Tuberous Sclerosis Complex (TSC) — Disease Characteristics Research Report

Target disease

• Disease name: Tuberous Sclerosis Complex (TSC)
• Category: Mendelian / autosomal dominant “mTORopathy” (prototypical)
• MONDO ID: MONDO:0001734 (“tuberous sclerosis”; OpenTargets disease node) (man2024thegeneticsof pages 1-2)

Executive summary (current understanding)

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant, multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin (conte2024therapeuticapproachesto pages 1-2, racioppi2024prenatalmtorinhibitors pages 1-2). Loss of TSC complex function increases RHEB-GTP and hyperactivates mTORC1, driving abnormal growth and benign tumor (hamartoma) formation across multiple organs (brain, kidneys, skin, heart, lungs) and causing major neurologic morbidity including epilepsy and neurodevelopmental disorders (dufneralmeida2024molecularandfunctional pages 1-2, man2024thegeneticsof pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2).

A quantitative evidence summary is provided in the table below.

Table: This table compiles high-yield quantitative findings for tuberous sclerosis complex across epidemiology, genetics, diagnostics, treatment, and burden of illness. It is useful as a compact evidence summary for knowledge-base population and citation tracking.

1. Disease information

1.1 What is the disease?

• Definition: TSC is described as “a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2” leading to mTORC1 hyperactivation and benign tumors in multiple organs, plus frequent epilepsy (conte2024therapeuticapproachesto pages 1-2).
• Alternative definition (genetics-focused): TSC is the “prototypical mTORopathy,” where variants in TSC1/TSC2 disrupt the TSC protein complex, a negative regulator of the mechanistic target of rapamycin pathway (man2024thegeneticsof pages 1-2).

1.2 Key identifiers (available from retrieved evidence)

• MONDO: MONDO:0001734 (man2024thegeneticsof pages 1-2)
• ICD-10 code used in epidemiology studies: Q85.1 (ascertainment code in Shizuoka and JMDC claims studies) (kishida2025epidemiologicalinsightsand pages 1-2, okanishi2024diagnosticflowanalysis pages 2-4)

Not retrieved in current tool run: OMIM/Orphanet/MeSH/ICD-11 identifiers and canonical synonym lists from those databases. (The present report therefore cites primary/review literature and claims-based ICD-10 mapping, but cannot provide authoritative OMIM/Orphanet IDs without additional retrieval.)

1.3 Synonyms / alternative names

Commonly used naming in the retrieved literature includes: - “tuberous sclerosis complex” (TSC) (man2024thegeneticsof pages 1-2, conte2024therapeuticapproachesto pages 1-2) - “tuberous sclerosis” (used in some clinical/claims contexts) (kishida2025epidemiologicalinsightsand pages 1-2)

1.4 Evidence sources

This report integrates: - Aggregated disease-level resources and cohorts (claims database epidemiology; multicenter real-world therapeutic outcome study) (cockerell2023effectivenessandsafety pages 1-2, okanishi2024diagnosticflowanalysis pages 4-5, kishida2025epidemiologicalinsightsand pages 1-2) - Reviews synthesizing clinical genetics and management (man2024thegeneticsof pages 1-2, conte2024therapeuticapproachesto pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2)

2. Etiology

2.1 Disease causal factors

• Primary genetic causes: Inactivating/pathogenic variants in TSC1 and TSC2 (racioppi2024prenatalmtorinhibitors pages 1-2, conte2024therapeuticapproachesto pages 1-2).
• Inheritance: Autosomal dominant; review-level synthesis notes approximately one-third inherited and approximately two-thirds de novo and/or mosaic in aggregate (man2024thegeneticsof pages 1-2).

Abstract quote (Genetics review, 2024): TSC is “characterized by the development of benign tumors in multiple organs” and “pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway.” (man2024thegeneticsof pages 1-2)

2.2 Risk factors

• Genetic risk: Presence of pathogenic TSC1/TSC2 variants. Variant location/domain in TSC2 is associated with severity in review synthesis (man2024thegeneticsof pages 1-2).
• Somatic mosaicism / undetected variants: ~15% of patients have no mutation identified by conventional testing, with many presumed due to somatic TSC1/TSC2 variants (man2024thegeneticsof pages 1-2).

2.3 Protective factors

No specific protective genetic variants or environmental protective factors were identified in the retrieved evidence set.

2.4 Gene–environment interactions

No clear gene–environment interactions were identified in the retrieved evidence set.

3. Phenotypes (clinical manifestations)

TSC manifests across the CNS, kidney, skin, heart, lungs, and other organs (conte2024therapeuticapproachesto pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2). A subset of phenotype frequency estimates from recent sources is listed below.

