RARE DISEASE
Tuberous sclerosis complex
Tuberous sclerosis complex
Tuberous sclerosis complex
Synonyms: Bourneville syndrome, Tuberous sclerosis
Synonyms: Bourneville syndrome, Tuberous sclerosis
Synonyms: Bourneville syndrome, Tuberous sclerosis
Drug discovery
19
drugs
With orphan designations
Overview
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by TSC1 or TSC2 gene mutations, leading to mTOR pathway dysregulation and multi-organ hamartomas. Clinical features include epilepsy, TSC-associated neuropsychiatric disorders (TAND), renal angiomyolipomas, cardiac rhabdomyomas, and dermatologic manifestations. Diagnosis involves genetic testing and clinical criteria, with surveillance for systemic complications [1][2][18].
Burden
Economic burden: Annual healthcare costs exceed €11,000 per patient with epilepsy, driven by medications, hospitalizations, and specialist care [4][9][14].
Morbidity/mortality: Neurologic sequelae (90% epilepsy, 40–50% intellectual disability) and renal complications are leading causes of morbidity; mortality linked to seizures, renal failure, or SEGAs [1][4][14].
Quality of life: TAND affects ~85% of patients, contributing to educational/career disruptions and caregiver strain [1][14].
Therapies
mTOR inhibitors (sirolimus, everolimus): Reduce tumor growth, manage refractory epilepsy, and improve pulmonary/renal outcomes [8][10][13].
Epilepsy management: Antiseizure medications (e.g., vigabatrin for infantile spasms), surgical resection of epileptogenic foci, and early seizure control to mitigate cognitive deficits [3][8][13].
Multidisciplinary care: Dermatologic interventions (e.g., mTOR inhibitor creams), renal surveillance, and neurodevelopmental support [6][13][16].
Categories: rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
2,502 drug discovery papers about Tuberous sclerosis complex, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,502 drug discovery papers about Tuberous sclerosis complex, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-06 | [Extremely severe pulmonary lymphangioleiomyomatosis with combined brain, liver, kidney, and lung involvement: a case report].
We reported a case of extremely severe tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) involving the brain, liver, kidneys, and lungs that was successfully treated with sirolimus, with a complete 17-year follow-up. The patient was diagnosed in 2008 and experienced rapid progression; by 2012, the patient had developed respiratory failure, severe anemia, renal insufficiency, and extreme abdominal distension. After 3 days of treatment with sirolimus, the aforementioned symptoms improved significantly, and respiratory failure resovled. Over the following 7 years of regular maintenance therapy, lung function declined only slightly each year, and the 6-minute walking test(6MWT) showed no decline. However, after sirolimus was discontinued from January 2020 to April 2021, the patient's lung function and 6MWT declined rapidly, with concurrent development of pneumothorax. Although sirolimus was subsequently resumed and remained effective, with no recurrence of pneumothorax or chylothorax, parameters such as lung function and 6MWT still did not recover significantly. This case suggests that TSC-LAM requires long-term maintenance therapy with sirolimus. Abrupt discontinuation of treatment may lead to rapid clinical deterioration.
2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
2026-07-24 | Case Report: Induction of labor and postpartum management for fetal cardiac rhabdomyoma: a genetic etiology-based analysis of three cases.
Fetal cardiac rhabdomyoma (CR) is a rare primary cardiac tumor often linked to tuberous sclerosis complex (TSC) caused by TSC1/TSC2 mutations, yet its genetic heterogeneity and individualized perinatal management remain incompletely defined. This case series reports three primigravid women with fetuses diagnosed with CR at different gestational ages, who received induced labor via various regimens. Genetic testing identified a paternally inherited TSC2 mutation in one case, a de novo TSC1 mutation in another, while genetic analysis was declined in the third. Distinct differences exist in recurrence risk, long-term neurological prognosis and corresponding clinical decision-making between de novo TSC1 variants and paternally inherited TSC2 mutations, which fully reflects prominent genetic heterogeneity among TSC-related fetal CR. This study demonstrates the clinical and genetic heterogeneity of fetal CR, and highlights that ultrasound evaluation, TSC1/TSC2 genetic testing, and multidisciplinary care are crucial for guiding induction timing, perinatal management, and genetic counseling to improve perinatal outcomes.
