Embryology, Central Nervous System, Malformations


The central nervous system (CNS) is composed of the brain and the spinal cord. They both develop from the embryonic ectoderm alongside other structures like the skin. Their development begins as early as the 3rd and 4th weeks of embryonic life, starting with the process of neurulation, which is the development of the neural tube. The neural tube closes spontaneously rostrally and caudally. In the fifth to sixth week, the first appearance of the brain, the prosencephalic development ensues. The primitive brain is comprised of the prosencephalon, mesencephalon, and rhombencephalon. The prosencephalon divides further into telencephalon and diencephalon through a series of developmental stages, namely: formation, cleavage, and development of the midline.[1][2][3] Any form of developmental alteration in these leads to the malformation of the developing brain.[4]

The article describes the embryology of the central nervous system, the developmental malformation of the cerebral cortex and spinal cord. Developmental malformation of the brain and spinal cord leads to various diseases from microcephaly to spinal bifida. The stages of development of the cerebral cortex encompass three main steps. Defects in one or a combination of these steps form the basis of classification of abnormality of the cortical development as:

The proliferation of neural cells: an abnormally high proliferation of the neural cells can lead to megalencephaly, and decreased proliferation leads to microcephaly.

Neuronal migration: the outcome of partial neuronal migration is heterotopia and lissencephaly; excessive neuronal migration causes cobblestone malformation.

Postmigrational cortical organization and connectivity: irregular events in the post-migrational cortical organization causes focal cortical dysplasias and polymicrogyria.[1][5][6][7]

The defects of neural tube fusion consist of encephalocele, meningocele, myelomeningocele, and spina bifida occulta.[8] Specifically, alterations in the closure of the rostral neural tube result in conditions like anencephaly or encephalocele. Myelomeningocele occurs from the incomplete causal fusion of the neural tube. Anencephaly typically occurs before the 24th day of life, while encephalocele and myelomeningocele occur about the 26th day of life.[1]



Several studies have implicated environmental factors in the malformation of the central nervous system of an embryo. These include folate deficiency, illicit drug use, and prescribe medications that affect folate metabolism in the body.

Cellular/Biochemical/Molecular Mechanism

The PI3K-AKT3-TSC2-mTOR Pathway

Both genetic and molecular factors may disrupt the normal development of the cerebral cortex. Any form of alteration in the genes that control growth and metabolic pathways leads to cortical development malformation. Generally, the mammalian target of the rapamycin (mTOR) pathway has been strongly recognized in these malformations. The inhibition of TSC or activation of PIK3CA or AKT3 hyperactivates the mTOR pathway leads to dysregulated cell growth.[9][4]

The majority of neural tube defects are sporadic. Genetic factors remain strongly implicated in the pathogenesis of NTDs, and the usual form of inheritance is multifactorial or polygenic. Maternal folate deficiency may contribute to NTD development in genetically susceptible individuals. Studies have shown that mutations in the genes involved in mitochondrial folate metabolism increase the risk. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and its variant form (C677T genotype) (MTHFR C677T) is associated with the risk for NTDs.[10] Maternal folate level is a risk factor; however, only an inconsequential number of cases. In many cases, the maternal folate levels are within the normal range or hardly clinically deficient. Folate facilitates the transportation of one-carbon units from the mitochondria to the cytoplasm and plays a vital role in the biosynthesis and methylation of nucleotide.[11]

Clinical Significance

Development Malformation of the Cerebral Cortex


Holoprosencephaly is a malformation of the prosencephalon characterized by incomplete separation of both cerebral hemispheres. Chromosomal abnormalities such as Patau and Edward syndromes carry a higher risk for holoprosencephaly as well as gestation complicated with diabetes. Patau syndrome (trisomy 13) is the most commonly associated syndrome.[1][12] Holoprosencephaly is usually incompatible with life, and most children born with this malformation have very high mortality early in postnatal life. The subtypes of holoprosencephaly in order of increasing severity are middle interhemispheric, lobar, semi-lobar, and alobar variants. A brain CT scan or MRI can confirm the diagnosis and differentiate the subtypes of holoprosencephaly.[13] Genes like the Bone Morphogenetic Protein (BMP), Sonic hedgehog (Shh), Fibroblast Growth Factor (FGF) are all suspected to be associated with holoprosencephaly.[14]

Agenesis of Corpus Callosum (ACC)

