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Journal of Extracellular Vesicles Jun 2023Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition...
Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2-deficient and TSC2-expressing cells and identified a distinct protein cargo in TSC2-deficient EVs, containing an enrichment of proteins thought to be involved in tumour-supporting signalling pathways. We show EVs from TSC2-deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV-associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.
Topics: Humans; Tumor Suppressor Proteins; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Extracellular Vesicles; Mechanistic Target of Rapamycin Complex 1; Tumor Microenvironment
PubMed: 37337371
DOI: 10.1002/jev2.12336 -
JAMA Dermatology Oct 2014The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are...
IMPORTANCE
The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are common in tuberous sclerosis complex (TSC) and are a frequent concern for patients. Recognition of these lesions is imperative for early diagnosis, given the treatment advances that may improve patient outcomes.
OBJECTIVE
To detail recommendations for the diagnosis, surveillance, and management of skin and dental lesions in TSC.
EVIDENCE REVIEW
The TSC Dermatology and Dentistry Subcommittee, 1 of 12 subcommittees, reviewed the relevant literature from 1997 to 2012.
FINDINGS
A consensus on skin and dental issues was achieved within the Dermatology and Dentistry Subcommittee before recommendations were presented, discussed, and agreed on in a group meeting of all subcommittees from June 14 to 15, 2012.
CONCLUSIONS AND RELEVANCE
Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor.
Topics: Age Factors; Consensus Development Conferences as Topic; Dental Enamel; Fibroma; Humans; Mouth Neoplasms; Practice Guidelines as Topic; Sensitivity and Specificity; Skin Diseases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 25029267
DOI: 10.1001/jamadermatol.2014.938 -
The Primary Care Companion For CNS... Jan 2024Tuberous sclerosis is an autosomal dominant genetic disorder that affects multiple organ systems and causes a wide range of physical manifestations. It commonly... (Review)
Review
Tuberous sclerosis is an autosomal dominant genetic disorder that affects multiple organ systems and causes a wide range of physical manifestations. It commonly involves the brain, skin, heart, eyes, kidneys, and lungs. Individuals mostly present with neuropsychiatric symptoms, comprising a noteworthy source of morbidity and mortality. : Ninety percent of individuals with tuberous sclerosis have associated neuropsychiatric manifestations including attention-deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability, which are typically underidentified and undertreated. : Lack of specific guidelines for management add to the significant burden of care. An individualized, multifaceted perspective, with particular focus on cognitive and psychosocial comorbidities, is key for managing tuberous sclerosis. .
Topics: Humans; Tuberous Sclerosis; Autism Spectrum Disorder; Skin; Brain; Heart
PubMed: 38198710
DOI: 10.4088/PCC.22nr03481 -
Molecular Autism Oct 2023Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental...
BACKGROUND
Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin.
METHODS
Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272.
RESULTS
Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin.
CONCLUSIONS
Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.
Topics: Humans; Tuberous Sclerosis; Tumor Suppressor Proteins; Sirolimus; Autism Spectrum Disorder; Mechanistic Target of Rapamycin Complex 1; Stem Cells
PubMed: 37880800
DOI: 10.1186/s13229-023-00572-3 -
Birth Characteristics Among Children Diagnosed with Neurofibromatosis Type 1 and Tuberous Sclerosis.The Journal of Pediatrics Dec 2021To evaluate whether children with neurofibromatosis type 1 (NF1) and tuberous sclerosis have different birth characteristics compared with the general population.
OBJECTIVE
To evaluate whether children with neurofibromatosis type 1 (NF1) and tuberous sclerosis have different birth characteristics compared with the general population.
STUDY DESIGN
We identified all individuals born in Sweden between 1973 and 2014 from the nationwide Medical Birth Register for whom information on both biological parents was available (n = 4 242 122). Individuals with NF1 and individuals with tuberous sclerosis were identified using data from Swedish population-based health data registers. Using logistic regression models, we assessed the associations between these 2 neurocutaneous syndromes and birth characteristics in a cohort that included 1804 subjects with NF1 and 450 with tuberous sclerosis.
RESULTS
Children with NF1 and tuberous sclerosis were significantly more likely to be born preterm and via cesarean delivery. In addition, children with NF1 were also more likely to be born with other birth characteristics, such as short length, a large head circumference, and a low Apgar score. Moreover, children with NF1 had an increased odds of being born with a high birth weight or large for gestational age (OR, 1.61; 95% CI, 1.42-1.82 and OR, 1.82; 95% CI, 1.60-2.06, respectively).
CONCLUSION
Children with NF1 and tuberous sclerosis differ from the general population in terms of several birth characteristics, with the strongest associations observed for high birth weight and large for gestational age in individuals with NF1.
Topics: Apgar Score; Birth Weight; Body Size; Case-Control Studies; Female; Humans; Infant, Newborn; Logistic Models; Male; Neurofibromatosis 1; Registries; Tuberous Sclerosis
PubMed: 34390698
DOI: 10.1016/j.jpeds.2021.08.009 -
American Journal of Medical Genetics.... Sep 2018Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into... (Review)
Review
Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into adulthood. The transition for patients with tuberous sclerosis complex (TSC) is complicated by the multisystemic nature of this condition, age-dependent manifestations, and high clinical variability and by the presence of intellectual disability in at least half of the individuals. In this article, we address the medical needs regarding each TSC-related manifestation in adulthood, and the services and support required. We review existing models of transition in different chronic conditions, discuss our experience in transitioning from the pediatric to the adult TSC Clinic at our Institution, and propose general rules to follow when establishing a transition program for TSC. Although a generalizable transition model for TSC is likely not feasible for all Institutions, a multidisciplinary TSC clinic is probably the best model, developed in accordance with the resources available and country-specific healthcare systems. Coordination of care and education of the adult team should be always sought regardless of the transition model.
