Tuberous Sclerosis Complex

Mendelian MONDO:0001734 Pathograph 45 Neurocutaneous Syndrome mTOR Pathway Disorder

Tuberous sclerosis complex (TSC) is the prototypical autosomal dominant "mTORopathy", caused by heterozygous loss-of-function variants in the tumour suppressor genes TSC1 (hamartin) or TSC2 (tuberin). The TSC1/TSC2 complex acts as a GTPase-activating protein (GAP) for RHEB; loss of function elevates RHEB-GTP and produces constitutive mTOR complex 1 (mTORC1) hyperactivation. Constitutive mTORC1 signalling drives translation and anabolic biosynthesis, suppresses autophagy, and produces hamartomas across multiple organ systems (brain, skin, kidneys, heart, lungs). At the lesion level, hamartoma growth typically follows a Knudson two-hit model with a somatic second hit at the TSC locus. Major clinical features include cortical tubers, subependymal nodules and giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas and cysts, facial angiofibromas, hypomelanotic macules, shagreen patches, and pulmonary lymphangioleiomyomatosis. TSC-associated neuropsychiatric disorders (TAND) — including drug-resistant epilepsy (often beginning as infantile spasms), intellectual disability, autism spectrum disorder, ADHD, anxiety, and mood disorders — are among the most disabling manifestations. Brain tumours, sudden unexpected death in epilepsy (SUDEP), and respiratory complications of lymphangioleiomyomatosis are the leading causes of mortality.

Ask OpenScientist

Ask a research question about Tuberous Sclerosis Complex. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

◆

Subtypes

TSC2-related TSC

Pathogenic variants in TSC2 on chromosome 16p13.3 (encoding tuberin) account for ~70-83% of molecularly solved TSC cases. TSC2-related disease is typically more severe than TSC1-related disease, with earlier seizure onset, higher cortical tuber burden, and a higher risk of intellectual disability and renal angiomyolipomas. Variants in critical domains of the catalytic TSC2 subunit correlate with increased disease severity.

TSC1-related TSC

Pathogenic variants in TSC1 on chromosome 9q34 (encoding hamartin) account for ~17-30% of molecularly solved TSC cases. TSC1-related disease is on average milder than TSC2-related disease, with later or absent seizures, fewer cortical tubers, and lower frequency of severe intellectual disability.

TSC2/PKD1 contiguous deletion syndrome

A contiguous deletion of TSC2 and the adjacent PKD1 gene on chromosome 16p13.3 produces TSC plus severe, early-onset polycystic kidney disease. Affected individuals develop multiple bilateral renal cysts in infancy and progress to kidney failure earlier than typical TSC.

NMI (no mutation identified)

Approximately 10-15% of clinically definite TSC cases have no germline pathogenic variant detected by conventional sequencing, frequently due to low-level somatic mosaicism or non-coding variants. NMI patients may have milder phenotypes.

◈

Mechanistic Hypotheses

Canonical TSC1 / TSC2 / mTORC1 Hyperactivation Model

canonical_tsc1_tsc2_mtorc1_hyperactivation_model CANONICAL

Tuberous sclerosis complex (TSC) is caused by germline heterozygous loss-of-function variants in TSC1 (hamartin, 9q34.13) or TSC2 (tuberin, 16p13.3). The TSC1-TSC2 complex functions as a GTPase- activating protein (GAP) for the Rheb GTPase, restraining mTORC1. Biallelic somatic loss ('second hit') in individual cells releases Rheb-GTP and drives constitutive mTORC1 activation, producing cell growth, proliferation, and characteristic hamartomas in nearly every organ system: cortical tubers and subependymal nodules (SEN/SEGA) in the brain, cardiac rhabdomyomas, renal angiomyolipomas, pulmonary lymphangioleiomyomatosis, hypomelanotic macules, facial angiofibromas. Neurologically, the mTORC1-hyperactivation lesion produces epilepsy (infantile spasms, refractory seizures), TSC-associated neuropsychiatric disorders (TAND), and intellectual disability. Rapamycin/everolimus and sirolimus (mTORC1 inhibitors) provide direct pharmacologic validation: shrinking SEGAs, angiomyolipomas, and LAM lesions and reducing seizure frequency, definitively confirming the mTORC1-hyperactivation axis as the canonical mechanism.

Retained as CANONICAL with seven critical clinically-consequential qualifications. The 2026 openscientist hypothesis-search report (kb/hypotheses/Tuberous_Sclerosis_Complex/canonical_tsc1_tsc2_mtorc1_hyperactivation_model) finds STRONGLY SUPPORTED. Core validation: cryo-EM TSC complex structure, biallelic loss in 94% of angiomyolipomas, 72% of no-mutation-identified TSC cases resolved as mosaic via deep sequencing, EXIST-1/2/3 Phase 3 RCTs (everolimus shrinks SEGAs/angiomyolipomas/LAM, reduces seizure frequency), and convergent DEPDC5/GATOR1 mTORopathies. Seven critical qualifications: (1) definitive RCT demonstrates everolimus does NOT improve IQ, autism, or neuropsychological function in children 4-17; (2) PREVeNT trial: preventive vigabatrin does NOT alter neurodevelopmental outcomes; (3) mTORC1-INDEPENDENT mechanisms contribute substantially — RHOA signaling, HMGA2-driven mesenchymal tumorigenesis, PERK/integrated stress response, KDM6A-ERK/SNAI1 fibrosis; (4) mTORC2 drives LAM-specific pathology via estradiol-COX-2- prostaglandin signaling INSENSITIVE to rapamycin; (5) neuronal hyperactivity becomes mTORC1-independent after a developmental critical window due to irreversible epigenetic changes; (6) rapalogues are CYTOSTATIC, not curative, with paradoxical autophagy induction; (7) myelin pathology — linked to cognitive and ASD outcomes — requires BALANCED (not simply inhibited) mTORC1 activity. Multi-pathway pathogenesis necessitates combination therapeutic strategies beyond mTORC1 inhibition. The PROTECT trial (pre-emptive mTOR inhibition in infants <4 months) is the definitive remaining test of early intervention within the critical developmental window.

Deep research

OpenScientist citations 41 citations 2026-05-25T13:04:52.103299

Show evidence (1 reference)

PMID:39334956 SUPPORT Human Clinical

"Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively."

Existing canonical mechanism citation in the dismech knowledge base, used as the seed for the hypothesis-search deep-research run.

⚙

Pathophysiology

TSC1/TSC2 Loss of Function (Germline First Hit)

Heterozygous loss-of-function variants in TSC1 (hamartin) or TSC2 (tuberin) disrupt the TSC1/TSC2 protein complex, which normally functions as a GTPase-activating protein (GAP) for the small GTPase RHEB. The germline pathogenic variant constitutes the "first hit" in a Knudson two-hit model; by itself it produces haploinsufficiency but typical hamartomatous lesions require a somatic second hit at the TSC locus.

TSC1 hgnc:12362 TSC2 hgnc:12363

positive regulation of GTPase activity GO:0043547 ↓ DECREASED negative regulation of TORC1 signaling GO:1904262 ↓ DECREASED

Downstream

Somatic Second Hit at TSC Locus A second somatic hit at the wild-type TSC1 or TSC2 allele in lesion precursor cells is required for full TSC1/TSC2 complex inactivation and focal hamartomatous lesion growth. This explains the focal, mosaic-like distribution of cortical tubers, angiomyolipomas, SEGAs, and rhabdomyomas despite a constitutional germline mutation.

Constitutive mTORC1 Hyperactivation Even before a second hit, partial loss of TSC complex function elevates RHEB-GTP and primes cells for mTORC1 hyperactivation; in lesion cells with biallelic loss the activation is constitutive.

Show evidence (4 references)

PMID:39334956 SUPPORT Human Clinical

Establishes that TSC results from heterozygous loss-of-function variants in TSC1/TSC2.

PMID:38540392 SUPPORT Human Clinical

"pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway"

Confirms the TSC1/TSC2 complex acts as a negative regulator (GAP) of the mTOR pathway and is disrupted by pathogenic variants.

PMID:39596632 SUPPORT Human Clinical

"TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1)."

Confirms TSC1/TSC2 protein complex as a negative regulator of mTORC1.

+ 1 more reference

Somatic Second Hit at TSC Locus

Loss of the wild-type TSC1 or TSC2 allele (loss of heterozygosity, LOH) or an acquired pathogenic variant in lesion precursor cells results in biallelic inactivation of the TSC complex and full release of RHEB-GTPase inhibition. The two-hit model accounts for the focal nature of hamartomas (cortical tubers, angiomyolipomas, SEGAs, rhabdomyomas, LAM) despite a germline heterozygous mutation. Approximately 10-15% of clinically definite TSC cases have no germline pathogenic variant identified, with low-level somatic mosaicism postulated as the underlying mechanism.

TSC1 hgnc:12362 TSC2 hgnc:12363

Downstream

Constitutive mTORC1 Hyperactivation Biallelic loss of TSC1/TSC2 in lesion cells removes GAP activity for RHEB and produces constitutive mTORC1 activation in the affected clone.

Show evidence (1 reference)

PMID:38540392 SUPPORT Human Clinical

"15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges."

Supports the role of somatic TSC1/TSC2 variants (mosaicism / second hit) in TSC pathogenesis and in conventionally negative cases.

Constitutive mTORC1 Hyperactivation

Loss of TSC1/TSC2 GAP activity allows persistent RHEB-GTP loading at the lysosomal membrane, leading to constitutive activation of mTORC1 kinase activity. Active mTORC1 phosphorylates downstream effectors (S6K1, 4E-BP1, ULK1, lipin-1, TFEB) that drive translation, anabolic biosynthesis, cell growth, and suppression of autophagy. mTORC1 signalling is constitutively active within all TSC-associated lesions and is the central, druggable pathobiological hub of the disease.

