methionine and subsequently SAM (Scaria and Thomas, 2005).
 Other Genetic disorders associated with NTDs include single
gene mutations (e.g. Meckel’s syndrome) and chromosomal
abnormalities (e.g trisomies 21, 13 and 18; and anterior sacral
VARIATIONS IN THE MTHFR GENE;
RELATIONSHIP WITH NTDs cont’d

 The MTHFR gene provides instructions for making MTHFR
which plays a role in processing amino acids used for making
proteins.
 Consequently, MTHFR is important for a chemical reaction
involving forms of folate. Specifically, this enzyme converts
N5, N10-MTHF to 5-MTHF. This reaction is required for the
multistep process that converts the amino acid homocysteine
to methionine (used to make proteins and other important
compounds)
ROLE OF MTHFR GENE IN
NTDs

METABOLIC ROLE OF FOLATE AND
ELEVATED HOMOCYSTEINE
 Several studies have demonstrated decreased levels of folate in serum of women
pregnant with a neural tube defect (NTD)-affected child during the first trimester.
Periconceptional supplementation with 0.4–5 mg of folic acid per day decreased the
recurrence risk of NTDs about fourfold (Blom and Smulders, 2010).
 One mechanism playing a possible a role in NTD etiology is methylation. Folates are
integral to intracellular one-carbon metabolism, which produces pyrimidines and
purines for DNA synthesis and s-adenosyl methionine, the universal methyl group
donor for all macromolecules (Blom and Smulders, 2010).
 The micronutrient form of folate, 5-methyltetrahydrofolate (MTHF) which circulates
in plasma, is the physiologically active form of folate that serves as a cofactor for
enzymatic reactions that involve the transfer of one-carbon moieties necessary for
purine and pyrimidine synthesis (Helmi and co., 2011).
 Several studies have revealed elevated levels of homocysteine in amniotic fluid and
maternal serum when foetus had NTDs. High levels of homocysteine may directly or
through indirect metabolic pathways interfere with neurulation and lead to NTDs
(Helmi and co., 2011).

Fig: The Folate Cycle
THF – Tetrahydrofolate
MTHFR – Methylene Tetrahydrofolate Reductase
FR – Folate receptors
MTR – Methionine synthase

ROLES OF FOLIC ACID IN NTDs
 Prevents and lessens risk of these birth defects
 Maintenance of DNA methylation
 Builds red and white blood cells in maternal and foetal
blood
 Builds maternal plateletes
 Facilitate normal growth of a foetus
 Metabolically, Folic acid is converted to its active coenzyme
form, THF, which acts as a donor or receiver of a one
carbon entity in different oxidation states (formyl,
methylene, or methyl).

 Riboflavin (Vit. B2) is linked to the metabolism of B-vitamins involved in
homocysteine remethylation and transsulfuration. Riboflavin is transformed
to FMN and FAD by the action of riboflavin kinase and FAD synthase (Rivlin
and c0., 2001).
 The majority of flavoenzymes, including methylenetetrahydrofolate
reductase (MTHFR), are FAD-dependent. The enzyme (MTHFR) uses
NADPH as a cofactor in addition to FAD, and catalyzes the transformation of
5,10-methylenetetrahydrofolate to 5- methyltetrahydrofolate (Rivlin and c0.,
2001).
 The reaction is irreversible in vivo and is the only source of 5-methylTHF,
which serves as the methyl donor for the cobalamin-dependent conversion
of homocysteine to methionine (Selhub, 1999).
ROLES OF RIBOFLAVIN AND COBALAMIN

 Few screening tests are available to help identify babies that are at increased
risk of having an NTD. These screening tests include:
 Quad screen: This blood test measures four substances (AFP, hCG,
Estriol and Inhibin – A) in a mother’s blood to tell if her pregnancy is at
an increased risk of having an NTD (March of Dimes, 2016).
 Ultrasound: This test can help detect pregnancies at increased risk of
encephalocele and other NTDs (March of Dimes, 2016).
 If a screening test shows an increased risk of NTDs, it may recommend
additional tests, such as amniocentesis and a detailed ultrasound of the
baby’s skull and spine.
 If an NTD is diagnosed early in pregnancy, one can talk to the health care
provider to learn more about the baby’s condition and birth and treatment
options. For example:
DETECTION OF NTDs

PREVENTION/TREATMENT OF NTDs
 The link between nutrition and the occurrence of neural-tube
defects provides a powerful tool for primary prevention.
 Folic acid and blood folate levels can be increased through:
 Fortification of staple foods
 Increased intake of supplements: 0.4 mg of folic acid per day at
least 1 month before conception and during the first trimester of
pregnancy. 4 mg of folic acid daily in the periconceptional
period for women with high risks.
 Increased consumption of foods with high levels of natural
folates e.g. Cereals (100-400 mcg), dark green vegetables (120-
160 mcg), citrus fruits (50-100 mcg)
 Treatment:
Pre-natal or post-natal surgery

CONCLUSION
 Any woman who is pregnant or planning on pregnancy should
consume 4 mg of Folic Acid on a daily basis.
 Encourage loved ones to start taking Folic acid if they are not
doing so already.
 Neural Tube Defects CAN be prevented.
 There is help for babies born with NTDs.
 Love the child NO MATTER WHAT because it’s a long and difficult
journey ahead
The etiology of NTD has not been fully understood, but it is now suggested that
there is a complex interplay between nutritional, environmental and genetic
factors.
However, the Incidence of NTD is on the increase in our environment. There is
need to formulate/implement the policy of pre-conceptional folic acid therapy
for all woman of childbearing age as a preventive measure as done in many
developed countries.
We should note the following:

NEURAL TUBE DEFECTS (NTDs) IN INFANTS