Abstract
Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gain-of-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.
Highlights
The first clinical description of tuberous sclerosis complex (TSC) was of L
The TSC1 and TSC2 genes encode for the proteins hamartin and tuberin that form a GTPase activating protein (GAP) complex and inhibit RAS homologue enriched in brain (RHEB; Garami et al, 2003; Inoki et al, 2003; Tee et al, 2003; Zhang et al, 2003)
The timing of somatic cell mutation, the number of clones with de novo mutations, and the cells in which the mutation occurs contribute to the severity of TSC manifestations. An example of this theoretical timing is that mutations in TSC2 that cause hemimegalencephaly may occur in early neuroepithelial stem cells, those that occur later in embryonic radial glia may cause cortical tubers or focal cortical dysplasias, and later mutations in subventricular zone (SVZ) neural stem cells (NSCs) may cause SUBEPENDYMAL GIANT-CELL ASTROCYTOMAS (SEGAs) (Figures 2F–H; Henske et al, 1997; Chan et al, 2004; Crino et al, 2010; Qin et al, 2010a; D’Gama et al, 2017; Lim et al, 2017; Martin et al, 2017)
Summary
The first clinical description of tuberous sclerosis complex (TSC) was of L. Bourneville and Édouard Brissaud later examined a fouryear-old boy that had similar cortical protuberances, seizures, and learning difficulties (Poirier and Ricou, 2010; Brigo et al, 2018). They found growths contiguous with the ventricular walls and tumors in the kidneys. It is Bourneville to whom credit is given for first describing the pathognomic features of TSC These early clinical observations provide several important theoretical contributions. It should not be surprising to learn that as medical, genetic, and imaging technology have progressed, that TSC can be diagnosed in utero
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