Topics: Adolescent; Adult; Epilepsy; Humans; Intellectual Disability; Italy; Kidney Diseases; Lung Diseases; Patient Care; Transition to Adult Care; Tuberous Sclerosis
PubMed: 30253036
DOI: 10.1002/ajmg.c.31653 -
Neuropediatrics Oct 2010Tuberous sclerosis complex (TSC) is an important cause of epilepsy and autism, as well as renal and pulmonary disease in adults and children. Affected individuals are... (Review)
Review
Tuberous sclerosis complex (TSC) is an important cause of epilepsy and autism, as well as renal and pulmonary disease in adults and children. Affected individuals are subject to hamartomas in various organ systems which result from constitutive activation of the protein kinase mTOR (mammalian target of rapamycin). The clinical course, prognosis and appropriate therapy for TSC patients are often different from that for individuals with epilepsy, renal tumors, or interstitial lung disease, from other causes. Additionally, TSC serves as a model for other conditions in which the mTOR pathways are also up-regulated. This article reviews the molecular pathophysiology and management of neurological, renal and pulmonary manifestations of the disorder. The use of mTOR inhibitors such as rapamycin and everolimus is discussed and recent clinical trials of these drugs in TSC are reviewed.
Topics: Adult; Brain; Child; Humans; Kidney; Lung; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 21210335
DOI: 10.1055/s-0030-1269906 -
Journal of Neurodevelopmental Disorders Dec 2021Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric difficulties, appropriately termed TSC-Associated Neuropsychiatric Disorders (TAND). The...
BACKGROUND
Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric difficulties, appropriately termed TSC-Associated Neuropsychiatric Disorders (TAND). The objectives of the study were to analyze the rates of TAND symptoms in a cohort of patients seen at the TSC Center of Excellence at Cincinnati Children's Hospital and to identify clinically meaningful profiles based on TAND symptoms.
METHODS
Data from the TAND Checklist was obtained from participants seen at the TSC Center of Excellence at Cincinnati Children's Hospital Medical Center from June 2015 to August 2018. Cluster and factor analyses for each TAND symptom were performed. Factor scores were then calculated for participants, and a K-means cluster analysis of these scores was used to empirically identify distinct overall TAND symptom profiles occurring in TSC.
RESULTS
A total of 1545 checklists was completed for 668 participants (37% adults and 63% children). Approximately 90% of participants reported at least one TAND symptom with an average of 12 symptoms (out of 29). Symptom rates ranged between 5 and 60%. The most common symptoms were neuropsychologic symptoms. A seven-cluster and seven-factor solution were found to be optimal. K-means cluster analysis resulted in a seven-profile solution, ranging from low to high symptom burden.
CONCLUSION
This study is the first to identify natural phenotypic profiles of TAND symptoms. Study of specific TAND subpopulations with shared profiles may facilitate better understanding of the underlying biology of TAND and better assessment of more targeted treatments.
Topics: Adult; Checklist; Child; Cluster Analysis; Cohort Studies; Humans; Mental Disorders; Tuberous Sclerosis
PubMed: 34903167
DOI: 10.1186/s11689-021-09408-8 -
IUBMB Life Dec 2016Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including... (Review)
Review
Tuberous sclerosis complex (TSC) is a rare multi-system disorder, primary manifestations of which are benign tumors and lesions in various organs of the body, including the brain. TSC patients often suffer from epilepsy, mental retardation, and autism spectrum disorder (ASD). Therefore, TSC serves as a model of epilepsy, ASD, and tumorigenesis. TSC is caused by the lack of functional Tsc1-Tsc2 complex, which serves as a major cellular inhibitor of mammalian Target of Rapamycin Complex 1 (mTORC1). mTORC1 is a kinase controlling most of anabolic processes in eukaryotic cells. Consequently, mTORC1 inhibitors, such as rapamycin, serve as experimental or already approved drugs for several TSC symptoms. However, rapalogs, although quite effective, need to be administered chronically and likely for a lifetime, since therapy discontinuation results in tumor regrowth and epilepsy recurrence. Recent studies revealed that metabolism and excitability (in the case of neurons) of cells lacking Tsc1-Tsc2 complex are changed, and these features may potentially be used to treat some of TSC symptoms. In this review, we first provide basic facts about TSC and its molecular background, to next discuss the newest findings in TSC cell biology that can be used to improve existing therapies of TSC and other diseases linked to mTORC1 hyperactivation. © 2016 IUBMB Life, 68(12):955-962, 2016.
Topics: Animals; Brain; Epilepsy; Humans; Mutation; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 27797139
DOI: 10.1002/iub.1579 -
Archives of Disease in Childhood Jun 1995
Review
Topics: Adolescent; Child; Humans; Prognosis; Tuberous Sclerosis
PubMed: 7618927
DOI: 10.1136/adc.72.6.471