Neural Tube Defects
The technical names of the two major neural tube birth defects reduced by adequate folate intake are anencephaly and spina bifida. Babies with anencephaly do not develop a brain and are stillborn or die shortly after birth. Those with spina bifida have a defect of the spinal column that can result in varying degrees of handicap, from mild and hardly noticeable cases of scoliosis (a sideways bending of the spine) to paralysis and bladder or bowel incontinence. With proper medical treatment, most babies born with spina bifida can survive to adulthood. But they may require leg braces, crutches, and other devices to help them walk, and they may have learning disabilities. About 30 percent have slight to severe mental retardation. The National Centers for Disease Control and Prevention estimate that about 2,500 infants with spina bifida and anencephaly are born each year in the United States (E-Medicine).
Neural tube defects (NTD) occur because of a defect in the neurulation process. Since the anterior and posterior neuropores close last, they are the most vulnerable to defects. Consequently, a majority of NTDs arise in these areas. NTDs can be classified, based on embryological considerations and the presence or absence of exposed neural tissue, as open or closed types.
• Open NTDs frequently involve the entire CNS (eg, associated hydrocephalus,
Chiari II malformation) and are due to failure of primary neurulation. Neural
tissue is exposed with associated cerebrospinal fluid (CSF) leakage.
• Closed NTDs are localized and confined to the spine (brain rarely affected) and result from a defect in secondary neurulation. Neural tissue is not exposed and the defect is fully epithelialized, although the skin covering the defect may be dysplastic.
Cranial presentations include the following: Anencephaly ,Encephalocele (meningocele or meningomyelocele),Craniorachischisis totalis,Congenital dermal sinus
Spinal presentations include the following: Spina bifida aperta (cystica),Myelomeningocele,Meningocele ,Myeloschisis ,Congenital dermal sinus,Lipomatous malformations (lipomyelomeningoceles),Split-cord malformations ,Diastematomyelia,Diplomyelia,Caudal agenesis
Pathophysiology: Two distinct processes appear to be involved in the formation of the neural tube: primary neurulation and secondary neurulation (ie, canalization). The neural plate and the notochord are formed during early embryonic development. The neural groove develops by the third gestational week. Subsequently, the neural folds form bilaterally.
Open NTDs have been suggested to result from defective primary neurulation while defective secondary neurulation gives rise to closed NTDs. However, this issue is not settled. Another possible explanation is that open NTDs (spina bifida in particular) result from defects in either primary or secondary neurulation, depending on their site being cranial or caudal to the posterior neuropore (ie, upper and lower spina bifida, respectively)(E-Medicine).
• Anencephaly is incompatible with life.
• Other NTDs may give rise to progressive neurological deterioration, which may present early after.
• The most common NTD compatible with life is myelomeningocele (see Picture 1 and Picture 2).
• Anencephaly has a female preponderance, especially among premature births, with a female-to-male ratio of 3:1.
• Other NTDs above the thoracolumbar junction show a mild female preponderance.
• No such gender difference has been noted in more distal forms of spina bifida.
• Open NTDs are readily visible at birth, with the majority being discovered during pregnancy.
• Closed NTDs may remain undetected for years, even decades, especially in the absence of cutaneous markers(E-Medicine).
• Most open NTDs are readily apparent at the time of birth.
• Closed NTDs have a variable presentation.
o The most common presentation of a closed NTD is an obvious abnormality along the spine such as a fluid-filled cystic mass, area of hypopigmentation or hyperpigmentation, cutis aplasia, congenital dermal sinus, capillary telangiectasia/hemangioma, hairy patch, skin appendages, or asymmetrical gluteal cleft.
•Common to all these patients is a fully epithelialized lesion and no visible neural tissue.