ACC is a partial development or complete absence of the corpus callosum, which is the connecting structure between the two cerebral hemispheres.[15] A frameshift (loss of function) mutation of the DCC Netrin 1 receptor gene correlates with agenesis of the corpus callosum, and most of the cases had no neurological symptoms.[16] The clinical and radiological manifestations of this disease vary; MRI is a good imaging modality for diagnosis. Studies have shown a strong connection between individuals with ACC share many common features with autism, such as stereotypy. Antisocial behavior and lying are also commonly reported features with callosal dysgenesis.[17][18]

Septooptical Dysplasia

This condition is an abnormality of the forebrain comprised of the triad of a defect in the midline forebrain structures - septum pellucidum n (with or without agenesis of the corpus callosum), hypoplasia of the optic nerve (cranial nerve II), and pituitary insufficiency.  It most likely occurs in the 4th to 6th weeks of life. It is an uncommon condition with an incidence of 1 in 10,000 live births. It has links with a mutation in the HESX1, SOX2, and SOX3, or OXT2.[19][20] These produce a constellation of neurological symptoms like optic nerve abnormalities such as nystagmus and other clinical symptoms, such as pituitary insufficiencies.


Megalencephaly is an increased head size above two standard deviations. Clinically, it is more applicable to define it as brain size greater than three standard deviations above the mean to exclude familial megalencephaly. It occurs due to congenital defects in neuronal migration or abnormal cell proliferation, or a combination of both. Megalencephaly is classified based on etiology, genetic abnormalities in metabolism, and development. Mutations in genes controlling major molecular pathways like the phosphatidylinositol 3-kinase (PI3K/AKT) have been implicated. On the other hand, megalencephaly requires differentiation from macrocephaly, which is an unusual increase in occipitofrontal circumference (OFC) at least two standard deviations caused by structural abnormalities of the cranium, brain, or cerebrospinal fluid (CSF) and related structures.[21][22][5][23]


This is a one-sided cerebral hemisphere enlargement involving part of or the whole cerebral hemisphere. Commonly seen in association with hemimegaloencephaly, neurocutaneous syndromes like linear sebaceous syndrome, tuberous sclerosis, and neurofibromatosis. The common presentation of this disease includes psychomotor retardation, intractable seizures, cranial nerve palsies, and hemiparesis. The presence of seizures in the first year of life is indicative of a poor prognosis.[24][25] Several studies identified mutations in genes controlling major molecular pathways like the phosphatidylinositol 3-kinase (PI3K/AKT)-mTOR.[26]

Periventricular Heterotopia

This pathology is a genetic disease due to a failure of neurons to migrate, leading to abnormally located nodules around the ventricles. The most common clinical manifestation is an afebrile seizure. Research has shown it to occur alongside other conditions like EDS, Williams syndrome, and Ci du Chat. However, mutations in the filamin A (FLNA (Xq28) and ADP ribosylation factor guanine nucleotide exchange factor 2 (ARFGEF2 (20q13). X-linked FLNA while the ARFGEF2 autosomal recessive.[27][28][29]


Lissencephaly-pachygyria is a spectrum of abnormal development of the cerebral gyri and sulci resulting from the abnormal migration of neurons. The term for a partial development is pachygyria, and complete absence is agyria. Pachygyria typically have milder symptoms compared to lissencephaly. Type one is known to be the classic lissencephaly, and type two is the cobblestone complex.[30][31] The cobblestone lissencephaly malformation is associated with the TUBA1A and GPR56 gene mutations. The cobblestone defect results from the combination of the excessive migration of neural crest cells into the leptomeninges and abnormalities in the surface of the cerebral pia layer. The commonest gene mutations implicated in lissencephaly are LIS1 and DCX. Others include cell structure proteins like actin, dynein, kinesin, tubulin genes, CASP2, and RIPK1 domain-containing adaptor with death domain (CRADD).[32][33]


