Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse DOI Creative Commons
Sharon W. Way, James T Mckenna, Ulrike Mietzsch

и другие.

Human Molecular Genetics, Год журнала: 2009, Номер 18(7), С. 1252 - 1265

Опубликована: Янв. 8, 2009

Tuberous sclerosis complex (TSC) is an autosomal dominant, tumor predisposition disorder characterized by significant neurodevelopmental brain lesions, such as tubers and subependymal nodules. The neuropathology of TSC often associated with seizures intellectual disability. To learn about the developmental perturbations that lead to these we created a mouse model selectively deletes Tsc2 gene from radial glial progenitor cells in developing cerebral cortex hippocampus. These mutant mice were severely runted, developed post-natal megalencephaly died between 3 4 weeks age. Analysis pathology demonstrated cortical hippocampal lamination defects, heterotopias, enlarged dysplastic neurons glia, abnormal myelination astrocytosis. histologic abnormalities accompanied activation mTORC1 pathway assessed increased phosphorylated S6 lysates tissue sections. Developmental analysis loss subventricular Tbr2-positive basal cell pool at expense early born Tbr1-positive post-mitotic neurons. results establish novel concept function progenitors one initiating event development lesions well underscore importance regulation neural pools. Given similarities human this will be useful further understanding pathophysiology, testing potential therapies identifying other genetic pathways are altered TSC.

Язык: Английский

Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference DOI Creative Commons
Hope Northrup, Darcy A. Krueger, Hope Northrup

и другие.

Pediatric Neurology, Год журнала: 2013, Номер 49(4), С. 243 - 254

Опубликована: Сен. 20, 2013

BackgroundTuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis fundamental implementation appropriate medical surveillance treatment. Although significant advances have been made past 15 years understanding treatment tuberous complex, current diagnostic criteria not critically evaluated or updated since last consensus conference 1998.MethodsThe 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 relevant subspecialty. Each subcommittee focused on specific disease area important implications charged reviewing prevalence specificity disease-associated findings their impact suspecting confirming complex.ResultsClinical features be principal means diagnosis. Key changes compared 1998 are new inclusion genetic testing results reducing classes three (possible, probable, definite) two definite). Additional minor criterion were for additional clarification simplification.ConclusionsThe Diagnostic Criteria provide current, using best available evidence establish individuals.

Язык: Английский

Процитировано

1358
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial DOI
John J. Bissler, J.C. Kingswood, Elżbieta Radzikowska

и другие.

The Lancet, Год журнала: 2013, Номер 381(9869), С. 817 - 824

Опубликована: Янв. 11, 2013

Язык: Английский

Процитировано

813
Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference DOI Creative Commons
Darcy A. Krueger, Hope Northrup, Hope Northrup

и другие.

Pediatric Neurology, Год журнала: 2013, Номер 49(4), С. 255 - 265

Опубликована: Сен. 19, 2013

Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations progression can be life-threatening with significant impact on cost quality of life. Current surveillance management practices are highly variable region country, reflective the fact that last consensus recommendations occurred in 1998 an updated, comprehensive standard lacking incorporates latest scientific evidence current best clinical practices.The 2012 International Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by clinician advanced expertise tuberous relevant medical subspecialty. Each subcommittee focused specific area important implications charged formulating key questions to address within its focus area, reviewing literature, evaluating strength data, providing recommendation accordingly.The updated for summarized here. entire lifespan patient, infancy adulthood, including both individuals where diagnosis newly made as well already established.The Recommendations provide evidence-based, standardized approach optimal care provided complex.

Язык: Английский

Процитировано

793
The Neurology of mTOR DOI Creative Commons
Jonathan O. Lipton, Mustafa Şahin

Neuron, Год журнала: 2014, Номер 84(2), С. 275 - 291

Опубликована: Окт. 1, 2014

Язык: Английский

Процитировано

659
The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes DOI Creative Commons
Jerzy Węgiel,

Izabela Kuchna,

Krzysztof Nowicki

и другие.