TORC1 signaling GO:0038202 ↑ INCREASED positive regulation of TOR signaling GO:0032008 ↑ INCREASED

Downstream

Translation and Anabolic Biosynthesis Upregulation Active mTORC1 phosphorylates S6K1 and 4E-BP1 to drive cap-dependent translation and ribosome biogenesis, and stimulates lipid biosynthesis via SREBP1 and lipin-1.

Autophagy Suppression Active mTORC1 phosphorylates and inhibits ULK1 and TFEB, suppressing autophagy initiation and lysosomal biogenesis.

mTOR-Driven Multisystem Hamartoma Growth The combined cell-autonomous effects of mTORC1 hyperactivation (translation, anabolic biosynthesis, autophagy suppression, dysregulated growth and differentiation) produce hamartomatous lesions across organs.

Show evidence (3 references)

PMID:39334956 SUPPORT Human Clinical

"Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC."

Directly links pathogenic TSC1/TSC2 variants to mTORC1 hyperactivation and to multisystem hamartomas plus drug-resistant epilepsy.

PMID:38991206 SUPPORT Human Clinical

"The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism."

Reinforces mTOR pathway hyperactivation as the central consequence of TSC1/TSC2 loss.

PMID:29478616 SUPPORT Human Clinical

"These proteins form a complex to constitutively inhibit the mammalian target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions."

Establishes that mTOR signalling is constitutively active in all TSC lesions.

Translation and Anabolic Biosynthesis Upregulation

Hyperactive mTORC1 phosphorylates S6K1 and 4E-BP1, releasing eIF4E and enabling cap-dependent translation initiation, ribosome biogenesis, and cell growth. mTORC1 also stimulates de novo lipid biosynthesis (SREBP1, lipin-1) and nucleotide synthesis. The net effect is upregulation of anabolic metabolism and excessive cell growth — the cell-biological basis of hamartoma expansion.

translational initiation GO:0006413 ↑ INCREASED regulation of translation GO:0006417 ↑ INCREASED lipid biosynthetic process GO:0008610 ↑ INCREASED cell growth GO:0016049 ↑ INCREASED

Downstream

mTOR-Driven Multisystem Hamartoma Growth Anabolic translation and lipid biosynthesis programs supply the macromolecular building blocks for excess cell growth in hamartomatous lesions across organs.

Show evidence (2 references)

PMID:39334956 SUPPORT Human Clinical

"Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation"

Supports mTOR pathway as the regulator of cell proliferation, growth, and differentiation that is dysregulated in TSC.

PMID:27226234 SUPPORT Human Clinical

"the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis"

Identifies translation/protein synthesis and lipid synthesis as canonical mTOR-regulated outputs that are upregulated in TSC.

Autophagy Suppression

Active mTORC1 phosphorylates ULK1 (Ser757) to block autophagosome initiation and phosphorylates TFEB to retain it in the cytoplasm, blunting lysosomal biogenesis. Reduced autophagic flux leads to accumulation of damaged organelles and metabolic stress in TSC-deficient cells, contributing to dysplastic phenotypes and tuber formation. Autophagy suppression also underlies sensitivity to mTOR inhibitor therapy.

negative regulation of autophagy GO:0010507 ↑ INCREASED

Downstream

mTOR-Driven Multisystem Hamartoma Growth Suppressed autophagy blunts clearance of damaged organelles and protein aggregates and contributes to dysplastic, hamartomatous growth in TSC-deficient cells.

Show evidence (1 reference)

PMID:27226234 SUPPORT Human Clinical

"the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis"

Identifies autophagy as a canonical mTOR-regulated output dysregulated in TSC.

mTOR-Driven Multisystem Hamartoma Growth

Constitutive mTORC1 activity increases anabolic growth programs and cell population expansion. The shared consequence is hamartomatous or dysplastic lesion formation in the brain, kidney, skin, heart, and lung, with each organ producing a characteristic downstream clinical phenotype.

mTOR signaling pathway GO:0031929 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED

brain UBERON:0000955 kidney UBERON:0002113 heart UBERON:0000948 lung UBERON:0002048 skin UBERON:0002097

Downstream

Neuroglial Dysplasia and Cortical Network Disorganization mTOR-driven growth dysregulation in the brain produces cortical and subependymal lesions and abnormal neuronal-glial networks.

Subependymal Glioneuronal Tumor Growth mTOR activation promotes growth of subependymal nodules and SEGAs.

Renal Angiomyolipoma Growth mTOR-driven proliferation in renal mesenchymal and smooth-muscle-like lesion components produces angiomyolipomas.

Cutaneous Fibrovascular Hamartoma Formation mTOR-driven growth in skin stromal and vascular compartments produces fibrovascular hamartomatous lesions.

Cardiac Rhabdomyoma Formation mTOR-driven growth dysregulation in developing cardiac muscle produces rhabdomyomas.

Pulmonary Lymphangioleiomyomatosis Growth mTOR-driven smooth-muscle-like cell proliferation in lung contributes to lymphangioleiomyomatosis.

Show evidence (2 references)

PMID:29478616 SUPPORT Human Clinical

Supports constitutive mTOR signaling as the shared mechanism across TSC lesions.

PMID:27226234 SUPPORT Human Clinical

"Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. "

Identifies the main affected organs and downstream neurologic manifestations that the pathograph branches connect to mTOR activation.

Neuroglial Dysplasia and Cortical Network Disorganization

Brain mTORC1 hyperactivation disrupts neuronal and glial differentiation, radial migration, and dendritic morphology, producing cortical tubers, radial migration lines, and dysmorphic giant neurons. These lesions and network abnormalities provide the pathophysiologic bridge from TSC1/TSC2 mutation to infantile spasms, drug-resistant focal seizures, and TSC-associated neuropsychiatric disorders (TAND).

neuron CL:0000540 astrocyte CL:0000127

nervous system development GO:0007399 ↕ DYSREGULATED neuron differentiation GO:0030182 ↕ DYSREGULATED cell population proliferation GO:0008283 ↑ INCREASED

brain UBERON:0000955

Downstream

Cortical Tubers Neuroglial developmental dysplasia forms cortical tubers composed of abnormal glial and neural cells, including dysmorphic giant neurons. Disrupted radial migration also produces linear bands of dysplastic neurons visible on MRI as radial migration lines.

Infantile Spasms Cortical malformations produce epileptogenic networks that frequently manifest as infantile spasms in the first year of life.

Epileptic Seizures Cortical tubers and abnormal cortical networks create epileptogenic circuits leading to focal-onset and often drug-resistant seizures.

Intellectual Disability Early brain dysplasia and seizure burden contribute to cognitive disability within the TSC-associated neuropsychiatric disorder spectrum.

Global Developmental Delay Disrupted cortical development and infantile-onset seizures produce global developmental delay in early childhood.

Autism Spectrum Disorder Altered cortical development and early epileptogenic network dysfunction contribute to autism spectrum disorder within the TAND spectrum.

Attention Deficit Hyperactivity Disorder Cortical network dysfunction contributes to attention and impulse-control symptoms within the TAND spectrum.

Anxiety Network-level dysfunction in TSC-affected cortical and limbic circuits contributes to anxiety, mood disorders, and behavioural symptoms within the TAND spectrum.

Show evidence (2 references)

PMID:27226234 SUPPORT Human Clinical

Supports brain lesions, seizures, autism spectrum disorder, and cognitive disability as linked TSC manifestations.

PMID:38991206 SUPPORT Human Clinical

"the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"

Identifies cortical tubers and radial migration lines as the brain malformations and links them to seizures, autism, and cognitive disability.

Subependymal Glioneuronal Tumor Growth

mTOR-driven growth along the ventricular subependymal region produces subependymal nodules; a subset enlarge into subependymal giant cell astrocytomas that may obstruct cerebrospinal fluid flow.

astrocyte CL:0000127

cell population proliferation GO:0008283 ↑ INCREASED

brain UBERON:0000955

Downstream

Subependymal Nodules Subependymal hamartomatous growth produces nodules along the lateral ventricle walls.

Subependymal Giant Cell Astrocytoma Progressive subependymal glioneuronal growth can produce SEGAs near the foramen of Monro.

Show evidence (1 reference)

PMID:32222129 SUPPORT Human Clinical

"Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. "

Links SEGAs to the mTOR inhibitor-responsive TSC disease mechanism.

Renal Angiomyolipoma Growth

Constitutive mTORC1 signalling in renal tumour cells (perivascular epithelioid cell, PEC, lineage) expands vascular, smooth-muscle-like, and adipocytic lesion components, producing renal angiomyolipomas. Lesions >4 cm risk haemorrhage. Cystic lesions and a small minority of renal cell carcinomas also arise from mTOR-driven proliferation in renal epithelium.

smooth muscle cell CL:0000192 adipocyte CL:0000136 endothelial cell CL:0000115

smooth muscle cell proliferation GO:0048659 ↑ INCREASED angiogenesis GO:0001525 ↑ INCREASED cell population proliferation GO:0008283 ↑ INCREASED

kidney UBERON:0002113

Downstream

Renal Angiomyolipoma Expansion of renal vascular, smooth-muscle-like, and adipocytic tumor components produces angiomyolipoma.

Renal Cyst mTOR-driven proliferation of renal tubular epithelium produces multiple bilateral renal cysts; cysts are particularly numerous and early-onset in TSC2-PKD1 contiguous deletion syndrome.

Renal Hemorrhage Vascular components of large angiomyolipomas (>4 cm) are prone to spontaneous haemorrhage, a leading kidney-related cause of morbidity.

Show evidence (2 references)

PMID:27226234 SUPPORT Human Clinical

"Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary..."

Supports renal angiomyolipomas as an mTOR inhibitor-responsive TSC lesion.

PMID:38991206 SUPPORT Human Clinical

"Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function."

Confirms that mTOR-driven renal manifestations include angiomyolipomas, cystic lesions, and renal cell carcinoma, with morbidity from bleeding and loss of kidney function.