3.1 Neurologic phenotypes

1. Epilepsy
2. Type: symptom/clinical syndrome
3. Frequency: reported 62–93% in a 2024 therapeutic review (conte2024therapeuticapproachesto pages 1-2).
4. Drug-resistance: “pharmacoresistant epilepsy… affecting approximately two-thirds of patients” (2024 review) (racioppi2024prenatalmtorinhibitors pages 1-2).

5. HPO suggestions: HP:0001250 (Seizures); HP:0012469 (Infantile spasms) (conceptually aligned with reported early epilepsy burden) (conte2024therapeuticapproachesto pages 1-2, racioppi2024prenatalmtorinhibitors pages 2-3).

6. Neurodevelopmental and neuropsychiatric involvement (TAND, autism, intellectual disability)

7. Type: behavioral/psychiatric + developmental
8. Frequency: about half with intellectual disability and a similar proportion with autism spectrum disorder (racioppi2024prenatalmtorinhibitors pages 1-2). TAND is described as affecting ~90% across the lifetime (racioppi2024prenatalmtorinhibitors pages 2-3).

9. HPO suggestions: HP:0000717 (Autism); HP:0001249 (Intellectual disability); HP:0001263 (Global developmental delay).

10. CNS lesions

11. Type: imaging/pathology findings
12. Includes cortical tubers, subependymal nodules, radial migration lines, and SEGA (racioppi2024prenatalmtorinhibitors pages 1-2, conte2024therapeuticapproachesto pages 1-2).
13. SEGA prevalence: “up to 20% among TSC patients” (conte2024therapeuticapproachesto pages 1-2).
14. HPO suggestions: HP:0009720 (Cortical tuber); HP:0009718 (Subependymal nodule); HP:0006787 (Subependymal giant cell astrocytoma).

3.2 Renal phenotypes

• Renal angiomyolipomas (AMLs), renal cysts, RCC risk are emphasized as clinically important; a nephrology review notes kidney involvement includes AML and cystic disease and can lead to bleeding/pain/renal function loss (monich2024tuberoussclerosiscomplex pages 1-2).
• HPO suggestions: HP:0006770 (Renal angiomyolipoma); HP:0000107 (Renal cysts).

3.3 Pulmonary phenotypes

• LAM: “incidence of about 30% in patients with TSC” (review) (conte2024therapeuticapproachesto pages 1-2).
• HPO suggestions: HP:0004297 (Lymphangioleiomyomatosis).

3.4 Cardiac phenotypes

• Cardiac rhabdomyoma is a key prenatal/early-life marker, often prompting prenatal suspicion of TSC (racioppi2024prenatalmtorinhibitors pages 1-2). In a Japanese claims cohort diagnosed <2 years, cardiac rhabdomyoma was present in 54.8% (okanishi2024diagnosticflowanalysis pages 5-7).
• HPO suggestions: HP:0009729 (Cardiac rhabdomyoma).

3.5 Skin phenotypes

• Common features include facial angiofibromas, hypomelanotic macules, shagreen patches, and ungual fibromas (diagnostic criteria table) (jurca2023tuberoussclerosistype media b5f360a7).
• HPO suggestions: HP:0000957 (Facial angiofibroma); HP:0001010 (Hypopigmented skin lesions); HP:0000976 (Shagreen patch); HP:0009728 (Ungual fibromas).

Quality-of-life impact (recent quantitative evidence)

Adults with TSC-related epilepsy have substantially reduced generic QoL compared with other epilepsy types, with EQ-5D-3L index (TTO) 0.705 and EQ-VAS 0.577 reported in a 2024 German matched case–control study (lappe2024amulticentermatched pages 1-2).

4. Genetic / molecular information

4.1 Causal genes

• TSC1 and TSC2 are causal tumor suppressor genes; heterozygous loss-of-function variants lead to TSC (conte2024therapeuticapproachesto pages 1-2, man2024thegeneticsof pages 1-2).

4.2 Pathogenic variants and molecular diagnostic yield

• A 2024 cohort study identified pathogenic alterations in 106/116 (91%) individuals with definite clinical diagnosis, with TSC2 representing 83% of solved cases and TSC1 17% (dufneralmeida2024molecularandfunctional pages 1-2).
• No mutation identified (NMI): ~15% by conventional testing, frequently hypothesized to represent somatic/mosaic TSC1/TSC2 variants (man2024thegeneticsof pages 1-2).

4.3 Somatic vs germline; two-hit model

• Mosaicism is emphasized as a cause of negative conventional genetic testing and milder phenotypes in reviews (man2024thegeneticsof pages 1-2, dufneralmeida2024molecularandfunctional pages 1-2).

4.4 Mechanistic pathway (current consensus)

A mechanistic chain supported by 2024 evidence: 1. TSC1/TSC2 loss of function disrupts the TSC1/2 complex (dufneralmeida2024molecularandfunctional pages 1-2). 2. The complex is a GAP for RHEB; inactivation increases RHEB-GTP (dufneralmeida2024molecularandfunctional pages 1-2). 3. Increased RHEB-GTP activates mTORC1, elevating downstream phosphorylation and increasing anabolic metabolism/cell growth (dufneralmeida2024molecularandfunctional pages 1-2). 4. Tissue-level consequences: hamartomas and CNS malformations/lesions, epilepsy, kidney tumors (conte2024therapeuticapproachesto pages 1-2, man2024thegeneticsof pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2).

