{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:29:04Z","timestamp":1788222544154,"version":"build-2803163510"},"reference-count":87,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Oradea"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background\/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC.<\/jats:p>","DOI":"10.3390\/life15030368","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T06:15:33Z","timestamp":1740550533000},"page":"368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs"],"prefix":"10.3390","volume":"15","author":[{"given":"Aurora Alexandra","family":"Jurca","sequence":"first","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru Daniel","family":"Jurca","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8442-6791","authenticated-orcid":false,"given":"Codruta Diana","family":"Petchesi","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania"},{"name":"Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN THACA), 410469 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Bembea","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Maria","family":"Jurca","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania"},{"name":"Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN THACA), 410469 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-615X","authenticated-orcid":false,"given":"Emilia","family":"Severin","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Medicine and Pharmacy \u201cCarol Davila\u201d, Dionisie Lupu Street, Number 37, District 2, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanziana","family":"Jurca","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Pharmacy, University of Oradea, December Sq., 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5071-9601","authenticated-orcid":false,"given":"Cosmin Mihai","family":"Vesa","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 1 December Sq., 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Racioppi, G., Proietti Checchi, M., Sforza, G., Voci, A., Mazzone, L., Valeriani, M., and Moavero, R. (2024). Prenatal mTOR Inhibitors in Tuberous Sclerosis Complex: Current Insights and Future Directions. J. Clin. Med., 13.","DOI":"10.3390\/jcm13216335"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0387-7604(94)00130-8","article-title":"History of the Tuberous Sclerosis Complex","volume":"17","year":"1995","journal-title":"Brain Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e6555","DOI":"10.1002\/ccr3.6555","article-title":"Diagnosis of Tuberous Sclerosis Complex in Adulthood: A Case Report","volume":"10","year":"2022","journal-title":"Clin. Case Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1001\/archneur.57.5.662","article-title":"National Institutes of Health Consensus Conference: Tuberous Sclerosis Complex","volume":"57","author":"Hyman","year":"2000","journal-title":"Arch. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1017\/S0012162206001058","article-title":"Tuberous Sclerosis Complex: Clinical Features, Diagnosis, and Prevalence within Northern Ireland","volume":"48","author":"Devlin","year":"2006","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1016\/S0140-6736(05)78872-3","article-title":"Prevalence of Tuberous Sclerosis Estimated by Capture-Recapture Analysis","volume":"351","author":"Shiell","year":"1998","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13023-016-0553-5","article-title":"TOSCA consortium and TOSCA investigators. TuberOus SClerosis registry to increase disease Awareness (TOSCA)\u2014baseline data on 2093 patients","volume":"12","author":"Kingswood","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_8","unstructured":"Wellcome Collection (2024, November 30). Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes\/Edited by Paolo Curatolo. Available online: https:\/\/wellcomecollection.org\/works\/r49upmjm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.001","article-title":"Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference","volume":"49","author":"Northrup","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1093\/hmg\/ddt597","article-title":"Sun Exposure Causes Somatic Second-Hit Mutations and Angiofibroma Development in Tuberous Sclerosis Complex","volume":"23","author":"Tyburczy","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1001\/jamadermatol.2014.938","article-title":"Dermatologic and Dental Aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements","volume":"150","author":"Teng","year":"2014","journal-title":"JAMA Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/j.1399-0004.1987.tb03304.x","article-title":"Pitted Enamel Hypoplasia in Tuberous Sclerosis Patients and First-degree Relatives","volume":"32","author":"Lygidaias","year":"1987","journal-title":"Clin. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1148\/radiol.2019192094","article-title":"Use of Intravenous Iodinated Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation","volume":"294","author":"Davenport","year":"2020","journal-title":"Radiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1148\/radiol.2020191931","article-title":"Risk of Acute Kidney Injury Following Contrast-Enhanced CT in Hospitalized Pediatric Patients: A Propensity Score Analysis","volume":"294","author":"Gilligan","year":"2020","journal-title":"Radiology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00467-012-2341-3","article-title":"Performance of Cystatin C-Based Equations in a Pediatric Cohort at High Risk of Kidney Injury","volume":"28","author":"Nehus","year":"2013","journal-title":"Pediatr. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.crad.2009.09.014","article-title":"The Radiological Diagnosis and Treatment of Renal Angiomyolipoma\u2014Current Status","volume":"65","author":"Halpenny","year":"2010","journal-title":"Clin. Radiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.crad.2005.01.009","article-title":"Tuberose Sclerosis Complex: Analysis of Growth Rates Aids Differentiation of Renal Cell Carcinoma from Atypical or Minimal-Fat-Containing Angiomyolipoma","volume":"60","author":"Patel","year":"2005","journal-title":"Clin. Radiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1378\/chest.12-2813","article-title":"Lymphangioleiomyomatosis Screening in Women with Tuberous Sclerosis","volume":"144","author":"Cudzilo","year":"2013","journal-title":"Chest"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Islam, M.P., and Steve Roach, E. (2015). Tuberous Sclerosis Complex. Rosenberg\u2019s Molecular and Genetic Basis of Neurological and Psychiatric Disease, Elsevier.","DOI":"10.1016\/B978-0-12-410529-4.00080-2"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.clinimag.2020.12.041","article-title":"Diagnostic Accuracy of Low-Dose and Ultra-Low-Dose CT in Detection of Chest Pathology: A Systematic Review","volume":"74","author":"Graumann","year":"2021","journal-title":"Clin. Imaging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1097\/00000478-199804000-00012","article-title":"Micronodular Pneumocyte Hyperplasia","volume":"22","author":"Muir","year":"1998","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1097\/RCT.0b013e318264e404","article-title":"Multifocal Micronodular Pneumocyte Hyperplasia: Computed Tomographic Appearance and Follow-up in Tuberous Sclerosis Complex","volume":"36","author":"Muzykewicz","year":"2012","journal-title":"J. Comput. Assist. Tomogr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"439","DOI":"10.4103\/lungindia.lungindia_489_17","article-title":"Minimum-Intensity Projection Images in High-Resolution Computed Tomography Lung: Technology Update","volume":"35","author":"Ghonge","year":"2018","journal-title":"Lung India"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1513\/AnnalsATS.202008-911OC","article-title":"Lymphangioleiomyomatosis Association with Underlying Genotype in Patients with Tuberous Sclerosis Complex","volume":"18","author":"Tian","year":"2021","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_25","first-page":"239","article-title":"Multifocal Micronodular Pneumocyte Hyperplasia Associated with Tuberous Sclerosis Complex: A Case Report without Lymphangioleiomyomatosis Association","volume":"23","author":"Rodrigues","year":"2017","journal-title":"Rev. Port. Pneumol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e001493","DOI":"10.1161\/JAHA.114.001493","article-title":"Cardiovascular Manifestations of Tuberous Sclerosis Complex and Summary of the Revised Diagnostic Criteria and Surveillance and Management Recommendations from the International Tuberous Sclerosis Consensus Group","volume":"3","author":"Hinton","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.ophtha.2012.03.020","article-title":"Tuberous Sclerosis Complex: Genotype\/Phenotype Correlation of Retinal Findings","volume":"119","author":"Aronow","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/ceo.12806","article-title":"Ophthalmic Manifestations of Tuberous Sclerosis: A Review","volume":"45","author":"Hodgson","year":"2017","journal-title":"Clin. Experiment. Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/S0161-6420(02)01968-1","article-title":"Photodynamic therapy of circumscribed choroidal hemangioma","volume":"110","author":"Porrini","year":"2003","journal-title":"Ophthalmology"},{"key":"ref_30","first-page":"5592","article-title":"Long-Term Results of Photodynamic Therapy for Circumscribed Choroidal Hemangioma","volume":"59","author":"Hayashi","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.pediatrneurol.2021.07.011","article-title":"Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations","volume":"123","author":"Northrup","year":"2021","journal-title":"Pediatr. Neurol."