Cutaneous Fibrovascular Hamartoma Formation

mTORC1-driven growth dysregulation in skin stromal, vascular, and melanocyte compartments produces a spectrum of cutaneous lesions: facial angiofibromas, fibrous cephalic plaques, ungual/subungual fibromas, shagreen patches (connective-tissue nevi), hypomelanotic macules, and confetti-like hypopigmented macules.

fibroblast CL:0000057 melanocyte CL:0000148 endothelial cell CL:0000115

cell population proliferation GO:0008283 ↑ INCREASED angiogenesis GO:0001525 ↑ INCREASED

skin UBERON:0002097

Downstream

Facial Angiofibromas Fibrovascular hamartoma formation in facial skin produces angiofibromas.

Shagreen Patch Connective-tissue hamartoma formation in skin produces shagreen patches.

Hypomelanotic Macules Melanocyte mTORC1 hyperactivation alters melanogenesis to produce hypopigmented (ash-leaf) macules, often the earliest visible cutaneous sign of TSC.

Confetti-like Hypopigmented Macules Diffuse confetti-like 1-3 mm hypopigmented macules on the limbs are a minor diagnostic feature of TSC.

Subungual Fibromas Periungual or subungual fibromas (Koenen tumours) form on or beside fingernails/toenails and typically appear in adolescence and adulthood.

Dental Enamel Pits Hamartomatous overgrowth and developmental dysregulation in dental tissues produce multiple pinpoint enamel pits, a highly prevalent and under-recognized minor diagnostic feature.

Show evidence (2 references)

PMID:32222129 SUPPORT Human Clinical

"Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. "

Supports TSC-associated skin lesions as a diagnostic manifestation downstream of the disease mechanism.

PMID:36833359 SUPPORT Human Clinical

"facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs"

Illustrates the spectrum of TSC cutaneous lesions in a single confirmed-TSC patient — angiofibromas, depigmented (hypomelanotic) macules, periungual fibromas.

Cardiac Rhabdomyoma Formation

During fetal and early postnatal life, mTORC1-driven growth dysregulation in fetal cardiomyocytes produces benign rhabdomyomas; these are typically multiple, often detectable prenatally on fetal echocardiography, and are the earliest TSC manifestation. Most rhabdomyomas regress spontaneously during childhood as cardiomyocyte proliferative capacity wanes; large or multiple lesions can cause hydrops fetalis, arrhythmias, or outflow obstruction.

cardiac muscle cell CL:0000746 fetal cardiomyocyte CL:0002495

heart development GO:0007507 ↕ DYSREGULATED cell growth GO:0016049 ↑ INCREASED

heart UBERON:0000948

Downstream

Cardiac Rhabdomyoma mTOR-driven cardiac muscle growth dysregulation produces benign rhabdomyomas.

Show evidence (2 references)

PMID:32222129 SUPPORT Human Clinical

"Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. "

Supports cardiac rhabdomyomas as an early TSC manifestation.

PMID:39518472 SUPPORT Human Clinical

"Tuberous sclerosis complex (TSC) can present prenatally, often with cardiac rhabdomyomas, which, if large, may cause complications such as hydrops fetalis and reduced cardiac output."

Confirms prenatal cardiac rhabdomyoma as the earliest manifestation and notes complications (hydrops fetalis, reduced cardiac output) of large rhabdomyomas.

Retinal Hamartoma Formation

mTORC1 hyperactivation in retinal glia produces nodular astrocytic hamartomas and achromic patches in the retina. Retinal hamartomas are typically asymptomatic but contribute to TSC's clinical diagnostic criteria and confirm CNS dissemination of the mTOR-driven lesion process.

astrocyte CL:0000127

cell population proliferation GO:0008283 ↑ INCREASED

retina UBERON:0000966

Downstream

Retinal Hamartoma mTOR-driven proliferation of retinal astrocytes produces nodular retinal hamartomas (and associated achromic patches).

Pulmonary Lymphangioleiomyomatosis Growth

In the lung, mTOR pathway activation supports proliferation of smooth-muscle-like LAM cells and cystic remodeling, producing pulmonary lymphangioleiomyomatosis and reduced pulmonary function.

smooth muscle cell CL:0000192

regulation of smooth muscle cell proliferation GO:0048660 ↑ INCREASED

lung UBERON:0002048

Downstream

Pulmonary Lymphangioleiomyomatosis Proliferation of smooth-muscle-like LAM cells in lung produces pulmonary lymphangioleiomyomatosis.

Show evidence (2 references)

PMID:27226234 SUPPORT Human Clinical

Supports pulmonary lymphangioleiomyomatosis as an mTOR inhibitor-responsive TSC manifestation.

PMID:23539171 SUPPORT Human Clinical

"These results suggest that most women with TSC ultimately develop cystic changes consistent with LAM and that most cases can be identified from a single CT imaging slice at the level of the carina. "

Supports cystic lung remodeling as the pulmonary LAM phenotype in women with TSC.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 1

Cardiac Rhabdomyoma FREQUENT Cardiac rhabdomyoma HP:0009729

Show evidence (2 references)

PMID:39617898 SUPPORT Human Clinical

"cardiac rhabdomyoma had the highest incidence (54.8%) among Cohort 2 patients."

Real-world claims data showing cardiac rhabdomyoma as the most frequent early-life (under 2 years) TSC manifestation.

PMID:39518472 SUPPORT Human Clinical

"Tuberous sclerosis complex (TSC) can present prenatally, often with cardiac rhabdomyomas, which, if large, may cause complications such as hydrops fetalis and reduced cardiac output."

Confirms prenatal cardiac rhabdomyoma as an early TSC presentation with potential complications.

Genitourinary 3

Renal Angiomyolipoma VERY_FREQUENT Renal angiomyolipoma HP:0006772

Show evidence (3 references)

PMID:27226234 SUPPORT Human Clinical

"Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders"

Kidney tumors including angiomyolipomas are listed as a major feature of TSC.

PMID:38991206 SUPPORT Human Clinical

Confirms renal angiomyolipomas as a major TSC kidney manifestation, with morbidity from progression, bleeding, and loss of kidney function.

PMID:38042867 SUPPORT Human Clinical

"In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months."

Real-world quantification of mTOR inhibitor-induced AML lesion size reduction.

Renal Cyst FREQUENT Renal cyst HP:0000107

Show evidence (1 reference)

PMID:38991206 SUPPORT Human Clinical

"Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas"

Confirms cystic renal lesions as a TSC kidney manifestation.

Renal Hemorrhage OCCASIONAL Hematuria HP:0000790

Show evidence (1 reference)

PMID:38991206 SUPPORT Human Clinical

"surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage."

Identifies severe renal hemorrhage as a complication of TSC kidney lesions and its management.

Integument 2

Subungual Fibromas FREQUENT Subungual fibromas HP:0009724

Show evidence (1 reference)

PMID:36833359 SUPPORT Human Clinical

"periungual fibroma in both lower limbs"

Confirms periungual fibromas as a documented TSC cutaneous feature.

Shagreen Patch FREQUENT Shagreen patch HP:0009721

Nervous System 6

Epileptic Seizures VERY_FREQUENT Seizure HP:0001250

Sequelae: Sudden Unexpected Death in Epilepsy

Show evidence (3 references)

PMID:27226234 SUPPORT Human Clinical

Seizures are listed as a major feature of TSC.

PMID:39334956 SUPPORT Human Clinical

Identifies drug-resistant epilepsy as a typical feature of TSC and links it to mTORC1 hyperactivation.

PMID:39617898 SUPPORT Human Clinical

"Epilepsy was the manifestation with the highest incidence (29.2%) among Cohort 1 patients"

Provides a quantitative claims-based observation of epilepsy frequency among TSC patients in Japan.

Intellectual Disability FREQUENT Intellectual disability HP:0001249

Show evidence (2 references)

PMID:32222129 SUPPORT Human Clinical

"TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated."

Confirms intellectual disability as a significant TAND feature in TSC.

PMID:38991206 SUPPORT Human Clinical

"manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"

Confirms cognitive disability (intellectual disability) as a TSC manifestation alongside seizures and autism.

Global Developmental Delay FREQUENT Global developmental delay HP:0001263

Autism Spectrum Disorder FREQUENT Autism HP:0000717

Show evidence (2 references)

PMID:27226234 SUPPORT Human Clinical

"TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability."

Autism spectrum disorder is identified as part of the TSC-associated neuropsychiatric disorder spectrum.

PMID:38991206 SUPPORT Human Clinical

"manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"

Confirms autism as a TSC manifestation alongside cortical tubers and cognitive disability.

Attention Deficit Hyperactivity Disorder FREQUENT Attention deficit hyperactivity disorder HP:0007018

Anxiety FREQUENT Anxiety HP:0000739

Respiratory 1

Pulmonary Lymphangioleiomyomatosis FREQUENT Multiple pulmonary cysts HP:0005948

Show evidence (2 references)

PMID:27226234 SUPPORT Human Clinical

Supports pulmonary lymphangioleiomyomatosis as a TSC manifestation with mTOR inhibitor-responsive biology.

PMID:23539171 SUPPORT Human Clinical

"Forty-eight (47.5%) met criteria for TSC-LAM on the initial CT scan."

This female TSC clinic cohort supports a FREQUENT frequency band for LAM in women with TSC.

Constitutional 1

Sudden Unexpected Death in Epilepsy VERY_RARE Sudden death HP:0001699

Show evidence (1 reference)

PMID:39334956 SUPPORT Human Clinical

"Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality."

Identifies sudden unexpected death from epilepsy as a leading cause of TSC mortality.

Neoplasm 4

Facial Angiofibromas VERY_FREQUENT Angiofibromas HP:0010615

Cortical Tubers VERY_FREQUENT Cortical tubers HP:0009717

Show evidence (1 reference)

PMID:38991206 SUPPORT Human Clinical

"manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"

Identifies cortical tubers as a defining TSC manifestation.