Direct quote (mechanism, 2024 study): “Inactivation of the TSC1/2 results in increased levels of RHEB-GTP, activation of TORC1 kinase activity… thus leading to up-regulation of anabolic metabolism and excessive cell growth.” (dufneralmeida2024molecularandfunctional pages 1-2)

4.5 Modifier genes, epigenetics, chromosomal abnormalities

Not established from the retrieved evidence set. (The report therefore cannot reliably list validated modifier loci or epigenetic signatures for TSC without additional retrieval.)

5. Environmental information

TSC is primarily a monogenic disorder; no specific environmental triggers, lifestyle factors, or infectious causes were identified in the retrieved evidence set (man2024thegeneticsof pages 1-2, conte2024therapeuticapproachesto pages 1-2).

6. Mechanism / pathophysiology (expanded)

6.1 Molecular pathways

• Central pathway: mTORC1 signaling dysregulated by TSC1/TSC2 LOF (dufneralmeida2024molecularandfunctional pages 1-2, conte2024therapeuticapproachesto pages 1-2).

GO term suggestions (biological process): - GO:0008283 (cell population proliferation) - GO:0006412 (translation) / GO:0006091 (generation of precursor metabolites and energy) as downstream readouts of anabolic metabolism (supported conceptually by “up-regulation of anabolic metabolism”) (dufneralmeida2024molecularandfunctional pages 1-2) - GO:0010506 (regulation of autophagy) as a canonical mTOR-regulated process (not explicitly stated in retrieved excerpts; include as hypothesis-level annotation)

6.2 Cellular processes

• Dysregulated growth and differentiation (“cell proliferation, growth, and differentiation” framed in therapeutic review) (conte2024therapeuticapproachesto pages 1-2).

6.3 Cell types (CL suggestions)

Based on organs and lesions described: - CL:0000540 (neuron) and CL:0000127 (astrocyte) for CNS involvement and glial components of tubers/SEGAs (CNS lesion context) (conte2024therapeuticapproachesto pages 1-2). - CL:0000887 (smooth muscle cell) as a plausible LAM-relevant cell type (LAM mentioned but not mechanistically detailed in retrieved excerpts) (conte2024therapeuticapproachesto pages 1-2).

6.4 Causal chain to clinical manifestations (examples)

• Epilepsy / neurodevelopment: TSC1/2 LOF → mTORC1 hyperactivation → altered brain development and cortical lesions (tubers) → early-onset seizures; early seizures contribute to neurodevelopmental impairment (review synthesis emphasizes neurologic burden and early window concepts) (racioppi2024prenatalmtorinhibitors pages 1-2, conte2024therapeuticapproachesto pages 1-2).
• Renal AML: mTORC1 hyperactivation in renal tissues → AML growth → bleeding risk and kidney function impairment; everolimus reduces AML size and bleeding risk in trial syntheses and real-world data (monich2024tuberoussclerosiscomplex pages 1-2, monich2024tuberoussclerosiscomplex pages 5-7).

7. Anatomical structures affected

7.1 Organ-level involvement (with UBERON suggestions)

• Brain (UBERON:0000955): cortical tubers, SEN, SEGA, epilepsy (conte2024therapeuticapproachesto pages 1-2, racioppi2024prenatalmtorinhibitors pages 1-2).
• Kidney (UBERON:0002113): renal angiomyolipomas, cysts, RCC risk (monich2024tuberoussclerosiscomplex pages 1-2).
• Heart (UBERON:0000948): cardiac rhabdomyomas (racioppi2024prenatalmtorinhibitors pages 1-2, okanishi2024diagnosticflowanalysis pages 5-7).
• Lung (UBERON:0002048): lymphangioleiomyomatosis (LAM) (conte2024therapeuticapproachesto pages 1-2).
• Skin (UBERON:0002097): angiofibromas, hypomelanotic macules, shagreen patch, ungual fibromas (jurca2023tuberoussclerosistype media b5f360a7).

7.2 Subcellular localization (GO cellular component suggestions)

Not explicitly specified in retrieved evidence; mechanistic elements imply cytosolic signaling complexes: - GO:0005829 (cytosol) - GO:0016020 (membrane) (RHEB signaling context; not explicitly stated in excerpts)

8. Temporal development

8.1 Onset

• TSC can present prenatally, often with cardiac rhabdomyomas (racioppi2024prenatalmtorinhibitors pages 1-2).
• Early-life diagnosis (<2 years) in claims data has median diagnosis age 5 months (Japan cohort 2) (okanishi2024diagnosticflowanalysis pages 5-7).

