Neural tube defects

SIGNIFICANCE: Neural tube defects (NTDs), such as anencephaly and spina bifida (SB), occur when the neural tube fails to close normally during embryogenesis. The risk of NTDs can be reduced by taking folic acid before conception and during the first trimester of pregnancy. Research indicates NTDs are the result of both environmental and genetic factors.

Formation of the Neural Tube

The neural tube develops out of the neural plate and differentiates into the brain and spinal cord. Neurulation is a complex process of organized gene expression in which the thickened epithelial cells that make up the neural plate change shape, migrate, and differentiate at precise intervals to form a hollow tube. During convergent extension (CE), cells narrow and lengthen and the borders fold, forming the neural groove, which becomes progressively deeper with cell division. The neural tube begins to form as the dorsal folds meet and fuse along the midline. Closure begins in the cervical region, extends along the rostral/caudal plane, and ends at the anterior and posterior neuropores around twenty-four and twenty-eight days after conception, respectively. At the cephalic (head) end of the neural tube, three cavities form and differentiate into the forebrain, midbrain, and hindbrain; midway, the walls (epithelium) develop into cells of the nervous system; and the caudal (tail) end becomes the spinal cord. NTDs can result when any of the steps in this process is disrupted.

Classification of Neural Tube Defects

Anencephaly is caused by disruption of the anterior neuropore, resulting in the absence of significant areas of the brain and skull. The region normally occupied by the cerebral hemispheres consists of a formless mass of highly vascular connective tissue; most of the bones of the skull are simply missing. Almost all infants with anencephaly are stillborn or die soon after birth. Encephalocele is a related condition in which parts of the brain and the sac-like membrane covering it protrude outside the skull; severity of dysfunction depends on the extent of neural tissue involvement.

The severe form of spina bifida is characterized by herniation of neural tissues and cystic swelling. Protrusion of both the meninges (protective coatings) and the spinal cord through the open site is called a myelomeningocele or meningomyelocele and results in dysfunction to nerves at and below the site. The higher up the lesion is along the vertebral column, the greater the nerve damage. Most born with a myelomeningocele also have hydrocephalus (80–85 percent) and a neurogenic bladder (up to 90 percent); many require surgery for a tethered cord (20–50 percent) and/or Arnold-Chiari malformation (33 percent).

Meningocele is a more moderate form of spina bifida in which the sac-like protrusion contains meninges and spinal fluid but no spinal cord. It usually causes no nerve damage. Occult spinal dysraphism is a mild form in which there may be a dimple with tufts of hair on the lower back.

Prevalence of Neural Tube Defects

Rates of NTDs have been declining (as much as 30 to 40 percent) in most areas of the world, due to dietary changes made when spina bifida was linked to a lack of absorption of folic acid. Nevertheless, spina bifida still occurs in 1 to 2 of every 2,500 births worldwide.

Women deficient in vitamin B₁₂ have up to five times the risk of having an affected child. Besides folate deficiency, other risk factors include certain genetic factors, such as a previous NTD birth (2 percent higher risk), obesity, Hispanic ethnicity, and exposure to high temperatures. At-risk women are advised to have their alpha-fetoprotein levels measured. Amniocentesis and ultrasound can help in detecting an NTD in the developing fetus.

Genetic Aspects of Neural Tube Defects

Normal folate metabolism is necessary for DNA synthesis and methylation, cell division, and tissue growth. Folate pathway genes have been extensively examined for their association with NTDs. A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene that causes decreased enzyme activity in folate absorption was the first genetic link to NTD risk. The A222V (also known as C677T) allele of the MTHFR gene and single nucleotide polymorphisms (SNPs) of the betaine-homocysteine S-methyltransferase (BHMT) gene are both mutations that are suspected of posing significant risk for NTDs.