Subependymal Nodules VERY_FREQUENT Subependymal nodules HP:0009716

Subependymal Giant Cell Astrocytoma OCCASIONAL Subependymal giant-cell astrocytoma HP:0009718

Show evidence (1 reference)

PMID:38042867 SUPPORT Human Clinical

"SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months."

Real-world data showing substantial mTOR inhibitor-driven SEGA volume reductions, supporting SEGA as an mTOR-pathway-driven phenotype.

Other 5

Infantile Spasms FREQUENT Infantile spasms HP:0012469

Hypomelanotic Macules VERY_FREQUENT Hypomelanotic macule HP:0009719

Confetti-like Hypopigmented Macules OCCASIONAL Confetti-like hypopigmented macules HP:0007449

Dental Enamel Pits VERY_FREQUENT Dental enamel pits HP:0009722

Retinal Hamartoma OCCASIONAL Retinal hamartoma HP:0009594

🧬

Genetic Associations

TSC1 (Pathogenic Mutations)

Show evidence (3 references)

PMID:29478616 SUPPORT Human Clinical

"There are over 2000 known allelic variants for TSC, including nonsense and misssense mutation, and all pathogenic mutations are inactivating, leading to loss-of-function effects on the encoded proteins, TSC1 and TSC2."

Confirms TSC1 inactivating mutations as causative.

PMID:39596632 SUPPORT Human Clinical

"Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2."

Quantitative cohort data on TSC1 vs TSC2 contribution among molecularly solved cases.

CGGV:assertion_61b07bb0-1385-4344-8b6c-571f6a271000-2019-01-23T170000.000Z SUPPORT Other

ClinGen classifies the TSC1-tuberous sclerosis gene-disease relationship as definitive with autosomal dominant inheritance.

TSC2 (Pathogenic Mutations)

Show evidence (4 references)

PMID:27226234 SUPPORT Human Clinical

"Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2."

Confirms TSC1 and TSC2 as the causative genes.

PMID:38540392 SUPPORT Human Clinical

"Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity."

Establishes the TSC2 genotype-phenotype severity correlation.

PMID:39596632 SUPPORT Human Clinical

"Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2."

Quantitative cohort data showing TSC2 as the predominant causal gene among molecularly solved cases (~83%).

+ 1 more reference

Somatic Mosaicism (Mosaic Pathogenic Variants)

Show evidence (1 reference)

PMID:38540392 SUPPORT Human Clinical

Quantifies the prevalence and likely mosaic origin of conventionally negative TSC cases.

💊

Medical Actions

mTOR Inhibitor Therapy (Everolimus)

Action: Pharmacotherapy NCIT:C15986

Agent: everolimus CHEBI:68478

Everolimus is an mTOR inhibitor with FDA approval for TSC-associated subependymal giant cell astrocytomas, renal angiomyolipomas, and as adjunctive treatment for refractory seizures. Real-world data show ≥50% seizure reduction in ~31% of patients (46% in those <18 years), AML longest-diameter reduction in 38% with stabilization in 59%, and substantial SEGA volume reductions.

Mechanism Target:

INHIBITS Constitutive mTORC1 Hyperactivation — Everolimus directly inhibits mTORC1 kinase activity by allosteric binding to FKBP12, counteracting the central pathobiological hub of TSC.

Show evidence (1 reference)

PMID:39334956 SUPPORT Human Clinical

Identifies mTORC1 hyperactivation as the central drug target counteracted by mTOR inhibitors in TSC.

INHIBITS mTOR-Driven Multisystem Hamartoma Growth — Everolimus inhibits mTORC1 signalling, counteracting the shared lesion-growth mechanism downstream of TSC1/TSC2 loss.

Show evidence (1 reference)

PMID:29478616 SUPPORT Human Clinical

"The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown to reduce renal and brain lesion size, and improve pulmonary function in TSC, and these compounds may also decrease seizure frequency. "

Supports mTOR inhibition as a pathway-directed treatment for multiple downstream TSC manifestations.

INHIBITS Renal Angiomyolipoma Growth — Everolimus reduces renal angiomyolipoma size and stabilises lesions in most treated patients.

Show evidence (1 reference)

PMID:38042867 SUPPORT Human Clinical

Real-world quantification of mTOR-inhibitor effect on AML.

INHIBITS Subependymal Glioneuronal Tumor Growth — Everolimus reduces SEGA volume substantially with long-term treatment.

Show evidence (1 reference)

PMID:38042867 SUPPORT Human Clinical

"SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months."

Real-world example SEGA shrinkage on everolimus.

INHIBITS Pulmonary Lymphangioleiomyomatosis Growth — mTOR inhibitor therapy improves pulmonary function in TSC-associated lung disease.

Target Phenotypes: Subependymal giant-cell astrocytoma HP:0009718 Renal angiomyolipoma HP:0006772 Seizures HP:0001250

Show evidence (2 references)

PMID:32222129 SUPPORT Human Clinical

Confirms FDA approval of everolimus for three TSC indications.

PMID:38042867 SUPPORT Human Clinical

"Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment."

Real-world seizure response rate to adjunctive everolimus in TSC.

Vigabatrin for Infantile Spasms

Action: Pharmacotherapy NCIT:C15986

Agent: vigabatrin CHEBI:63638

Vigabatrin is the first-line treatment for TSC-associated infantile spasms, with high response rates specific to this population. Vigabatrin is also being evaluated for pre-symptomatic prevention of TSC seizures in infants with epileptiform EEG (e.g., NCT04987463 — rapamycin vs vigabatrin prevention).

Mechanism Target:

MODULATES Neuroglial Dysplasia and Cortical Network Disorganization — Vigabatrin irreversibly inhibits GABA transaminase, elevating synaptic GABA levels and reducing the hyperexcitability of dysplastic cortical tubers that drives infantile spasms and seizures in TSC.

Target Phenotypes: Infantile spasms HP:0012469 Seizures HP:0001250

mTOR Inhibitor Therapy (Sirolimus/Rapamycin)

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Sirolimus (rapamycin) is an mTOR inhibitor FDA-approved for lymphangioleiomyomatosis. Topical sirolimus formulations are also effective for facial angiofibromas.

Mechanism Target:

INHIBITS Constitutive mTORC1 Hyperactivation — Sirolimus directly inhibits mTORC1 by FKBP12-mediated allosteric binding, the same mechanism as everolimus.

INHIBITS Pulmonary Lymphangioleiomyomatosis Growth — Sirolimus inhibits mTOR signaling in the LAM branch downstream of TSC1/TSC2 loss.

Target Phenotypes: Pulmonary lymphangioleiomyomatosis HP:0005948

Show evidence (1 reference)

PMID:32222129 SUPPORT Human Clinical

"Rapamycin has been FDA approved for lymphangioleiomyomatosis."

Supports rapamycin/sirolimus as a distinct FDA-approved treatment for lymphangioleiomyomatosis in TSC.

Topical Sirolimus for Facial Angiofibromas

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Topical sirolimus formulations applied to facial skin reduce the size and erythema of TSC-associated facial angiofibromas with minimal systemic exposure. Multiple clinical trials have demonstrated efficacy (NCT01526356, NCT03140449).

Mechanism Target:

INHIBITS Cutaneous Fibrovascular Hamartoma Formation — Topical mTOR inhibition reduces dermal fibroblast/vascular proliferation driving angiofibroma growth.

Target Phenotypes: Angiofibromas HP:0010615

Cannabidiol for Drug-Resistant TSC Epilepsy

Action: Pharmacotherapy NCIT:C15986

Agent: cannabidiol CHEBI:69478

Plant-derived cannabidiol (Epidiolex) is FDA-approved as adjunctive therapy for drug-resistant TSC-associated seizures based on randomized controlled trial evidence.

Mechanism Target:

MODULATES Neuroglial Dysplasia and Cortical Network Disorganization — Cannabidiol suppresses seizure activity in TSC-associated drug-resistant epilepsy, modulating the hyperexcitable cortical network formed by neuroglial dysplastic tubers.

Target Phenotypes: Seizures HP:0001250

Epilepsy Surgery

Action: surgical procedure MAXO:0000004

Surgical resection of an epileptogenic tuber may be considered for drug-resistant focal seizures when a dominant epileptogenic lesion can be localised by imaging and electrophysiology.

Mechanism Target:

MODULATES Neuroglial Dysplasia and Cortical Network Disorganization — Resection of epileptogenic tubers removes the dysplastic cortical tissue that anchors reentrant seizure circuits, directly eliminating the neuroglial dysplasia substrate responsible for focal drug-resistant epilepsy.

Target Phenotypes: Seizures HP:0001250

Renal AML Embolization or Nephrectomy

Action: surgical procedure MAXO:0000004

Selective renal artery embolization or partial/total nephrectomy is reserved for complications of large angiomyolipomas (especially severe haemorrhage) unresponsive to mTOR inhibitor therapy.

Mechanism Target:

MODULATES Renal Angiomyolipoma Growth — Embolization devascularizes and shrinks bleeding AMLs; nephrectomy removes the growth entirely. Both procedures eliminate the acute hemorrhagic complication of mTOR-driven renal angiomyolipoma growth without affecting the upstream mTORC1 dysregulation.

Target Phenotypes: Renal angiomyolipoma HP:0006772

Show evidence (1 reference)

PMID:38991206 SUPPORT Human Clinical

"surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage."

Establishes embolization and nephrectomy as second-line for AML complications unresponsive to mTOR inhibitors.

Multidisciplinary TSC Clinic Care

Action: supportive care MAXO:0000950

Care at a dedicated multidisciplinary TSC clinic is associated with earlier diagnosis (median 11.5 vs 19.0 months for epilepsy presentations, p=0.0379) and better surveillance and management of multisystem manifestations.