8.2 Progression

Course is lifelong and multisystem; claims and real-world treatment studies imply need for ongoing surveillance and long-term therapy monitoring (monich2024tuberoussclerosiscomplex pages 1-2, cockerell2023effectivenessandsafety pages 1-2).

9. Inheritance and population

9.1 Epidemiology (recent quantitative data)

• Incidence (review ranges): 1:6,000–1:10,000 live births (conte2024therapeuticapproachesto pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2) and 1:5,800–1:13,520 live births (man2024thegeneticsof pages 1-2).
• Regional prevalence (Japan, Shizuoka claims database): adjusted prevalence 10.2 per 100,000 using ICD-10 Q85.1 (April 2012–Sep 2020) (kishida2025epidemiologicalinsightsand pages 1-2, kishida2025epidemiologicalinsightsand pages 2-4).
• Age-specific prevalence reported for Shizuoka 2019 shows higher prevalence in youth (e.g., male 0–19: 18.29/100,000; female 0–19: 15.38/100,000) (kishida2025epidemiologicalinsightsand pages 2-4).

9.2 Inheritance pattern and penetrance

• Autosomal dominant inheritance is consistent across recent sources (man2024thegeneticsof pages 1-2, conte2024therapeuticapproachesto pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2).

9.3 Demographics

• Shizuoka cohort: sex distribution approximately balanced (48.2% male, 51.8% female in one analytic subset) with marked age effects and higher prevalence in young males in some analyses (kishida2025epidemiologicalinsightsand pages 1-2, kishida2025epidemiologicalinsightsand pages 2-4).

10. Diagnostics

10.1 Clinical criteria

A diagnostic criteria table was retrieved as an image (Table 2) listing major and minor features and genetic criteria.

• Rule (as summarized in the figure extraction): Definite diagnosis can be made with two major features, or one major + ≥2 minor features, or identification of a pathogenic TSC1/TSC2 variant (jurca2023tuberoussclerosistype media b5f360a7).

10.2 Genetic testing (utility)

• Molecular genetic diagnosis “confirms the clinical diagnosis” and supports surveillance (dufneralmeida2024molecularandfunctional pages 1-2).
• Diagnostic yield in a recent cohort was 91% (106/116) (dufneralmeida2024molecularandfunctional pages 1-2).
• Conventional testing may miss ~15% due to mosaicism/undetected variants (man2024thegeneticsof pages 1-2).

10.3 Real-world diagnostic delay and the role of TSC clinics (2024)

A 2024 Japanese claims analysis quantified diagnostic delay: - Median time-to-diagnosis for TSC-specific manifestations was 1 month vs 11 months for more non-specific manifestations (p=0.0035) (okanishi2024diagnosticflowanalysis pages 4-5). - For epilepsy, care at a facility with a TSC clinic shortened median time-to-diagnosis (11.5 vs 19.0 months, p=0.0379) (okanishi2024diagnosticflowanalysis pages 5-7).

11. Outcome / prognosis (burden, morbidity)

11.1 Major morbidity/mortality themes

A 2024 therapeutic review states that “brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality” (conte2024therapeuticapproachesto pages 1-2).

11.2 Quality of life and socioeconomic burden (2024)

A 2024 German matched case–control analysis provides quantified burden in adults with TSC-related epilepsy: - EQ-5D-3L: TTO 0.705; VAS 0.577 (lower than other epilepsy cohorts) (lappe2024amulticentermatched pages 1-2). - Costs: mean total direct costs €7,602 (median €2,620) and indirect productivity costs €7,185 over 3 months (median €11,925) (lappe2024amulticentermatched pages 1-2). - Unemployment: 60% in TSC cohort (lappe2024amulticentermatched pages 1-2).

12. Treatment

12.1 Pharmacotherapy: mTOR inhibitors (everolimus/sirolimus)

Mechanism: mTOR inhibitors counteract mTORC1 hyperactivation due to TSC1/TSC2 loss (conte2024therapeuticapproachesto pages 1-2, monich2024tuberoussclerosiscomplex pages 1-2).

Real-world effectiveness and safety (Dec 2023): Multicenter Norway/Denmark cohort (N=64) treated with everolimus: - Epilepsy: ≥50% seizure reduction in 31% (14/45) (cockerell2023effectivenessandsafety pages 4-6). - Renal AML: response (≥30% LD reduction) ~35–38% with most others stable (cockerell2023effectivenessandsafety pages 4-6). - SEGA: example volume reductions 71%, 43%, 48% after long-term treatment (cockerell2023effectivenessandsafety pages 6-7). - Adverse events: 95% experienced AEs; stomatitis/oral ulceration 63%; URTI 38%; grade 3–4 AEs 36%; discontinuation 14% (9/64) (cockerell2023effectivenessandsafety pages 1-2, cockerell2023effectivenessandsafety pages 7-9).

