Pathogenesis of TSC in the Brain

Crino, Peter B.; Mehta, Rupal I.; Vinters, Harry V.

doi:10.1002/9783527630073.ch9

Cited by 16 publications

(14 citation statements)

References 48 publications

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“…More recent studies have identified a wider spectrum of abnormalities in the TSC patient brain, including cysts (35), cerebellar pathology (17), and MRI abnormalities of uncertain origin and nature (28), as well as isolated giant and dysplastic cells in otherwise apparently normal regions of cortex (7). …”

Section: Discussionmentioning

confidence: 99%

“…Tuberous sclerosis complex (TSC) is a highly variable but often severe neurocutaneous syndrome characterized by the development of hamartomas in multiple tissues and organs at different stages of development (7,8,11). Brain cortical tubers, subependymal giant cell astrocytomas (SEGAs), facial angiofibroma, peri-ungual fibromas, cardiac rhabdomyoma, renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) are all common in this disorder.TSC is caused by inactivating small mutations or larger genomic deletions in either TSC1 or TSC2 (2,9,19,30).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of TSC Cortical Tubers by Deep Sequencing of TSC1, TSC2 and KRAS Demonstrates that Small Second‐Hit Mutations in these Genes are Rare Events

et al. 2010

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Tuberous sclerosis complex (TSC) is an often severe neurocutaneous syndrome. Cortical tubers are the predominant neuropathological finding in TSC, and their number and location has been shown to correlate roughly with the severity of neurologic features in TSC. Past studies have shown that genomic deletion events in TSC1 or TSC2 are very rare in tubers, and suggested the potential involvement of the MAPK pathway in their pathogenesis. We used deep sequencing to assess all coding exons of TSC1 and TSC2, and the activating mutation hot spots within KRAS in 46 tubers from TSC patients. Germline heterozygous mutations were identified in 81% of tubers. The same secondary mutation in TSC2 was identified in 6 tuber samples from one individual. Further study showed that this second hit mutation was widely distributed in the cortex from one cerebral hemisphere of this individual at frequencies up to 10%. No other secondary mutations were found in the other 40 tubers analyzed. These data indicate that small second hit mutations in any of these three genes are very rare in TSC tubers. However, in one TSC individual, a second hit TSC2 point mutation occurred early during brain development, and likely contributed to tuber formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of TSC Cortical Tubers by Deep Sequencing of TSC1, TSC2 and KRAS Demonstrates that Small Second‐Hit Mutations in these Genes are Rare Events

et al. 2010

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“…42 SEGAs have an incidence of 5–15% in TSC and may also be detected prenatally or at birth, although they are much more likely to arise during childhood or adolescence and it would be unusual for one to occur after the age of 20 years if not already previously present. 42 It is widely accepted that SEGAs typically arise from SEN, especially near the foramen of Monro. Although benign and typically slow-growing, they can cause serious neurologic compromise including obstructive hydrocephalus.…”

Section: Clinical Diagnostic Criteriamentioning

confidence: 99%

Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

Northrup

Krueger²

2013

Pediatric Neurology

1,276

1,205

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BACKGROUND Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of disease-associated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex. RESULTS Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals.

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“…SENs are benign growths that develop along the wall of the ependymal lining of the lateral and third ventricles. They are observed in 80% of TSC patients and are often detected prenatally or at birth . SEGA is a growing tumor larger than 1 cm in diameter, typically occurring near the foramen of Monro.…”

Section: Clinical Features and Treatments Of Tuberous Sclerosis Complexmentioning

confidence: 99%

“…They are observed in 80% of TSC patients and are often detected prenatally or at birth. 62 SEGA is a growing tumor larger than 1 cm in diameter, typically occurring near the foramen of Monro. SEGA is observed in 5-15% of patients with TSC, and can produce clinical symptoms and obstructive hydrocephalus ( Fig.…”

Section: Cortical Dysplasia and Tumorsmentioning

confidence: 99%

Tuberous sclerosis complex: Recent advances in manifestations and therapy

et al. 2017

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Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by generalized involvement and variable manifestations with a birth incidence of 1:6000. In a quarter of a century, significant progress in tuberous sclerosis complex has been made. Two responsible genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively, were discovered in the 1990s, and their functions were elucidated in the 2000s. Hamartin-Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex 1 activity, which is a center for various functions. Constitutive activation of mammalian target of rapamycin complex 1 causes variable manifestations in tuberous sclerosis complex. Recently, genetic tests were launched to diagnose tuberous sclerosis complex, and mammalian target of rapamycin complex 1 inhibitors are being used to treat tuberous sclerosis complex patients. As a result of these advances, new diagnostic criteria have been established and an indispensable new treatment method; that is, "a cross-sectional medical examination system," a system to involve many experts for tuberous sclerosis complex diagnosis and treatments, was also created. Simultaneously, the frequency of genetic tests and advances in diagnostic technology have resulted in new views on symptoms. The numbers of tuberous sclerosis complex patients without neural symptoms are increasing, and for these patients, renal manifestations and pulmonary lymphangioleiomyomatosis have become important manifestations. New concepts of tuberous sclerosis complex-associated neuropsychiatric disorders or perivascular epithelioid cell tumors are being created. The present review contains a summary of recent advances, significant manifestations and therapy in tuberous sclerosis complex.

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Pathogenesis of TSC in the Brain

Cited by 16 publications

References 48 publications

Analysis of TSC Cortical Tubers by Deep Sequencing of TSC1, TSC2 and KRAS Demonstrates that Small Second‐Hit Mutations in these Genes are Rare Events

Analysis of TSC Cortical Tubers by Deep Sequencing of TSC1, TSC2 and KRAS Demonstrates that Small Second‐Hit Mutations in these Genes are Rare Events

Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

Tuberous sclerosis complex: Recent advances in manifestations and therapy

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