What are the two most common congenital malformations of the nervous system?

Published

2008-11-20

How to Cite

1.

Hadžagić-Ćatibušić F, Maksić H, Užičanin S, Heljić S, Zubčević S, Merhemić Z, Čengić A, Kulenović E. Congenital Malformations of the Central Nervous System: Clinical Approach. Bosn J of Basic Med Sci [Internet]. 2008Nov.20 [cited 2022Dec.26];8(4):356-60. Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/2897

Despite recent progress in epidemiologic and clinical research, the exact etiology of NTDs has remained undetermined. It is in common agreement that the interactions between genetic and environmental factors are the possible etiopathogenic factors [14, 15]. More than 70% of cases of NTDs are found to have a genetic etiology [16].

Some of the potential non-genetic environmental risk factors for NTD-affected pregnancy are poor socioeconomic status, maternal hyperthermia; maternal exposure to high doses of irradiation, certain chemicals, and drugs; cigarette smoking; maternal metabolic diseases, and advanced parental age, including those of both mother and father. Pregnancies associated with a fetus with NTD have higher chances of going into preterm labor and being delivered prematurely [5, 17, 18]. In 2008, a large study in California reported that mothers who do not graduate from high school or live in neighborhoods under poor socioeconomic conditions have a greater risk of delivering an NTD-affected child [19]. Brough et al. elaborated in their study that the mothers with higher socioeconomic and educational levels are more likely to consume folic acid during preconception and early gestational age when the neural tube is developing [20], and this might have contributed to the findings of the California study. A meta-analysis regarding the effect of maternal age on the risk of NTD reported that mothers older than 40 and younger than 19 years of age had increased risks of NTD-affected pregnancies [21], the chances being higher for spinal Bifida but not for anencephaly. Studies have assessed the role of parental occupational exposures in the development of NTDs. Brender et al. found self-reported multiple pesticide exposure to be a risk factor for fetal NTD [22]. The role of paternal exposures to hazardous materials in increasing the risk of NTDs in offsprings was emphasized when studies showed that fathers who work as a cook, gardener, janitor, and cleaner have higher chances of getting a child with spina bifida, as these professions have a higher likelihood of exposure to hazardous chemicals [23]. The occupational exposure of fathers to metal-working oil mists and hydrocarbons do not show any association with NTD risk [24]. Caffeine has been investigated as another risk factor for NTDs. Past studies have shown that higher Caffeine consumption during the year before pregnancy increases the risk of spina bifida [25]. The use of antimicrobial medications during the preconception period and first trimester of pregnancy are found to be associated with a higher risk of anencephaly [26].

4.1 Genetics of congenital CNS anomalies

In addition to the potential environmental risk factors as outlined above, congenital CNSA may be a consequence of genetic disorders. NTD, including encephalocele, spina bifida, and exencephaly, have become less prevalent since the widespread consumption of folic acid by pregnant women. So the etiology has shifted toward mutations in folate-responsive or folate-dependent pathways [27]. Knowing the underlying genetic disorders for congenital CNS anomalies helps in counseling about the existing pregnancy, as well as the risk of recurrence in future ones. Sophisticated genetic investigations are available to detect chromosomal anomalies in the cases of NTD.

While a low rate of karyotype abnormality has been reported in isolated ventriculomegaly (0 to 3.8%) [28], Dandy-Walker malformation has been associated with 50% of aneuploidies if associated with other anomalies [29]. In a nearly similar pattern, isolated holoprosencephaly is not accompanied by any significant genetic anomaly; however, 25 to 50% of cases have been reported to have aneuploidies if associated with other organ anomalies. Holoprosencephaly is detected in 70% of Trisomy 13 cases. In the cases with NTDs, Trisomy 13 and 18 are the most commonly reported aneuploidies [30]. Studies have reported notable connections between deletions on the long arm of the 13th chromosome and CNS anomalies [31].

Genes participating in folate metabolism have been studied for the pathogenesis of NTDs. The C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR), encode a key enzyme of folate metabolism responsible for homocysteine remethylation [16]. These polymorphisms are associated with a 1.8fold increase in the risk of NTDs. More than 200 genetic models of NTD have been described in mice that can affect the open NTD phenotypes, such as anencephaly, open spina bifida and craniorachischisis. Their roles in human NTDs are understudy. Some inbred strain variation in the penetrance and expressivity of NTD phenotypes in mice have suggested the roles of modifier gene function. The Cecr2 mutation that causes exencephaly in mice is strongly affected in its expression by one or more modifier genes on Chromosome 19. Strain differences have also been described for non-genetic causes of NTD, including hypoglycemia, hyperthermia, valproic acid, and cytochalasins.

4.2 Embryologic formation of neural tube

Formation of the brain and spinal cord begins with the development of the neural tube through the embryonic process of neurulation. The neural tube is the origin of the brain and spinal cord. The process of neurulation, has two separate phases in mammalian embryos, termed primary and secondary neurulation [32].

Primary neurulation occurs in the third and fourth weeks of development, during which the flat layer of ectodermal cells is transformed into a hollow tube. On the 18th day of fertilization, the neural plate is formed by a thickening of the embryonal midline dorsal ectoderm. The neural plate develops from the cranial end of the embryo moving toward the caudal end.This sentence is deleted ---Then, the edges of the neural plate move upward to form the neural fold---. On 19th day, the border of the neural plate becomes elevated and folds longitudinally from the head to the tail, which results in the formation of a neural groove. By the 23rd day, the folds get merged and make the neural tube which is open at both ends. “Closure,” a process in which both open ends of the neural tube (neuropores) are closed, occurs on the 26th and 28th day of gestational age in rostral and caudal ends, respectively. This neural tube closure is initiated at the hindbrain/cervical boundary (Closure 1). Fusion extends into the hindbrain and along the spinal region, leading to several closure sites appearing at the midbrain/forebrain boundary (Closure 2) and at the rostral extremity of the forebrain (Closure 3). The progression of fusion (‘zippering’) continues along the spine, ending in the last closure at the posterior neuropore at the level of the second sacral segment. This process of neural folding is called ‘primary’ neurulation.

Stem cell proliferation is the main mechanism involved in secondary neurulation, which is limited to the tailbud. During this process, a rod-like condensation is formed, which subsequently becomes cavitated. Cavitation transforms the rod into a tube which remains in continuation with the tube constructed as the result of primary neurulation. Tail bud develops in tailed mammalians, and as the anatomy of humans is tailless, secondary neurulation does not seem to be involved in the formation of neural tube defects [8]. Instead, the lateral sclerotome cells derived from the multipotential tail bud cell population organize themselves around the secondary neural tube to form the sacral and coccygeal vertebrae. Subsequently, the caudal-most neural tube degenerates via apoptosis.

Primary neurulation is essential for the formation of the brain and spinal cord. Failure of Closure 1 leads to the most severe NTD, called craniorachischisis, which comprises an open neural tube encompassing the midbrain, hindbrain, and spinal region. In the presence of normal completion of closure one incomplete closure of the cranial neural tube leads to anencephaly with may have the defect confined to the midbrain (meroanencephaly) or extending into the hindbrain (holoanencephaly). Failure of Closure 3 is uncommon and presents with abnormal face with anencephaly. In the spinal region, failure of final closure at the posterior neuropore yields an open spina bifida (myelomeningocele). In this anomaly, the upper limit of SB depends upon the timing of the arrest of the progression of zippering and, as such, may end up at varying axial levels.

A hypothesis forwarded by Morgagni believes that the increased intraventricular pressure caused by over-production of cerebrospinal fluid (CSF), leads to the reopening of an already closed neural tube [33, 34, 35].

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