Show evidence (1 reference)

PMID:39617898 SUPPORT Human Clinical

"those attending facilities with a TSC clinic were diagnosed with TSC more quickly than those attending facilities without a TSC clinic (median: 11.5 and 19.0 months, respectively; p = 0.0379)."

Quantifies the diagnostic-time benefit of dedicated TSC clinics.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is recommended for TSC families given the autosomal dominant inheritance pattern, variable expressivity, and reproductive options (preimplantation/prenatal testing) when the familial variant is known.

🔬

Clinical Trials

NCT05534672 PHASE_III RECRUITING

Placebo-controlled randomized trial of rapamycin (sirolimus) for drug-resistant epilepsy associated with TSC.

Target Phenotypes: Seizures HP:0001250

NCT04987463 PHASE_III RECRUITING

Trial comparing rapamycin (sirolimus) vs vigabatrin for prevention of TSC-related seizures and neurodevelopmental impairment in infants identified before seizure onset.

Target Phenotypes: Infantile spasms HP:0012469 Seizures HP:0001250

NCT01526356 PHASE_II COMPLETED

Trial of topical sirolimus formulations for TSC-associated facial angiofibromas demonstrating reduction in lesion size and erythema.

Target Phenotypes: Angiofibromas HP:0010615

{ }

Source YAML

click to show

name: Tuberous Sclerosis Complex
creation_date: "2026-03-06T00:00:00Z"
updated_date: "2026-04-28T12:00:00Z"
description: >
  Tuberous sclerosis complex (TSC) is the prototypical autosomal dominant
  "mTORopathy", caused by heterozygous loss-of-function variants in the tumour
  suppressor genes TSC1 (hamartin) or TSC2 (tuberin). The TSC1/TSC2 complex acts
  as a GTPase-activating protein (GAP) for RHEB; loss of function elevates
  RHEB-GTP and produces constitutive mTOR complex 1 (mTORC1) hyperactivation.
  Constitutive mTORC1 signalling drives translation and anabolic biosynthesis,
  suppresses autophagy, and produces hamartomas across multiple organ systems
  (brain, skin, kidneys, heart, lungs). At the lesion level, hamartoma growth
  typically follows a Knudson two-hit model with a somatic second hit at the
  TSC locus. Major clinical features include cortical tubers, subependymal
  nodules and giant cell astrocytomas, cardiac rhabdomyomas, renal
  angiomyolipomas and cysts, facial angiofibromas, hypomelanotic macules,
  shagreen patches, and pulmonary lymphangioleiomyomatosis. TSC-associated
  neuropsychiatric disorders (TAND) — including drug-resistant epilepsy
  (often beginning as infantile spasms), intellectual disability, autism
  spectrum disorder, ADHD, anxiety, and mood disorders — are among the most
  disabling manifestations. Brain tumours, sudden unexpected death in epilepsy
  (SUDEP), and respiratory complications of lymphangioleiomyomatosis are the
  leading causes of mortality.
category: Mendelian
disease_term:
  preferred_term: Tuberous Sclerosis Complex
  term:
    id: MONDO:0001734
    label: tuberous sclerosis
parents:
- Neurocutaneous Syndrome
- mTOR Pathway Disorder
has_subtypes:
- name: TSC2
  display_name: TSC2-related TSC
  description: >
    Pathogenic variants in TSC2 on chromosome 16p13.3 (encoding tuberin) account
    for ~70-83% of molecularly solved TSC cases. TSC2-related disease is
    typically more severe than TSC1-related disease, with earlier seizure onset,
    higher cortical tuber burden, and a higher risk of intellectual disability
    and renal angiomyolipomas. Variants in critical domains of the catalytic
    TSC2 subunit correlate with increased disease severity.
- name: TSC1
  display_name: TSC1-related TSC
  description: >
    Pathogenic variants in TSC1 on chromosome 9q34 (encoding hamartin) account
    for ~17-30% of molecularly solved TSC cases. TSC1-related disease is on
    average milder than TSC2-related disease, with later or absent seizures,
    fewer cortical tubers, and lower frequency of severe intellectual disability.
- name: TSC2-PKD1 Contiguous Deletion
  display_name: TSC2/PKD1 contiguous deletion syndrome
  description: >
    A contiguous deletion of TSC2 and the adjacent PKD1 gene on chromosome
    16p13.3 produces TSC plus severe, early-onset polycystic kidney disease.
    Affected individuals develop multiple bilateral renal cysts in infancy and
    progress to kidney failure earlier than typical TSC.
- name: No Mutation Identified
  display_name: NMI (no mutation identified)
  description: >
    Approximately 10-15% of clinically definite TSC cases have no germline
    pathogenic variant detected by conventional sequencing, frequently due to
    low-level somatic mosaicism or non-coding variants. NMI patients may have
    milder phenotypes.
prevalence:
- population: Global
  percentage: "0.012"
  notes: >
    Pooled live-birth incidence estimates of 1 in 5,800–13,520 (Man 2024) and
    1 in 6,000–10,000 (Conte 2024; Monich 2024).
- population: Japan (Shizuoka Prefecture)
  percentage: "0.0102"
  notes: >
    Adjusted population prevalence of 10.2 per 100,000 in a 2012-2020
    retrospective cohort using ICD-10 Q85.1 ascertainment (Kishida 2025).
progression:
- phase: Onset
  age_range: Prenatal to infancy
  notes: >
    Cardiac rhabdomyomas are often detected prenatally and are the most common
    early-life manifestation (54.8% of cases diagnosed under 2 years; Okanishi
    2024). Infantile spasms typically begin in the first year of life.
- phase: Childhood
  age_range: 1-12 years
  notes: >
    Cortical tubers, subependymal nodules, hypomelanotic macules and facial
    angiofibromas become evident; intellectual disability and autism spectrum
    disorder emerge. Drug-resistant epilepsy affects ~two-thirds (Racioppi 2024).
- phase: Adolescence and adulthood
  age_range: ≥12 years
  notes: >
    Subependymal giant cell astrocytomas may enlarge and obstruct CSF flow;
    renal angiomyolipomas grow and risk haemorrhage; pulmonary
    lymphangioleiomyomatosis develops in women (~30%). SUDEP, AML haemorrhage
    and respiratory failure are leading causes of mortality.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_tsc1_tsc2_mtorc1_hyperactivation_model
  hypothesis_label: Canonical TSC1 / TSC2 / mTORC1 Hyperactivation Model
  status: CANONICAL
  description: >-
    Tuberous sclerosis complex (TSC) is caused by germline heterozygous loss-of-function variants in
    TSC1 (hamartin, 9q34.13) or TSC2 (tuberin, 16p13.3). The TSC1-TSC2 complex functions as a GTPase-
    activating protein (GAP) for the Rheb GTPase, restraining mTORC1. Biallelic somatic loss ('second
    hit') in individual cells releases Rheb-GTP and drives constitutive mTORC1 activation, producing
    cell growth, proliferation, and characteristic hamartomas in nearly every organ system: cortical
    tubers and subependymal nodules (SEN/SEGA) in the brain, cardiac rhabdomyomas, renal
    angiomyolipomas, pulmonary lymphangioleiomyomatosis, hypomelanotic macules, facial angiofibromas.
    Neurologically, the mTORC1-hyperactivation lesion produces epilepsy (infantile spasms, refractory
    seizures), TSC-associated neuropsychiatric disorders (TAND), and intellectual disability.
    Rapamycin/everolimus and sirolimus (mTORC1 inhibitors) provide direct pharmacologic validation:
    shrinking SEGAs, angiomyolipomas, and LAM lesions and reducing seizure frequency, definitively
    confirming the mTORC1-hyperactivation axis as the canonical mechanism.
  notes: >-
    Retained as CANONICAL with seven critical
    clinically-consequential qualifications. The 2026
    openscientist hypothesis-search report
    (kb/hypotheses/Tuberous_Sclerosis_Complex/canonical_tsc1_tsc2_mtorc1_hyperactivation_model)
    finds STRONGLY SUPPORTED. Core validation: cryo-EM TSC
    complex structure, biallelic loss in 94% of angiomyolipomas,
    72% of no-mutation-identified TSC cases resolved as mosaic
    via deep sequencing, EXIST-1/2/3 Phase 3 RCTs (everolimus
    shrinks SEGAs/angiomyolipomas/LAM, reduces seizure
    frequency), and convergent DEPDC5/GATOR1 mTORopathies.
    Seven critical qualifications: (1) definitive RCT
    demonstrates everolimus does NOT improve IQ, autism, or
    neuropsychological function in children 4-17; (2) PREVeNT
    trial: preventive vigabatrin does NOT alter
    neurodevelopmental outcomes; (3) mTORC1-INDEPENDENT
    mechanisms contribute substantially — RHOA signaling,
    HMGA2-driven mesenchymal tumorigenesis, PERK/integrated
    stress response, KDM6A-ERK/SNAI1 fibrosis; (4) mTORC2
    drives LAM-specific pathology via estradiol-COX-2-
    prostaglandin signaling INSENSITIVE to rapamycin;
    (5) neuronal hyperactivity becomes mTORC1-independent after
    a developmental critical window due to irreversible
    epigenetic changes; (6) rapalogues are CYTOSTATIC, not
    curative, with paradoxical autophagy induction;
    (7) myelin pathology — linked to cognitive and ASD outcomes —
    requires BALANCED (not simply inhibited) mTORC1 activity.
    Multi-pathway pathogenesis necessitates combination
    therapeutic strategies beyond mTORC1 inhibition. The PROTECT
    trial (pre-emptive mTOR inhibition in infants <4 months) is
    the definitive remaining test of early intervention within
    the critical developmental window.
  evidence:
  - reference: PMID:39334956
    reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively."
    explanation: >
      Existing canonical mechanism citation in the dismech
      knowledge base, used as the seed for the hypothesis-search
      deep-research run.
pathophysiology:
- name: TSC1/TSC2 Loss of Function (Germline First Hit)
  description: >
    Heterozygous loss-of-function variants in TSC1 (hamartin) or TSC2 (tuberin)
    disrupt the TSC1/TSC2 protein complex, which normally functions as a
    GTPase-activating protein (GAP) for the small GTPase RHEB. The germline
    pathogenic variant constitutes the "first hit" in a Knudson two-hit model;
    by itself it produces haploinsufficiency but typical hamartomatous lesions
    require a somatic second hit at the TSC locus.
  genes:
  - preferred_term: TSC1
    term:
      id: hgnc:12362
      label: TSC1
  - preferred_term: TSC2
    term:
      id: hgnc:12363
      label: TSC2
  biological_processes:
  - preferred_term: positive regulation of GTPase activity
    modifier: DECREASED
    term:
      id: GO:0043547
      label: positive regulation of GTPase activity
  - preferred_term: negative regulation of TORC1 signaling
    modifier: DECREASED
    term:
      id: GO:1904262
      label: negative regulation of TORC1 signaling
  evidence:
  - reference: PMID:39334956
    reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively."
    explanation: Establishes that TSC results from heterozygous loss-of-function variants in TSC1/TSC2.
  - reference: PMID:38540392
    reference_title: "The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway"