As the name implies is simply an abnormally formed cerebral cortex that has multiple small gyri. The severity of the symptoms is strongly related to the extent of brain involvement with the unilateral focal variant as the mildest form of this disease. It has little or no symptoms and is mostly controlled with antiepileptic medications. The most severe is the bilateral frontoparietal polymicrogyria with significant neurological manifestations. This severe form gets inherited in an autosomal recessive pattern, and the defect is on chromosome 16q12-21.[34] Polymicrogyria is commonly associated with Aicardi, Delleman, DiGeorge 22q11.2 (deletion), Sturge–Weber, and Warburg Micro syndromes.[35][36] Mutations in genes controlling major molecular pathways like the phosphatidylinositol 3-kinase (PI3K/AKT) have been implicated. Researchers have also noted that cobblestone lissencephaly is commonly associated with polymicrogyria. (25047116). Schizencephaly generally classifies as a subtype of polymicrogyria., a rare brain malformation described as a split-brain or cleft that transverse the brain pia mater to the ventricles.[37][38][23][33]

Focal Cortical Dysplasia[34]

Focal cortical dysplasias (FCDs) is an umbrella name consisting of several subgroups of abnormal lamination of the cerebral cortex.[4] It has been demonstrated to be the most frequent cause of seizures, not amenable to medications. FCD generally is more prevalent in males than females.[39] Type I FCD is an abnormal absence of cortical lamination. If it occurs in radial patterns, it is subclassified as Ia and Ib if tangential, Ic, on the other hand, is a combination of both patterns.[40][4] In contrast, to type I, which is mild and more likely in adults, type II FCD is more clinically severe and observed more in children.[41]

Strong ideas have been advanced to demonstrate that tuberous sclerosis 1 and 2 (TSC1 and TSC2), as well as phosphatase and tensin homolog (PTEN) genes that regulate mTOR, are also the causes of FCD type 2b because it shares common features with tuberous sclerosis.[5][39]

FCD type III is either type I or II co-occurring with other brain lesions.[41] If hippocampus sclerosis is present, it is further classified as IIIa, with tumors as IIIb, vascular malformations as IIIc, and extrinsic pathologic insults such as hypoxia, trauma, and encephalitis as IIId.[4][40]

Developmental Malformation of the Spinal Cord

Neural tube defects (NTDs) are malformations of the brain and spinal cord resulting from the failure of the neural tube closure in the third and fourth week of intrauterine development. They are the most prevalent congenital malformation of the CNS.[8]  Even though routine prenatal folic acid supplementation has been effective in decreasing the disease prevalence, it remains one of the most common abnormalities of the newborn.[42] There are two major forms of NTDs, which are anencephaly and spina bifida.

Spina bifida is a common NTDs in which the spinal cord is exposed or protrudes to the surface with the meninges into a sac-like through a defect in the vertebral wall. It includes myelomeningocele, meningocele, and myelocele.[43][44] When this closure defect involves the herniation of only cerebrospinal fluid, it is called myelocele, myelocele containing meninges is meningomyelocele, and with both meninges and spinal cord, it is called myelomeningocele. Commonly associated with spina bifida are hydrocephalus and Arnold-Chiari malformation type II (a combination of myelomeningocele and cerebellar tonsil herniation).[45][1]

Anencephaly is one of the common types of NTDs with a congenital absence of the brain or parts of the brain and cranium. It occurs as a result of the failure of the cranial portion of neural tube closure.[43][44]

Encephalocele is a rare NTD in which the brain protrudes through an abnormal opening of the cranium with or without the meninges, leaving a projection of a bag-like structure handing on the head.[46] It is also frequently associated with other CNS abnormalities like hydrocephalus, especially with the posterior encephaloceles.[47] This condition may result from aqueductal stenosis or torsion and may also be a post-surgical complication of encephalocele repair.[48]


Most central nervous system (CNS) malformations are recognizable during routine laboratory screening and ultrasound scans. A second trimester elevated alpha-fetoprotein (AFP) in triple screen raises a very high suspicion for neural tube defects.[49] Further diagnostic workup is required if any abnormalities are detected.[13] Treatment of congenital malformation of the CNS requires a multidisciplinary approach and supportive management such as antiepileptics, gastrostomy tubes, and other surgical modalities.[13] The most widely practiced prevention for spina bifida is folic acid supplementation, with preconception use more beneficial than use in pregnancy. In spina bifida, the spinal cord is exposed to the amniotic fluid that contributes to the further damage of the nervous tissues. Newly practiced in-utero surgical procedures to prevent the neurodegeneration of the exposed spinal cord have helped preserve the structures and improve outcomes.[50]

Article Details

Article Author

Ayesan Rewane

Article Editor:

Sunil Munakomi


3/9/2022 1:03:11 PM



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