•A closed NTD can present without a cutaneous marker.
o The second most common reason for seeking medical attention is asymmetry of the legs and/or feet. One calf can be thinner, with a smaller foot on the same side, higher arch, and hammering or clawing of the toes.
o Other children exhibit progressive spinal deformities such as scoliosis.
o Some children present with a picture of progressive neurological deficits that may include weakness in one distal lower extremity, sensory loss in the same distribution, and bladder or bowel dysfunction.
o Low back pain also can occur, sometimes without neurological deficit. Pain is more common in older children or adolescents.
o Adults can present with the sudden onset of pain, motor and sensory loss, and bladder dysfunction after an acute trauma (eg, fall, motor vehicle accident, placement in lithotomy position). The reason for such presentation may be related to tethering of the cord (the distal end of the spinal cord is fixed in position). Mechanical forces associated with motion may produce compression and/or vascular insufficiency.
o A patient with a closed NTD such as a congenital dermal sinus with an intraspinal dermoid cyst or a neurenteric cyst can present with symptoms of spinal cord compression due to enlargement of the mass.
o A patient with a dermal sinus also can present with bacterial meningitis or spinal abscess.
o Neurenteric or dermoid cysts also can present with repeated bouts of aseptic meningitis due to leaking of the contents into the spinal subarachnoid space(E-Medicine).
A complete neurological assessment of the newborn with an open NTD should be
performed to document the many possible structural and neurological problems.
This provides a baseline for future comparison.
• Particularly important aspects of the evaluation are measurement of head circumference, assessment of general vigor (especially cry and sucking), upper extremity motor function, anal sphincter, and urinary stream, as well as thorough motor and sensory examination of the lower extremities and trunk.
• Usually the level of sensory dysfunction is slightly greater than the dysfunction detected on the motor examination.
• Motor examination involves observation of muscle bulk, spontaneous active movements, movements in response to stimulation, as well as assessment of muscle tone by palpation.
• Further information regarding the level of neurological dysfunction can be obtained from evaluation of hip and foot deformities. If the disparity in segmental level between the 2 sides is more than 1 level, an occult neurological problem must be suspected (eg, hemimyelia).
• The spine should be examined carefully, with determination of the size and site of the lesion.
o The shape of the defect, size of the placode, and health and laxity of the surrounding skin and soft tissue should be noted carefully.
o The presence of early spinal deformity (eg, kyphosis) also should be assessed(E-Medicine).
Myelomeningocele in a newborn
Myelomeningocele in a newborn - Lateral view
The average diet in the United States contains 200 µg of naturally occurring
food folate, which is less bioavailable than folic acid.Additional intake of
foods rich in folate could raise the average intake, but it has not been demonstrated
that increased consumption of food folate would prevent NTDs as effectively
as a daily vitamin supplement containing 400 µg of folic acid. A small
comparison study suggests that blood folate concentrations are increased much
more by folic acid supplementation than by naturally occurring food folate in
Folic acid is very important for all women who may become pregnant. Adequate folate intake during the periconceptional period, the time just before and just after a woman becomes pregnant, helps protect against a number of congenital malformations including neural tube defects. Neural tube defects result in malformations of the spine (spina bifida), skull, and brain (anencephaly). The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception. Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of some serious birth defects. Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The Recommended Dietary Allowance (RDA) for folate equivalents for pregnant women is 600 micrograms(E-Medicine).
Spina bifida, a type of neural tube defect, is a Latin term which means "split spine" and describes birth defects caused by an incomplete closure of one or more vertebral arches of the spine, resulting in malformations of the spinal cord. The spinal membranes and spinal cord may protrude through the absence of vertebral arches (called clefts).
Role of Folate: Folate deficiencies are often associated with spina bifida, as one possible causal mechanism relates to the important role of folate for one-carbon metabolism in nucleic acid and amino acid biosynthesis in rapidly dividing cells. Another theory implicates impaired cellular remodeling (apoptosis) of the neural tube in folate-associated NTDs
• Folate is responsible for the conversion of homocysteine to methione
along with B12.
o The enzyme that metabolizes homocysteine to methionine (methionine synthase) uses vitamin B12 as a cofactor. If women have a deficiency in methionine synthase, it can lead to a lack of proper amounts of nucleic acid precursors during critical times early in the pregnancy.
Folate recycling pathway.
• Folate is also involved in DNA synthesis.
o Formation of the pyrimidine deoxythymidylate
o Adds formyl and methylidine to synthesize the purine ring
• Food Sources:
o Abundant in plants (whole grains, raw plants and yeast extracts)
• The Public Health Service and Institute of Medicine recommend that
women of child-bearing age consume at least 400ug/day of synthetic folate. (Carmicheal,
o This amount is present in most multivitamin and mineral supplements.
o United States FDA has mandated that cereal grain be enriched with folic acid.
o This has increased the folic acid intake to approximately 200ug/day. (Goldberg, et al.)