    explanation: Confirms the TSC1/TSC2 complex acts as a negative regulator (GAP) of the mTOR pathway and is disrupted by pathogenic variants.
  - reference: PMID:39596632
    reference_title: "Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1)."
    explanation: Confirms TSC1/TSC2 protein complex as a negative regulator of mTORC1.
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis."
    explanation: Establishes the protein complex as inhibitor of mTOR and links loss to dysregulated growth, autophagy, and protein/lipid synthesis.
  downstream:
  - target: Somatic Second Hit at TSC Locus
    description: >
      A second somatic hit at the wild-type TSC1 or TSC2 allele in lesion
      precursor cells is required for full TSC1/TSC2 complex inactivation and
      focal hamartomatous lesion growth. This explains the focal, mosaic-like
      distribution of cortical tubers, angiomyolipomas, SEGAs, and rhabdomyomas
      despite a constitutional germline mutation.
    causal_link_type: DIRECT
  - target: Constitutive mTORC1 Hyperactivation
    description: >
      Even before a second hit, partial loss of TSC complex function elevates
      RHEB-GTP and primes cells for mTORC1 hyperactivation; in lesion cells
      with biallelic loss the activation is constitutive.
    causal_link_type: DIRECT
- name: Somatic Second Hit at TSC Locus
  description: >
    Loss of the wild-type TSC1 or TSC2 allele (loss of heterozygosity, LOH) or
    an acquired pathogenic variant in lesion precursor cells results in
    biallelic inactivation of the TSC complex and full release of RHEB-GTPase
    inhibition. The two-hit model accounts for the focal nature of hamartomas
    (cortical tubers, angiomyolipomas, SEGAs, rhabdomyomas, LAM) despite a
    germline heterozygous mutation. Approximately 10-15% of clinically definite
    TSC cases have no germline pathogenic variant identified, with low-level
    somatic mosaicism postulated as the underlying mechanism.
  genes:
  - preferred_term: TSC1
    term:
      id: hgnc:12362
      label: TSC1
  - preferred_term: TSC2
    term:
      id: hgnc:12363
      label: TSC2
  evidence:
  - reference: PMID:38540392
    reference_title: "The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges."
    explanation: Supports the role of somatic TSC1/TSC2 variants (mosaicism / second hit) in TSC pathogenesis and in conventionally negative cases.
  downstream:
  - target: Constitutive mTORC1 Hyperactivation
    description: >
      Biallelic loss of TSC1/TSC2 in lesion cells removes GAP activity for RHEB
      and produces constitutive mTORC1 activation in the affected clone.
    causal_link_type: DIRECT
- name: Constitutive mTORC1 Hyperactivation
  description: >
    Loss of TSC1/TSC2 GAP activity allows persistent RHEB-GTP loading at the
    lysosomal membrane, leading to constitutive activation of mTORC1 kinase
    activity. Active mTORC1 phosphorylates downstream effectors (S6K1, 4E-BP1,
    ULK1, lipin-1, TFEB) that drive translation, anabolic biosynthesis, cell
    growth, and suppression of autophagy. mTORC1 signalling is constitutively
    active within all TSC-associated lesions and is the central, druggable
    pathobiological hub of the disease.
  biological_processes:
  - preferred_term: TORC1 signaling
    modifier: INCREASED
    term:
      id: GO:0038202
      label: TORC1 signaling
  - preferred_term: positive regulation of TOR signaling
    modifier: INCREASED
    term:
      id: GO:0032008
      label: positive regulation of TOR signaling
  evidence:
  - reference: PMID:39334956
    reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC."
    explanation: Directly links pathogenic TSC1/TSC2 variants to mTORC1 hyperactivation and to multisystem hamartomas plus drug-resistant epilepsy.
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism."
    explanation: Reinforces mTOR pathway hyperactivation as the central consequence of TSC1/TSC2 loss.
  - reference: PMID:29478616
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These proteins form a complex to constitutively inhibit the mammalian target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions."
    explanation: Establishes that mTOR signalling is constitutively active in all TSC lesions.
  downstream:
  - target: Translation and Anabolic Biosynthesis Upregulation
    description: >
      Active mTORC1 phosphorylates S6K1 and 4E-BP1 to drive cap-dependent
      translation and ribosome biogenesis, and stimulates lipid biosynthesis
      via SREBP1 and lipin-1.
    causal_link_type: DIRECT
  - target: Autophagy Suppression
    description: >
      Active mTORC1 phosphorylates and inhibits ULK1 and TFEB, suppressing
      autophagy initiation and lysosomal biogenesis.
    causal_link_type: DIRECT
  - target: mTOR-Driven Multisystem Hamartoma Growth
    description: >
      The combined cell-autonomous effects of mTORC1 hyperactivation
      (translation, anabolic biosynthesis, autophagy suppression, dysregulated
      growth and differentiation) produce hamartomatous lesions across organs.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32222129
      reference_title: "Tuberous sclerosis: a review of the past, present, and future."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem
        disorder that is characterized by cellular and tissue dysplasia in
        several organs. With the advent of genetic and molecular techniques,
        mutations in the TSC1 or TSC2 genes were discovered to be responsible
        for mTOR overactivation, which is the underlying mechanism of
        pathogenesis.
      explanation: >
        Directly links TSC1/TSC2 mutations to mTOR overactivation and
        multisystem cellular and tissue dysplasia.
- name: Translation and Anabolic Biosynthesis Upregulation
  description: >
    Hyperactive mTORC1 phosphorylates S6K1 and 4E-BP1, releasing eIF4E and
    enabling cap-dependent translation initiation, ribosome biogenesis, and
    cell growth. mTORC1 also stimulates de novo lipid biosynthesis (SREBP1,
    lipin-1) and nucleotide synthesis. The net effect is upregulation of
    anabolic metabolism and excessive cell growth — the cell-biological basis
    of hamartoma expansion.
  biological_processes:
  - preferred_term: translational initiation
    modifier: INCREASED
    term:
      id: GO:0006413
      label: translational initiation
  - preferred_term: regulation of translation
    modifier: INCREASED
    term:
      id: GO:0006417
      label: regulation of translation
  - preferred_term: lipid biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0008610
      label: lipid biosynthetic process
  - preferred_term: cell growth
    modifier: INCREASED
    term:
      id: GO:0016049
      label: cell growth
  evidence:
  - reference: PMID:39334956
    reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation"
    explanation: Supports mTOR pathway as the regulator of cell proliferation, growth, and differentiation that is dysregulated in TSC.
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis"
    explanation: Identifies translation/protein synthesis and lipid synthesis as canonical mTOR-regulated outputs that are upregulated in TSC.
  downstream:
  - target: mTOR-Driven Multisystem Hamartoma Growth
    description: >
      Anabolic translation and lipid biosynthesis programs supply the
      macromolecular building blocks for excess cell growth in hamartomatous
      lesions across organs.
    causal_link_type: DIRECT
- name: Autophagy Suppression
  description: >
    Active mTORC1 phosphorylates ULK1 (Ser757) to block autophagosome
    initiation and phosphorylates TFEB to retain it in the cytoplasm, blunting
    lysosomal biogenesis. Reduced autophagic flux leads to accumulation of
    damaged organelles and metabolic stress in TSC-deficient cells, contributing
    to dysplastic phenotypes and tuber formation. Autophagy suppression also
    underlies sensitivity to mTOR inhibitor therapy.
  biological_processes:
  - preferred_term: negative regulation of autophagy
    modifier: INCREASED
    term:
      id: GO:0010507
      label: negative regulation of autophagy
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis"
    explanation: Identifies autophagy as a canonical mTOR-regulated output dysregulated in TSC.
  downstream:
  - target: mTOR-Driven Multisystem Hamartoma Growth
    description: >
      Suppressed autophagy blunts clearance of damaged organelles and protein
      aggregates and contributes to dysplastic, hamartomatous growth in
      TSC-deficient cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced autophagic flux
    - accumulation of damaged organelles
- name: mTOR-Driven Multisystem Hamartoma Growth
  description: >
    Constitutive mTORC1 activity increases anabolic growth programs and cell
    population expansion. The shared consequence is hamartomatous or dysplastic
    lesion formation in the brain, kidney, skin, heart, and lung, with each
    organ producing a characteristic downstream clinical phenotype.
  biological_processes:
  - preferred_term: mTOR signaling pathway
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:29478616
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      These proteins form a complex to constitutively inhibit the mammalian
      target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR
      signaling is constitutively active within all TSC-associated lesions.
    explanation: >
      Supports constitutive mTOR signaling as the shared mechanism across TSC
      lesions.
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Major features of the disease include tumours of the brain, skin, heart,
      lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders,
      which can include autism spectrum disorder and cognitive disability.
    explanation: >
      Identifies the main affected organs and downstream neurologic
      manifestations that the pathograph branches connect to mTOR activation.
  downstream:
  - target: Neuroglial Dysplasia and Cortical Network Disorganization
    description: >
      mTOR-driven growth dysregulation in the brain produces cortical and
      subependymal lesions and abnormal neuronal-glial networks.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal neuronal and glial differentiation
    - cortical tuber and subependymal lesion formation
  - target: Subependymal Glioneuronal Tumor Growth
    description: >
      mTOR activation promotes growth of subependymal nodules and SEGAs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - subependymal cell growth
    - glioneuronal tumor expansion
  - target: Renal Angiomyolipoma Growth
    description: >
      mTOR-driven proliferation in renal mesenchymal and smooth-muscle-like
      lesion components produces angiomyolipomas.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - smooth muscle cell proliferation
    - angiogenic and adipocytic tumor components