Many genes have been studied in animal models and implicated in NTDs. The signal transduction protein of the sonic hedgehog gene (SHH) controls the loci of bending points during conversion of the neural plate to the neural fold. The Ras association domain family member 7 (RASSF7), a gene with protein product, is required to complete mitosis in the neural tube. The most important of the altered gene expressions include abnormalities in wingless (Wnt) signaling and mutations in Vang-like 1 (VANGL1), a gene that is part of the Wnt signaling pathway and controls the activity of genes needed at specific times during development. Wnt signaling is involved in many aspects of embryonic development, including formation of the neural tube, in which it directs cell polarity orientation, regulation of nerve cell migration, and CE movements. The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene, involved in the folate pathway, has also been studied extensively for its possible role in the pathogenesis of NTDs.

Despite these strides, the genetic basis of NTDs remains complex and poorly understood, involving a combination of multiple gene-gene and gene-environment interactions. To form, the neural tube requires precise spatial and temporal gene expression. Specific genes determine cell fate and lateral inhibition pathways, others control the frequency of mitosis, gene receptors are involved in fusion in the cranial epithelium or fusion of the neural fold, and regulatory genes program development of the brain stem and midbrain.

Impact

Research linking the A222V mutation in the MTHFR gene to NTDs was an important milestone that resulted in a significant reduction in the incidence of these birth defects after the US Food and Drug Administration (FDA) issued a mandate in 1998 that manufacturers fortify all enriched cereal grain products with folic acid. This was preceded by a 1992 advisory from the US Public Health Service that all women of childbearing age take a daily supplement of folic acid. In 2009, the US Preventive Services Task Force (USPSTF) updated the advisory, increasing the recommended dosage of folic acid from 0.4 milligram (mg) to between 0.4 and 0.8 mg.

Because neurulation occurs so early in fetal development, it cannot be examined in humans. However, researchers have been able to detect some faulty neurulation-related genes in humans. Three missense mutations of the protein-coding VANGL1 gene (V239I, R274Q, and M328T) were identified in patients with spina bifida. The V239I variant was found to nullify interactions of VANGL1 Disheveled (Dvl) proteins 1, 2, 3. (A related study found VANGL1 mutant mice produced offspring with NTDs.) Researchers conducted a whole genome association analysis of forty-five families who had a previous anencephalic pregnancy and identified eleven SNPs on six different genes as possible risk factors for anencephaly. Two of these, the InaD-like (Drosophila) gene (INADL) and the myelin gene (MYT1L), were found to be involved in neural tube closure. INADL is located on chromosome 1 and affects the movement of cells to their correct position; MYT1L is located on chromosome 2 and controls other genes that affect the development of the nervous system.

Although research has indicated that faulty genes involved in folate metabolism and/or neurulation pathways are the most likely candidate genes for NTDs, there are still many questions as to the genetic mechanisms of neural tube closure. Because many genes tend to multitask and participate in more than one function, it is difficult to analyze single gene expressions. The key to lowering the incidence of NTDs is continued research to elucidate other gene variants and signaling pathways that affect neurulation and folate metabolism.

Key Terms

• alpha-fetoproteinplasma protein produced by the fetus; elevated level indicates risk of an NTD
• anencephalyNTD caused by failure of the cerebral hemispheres of the brain and cranium to develop; incompatible with life
• Arnold-Chiari malformationherniation of the hindbrain in which the cerebellar vermis and part of the brain stem become pushed into the cervical spine
• neural tubethe embryonic precursor to the spinal cord and brain that forms as the neural plate folds and normally closes by the twenty-eighth day of gestation
• spina bifidaNTD meaning “open spine” that is caused by failure of the posterior neuropore to close normally during gestation, resulting in protrusion of a portion of the spinal cord outside the vertebral column; surgically closed shortly after birth
• hydrocephalusexcessive accumulation of cerebrospinal fluid in the brain, causing enlargement of the ventricles; requires surgical insertion of a shunt to drain
• neurogenic bladdermalfunctioning bladder caused by paralytic pelvic floor, resulting in incontinence, urinary reflux, and UTIs; requires lifelong clean intermittent catherization (CIC) and kidney function assessment
• tethered cordlow-lying position of the spinal cord when it scars to the skin after surgical closure and becomes stretched as the child grows

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