Tuberous sclerosis

TSC1.2 Tuberous sclerosis complex hamartomas of the brain, heart, kidneys, skin, lungs, and eyes... 

Blindness (several forms) Deafness (several forms) Marfan syndrome Achondroplasia Neurofibromatosis Myotonic dystrophy Tuberous sclerosis All others... 

Manning, B. D., and Cantley, L. C. (2003). United at last The tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signaling. Biochem. Soc. Trans. 31, 573-578. 

Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., and Candey, L. C. (2002). Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151—162. 

Rolfe, M., McLeod, L. E., Pratt, P. F., and Proud, C. G. (2005). Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). Biochem. J. 388, 973-984. 

Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. The PDA has recently approved everolimus for organ rejection prophylaxis on April 22, 2010. A Phase II trial reports it is effective in the treatment of subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis. In Oct 2010, the PDA approved its use in SEGA unsuitable for surgery. As of Oct 2010 Phase III trials are under way in breast cancer, gastric cancer, hepatocellular carcinoma, pancreatic neuroendocrine tumors (NET), and lymphoma. ... 

Extensive preclinical studies have shown that sensitivity to mTOR inhibition may correlate with aberrant activation of the PI3K pathway or loss of functional tuberous sclerosis complex (TSC), as occurred in patients with tuberous sclerosis syndrome [151,152]. Rapamycin (compound 31, Fig. 6), which was the first compound shown to inhibit mTOR kinase activity, is an approved drug for prevention of allograft rejection. Rapamycin is a macrocyclic... 

Corticotropin has been reported to cause enlargement of cardiac tumors in tuberous sclerosis (1). 

Vigabatrin is used as an adjunctive antiepileptic in patients with resistant partial epilepsy with or without secondary generalization, unresponsive to other therapy [2]. Nowadays, vigabatrin is rarely used in the treatment of partial seizures due to several irreversible visual field constrictions associated with its chronic use [57-62], It is regarded by many authorities as a drug of choice in infants with west syndrome (infantile spasms), particularly in cases associated with tuberous sclerosis [62],... 

Tuberous Sclerosis as an Underlying Basis for Infantile Spasm Raymond S. Yeung... 

In 1976, the US Food and Drug Administration (FDA) published a Gamma Benzene Hexachloride (Kwell) Alert, based in part on several poorly documented cases of convulsions after topical treatment with lindane (6). Indeed, several authors have reported convulsions (7-9), but in most cases lindane had been inappropriately used (4,7), while another case took place in unusual therapeutic circumstances (prematurity, marasmus, pneumonia, congestive heart failure, ventricular septal defect) (8). A child with convulsions after the application of lindane had tuberous sclerosis and may therefore have had a reduced threshold for convulsions (9). 

The mammalian target of rapamycin complex 1 (mTORCl) system as it is affected by increased nutrients (f AA). The increased AA may interact with the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2), which inhibit Ras homologue enriched in brain (Rheb). The increased AA may also act on Rheb or mTOR directly. Rapamycin inhibits mTOR in this complex, which includes Raptor and the G protein, GpL, which binds to the kinase domain of mTOR both facilitate mTOR signaling. Output from the Raptor protein in mTORCl includes the activation of the ribosomal subunit, S6K, and inhibition of the 4E-binding protein (4E-BP), both of which lead to protein synthesis and cellular hypertrophy. mTOR directly stimulates ribosome synthesis and inhibits autophagy. Arrows indicate stimulatory effects, T-bars indicate inhibition... 

About 5% to 10% of GI neuroendocrine tumors are associated with a hereditary disease. The inherited syndromes and their associated genes include multiple endocrine neoplasia type I MENl gene), neurofibromatosis type 1 NFl gene), von Hippel-Lindau disease VHL gene), and the tuberous sclerosis complex TSCl or TSC2 gene).406... 

Gyure KA, Hart WR, Kennedy AW. Lymphangiomyomatosis of the uterus associated with tuberous sclerosis and malignant neoplasia of the female genital tract A report of two cases. Int J Gynecol Pathol. 1995 14 344-351. 

Cortical dysplasia consists of disrupted cortical architecture and abnormally enlarged cells, some with IFIC staining of neurons, some with GFAP-positive astrocytes, and some individual cells that stain for both glial and neuronal markers.Cortical tubers, seen with tuberous sclerosis, are cortical dysplasias. Other dys-plastic abnormalities are described in the Neuronal Tumors section earlier in this chapter. 

Kimura N, Watanabe M, Date F, et al. HMB-45 and tuberin in hamartomas associated with tuberous sclerosis. Mod Pathol. 1997 10 952-959. 

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