2026-07-19 | Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII). I. Treatments in preclinical and early clinical development.
Over the last 34 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided an interactive forum for stakeholders to discuss investigational and recently licensed treatments for seizures and epilepsy. The Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII) took place in Madrid, Spain, on May 3-6, 2026. This article provides summaries of eight treatments in preclinical and early clinical development that were presented at EILAT XVIII. These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage-gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA-7136, a selective allosteric RAS/mitogen-activated protein kinase-extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ-aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug-resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a filamin A modulator under investigation for the treatment of tuberous sclerosis complex-related epilepsy; SN-2000, a selective allosteric phosphodiesterase 4B inhibitor, in development for the treatment of focal seizures; and sodium selenate, a promoter of the dephosphorylation of pathological hyperphosphorylated tau in the brain, under investigation as a disease-modifying agent in mesial temporal lobe epilepsy. Treatments in more advanced clinical development are discussed in an accompanying article.
2026-07-12 | Co-Creation of the EpiCom Clinical Trial: Bringing the Tuberous Sclerosis Complex Patient Community, Healthcare Professionals, and the Pharmaceutical Industry Together.
Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect most patients with TSC and encompass a range of psychiatric, intellectual, neuropsychological, and behavioral manifestations of the disease. Epilepsy Comorbidities (EpiCom), an ongoing, phase 3b/4, open-label study, is assessing the effects of adjunctive therapy with a plant-derived, highly purified pharmaceutical formulation of cannabidiol (Epidiolex® [US]/Epidyolex® [EU], 100 mg/mL oral solution) on TAND, including behavioral outcomes, in participants with TSC-associated seizures. EpiCom was designed in collaboration with the TSC community including patients, caregivers, and healthcare professionals (HCPs), to incorporate stakeholder perspectives into study design and execution. To describe how collaboration among patient advocacy groups (PAGs), HCPs, and the clinical trial sponsor helped optimize the co-creation and execution of the EpiCom study. HCPs and PAG advisors, including caregivers of individuals with TSC, were identified across the USA and Europe and invited to participate in an advisory board meeting to discuss the challenges faced by the TSC community. Surveys collected PAG and HCP input on topics, including study objectives, outcome assessments, study design, eligibility criteria, and recruitment. PAG and HCP advisory board meetings were then conducted to capture patient/caregiver and HCP perspectives on the EpiCom study design, including the objectives, feasibility, resources needed for successful execution, and strategies to engage the patient community throughout the study. A joint PAG-HCP Steering Committee comprising 5 PAG representatives and 15 HCPs from the USA, Canada, and Europe was formed to guide study objectives and PAG engagement, and to provide study oversight. Advisory board meetings (9 PAG advisors; 14 HCPs) provided insight into the needs of the TSC community and ways to enhance collaboration with patients and caregivers. Feedback from the advisory boards and steering committee meetings refined the EpiCom study objectives and informed recruitment strategies, study duration, patient- and HCP-friendly study design considerations, preferred data collection methods, and communication plans. These insights supported the development of a decentralized clinical trial framework aimed at reducing participant burden and barriers. PAG input guided the decision to broaden study eligibility criteria by removing seizure severity and intelligence quotient requirements and include remote assessments to facilitate capturing data in everyday settings. HCP input guided inclusion of clinical outcome measures, including the use of the novel TAND Self-Report Quantified Checklist to assess behavioral changes. Proactively involving PAGs, caregivers, and HCPs enabled the co-creation of a study that explicitly addresses outcomes important to the broader TSC community. This patient- and caregiver-informed approach of EpiCom also highlights the need for stronger collaboration between industry and PAGs in clinical trials, including the opportunities and challenges of trial implementation. NCT05864846 (May 9, 2023).
2026-08-06 | [Extremely severe pulmonary lymphangioleiomyomatosis with combined brain, liver, kidney, and lung involvement: a case report].
