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The central nervous system (CNS) is composed of the brain and the spinal cord. They both develop from the embryonic ectoderm, alongside other structures such as 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 marks the onset of prosencephalic development. 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 developmental alteration in these leads to malformation of the developing brain.[4] The topic describes the embryology of the central nervous system and the developmental malformations of the cerebral cortex and spinal cord. Developmental malformations of the brain and spinal cord lead to a range of diseases, from microcephaly to spinal bifida. The stages of development of the cerebral cortex encompass 3 main steps. Defects in 1 or a combination of these steps form the basis of the classification of abnormality of the cortical development as: The proliferation of neural cells: Excessive proliferation can lead to megalencephaly, whereas decreased proliferation can lead to microcephaly. Neuronal migration: Partial migration results in heterotopia and lissencephaly; excessive migration causes cobblestone malformation. Postmigrational cortical organization and connectivity: Irregular events in the post-migrational cortical organization cause 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 closure 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]

Etiology/Pathophysiology Several studies have implicated environmental factors in the malformation of the central nervous system during embryonic development. These include folate deficiency, illicit drug use, and prescribed 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 alteration in the genes that regulate growth and metabolic pathways leads to malformation of cortical development. Generally, the mammalian target of the rapamycin (mTOR) pathway has been strongly recognized in these malformations. Inhibition of TSC or activation of PIK3CA or AKT3 hyperactivates the mTOR pathway, leading to dysregulated cell growth.[4][9] The majority of neural tube defects are sporadic. Genetic factors remain strongly implicated in the pathogenesis of NTDs, and inheritance is typically multifactorial or polygenic. Maternal folate deficiency may contribute to the development of NTDs 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) are 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 are hardly clinically deficient. Folate facilitates the transportation of 1-carbon units from the mitochondria to the cytoplasm and plays a vital role in the biosynthesis and methylation of nucleotides.[11]