Randomized trial evidence summarized in 2024 nephrology review: EXIST-2 AML response 42% vs 0% placebo; extension response increased to 54%, with ~97% showing some AML reduction (monich2024tuberoussclerosiscomplex pages 5-7).

MAXO suggestions: - Everolimus/sirolimus therapy: MAXO:0000748 (mTOR inhibitor therapy) (suggested; ontology mapping should be verified). - Embolization/nephrectomy for hemorrhage/complications: MAXO terms for embolization/nephrectomy (not retrieved directly, but surgical reserve for hemorrhage described) (monich2024tuberoussclerosiscomplex pages 1-2).

12.2 Epilepsy-specific therapy (including early/preventive concepts)

• Vigabatrin is described as first-line for early-onset seizures/infantile spasms in a 2024 review and is linked to high spasm control (review statement) (racioppi2024prenatalmtorinhibitors pages 2-3).

12.3 Surgical and interventional

• For kidney manifestations, mTOR inhibitors are “primary therapeutic option,” with nephrectomy/embolization reserved for complications such as severe renal hemorrhage (monich2024tuberoussclerosiscomplex pages 1-2).

12.4 Experimental / ongoing clinical trials (ClinicalTrials.gov)

Trials retrieved in the tool run include: - NCT04987463: rapamycin vs vigabatrin prevention of TSC symptoms in infants (phase 2/3) (clinical trials search result list) - NCT05534672: placebo-controlled rapamycin in drug-resistant epilepsy associated with TSC (phase 3; recruiting) (clinical trials search result list) - Multiple topical rapamycin trials for facial angiofibromas (e.g., NCT01526356, NCT03140449) (clinical trials search result list)

13. Prevention

13.1 Primary prevention

Not currently feasible for monogenic TSC except via reproductive options; no population-level primary prevention strategies were identified in the retrieved evidence.

13.2 Secondary prevention (early detection and early intervention)

• Prenatal detection of cardiac rhabdomyomas can trigger early TSC evaluation (racioppi2024prenatalmtorinhibitors pages 1-2).
• Dedicated TSC clinics may shorten time to diagnosis for epilepsy presentations (okanishi2024diagnosticflowanalysis pages 5-7).

13.3 Tertiary prevention

• Surveillance and timely treatment of kidney and CNS tumors and seizure control reduce complications (supported by nephrology and therapeutic reviews emphasizing monitoring and mTOR inhibitor treatment) (monich2024tuberoussclerosiscomplex pages 1-2, conte2024therapeuticapproachesto pages 1-2).

14. Other species / natural disease

Not addressed in the retrieved evidence set.

15. Model organisms

The prenatal mTOR inhibitor review reports three prenatal mouse studies and human pregnancy case reports/series (10 treated pregnant women) evaluating prenatal mTOR inhibitor exposure and rhabdomyoma reduction (racioppi2024prenatalmtorinhibitors pages 1-2). Additional organism models (e.g., conditional Tsc1/Tsc2 mice, zebrafish, iPSC-derived models) were not retrieved in this tool run.

Recent developments & real-world implementations (2023–2024 emphasis)

1. Real-world everolimus effectiveness and toxicity quantification (2023): multicenter observational outcomes provide practical estimates of seizure response (31%), AML shrinkage/stability, high AE burden (95%), and discontinuation (14%), underscoring the need for “close follow-up” in routine care (cockerell2023effectivenessandsafety pages 1-2).
2. Health-system pathways for earlier diagnosis (2024): claims-based analysis shows diagnostic delay is substantial for non-specific presentations and that specialty TSC clinics shorten time-to-diagnosis for epilepsy (p=0.0379), supporting center-of-excellence models (okanishi2024diagnosticflowanalysis pages 5-7).
3. Nephrology perspective (2024): reinforces shift toward mTOR inhibitors as first-line for renal manifestations and reserves invasive procedures for refractory complications (monich2024tuberoussclerosiscomplex pages 1-2).
4. Prenatal/early mTOR inhibition research direction (2024): early intervention strategies are being explored to reduce prenatal rhabdomyomas and potentially influence neurologic outcomes, but safety and neurodevelopmental benefit remain uncertain (racioppi2024prenatalmtorinhibitors pages 1-2).

Limitations of this tool run (data gaps)

• OMIM/Orphanet/MeSH/ICD-11 codes were not retrieved; thus identifiers and synonyms may be incomplete.
• PMIDs were not available in the retrieved snippets for most sources; DOIs and journal metadata are provided.
• Modifier genes, epigenetic signatures, omics profiles, and comprehensive model organism inventories were not available in the current evidence set.