We reported a case of extremely severe tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) involving the brain, liver, kidneys, and lungs that was successfully treated with sirolimus, with a complete 17-year follow-up. The patient was diagnosed in 2008 and experienced rapid progression; by 2012, the patient had developed respiratory failure, severe anemia, renal insufficiency, and extreme abdominal distension. After 3 days of treatment with sirolimus, the aforementioned symptoms improved significantly, and respiratory failure resovled. Over the following 7 years of regular maintenance therapy, lung function declined only slightly each year, and the 6-minute walking test(6MWT) showed no decline. However, after sirolimus was discontinued from January 2020 to April 2021, the patient's lung function and 6MWT declined rapidly, with concurrent development of pneumothorax. Although sirolimus was subsequently resumed and remained effective, with no recurrence of pneumothorax or chylothorax, parameters such as lung function and 6MWT still did not recover significantly. This case suggests that TSC-LAM requires long-term maintenance therapy with sirolimus. Abrupt discontinuation of treatment may lead to rapid clinical deterioration.
2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
2026-07-24 | Case Report: Induction of labor and postpartum management for fetal cardiac rhabdomyoma: a genetic etiology-based analysis of three cases.
Fetal cardiac rhabdomyoma (CR) is a rare primary cardiac tumor often linked to tuberous sclerosis complex (TSC) caused by TSC1/TSC2 mutations, yet its genetic heterogeneity and individualized perinatal management remain incompletely defined. This case series reports three primigravid women with fetuses diagnosed with CR at different gestational ages, who received induced labor via various regimens. Genetic testing identified a paternally inherited TSC2 mutation in one case, a de novo TSC1 mutation in another, while genetic analysis was declined in the third. Distinct differences exist in recurrence risk, long-term neurological prognosis and corresponding clinical decision-making between de novo TSC1 variants and paternally inherited TSC2 mutations, which fully reflects prominent genetic heterogeneity among TSC-related fetal CR. This study demonstrates the clinical and genetic heterogeneity of fetal CR, and highlights that ultrasound evaluation, TSC1/TSC2 genetic testing, and multidisciplinary care are crucial for guiding induction timing, perinatal management, and genetic counseling to improve perinatal outcomes.
2026-07-19 | Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII). I. Treatments in preclinical and early clinical development.
Over the last 34 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided an interactive forum for stakeholders to discuss investigational and recently licensed treatments for seizures and epilepsy. The Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII) took place in Madrid, Spain, on May 3-6, 2026. This article provides summaries of eight treatments in preclinical and early clinical development that were presented at EILAT XVIII. These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage-gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA-7136, a selective allosteric RAS/mitogen-activated protein kinase-extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ-aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug-resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a filamin A modulator under investigation for the treatment of tuberous sclerosis complex-related epilepsy; SN-2000, a selective allosteric phosphodiesterase 4B inhibitor, in development for the treatment of focal seizures; and sodium selenate, a promoter of the dephosphorylation of pathological hyperphosphorylated tau in the brain, under investigation as a disease-modifying agent in mesial temporal lobe epilepsy. Treatments in more advanced clinical development are discussed in an accompanying article.
2026-07-12 | Co-Creation of the EpiCom Clinical Trial: Bringing the Tuberous Sclerosis Complex Patient Community, Healthcare Professionals, and the Pharmaceutical Industry Together.
Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect most patients with TSC and encompass a range of psychiatric, intellectual, neuropsychological, and behavioral manifestations of the disease. Epilepsy Comorbidities (EpiCom), an ongoing, phase 3b/4, open-label study, is assessing the effects of adjunctive therapy with a plant-derived, highly purified pharmaceutical formulation of cannabidiol (Epidiolex® [US]/Epidyolex® [EU], 100 mg/mL oral solution) on TAND, including behavioral outcomes, in participants with TSC-associated seizures. EpiCom was designed in collaboration with the TSC community including patients, caregivers, and healthcare professionals (HCPs), to incorporate stakeholder perspectives into study design and execution. To describe how collaboration among patient advocacy groups (PAGs), HCPs, and the clinical trial sponsor helped optimize the co-creation and execution of the EpiCom study. HCPs and PAG advisors, including caregivers of individuals with TSC, were identified across the USA and Europe and invited to participate in an advisory board meeting to discuss the challenges faced by the TSC community. Surveys collected PAG and HCP input on topics, including study objectives, outcome assessments, study design, eligibility criteria, and recruitment. PAG and HCP advisory board meetings were then conducted to capture patient/caregiver and HCP perspectives on the EpiCom study design, including the objectives, feasibility, resources needed for successful execution, and strategies to engage the patient community throughout the study. A joint PAG-HCP Steering Committee comprising 5 PAG representatives and 15 HCPs from the USA, Canada, and Europe was formed to guide study objectives and PAG engagement, and to provide study oversight. Advisory board meetings (9 PAG advisors; 14 HCPs) provided insight into the needs of the TSC community and ways to enhance collaboration with patients and caregivers. Feedback from the advisory boards and steering committee meetings refined the EpiCom study objectives and informed recruitment strategies, study duration, patient- and HCP-friendly study design considerations, preferred data collection methods, and communication plans. These insights supported the development of a decentralized clinical trial framework aimed at reducing participant burden and barriers. PAG input guided the decision to broaden study eligibility criteria by removing seizure severity and intelligence quotient requirements and include remote assessments to facilitate capturing data in everyday settings. HCP input guided inclusion of clinical outcome measures, including the use of the novel TAND Self-Report Quantified Checklist to assess behavioral changes. Proactively involving PAGs, caregivers, and HCPs enabled the co-creation of a study that explicitly addresses outcomes important to the broader TSC community. This patient- and caregiver-informed approach of EpiCom also highlights the need for stronger collaboration between industry and PAGs in clinical trials, including the opportunities and challenges of trial implementation. NCT05864846 (May 9, 2023).
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
19 orphan drug designations for Tuberous sclerosis complex, including 5 approved therapies.
19 orphan drug designations for Tuberous sclerosis complex, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a potent, CNS active selective inhibitor of mTORC1 | small molecules | FDA | 2026-02-03 | — | LBR Regulatory and Clinical Consulting Services, Inc. |
vigabatrin | small molecules | FDA | 2024-11-02 | — | Pyros Pharmaceuticals Inc |
Ganaxolone | small molecules | EMA | 2021-10-15 | — | Immedica Pharma AB |
ganaxolone | small molecules | FDA | 2021-08-12 | — | Immedica Pharma AB |
sirolimus | small molecules | FDA | 2019-08-26 | — | AI Therapeutics, Inc. |
Cannabidiol [Epidyolex] | small molecules | EMA | 2018-01-17 | 2021-04-20 | Jazz Pharmaceuticals Ireland Limited |
Sirolimus [Hyftor] | small molecules | EMA | 2017-08-23 | 2023-05-26 | Plusultra Pharma GmbH |
Sirolimus | small molecules | EMA | 2017-06-20 | — | Desitin Arzneimittel GmbH |
sirolimus [Hyftor] | small molecules | FDA | 2017-05-17 | 2022-03-22 | NobelPharma Co., LTD |
sirolimus | small molecules | FDA | 2017-02-13 | — | Aucta Pharmaceuticals, Inc. |
cannabidiol [Epidiolex] | small molecules | FDA | 2016-04-19 | 2020-07-31 | Jazz Pharmaceuticals Research UK Limited |
rapamycin | small molecules | FDA | 2016-02-24 | — | AFT Pharmaceuticals Ltd. |
Sirolimus | small molecules | EMA | 2015-10-09 | — | Desitin Arzneimittel GmbH |
everolimus ointment | small molecules | FDA | 2015-09-10 | — | Aucta Pharmaceuticals, LLC |
Everolimus [Votubia] | small molecules | EMA | 2010-08-04 | — | Novartis Europharm Limited |
everolimus [Afinitor] | small molecules | FDA | 2009-06-08 | 2010-10-29 | Novartis Pharmaceuticals Corp. |
rapamycin | small molecules | FDA | 2007-03-20 | — | OncoImmune, Inc. |
Polyethylene glycol-modified uricase | — | FDA | 1999-09-14 | — | Swedish Orphan Biovitrum AB |
Polyethylene glycol-modified uricase | — | FDA | 1998-12-21 | — | Swedish Orphan Biovitrum AB |
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