},{"key":"ref_32","unstructured":"(2018). American Academy of Pediatric Dentistry: Periodicity of Examination, Preventive Dental Services, Anticipatory Guidance\/Counseling, and Oral Treatment for Infants, Children, and Adolescents. Pediatr. Dent., 40, 194\u2013204. Available online: https:\/\/pre-prod.aapd.org\/globalassets\/media\/policies_guidelines\/bp_periodicity.pdf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1111\/j.1528-1167.2009.02474.x","article-title":"The Natural History of Epilepsy in Tuberous Sclerosis Complex","volume":"51","author":"Major","year":"2010","journal-title":"Epilepsia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13023-018-0764-z","article-title":"Early Diagnosis of Tuberous Sclerosis Complex: A Race against Time. How to Make the Diagnosis before Seizures?","volume":"13","author":"Peron","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ejpn.2011.03.010","article-title":"Antiepileptic Treatment before the Onset of Seizures Reduces Epilepsy Severity and Risk of Mental Retardation in Infants with Tuberous Sclerosis Complex","volume":"15","author":"Kotulska","year":"2011","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1016\/S1090-3798(11)70235-5","article-title":"P09.4 Everolimus Therapy Shows Dose Proportionality in Patients with Tuberous Sclerosis Complex (TSC) Treated for Subependymal Giant-Cell Astrocytomas (SEGAs)","volume":"15","author":"Krueger","year":"2011","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/ana.24523","article-title":"Everolimus for Subependymal Giant Cell Astrocytoma: 5-Year Final Analysis: Everolimus for TSC-SEGA","volume":"78","author":"Franz","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jansen, A.C., Vanclooster, S., de Vries, P.J., Fladrowski, C., Beaure d\u2019Aug\u00e8res, G., Carter, T., Belousova, E., Benedik, M.P., Cottin, V., and Curatolo, P. (2020). Burden of Illness and Quality of Life in TuberOus SClerosis Complex: Findings from the TOSCA Study. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.00904"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/sj.ejhg.5201402","article-title":"Mutational Analysis of the TSC1 and TSC2 Genes in a Diagnostic Setting: Genotype\u2014Phenotype Correlations and Comparison of Diagnostic DNA Techniques in Tuberous Sclerosis Complex","volume":"13","author":"Sancak","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"630378","DOI":"10.3389\/fneur.2021.630378","article-title":"TuberOus SClerosis registry to increAse disease awareness (TOSCA) post-authorisation safety study of everolimus in patients with tuberous sclerosis complex","volume":"12","author":"Kingswood","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_41","unstructured":"CHECKLISTS\u2014TANDem (2024, October 27). TANDem\u2014Empowering Families Through Technology. Available online: https:\/\/tandconsortium.org\/checklists\/."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0387-7604(98)00022-9","article-title":"CT and MR Imaging of Cerebral Tuberous Sclerosis","volume":"20","author":"Inoue","year":"1998","journal-title":"Brain Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"399","DOI":"10.5603\/PJNNS.a2020.0070","article-title":"Role of Gadolinium-Based Contrast Agents in Neurological Disorders","volume":"54","author":"Golec","year":"2020","journal-title":"Neurol. Neurochir. Pol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.3906\/sag-2002-133","article-title":"Tuberous Sclerosis: A Review of the Past, Present, and Future","volume":"50","author":"Uysal","year":"2020","journal-title":"Turk. J. Med. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1159\/000320891","article-title":"Tuberous Sclerosis Complex Renal Disease","volume":"118","author":"Dixon","year":"2011","journal-title":"Nephron. Exp. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bissler, J.J., and Batchelor, D. (2022). Renal Involvement in Tuberous Sclerosis Complex. Pediatric Nephrology, Springer International Publishing.","DOI":"10.1007\/978-3-030-52719-8_118"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Jurca, C.M., Kozma, K., Petchesi, C.D., Zaha, D.C., Magyar, I., Munteanu, M., Faur, L., Jurca, A., Bembea, D., and Severin, E. (2023). Tuberous Sclerosis, Type II Diabetes Mellitus and the PI3K\/AKT\/mTOR Signaling Pathways\u2014Case Report and Literature Review. Genes, 14.","DOI":"10.3390\/genes14020433"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100875","DOI":"10.1016\/j.spen.2021.100875","article-title":"Tuberous Sclerosis Complex","volume":"37","author":"Islam","year":"2021","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng0195-70","article-title":"A Germline Insertion in the Tuberous Sclerosis (Tsc2) Gene Gives Rise to the Eker Rat Model of Dominantly Inherited Cancer","volume":"9","author":"Kobayashi","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1086\/316951","article-title":"Mutational Analysis in a Cohort of 224 Tuberous Sclerosis Patients Indicates Increased Severity of TSC2, Compared with TSC1, Disease in Multiple Organs","volume":"68","author":"Dabora","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/(SICI)1098-1004(199911)14:5<401::AID-HUMU6>3.0.CO;2-R","article-title":"Mutation Screening of the Entire Coding Regions of the TSC1 and the TSC2 Gene with the Protein Truncation Test (PTT) Identifies Frequent Splicing Defects","volume":"14","author":"Mayer","year":"1999","journal-title":"Hum. Mutat."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s004390000348","article-title":"Molecular Genetic Advances in Tuberous Sclerosis","volume":"107","author":"Sancak","year":"2000","journal-title":"Hum. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1093\/hmg\/6.12.2155","article-title":"SA Molecular Genetic and Phenotypic Analysis Reveals Differences between TSC1 and TSC2 Associated Familial and Sporadic Tuberous Sclerosis","volume":"6","author":"Jones","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","article-title":"TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Tyburczy, M.E., Dies, K.A., Glass, J., Camposano, S., Chekaluk, Y., Thorner, A.R., Lin, L., Krueger, D., Franz, D.N., and Thiele, E.A. (2015). Mosaic and Intronic Mutations in TSC1\/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005637"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.4049\/jimmunol.1102187","article-title":"The Role of Tuberous Sclerosis Complex 1 in Regulating Innate Immunity","volume":"188","author":"Pan","year":"2012","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/S1474-4422(07)70075-3","article-title":"Neurofibromatosis 1 and Neurofibromatosis 2: A Twenty First Century Perspective","volume":"6","author":"Ferner","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/lrb.2007.1016","article-title":"Update on Sturge-Weber Syndrome: Diagnosis, Treatment, Quantitative Measures, and Controversies","volume":"5","author":"Comi","year":"2007","journal-title":"Lymphat. Res. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1182\/blood-2010-04-280347","article-title":"Revised Diagnostic Criteria and Classification for the Autoimmune Lymphoproliferative Syndrome (ALPS): Report from the 2009 NIH International Workshop","volume":"116","author":"Oliveira","year":"2010","journal-title":"Blood"},{"key":"ref_61","first-page":"229","article-title":"Expert Consensus Document: Clinical and Molecular Diagnosis, Screening and Management of Beckwith-Wiedemann Syndrome: An International Consensus Statement","volume":"14","author":"Brioude","year":"2018","journal-title":"Yearb. Pediatr. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev.med.53.082901.104106","article-title":"Ischemic Stroke Therapy","volume":"53","author":"Stapf","year":"2002","journal-title":"Annu. Rev. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1136\/adc.2011.211995","article-title":"The Tuberous Sclerosis 2000 Study: Presentation, Initial Assessments and Implications for Diagnosis and Management","volume":"96","author":"Yates","year":"2011","journal-title":"Arch. Dis. Child."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/iub.1579","article-title":"Tuberous Sclerosis Complex: From Molecular Biology to Novel Therapeutic Approaches","volume":"68","author":"Switon","year":"2016","journal-title":"IUBMB Life"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Yoon, M.-S. (2017). The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients, 9.","DOI":"10.3390\/nu9111176"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2165\/11634580-000000000-00000","article-title":"Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex: A Double-Blind, Randomized, Controlled Trial to Evaluate the Safety and Efficacy of Topically Applied Rapamycin","volume":"12","author":"Koenig","year":"2012","journal-title":"Drugs R&D"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.semcancer.2019.08.005","article-title":"Recent Nanotechnological Interventions Targeting PI3K\/Akt\/MTOR Pathway: A Focus on Breast Cancer","volume":"59","author":"Sharma","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"902","DOI":"10.33263\/LIANBS91.902907","article-title":"Anti-Cancer Potential of Natural Products: Recent Trends, Scope and