• Important to note that an exact mechanism is not clear.
• Intake during early pregnancy is critical because most birth defects occur during the first few weeks of pregnancy
o Neural tube closure is completed by day 28 after conception (or 6 weeks after the last menstrual period.)
• Folic acid supplements taken in the periconceptional period have been shown to reduce the rate of NTDs by 50-70%. (Carmicheal,et al.)
• Most NTDs are multifactoral, having both genetic and environmental components.
• Elevated homocysteine levels are a risk factor and do cause NTDs in model animals. (Smith)
o It has been found that women who give birth to children with neural tube defects have higher homocysteine levels than pregnant women who had normal children.
• Because folate is involved in synthesis of nucleotides, its pathway is especially important to embryos during neurulation as it probably represents their only source of nucleotides. (Sadler)
o Nucleotides are essential for maintaining mitosis and if nucleotides are not supplied in the correct ratios mutations increase, DNA repair mechanisms fail and DNA synthesis decreases.
o Because mitosis is critical in neural tube formation, it is easy to consider a link between NTDs and folate’s role in nucleotide formation.
• It is also possible that decreased DNA synthesis caused by a lack of folate may increase the embryo’s sensitivity to teratogens. (Sadler)
o In increased amounts of folate, it protects against heart, craniofacial and other birth defects.
o The effect of folate on DNA synthesis might allow embryos to recover more quickly from an insult by producing more cells or by avoiding genetic mutations by providing large nucleotide pools for DNA repair.
• Folate is added to infant formulas, but unless directed by a pediatrician,
additional vitamin supplementation is not needed for healthy, full-term infants.
• Breast milk contains the vitamins and minerals essential for the baby.
• Usually is an isolated birth defect, although scientists believe that
genetic and environmental factors may act together to cause this and other nueral
tube defects (NTDs) (Relton et al.)
• 95% of babies with spina bifida and other NTDs are born to parents with no family history of these disorders.
• Appears to run in certain families, but particular pattern of inheritance is not known.
• If one child has spina bifida, the risk of recurrence in any subsequent pregnancy is greatly increased, to about one in 40.
• If there are two affected children, the risk in any subsequent pregnancy is about one in 20.
• Women with certain chronic health problems, including diabetes and seizure disorders (treated with certain anticonvulsant medications), have an increased risk (approximately 1/100) of having a baby with spina bifida. (Spina Bifida Association)
• Spina bifida occulta is the mildest form of spina bifida (occulta means
hidden). Most children with this type of defect never have any health problems.
The spinal cord is often unaffected.
• Spina bifida manifesta includes two types: meningocele and myelomeningocele.
• Meningocele involves the meninges, the membranes responsible for covering and protecting the brain and spinal cord. If the meninges push through the hole in the vertebrae, the sac is called a meningocele.
• Myelomeningocele is the most severe form of spina bifida (Zhu et al., 2005).-Most babies who are born with this type of spina bifida also have hydrocephalus, an accumulation of fluid in and around the brain.
Symptoms and Physiological Alterations:
• There are obvious signs if a child has spina bifida occulta. The spinal
cord does not protrude through the skin, although a patch of hair, a birthmark,
or a dimple may be present on the skin over the lower spine.
• Babies who are born with the meningocele form of the disease have a sac filled with fluid that is visible on the back.
• The sac is often covered by a thin layer of skin and can range in size from the dimensions of a grape to those of a grapefruit.
• Babies who are born with myelomeningocele also have a sac-like mass that bulges from the back, but a layer of skin may not always cover it.
• In some cases, the nerves of the spinal cord may be exposed.
• Most babies with myelomeningocele have hydrocephalus.
• Hydrocephalus is a build-up of cerebrospinal fluid (CSF) in the head.
• Due to a blockage to flow/drainage of CSF from the brain
• Causes inadequate absorption of the fluid because it doesn't get released into the bloodstream. (Spina Bifida Association, 2006)
Management of spina bifida, hydrocephalus and shunts. Photograph of the lumbar region of a newborn baby with myelomeningocele. The skin is intact, and the placode containing remnants of nervous tissue can be observed in the center of the lesion, which is filled with CSF.