Key source URLs (with publication dates)

• Cockerell et al. Orphanet J Rare Dis (Dec 2023): https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2)
• Man et al. Genes (Published 4 Mar 2024): https://doi.org/10.3390/genes15030332 (man2024thegeneticsof pages 1-2)
• Monich et al. Brazilian Journal of Nephrology (Published 05 Jul 2024): https://doi.org/10.1590/2175-8239-jbn-2024-0013en (monich2024tuberoussclerosiscomplex pages 1-2)
• Okanishi et al. Orphanet J Rare Dis (Dec 2024): https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 5-7)
• Conte et al. Biomolecules (21 Sep 2024): https://doi.org/10.3390/biom14091190 (conte2024therapeuticapproachesto pages 1-2)
• Racioppi et al. J Clin Med (23 Oct 2024): https://doi.org/10.3390/jcm13216335 (racioppi2024prenatalmtorinhibitors pages 1-2)
• Dufner‑Almeida et al. Genes (03 Nov 2024): https://doi.org/10.3390/genes15111432 (dufneralmeida2024molecularandfunctional pages 1-2)
• Lappe et al. Neurological Research and Practice (May 2024): https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2)
• Kishida et al. Orphanet J Rare Dis (May 2025): https://doi.org/10.1186/s13023-025-03799-w (kishida2025epidemiologicalinsightsand pages 1-2)

References

1. (man2024thegeneticsof pages 1-2): Alice Man, Matteo Di Scipio, Shan Grewal, Yujin Suk, Elisabetta Trinari, Resham Ejaz, and Robyn Whitney. The genetics of tuberous sclerosis complex and related mtoropathies: current understanding and future directions. Genes, 15:332, Mar 2024. URL: https://doi.org/10.3390/genes15030332, doi:10.3390/genes15030332. This article has 47 citations.

2. (conte2024therapeuticapproachesto pages 1-2): Elena Conte, Brigida Boccanegra, Giorgia Dinoi, Michael Pusch, Annamaria De Luca, Antonella Liantonio, and Paola Imbrici. Therapeutic approaches to tuberous sclerosis complex: from available therapies to promising drug targets. Biomolecules, 14:1190, Sep 2024. URL: https://doi.org/10.3390/biom14091190, doi:10.3390/biom14091190. This article has 19 citations.

3. (racioppi2024prenatalmtorinhibitors pages 1-2): Giacomo Racioppi, Martina Proietti Checchi, Giorgia Sforza, Alessandra Voci, Luigi Mazzone, Massimiliano Valeriani, and Romina Moavero. Prenatal mtor inhibitors in tuberous sclerosis complex: current insights and future directions. Journal of Clinical Medicine, 13:6335, Oct 2024. URL: https://doi.org/10.3390/jcm13216335, doi:10.3390/jcm13216335. This article has 8 citations.

4. (dufneralmeida2024molecularandfunctional pages 1-2): Luiz Gustavo Dufner-Almeida, Laís F. M. Cardozo, Mariana R. Schwind, Danielly Carvalho, Juliana Paula G. Almeida, Andrea Maria Cappellano, Thiago G. P. Alegria, Santoesha Nanhoe, Mark Nellist, Maria Rita Passos-Bueno, Silvana Chiavegatto, Nasjla S. Silva, Sérgio Rosemberg, Ana Paula A. Pereira, Sérgio Antônio Antoniuk, and Luciana A. Haddad. Molecular and functional assessment of tsc1 and tsc2 in individuals with tuberous sclerosis complex. Genes, 15:1432, Nov 2024. URL: https://doi.org/10.3390/genes15111432, doi:10.3390/genes15111432. This article has 9 citations.

5. (monich2024tuberoussclerosiscomplex pages 1-2): Aline Grosskopf Monich, John J. Bissler, and Fellype Carvalho Barreto. Tuberous sclerosis complex and the kidneys: what nephrologists need to know. Brazilian Journal of Nephrology, Sep 2024. URL: https://doi.org/10.1590/2175-8239-jbn-2024-0013en, doi:10.1590/2175-8239-jbn-2024-0013en. This article has 2 citations.

6. (kishida2025epidemiologicalinsightsand pages 1-2): Satoshi Kishida, Eiji Nakatani, Takeshi Usui, Shuhei Fujimoto, Seiichiro Yamamoto, and Yoshiki Miyachi. Epidemiological insights and healthcare challenges of tuberous sclerosis complex in shizuoka prefecture: a retrospective cohort study. Orphanet Journal of Rare Diseases, May 2025. URL: https://doi.org/10.1186/s13023-025-03799-w, doi:10.1186/s13023-025-03799-w. This article has 2 citations and is from a peer-reviewed journal.

7. (kishida2025epidemiologicalinsightsand pages 2-4): Satoshi Kishida, Eiji Nakatani, Takeshi Usui, Shuhei Fujimoto, Seiichiro Yamamoto, and Yoshiki Miyachi. Epidemiological insights and healthcare challenges of tuberous sclerosis complex in shizuoka prefecture: a retrospective cohort study. Orphanet Journal of Rare Diseases, May 2025. URL: https://doi.org/10.1186/s13023-025-03799-w, doi:10.1186/s13023-025-03799-w. This article has 2 citations and is from a peer-reviewed journal.