  - target: Cutaneous Fibrovascular Hamartoma Formation
    description: >
      mTOR-driven growth in skin stromal and vascular compartments produces
      fibrovascular hamartomatous lesions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - fibroblast proliferation
    - vascular remodeling
  - target: Cardiac Rhabdomyoma Formation
    description: >
      mTOR-driven growth dysregulation in developing cardiac muscle produces
      rhabdomyomas.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cardiac muscle cell growth
    - prenatal hamartoma formation
  - target: Pulmonary Lymphangioleiomyomatosis Growth
    description: >
      mTOR-driven smooth-muscle-like cell proliferation in lung contributes to
      lymphangioleiomyomatosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - smooth muscle cell proliferation
    - cystic lung remodeling
- name: Neuroglial Dysplasia and Cortical Network Disorganization
  description: >
    Brain mTORC1 hyperactivation disrupts neuronal and glial differentiation,
    radial migration, and dendritic morphology, producing cortical tubers,
    radial migration lines, and dysmorphic giant neurons. These lesions and
    network abnormalities provide the pathophysiologic bridge from TSC1/TSC2
    mutation to infantile spasms, drug-resistant focal seizures, and
    TSC-associated neuropsychiatric disorders (TAND).
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: nervous system development
    modifier: DYSREGULATED
    term:
      id: GO:0007399
      label: nervous system development
  - preferred_term: neuron differentiation
    modifier: DYSREGULATED
    term:
      id: GO:0030182
      label: neuron differentiation
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Major features of the disease include tumours of the brain, skin, heart,
      lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders,
      which can include autism spectrum disorder and cognitive disability.
    explanation: >
      Supports brain lesions, seizures, autism spectrum disorder, and cognitive
      disability as linked TSC manifestations.
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"
    explanation: Identifies cortical tubers and radial migration lines as the brain malformations and links them to seizures, autism, and cognitive disability.
  downstream:
  - target: Cortical Tubers
    description: >
      Neuroglial developmental dysplasia forms cortical tubers composed of
      abnormal glial and neural cells, including dysmorphic giant neurons.
      Disrupted radial migration also produces linear bands of dysplastic
      neurons visible on MRI as radial migration lines.
    causal_link_type: DIRECT
  - target: Infantile Spasms
    description: >
      Cortical malformations produce epileptogenic networks that frequently
      manifest as infantile spasms in the first year of life.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical tuber burden
    - abnormal neuronal excitability
  - target: Epileptic Seizures
    description: >
      Cortical tubers and abnormal cortical networks create epileptogenic
      circuits leading to focal-onset and often drug-resistant seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical tuber burden
    - abnormal neuronal excitability
  - target: Intellectual Disability
    description: >
      Early brain dysplasia and seizure burden contribute to cognitive
      disability within the TSC-associated neuropsychiatric disorder spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cortical development
    - early-onset epilepsy
  - target: Global Developmental Delay
    description: >
      Disrupted cortical development and infantile-onset seizures produce
      global developmental delay in early childhood.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cortical malformation
    - early-onset epilepsy
  - target: Autism Spectrum Disorder
    description: >
      Altered cortical development and early epileptogenic network dysfunction
      contribute to autism spectrum disorder within the TAND spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cortical development
    - early-onset epilepsy
  - target: Attention Deficit Hyperactivity Disorder
    description: >
      Cortical network dysfunction contributes to attention and impulse-control
      symptoms within the TAND spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cortical development
  - target: Anxiety
    description: >
      Network-level dysfunction in TSC-affected cortical and limbic circuits
      contributes to anxiety, mood disorders, and behavioural symptoms within
      the TAND spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered cortical and limbic network function
- name: Subependymal Glioneuronal Tumor Growth
  description: >
    mTOR-driven growth along the ventricular subependymal region produces
    subependymal nodules; a subset enlarge into subependymal giant cell
    astrocytomas that may obstruct cerebrospinal fluid flow.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy
      are the three FDA-approved indications in relation to TSC for the use of
      everolimus, which is a first generation mTOR inhibitor.
    explanation: >
      Links SEGAs to the mTOR inhibitor-responsive TSC disease mechanism.
  downstream:
  - target: Subependymal Nodules
    description: >
      Subependymal hamartomatous growth produces nodules along the lateral
      ventricle walls.
    causal_link_type: DIRECT
  - target: Subependymal Giant Cell Astrocytoma
    description: >
      Progressive subependymal glioneuronal growth can produce SEGAs near the
      foramen of Monro.
    causal_link_type: DIRECT
- name: Renal Angiomyolipoma Growth
  description: >
    Constitutive mTORC1 signalling in renal tumour cells (perivascular
    epithelioid cell, PEC, lineage) expands vascular, smooth-muscle-like, and
    adipocytic lesion components, producing renal angiomyolipomas. Lesions
    >4 cm risk haemorrhage. Cystic lesions and a small minority of renal cell
    carcinomas also arise from mTOR-driven proliferation in renal epithelium.
  cell_types:
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: smooth muscle cell proliferation
    modifier: INCREASED
    term:
      id: GO:0048659
      label: smooth muscle cell proliferation
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Remarkable progress in basic and translational research, in addition to
      several randomized controlled trials worldwide, has led to regulatory
      approval of the use of mTOR inhibitors for the treatment of renal
      angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary
      lymphangioleiomyomatosis
    explanation: >
      Supports renal angiomyolipomas as an mTOR inhibitor-responsive TSC lesion.
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function."
    explanation: Confirms that mTOR-driven renal manifestations include angiomyolipomas, cystic lesions, and renal cell carcinoma, with morbidity from bleeding and loss of kidney function.
  downstream:
  - target: Renal Angiomyolipoma
    description: >
      Expansion of renal vascular, smooth-muscle-like, and adipocytic tumor
      components produces angiomyolipoma.
    causal_link_type: DIRECT
  - target: Renal Cyst
    description: >
      mTOR-driven proliferation of renal tubular epithelium produces multiple
      bilateral renal cysts; cysts are particularly numerous and early-onset
      in TSC2-PKD1 contiguous deletion syndrome.
    causal_link_type: DIRECT
  - target: Renal Hemorrhage
    description: >
      Vascular components of large angiomyolipomas (>4 cm) are prone to
      spontaneous haemorrhage, a leading kidney-related cause of morbidity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - large AML burden
    - aneurysmal dysplastic vessels
- name: Cutaneous Fibrovascular Hamartoma Formation
  description: >
    mTORC1-driven growth dysregulation in skin stromal, vascular, and
    melanocyte compartments produces a spectrum of cutaneous lesions: facial
    angiofibromas, fibrous cephalic plaques, ungual/subungual fibromas,
    shagreen patches (connective-tissue nevi), hypomelanotic macules, and
    confetti-like hypopigmented macules.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  locations:
  - preferred_term: skin
    term:
      id: UBERON:0002097
      label: skin of body
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can
      suggest the diagnosis and underlie the importance of clinical vigilance.
    explanation: >
      Supports TSC-associated skin lesions as a diagnostic manifestation
      downstream of the disease mechanism.
  - reference: PMID:36833359
    reference_title: "Tuberous Sclerosis, Type II Diabetes Mellitus and the PI3K/AKT/mTOR Signaling Pathways-Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs"
    explanation: Illustrates the spectrum of TSC cutaneous lesions in a single confirmed-TSC patient — angiofibromas, depigmented (hypomelanotic) macules, periungual fibromas.
  downstream:
  - target: Facial Angiofibromas
    description: >
      Fibrovascular hamartoma formation in facial skin produces angiofibromas.
    causal_link_type: DIRECT
  - target: Shagreen Patch
    description: >
      Connective-tissue hamartoma formation in skin produces shagreen patches.
    causal_link_type: DIRECT
  - target: Hypomelanotic Macules
    description: >
      Melanocyte mTORC1 hyperactivation alters melanogenesis to produce
      hypopigmented (ash-leaf) macules, often the earliest visible cutaneous
      sign of TSC.
    causal_link_type: DIRECT
  - target: Confetti-like Hypopigmented Macules
    description: >
      Diffuse confetti-like 1-3 mm hypopigmented macules on the limbs are a
      minor diagnostic feature of TSC.
    causal_link_type: DIRECT
  - target: Subungual Fibromas
    description: >
      Periungual or subungual fibromas (Koenen tumours) form on or beside
      fingernails/toenails and typically appear in adolescence and adulthood.
    causal_link_type: DIRECT
  - target: Dental Enamel Pits
    description: >
      Hamartomatous overgrowth and developmental dysregulation in dental
      tissues produce multiple pinpoint enamel pits, a highly prevalent and
      under-recognized minor diagnostic feature.
    causal_link_type: DIRECT
- name: Cardiac Rhabdomyoma Formation
  description: >
    During fetal and early postnatal life, mTORC1-driven growth dysregulation
    in fetal cardiomyocytes produces benign rhabdomyomas; these are typically
    multiple, often detectable prenatally on fetal echocardiography, and are
    the earliest TSC manifestation. Most rhabdomyomas regress spontaneously
    during childhood as cardiomyocyte proliferative capacity wanes; large or
    multiple lesions can cause hydrops fetalis, arrhythmias, or outflow
    obstruction.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: fetal cardiomyocyte