Relevance","volume":"9","author":"Ram","year":"2020","journal-title":"Lett. Appl. NanoBioSci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.semcancer.2019.07.003","article-title":"mTOR: Role in Cancer, Metastasis and Drug Resistance","volume":"59","author":"Murugan","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.jaad.2015.07.018","article-title":"Improvement of Tuberous Sclerosis Complex (TSC) Skin Tumors during Long-Term Treatment with Oral Sirolimus","volume":"7","author":"Nathan","year":"2015","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1093\/neuonc\/nov152","article-title":"Differentiating the mTOR Inhibitors Everolimus and Sirolimus in the Treatment of Tuberous Sclerosis Complex","volume":"17","author":"MacKeigan","year":"2015","journal-title":"Neuro. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for Angiomyolipoma Associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis (EXIST-2): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial","volume":"381","author":"Bissler","year":"2013","journal-title":"Lancet"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.pcl.2015.03.005","article-title":"Tuberous Sclerosis Complex","volume":"62","author":"DiMario","year":"2015","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.2337\/db06-1016","article-title":"The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man","volume":"56","author":"Krebs","year":"2007","journal-title":"Diabetes"},{"key":"ref_75","unstructured":"Chakraborty, S. (2022). Molecular Mechanism of Rapamycin Resistance in Cancer Cells, City University of New York (CUNY)."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2640342","DOI":"10.1155\/2018\/2640342","article-title":"MTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?","volume":"2018","author":"Kezic","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1101\/gad.339895.120","article-title":"AMPK Regulation of Raptor and TSC2 Mediate Metformin Effects on Transcriptional Control of Anabolism and Inflammation","volume":"34","author":"Hellberg","year":"2020","journal-title":"Genes Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2020.01.015","article-title":"AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control","volume":"31","author":"Hall","year":"2020","journal-title":"Cell Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/bcp.13780","article-title":"The Journey of Metformin from Glycaemic Control to MTOR Inhibition and the Suppression of Tumour Growth: Metformin and Suppression of Tumour Growth","volume":"85","author":"Amin","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.cmet.2010.03.014","article-title":"Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner","volume":"11","author":"Kalender","year":"2010","journal-title":"Cell Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"100715","DOI":"10.1016\/j.eclinm.2020.100715","article-title":"The Metformin in Tuberous Sclerosis (MiTS) Study: A Randomised Double-Blind Placebo-Controlled Trial","volume":"32","author":"Amin","year":"2021","journal-title":"eClinicalMedicine"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.yebeh.2019.04.027","article-title":"Experience of Follow-up, Quality of Life, and Transition from Pediatric to Adult Healthcare of Patients with Tuberous Sclerosis Complex","volume":"96","author":"Bar","year":"2019","journal-title":"Epilepsy Behav."},{"key":"ref_84","unstructured":"(2024, December 01). International TSC Consensus Guidelines. Available online: https:\/\/www.tscinternational.org\/international-tsc-consensus-guidelines\/."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/ajmg.c.31653","article-title":"Healthcare Transition from Childhood to Adulthood in Tuberous Sclerosis Complex","volume":"178","author":"Peron","year":"2018","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/S0025-6196(12)61196-3","article-title":"Causes of Death in Patients with Tuberous Sclerosis","volume":"66","author":"Shepherd","year":"1991","journal-title":"Mayo Clin. Proc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.3389\/fneur.2019.01182","article-title":"The TOSCA registry for tuberous sclerosis- lessons learnt for future registry development in rare and complex diseases","volume":"10","author":"Marques","year":"2019","journal-title":"Front. Neurol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/3\/368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:42:49Z","timestamp":1760028169000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/3\/368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,26]]},"references-count":87,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["life15030368"],"URL":"https:\/\/doi.org\/10.3390\/life15030368","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,26]]}}}