8. (kishida2025epidemiologicalinsightsand pages 5-6): Satoshi Kishida, Eiji Nakatani, Takeshi Usui, Shuhei Fujimoto, Seiichiro Yamamoto, and Yoshiki Miyachi. Epidemiological insights and healthcare challenges of tuberous sclerosis complex in shizuoka prefecture: a retrospective cohort study. Orphanet Journal of Rare Diseases, May 2025. URL: https://doi.org/10.1186/s13023-025-03799-w, doi:10.1186/s13023-025-03799-w. This article has 2 citations and is from a peer-reviewed journal.

9. (racioppi2024prenatalmtorinhibitors pages 2-3): Giacomo Racioppi, Martina Proietti Checchi, Giorgia Sforza, Alessandra Voci, Luigi Mazzone, Massimiliano Valeriani, and Romina Moavero. Prenatal mtor inhibitors in tuberous sclerosis complex: current insights and future directions. Journal of Clinical Medicine, 13:6335, Oct 2024. URL: https://doi.org/10.3390/jcm13216335, doi:10.3390/jcm13216335. This article has 8 citations.

10. (jurca2023tuberoussclerosistype media b5f360a7): Claudia Maria Jurca, Kinga Kozma, Codruta Diana Petchesi, Dana Carmen Zaha, Ioan Magyar, Mihai Munteanu, Lucian Faur, Aurora Jurca, Dan Bembea, Emilia Severin, and Alexandru Daniel Jurca. Tuberous sclerosis, type ii diabetes mellitus and the pi3k/akt/mtor signaling pathways—case report and literature review. Genes, 14:433, Feb 2023. URL: https://doi.org/10.3390/genes14020433, doi:10.3390/genes14020433. This article has 23 citations.

11. (okanishi2024diagnosticflowanalysis pages 4-5): Tohru Okanishi, Ikuo Fujimori, Mariko Yamada, Takumi Tajima, Mari Wataya-Kaneda, Kuniaki Seyama, and Takashi Hatano. Diagnostic flow analysis of tuberous sclerosis complex in japan: a retrospective claims database study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03460-y, doi:10.1186/s13023-024-03460-y. This article has 2 citations and is from a peer-reviewed journal.

12. (okanishi2024diagnosticflowanalysis pages 1-2): Tohru Okanishi, Ikuo Fujimori, Mariko Yamada, Takumi Tajima, Mari Wataya-Kaneda, Kuniaki Seyama, and Takashi Hatano. Diagnostic flow analysis of tuberous sclerosis complex in japan: a retrospective claims database study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03460-y, doi:10.1186/s13023-024-03460-y. This article has 2 citations and is from a peer-reviewed journal.

13. (okanishi2024diagnosticflowanalysis pages 7-9): Tohru Okanishi, Ikuo Fujimori, Mariko Yamada, Takumi Tajima, Mari Wataya-Kaneda, Kuniaki Seyama, and Takashi Hatano. Diagnostic flow analysis of tuberous sclerosis complex in japan: a retrospective claims database study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03460-y, doi:10.1186/s13023-024-03460-y. This article has 2 citations and is from a peer-reviewed journal.

14. (okanishi2024diagnosticflowanalysis pages 5-7): Tohru Okanishi, Ikuo Fujimori, Mariko Yamada, Takumi Tajima, Mari Wataya-Kaneda, Kuniaki Seyama, and Takashi Hatano. Diagnostic flow analysis of tuberous sclerosis complex in japan: a retrospective claims database study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03460-y, doi:10.1186/s13023-024-03460-y. This article has 2 citations and is from a peer-reviewed journal.

15. (cockerell2023effectivenessandsafety pages 1-2): Ine Cockerell, Jakob Christensen, Christina E. Hoei-Hansen, Lotte Holst, Mikkel Grenaa Frederiksen, Aart Imran Issa-Epe, Bård Nedregaard, Ragnar Solhoff, Ketil Heimdal, Cecilie Johannessen Landmark, Caroline Lund, and Terje Nærland. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02982-1, doi:10.1186/s13023-023-02982-1. This article has 26 citations and is from a peer-reviewed journal.

16. (cockerell2023effectivenessandsafety pages 4-6): Ine Cockerell, Jakob Christensen, Christina E. Hoei-Hansen, Lotte Holst, Mikkel Grenaa Frederiksen, Aart Imran Issa-Epe, Bård Nedregaard, Ragnar Solhoff, Ketil Heimdal, Cecilie Johannessen Landmark, Caroline Lund, and Terje Nærland. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02982-1, doi:10.1186/s13023-023-02982-1. This article has 26 citations and is from a peer-reviewed journal.