Acta Neuropathologica, Год журнала: 2010, Номер 119(6), С. 755 - 770

Опубликована: Март 2, 2010

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, repetitive stereotyped patterns behavior. Abnormal acceleration brain growth early childhood, signs slower neurons, minicolumn developmental abnormalities suggest multiregional alterations. The aim this study was to detect the focal defects identify regions that are prone alterations autism. Formalin-fixed hemispheres 13 autistic (4–60 years age) 14 age-matched control subjects were embedded celloidin cut into 200-μm-thick coronal sections, which stained with cresyl violet used for neuropathological evaluation. Thickening subependymal cell layer two brains nodular dysplasia one indicative active neurogenesis children. Subcortical, periventricular, hippocampal cerebellar heterotopias detected four (31%) reflect abnormal neuronal migration. Multifocal cerebral resulted local distortion cytoarchitecture neocortex (31%), entorhinal cortex (15%), cornu Ammonis dentate gyrus brains. Cerebellar flocculonodular six (46%), vermis case, hypoplasia subject indicate failure development 62% subjects. Detection only changes 12 examined (92%) reflects dysregulation neurogenesis, migration maturation autism, may contribute heterogeneity phenotype.

Язык: Английский

Процитировано

547
Tuberous sclerosis complex: Advances in diagnosis, genetics, and management DOI
Robert A. Schwartz,

Geover Fernández,

Katarzyna Kotulska

и другие.

Journal of the American Academy of Dermatology, Год журнала: 2007, Номер 57(2), С. 189 - 202

Опубликована: Июль 17, 2007

Язык: Английский

Процитировано

380
A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders DOI Creative Commons
Claudia Bagni, R. Suzanne Zukin

Neuron, Год журнала: 2019, Номер 101(6), С. 1070 - 1088

Опубликована: Март 1, 2019

Язык: Английский

Процитировано

282
Molecular logic of mTORC1 signalling as a metabolic rheostat DOI
Alexander J. Valvezan, Brendan D. Manning

Nature Metabolism, Год журнала: 2019, Номер 1(3), С. 321 - 333

Опубликована: Март 4, 2019

Язык: Английский

Процитировано

263
Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing DOI Creative Commons

Magdalena E. Tyburczy,

Kira A. Dies,

Jennifer Glass

и другие.

PLoS Genetics, Год журнала: 2015, Номер 11(11), С. e1005637 - e1005637

Опубликована: Ноя. 5, 2015

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome due to germline mutations in either TSC1 or TSC2. 10–15% of TSC individuals have no mutation identified (NMI) after thorough conventional molecular diagnostic assessment. 53 subjects who were NMI studied using next generation sequencing search for these genes. Blood/saliva DNA including parental samples available from all subjects, and skin biopsy was six subjects. We 45 (85%). Mosaicism observed the majority (26 45, 58%), intronic also unusually common, seen 18 (40%). Seventeen (38%) at allele frequency < 5%, five 1%, two biopsies only, not appreciable blood saliva DNA. These findings illuminate extent mosaicism TSC, indicate importance full coverage detection, show that analysis TSC-related tumors can increase detection rate, it likely a third exists, enable provision genetic counseling substantial population are currently NMI.

Язык: Английский

Процитировано

255
mTOR inhibitors in cancer therapy DOI Creative Commons
Jianling Xie, Xuemin Wang, Christopher G. Proud

и другие.

F1000Research, Год журнала: 2016, Номер 5, С. 2078 - 2078

Опубликована: Авг. 25, 2016

The mammalian target of rapamycin, mTOR, plays key roles in cell growth and proliferation, acting at the catalytic subunit two protein kinase complexes: mTOR complexes 1 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic pathways accordingly hyperactive majority cancers. Inhibiting has therefore attracted great attention as an anti-cancer therapy. However, progress using inhibitors therapeutic agents oncology been limited a number factors, including fact that classic inhibitor, inhibits only some effects mTOR; existence feedback loops; crucial importance normal physiology.

Язык: Английский

Процитировано

250