• Children with spina bifida occulta usually need no treatment.
• In cases of spina bifida manifesta, the treatment depends on the type of spina bifida a child has and how severe it is.
• A child with the meningocele form of the disease usually has an operation during infancy in which doctors push the meninges back and close the hole in the vertebrae. Many children with this type of spina bifida have no other health problems down the road, unless there is nerve tissue involved with the sac.
• Babies born with the myelomeningocele form of the disease need more immediate attention and typically have surgery within the first 1 to 2 days of their lives. During this first surgery, doctors typically push the spine back into the vertebrae and close the hole to prevent infection and protect the spine.
• A baby who also has hydrocephalus will need an operation to place a shunt in the brain. The shunt is a thin tube that helps to relieve pressure on the brain by draining and diverting extra fluid.
• In addition, some children need subsequent surgeries to manage problems with the feet, hips, or spine.
• The location of the gap in the back often dictates what kind of adaptive aids or equipment that a child with myelomeningocele will need. Children with a gap high on the spinal column and more extensive paralysis will often need to use a wheelchair to move around, whereas those with a gap lower on the back may be able to use crutches, leg braces, or walkers. (Spina Bifida Association)
Spina bifida affects about 2,000 newborns a year in this country. Estimates
are that at least another 2,000 fetuses diagnosed with spina bifida are aborted
Genes Associated with the folate-homocysteine axis
• There is substantial evidence that the risk of spina bifida, a malformation of the caudal neural tube, may be associated with maternal or embryonic disturbances in the folate–homocysteine metabolic axis.
• Variants of genes that influence this pathway represent a group of candidate genes for spina bifida and other neural tube defects.
• A common variant of the gene for endothelial nitric oxide synthase (NOS3 G894T) was recently added to this group of NTD candidate genes, based on a report demonstrating that homozygosity for the T allele of this variant is associated with increased homocysteine levels in normal adult populations.
• The results of the present analyses suggest that the embryonic NOS3 G894T genotype is associated with the risk of spina bifida. (Brown et. al)
Genes Associated with embryonic development
• PRKACA and PRKACB are genes encoding the cAMP-dependent protein kinase A (PKA) catalytic subunits alpha and beta, respectively. PKA is known to be involved in embryonic development, as it downregulates the Hedgehog (Hh) signaling pathway, which is critical to normal pattern formation and morphogenesis.
• PKA-deficient mouse model, which has only a single catalytic subunit, provided intriguing evidence demonstrating a relationship between decreased PKA activity and risk for posterior NTDs in the thoracic to sacral regions of gene-knockout mice.
• Unlike most other mutant mouse models of NTDs, the PKA-deficient mice develop spina bifida with 100% penetrance.
• Zhu et al hypothesized that sequence variations in human genes encoding the catalytic subunits may alter the PKA activity and similarly increase the risk of spina bifida.
• Zhu et al sequenced the coding regions and the exon/intron boundaries of PRKACA and PRKACB. Our results did not reveal a strong association between these genes spina bifida risk (Zhu et al., 2005)
Genes Associated with folate metabolism
• A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly (congenital absence of all or a major part of the brain) , and 3.7% other NTDs.
• Allele and genotype frequencies were stratified according to offspring
NTD phenotype, and variation in the level of NTD risk was associated with different
phenotypes. All the
• three variants (MTHFR 677C>T, GCPII 1561C>T, and RFC-180G>A) were shown to significantly influence the risk of anencephalic pregnancy.
• The MTHFR 677C>T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers.
• The RFC-1 80G>A variant elevated the risk of SBO and anencephalic pregnancy.
• The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes (Relton et al, 2003).
• Marginal maternal deficiency in B12 may increase risk NTDs. (Groenen,
o B12 allows for “recycling” of folate
• Polymorphisms in methylenetetrahydrofolate reductase, methylenetetrahydrofolate
dehydrogenase, and the reduced folate carrier may be risk factors for NTDs.
(Mills, et al.)
o These are required for the “recycling” of folate.
o Problems with the genes that encode for these enzymes would make folate less available to the body. This would thus make folate less available to the developing embryo.
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