17. (cockerell2023effectivenessandsafety pages 2-4): Ine Cockerell, Jakob Christensen, Christina E. Hoei-Hansen, Lotte Holst, Mikkel Grenaa Frederiksen, Aart Imran Issa-Epe, Bård Nedregaard, Ragnar Solhoff, Ketil Heimdal, Cecilie Johannessen Landmark, Caroline Lund, and Terje Nærland. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02982-1, doi:10.1186/s13023-023-02982-1. This article has 26 citations and is from a peer-reviewed journal.

18. (cockerell2023effectivenessandsafety pages 6-7): Ine Cockerell, Jakob Christensen, Christina E. Hoei-Hansen, Lotte Holst, Mikkel Grenaa Frederiksen, Aart Imran Issa-Epe, Bård Nedregaard, Ragnar Solhoff, Ketil Heimdal, Cecilie Johannessen Landmark, Caroline Lund, and Terje Nærland. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02982-1, doi:10.1186/s13023-023-02982-1. This article has 26 citations and is from a peer-reviewed journal.

19. (cockerell2023effectivenessandsafety pages 7-9): Ine Cockerell, Jakob Christensen, Christina E. Hoei-Hansen, Lotte Holst, Mikkel Grenaa Frederiksen, Aart Imran Issa-Epe, Bård Nedregaard, Ragnar Solhoff, Ketil Heimdal, Cecilie Johannessen Landmark, Caroline Lund, and Terje Nærland. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02982-1, doi:10.1186/s13023-023-02982-1. This article has 26 citations and is from a peer-reviewed journal.

20. (cockerell2023effectivenessandsafety pages 10-12): Ine Cockerell, Jakob Christensen, Christina E. Hoei-Hansen, Lotte Holst, Mikkel Grenaa Frederiksen, Aart Imran Issa-Epe, Bård Nedregaard, Ragnar Solhoff, Ketil Heimdal, Cecilie Johannessen Landmark, Caroline Lund, and Terje Nærland. Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Orphanet Journal of Rare Diseases, Dec 2023. URL: https://doi.org/10.1186/s13023-023-02982-1, doi:10.1186/s13023-023-02982-1. This article has 26 citations and is from a peer-reviewed journal.

21. (monich2024tuberoussclerosiscomplex pages 5-7): Aline Grosskopf Monich, John J. Bissler, and Fellype Carvalho Barreto. Tuberous sclerosis complex and the kidneys: what nephrologists need to know. Brazilian Journal of Nephrology, Sep 2024. URL: https://doi.org/10.1590/2175-8239-jbn-2024-0013en, doi:10.1590/2175-8239-jbn-2024-0013en. This article has 2 citations.

22. (lappe2024amulticentermatched pages 1-2): Lisa Lappe, Christoph Hertzberg, Susanne Knake, Markus Knuf, Felix von Podewils, Laurent M. Willems, Stjepana Kovac, Johann Philipp Zöllner, Matthias Sauter, Gerhard Kurlemann, Thomas Mayer, Astrid Bertsche, Klaus Marquard, Sascha Meyer, Hannah Schäfer, Charlotte Thiels, Bianca Zukunft, Susanne Schubert-Bast, Jens-Peter Reese, Felix Rosenow, and Adam Strzelczyk. A multicenter, matched case–control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in germany. Neurological Research and Practice, May 2024. URL: https://doi.org/10.1186/s42466-024-00323-6, doi:10.1186/s42466-024-00323-6. This article has 8 citations and is from a peer-reviewed journal.

23. (lappe2024amulticentermatched pages 10-11): Lisa Lappe, Christoph Hertzberg, Susanne Knake, Markus Knuf, Felix von Podewils, Laurent M. Willems, Stjepana Kovac, Johann Philipp Zöllner, Matthias Sauter, Gerhard Kurlemann, Thomas Mayer, Astrid Bertsche, Klaus Marquard, Sascha Meyer, Hannah Schäfer, Charlotte Thiels, Bianca Zukunft, Susanne Schubert-Bast, Jens-Peter Reese, Felix Rosenow, and Adam Strzelczyk. A multicenter, matched case–control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in germany. Neurological Research and Practice, May 2024. URL: https://doi.org/10.1186/s42466-024-00323-6, doi:10.1186/s42466-024-00323-6. This article has 8 citations and is from a peer-reviewed journal.

24. (okanishi2024diagnosticflowanalysis pages 2-4): Tohru Okanishi, Ikuo Fujimori, Mariko Yamada, Takumi Tajima, Mari Wataya-Kaneda, Kuniaki Seyama, and Takashi Hatano. Diagnostic flow analysis of tuberous sclerosis complex in japan: a retrospective claims database study. Orphanet Journal of Rare Diseases, Dec 2024. URL: https://doi.org/10.1186/s13023-024-03460-y, doi:10.1186/s13023-024-03460-y. This article has 2 citations and is from a peer-reviewed journal.