    term:
      id: CL:0002495
      label: fetal cardiomyocyte
  biological_processes:
  - preferred_term: heart development
    modifier: DYSREGULATED
    term:
      id: GO:0007507
      label: heart development
  - preferred_term: cell growth
    modifier: INCREASED
    term:
      id: GO:0016049
      label: cell growth
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can
      suggest the diagnosis and underlie the importance of clinical vigilance.
    explanation: >
      Supports cardiac rhabdomyomas as an early TSC manifestation.
  - reference: PMID:39518472
    reference_title: "Prenatal mTOR Inhibitors in Tuberous Sclerosis Complex: Current Insights and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberous sclerosis complex (TSC) can present prenatally, often with cardiac rhabdomyomas, which, if large, may cause complications such as hydrops fetalis and reduced cardiac output."
    explanation: Confirms prenatal cardiac rhabdomyoma as the earliest manifestation and notes complications (hydrops fetalis, reduced cardiac output) of large rhabdomyomas.
  downstream:
  - target: Cardiac Rhabdomyoma
    description: >
      mTOR-driven cardiac muscle growth dysregulation produces benign
      rhabdomyomas.
    causal_link_type: DIRECT
- name: Retinal Hamartoma Formation
  description: >
    mTORC1 hyperactivation in retinal glia produces nodular astrocytic
    hamartomas and achromic patches in the retina. Retinal hamartomas are
    typically asymptomatic but contribute to TSC's clinical diagnostic
    criteria and confirm CNS dissemination of the mTOR-driven lesion process.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: retina
    term:
      id: UBERON:0000966
      label: retina
  downstream:
  - target: Retinal Hamartoma
    description: >
      mTOR-driven proliferation of retinal astrocytes produces nodular retinal
      hamartomas (and associated achromic patches).
    causal_link_type: DIRECT
- name: Pulmonary Lymphangioleiomyomatosis Growth
  description: >
    In the lung, mTOR pathway activation supports proliferation of
    smooth-muscle-like LAM cells and cystic remodeling, producing pulmonary
    lymphangioleiomyomatosis and reduced pulmonary function.
  cell_types:
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  biological_processes:
  - preferred_term: regulation of smooth muscle cell proliferation
    modifier: INCREASED
    term:
      id: GO:0048660
      label: regulation of smooth muscle cell proliferation
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Remarkable progress in basic and translational research, in addition to
      several randomized controlled trials worldwide, has led to regulatory
      approval of the use of mTOR inhibitors for the treatment of renal
      angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary
      lymphangioleiomyomatosis
    explanation: >
      Supports pulmonary lymphangioleiomyomatosis as an mTOR inhibitor-responsive
      TSC manifestation.
  - reference: PMID:23539171
    reference_title: "Lymphangioleiomyomatosis screening in women with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      These results suggest that most women with TSC ultimately develop cystic
      changes consistent with LAM and that most cases can be identified from a
      single CT imaging slice at the level of the carina.
    explanation: >
      Supports cystic lung remodeling as the pulmonary LAM phenotype in women
      with TSC.
  downstream:
  - target: Pulmonary Lymphangioleiomyomatosis
    description: >
      Proliferation of smooth-muscle-like LAM cells in lung produces pulmonary
      lymphangioleiomyomatosis.
    causal_link_type: DIRECT
phenotypes:
- category: Neurologic
  name: Epileptic Seizures
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Epilepsy occurs in 62-93% of TSC patients (typically reported as ~80-90%),
    often beginning in infancy as infantile spasms and evolving into
    drug-resistant focal epilepsy in approximately two-thirds of patients.
    Epilepsy is the most common neurological manifestation and a major cause of
    morbidity and reduced quality of life.
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability."
    explanation: Seizures are listed as a major feature of TSC.
  - reference: PMID:39334956
    reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC."
    explanation: Identifies drug-resistant epilepsy as a typical feature of TSC and links it to mTORC1 hyperactivation.
  - reference: PMID:39617898
    reference_title: "Diagnostic flow analysis of tuberous sclerosis complex in Japan: a retrospective claims database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy was the manifestation with the highest incidence (29.2%) among Cohort 1 patients"
    explanation: Provides a quantitative claims-based observation of epilepsy frequency among TSC patients in Japan.
  sequelae:
  - target: Sudden Unexpected Death in Epilepsy
    description: >
      TSC-associated drug-resistant epilepsy carries a substantial risk of
      sudden unexpected death in epilepsy (SUDEP); brain tumours, SUDEP, and
      respiratory conditions are the three leading causes of mortality in TSC.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - prolonged drug-resistant seizures
    - autonomic dysregulation in seizure
- category: Neurologic
  name: Infantile Spasms
  frequency: FREQUENT
  description: >
    Infantile spasms are an age-specific epileptic encephalopathy of the first
    year of life and are the most common initial seizure type in TSC.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
- category: Neurologic
  name: Intellectual Disability
  frequency: FREQUENT
  description: >
    Cognitive impairment occurs in approximately 50% of TSC patients, ranging
    from mild learning difficulties to severe intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated."
    explanation: Confirms intellectual disability as a significant TAND feature in TSC.
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"
    explanation: Confirms cognitive disability (intellectual disability) as a TSC manifestation alongside seizures and autism.
- category: Neurologic
  name: Global Developmental Delay
  frequency: FREQUENT
  description: >
    Disrupted cortical development plus early-onset epilepsy produces global
    developmental delay during infancy and toddlerhood, often preceding a
    formal intellectual disability diagnosis.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
- category: Behavioral
  name: Autism Spectrum Disorder
  frequency: FREQUENT
  description: >
    Autism spectrum disorder is present in approximately 40-50% of TSC patients
    and is associated with early-onset seizures and cortical tuber burden;
    TAND collectively affects ~90% of TSC patients across the lifespan.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability."
    explanation: Autism spectrum disorder is identified as part of the TSC-associated neuropsychiatric disorder spectrum.
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"
    explanation: Confirms autism as a TSC manifestation alongside cortical tubers and cognitive disability.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  frequency: FREQUENT
  description: >
    Attention deficits and hyperactivity occur as part of the TSC-associated
    neuropsychiatric disorders (TAND) spectrum.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
- category: Behavioral
  name: Anxiety
  frequency: FREQUENT
  description: >
    Anxiety symptoms are a common psychiatric component of TAND, contributing
    to reduced quality of life.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
- category: Dermatologic
  name: Facial Angiofibromas
  frequency: VERY_FREQUENT
  description: >
    Facial angiofibromas are present in approximately 75% of TSC patients,
    typically appearing in early childhood as red papules on the malar regions.
    They are a major diagnostic feature.
  phenotype_term:
    preferred_term: Angiofibromas
    term:
      id: HP:0010615
      label: Angiofibromas
- category: Dermatologic
  name: Hypomelanotic Macules
  frequency: VERY_FREQUENT
  description: >
    Hypomelanotic ("ash-leaf") macules are oval or polygonal hypopigmented
    skin patches present in ~90% of TSC patients and often visible from birth.
    Three or more macules ≥5 mm constitute a major diagnostic criterion. They
    are frequently the earliest visible cutaneous sign of TSC.
  phenotype_term:
    preferred_term: Hypomelanotic macule
    term:
      id: HP:0009719
      label: Hypomelanotic macule
- category: Dermatologic
  name: Confetti-like Hypopigmented Macules
  frequency: OCCASIONAL
  description: >
    Confetti-like 1-3 mm hypopigmented macules typically distributed on the
    arms and legs are a minor diagnostic feature of TSC.
  phenotype_term:
    preferred_term: Confetti-like hypopigmented macules
    term:
      id: HP:0007449
      label: Confetti-like hypopigmented macules
- category: Dermatologic
  name: Subungual Fibromas
  frequency: FREQUENT
  description: >
    Periungual or subungual fibromas (Koenen tumours) are firm flesh-coloured
    growths on or beside the nails, typically appearing in adolescence and
    adulthood. They are a major diagnostic feature.
  phenotype_term:
    preferred_term: Subungual fibromas
    term:
      id: HP:0009724
      label: Subungual fibromas
  evidence:
  - reference: PMID:36833359
    reference_title: "Tuberous Sclerosis, Type II Diabetes Mellitus and the PI3K/AKT/mTOR Signaling Pathways-Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "periungual fibroma in both lower limbs"
    explanation: Confirms periungual fibromas as a documented TSC cutaneous feature.
- category: Dermatologic
  name: Shagreen Patch
  frequency: FREQUENT
  description: >
    Shagreen patches are connective tissue nevi presenting as skin-colored or
    pigmented plaques, typically on the lower back. They are a major
    diagnostic feature.
  phenotype_term:
    preferred_term: Shagreen patch
    term:
      id: HP:0009721
      label: Shagreen patch
- category: Dental
  name: Dental Enamel Pits
  frequency: VERY_FREQUENT
  description: >
    Multiple pinpoint dental enamel pits (>3 in primary dentition) are a
    minor diagnostic feature of TSC, present in the majority of patients but
    frequently overlooked.
  phenotype_term:
    preferred_term: Dental enamel pits
    term:
      id: HP:0009722
      label: Dental enamel pits
- category: Neurologic
  name: Cortical Tubers
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    Cortical tubers are hamartomatous lesions at the gray-white matter interface
    containing abnormal glial and neural cells (including dysmorphic giant
    neurons). They are a hallmark brain lesion in TSC and the substrate of
    drug-resistant focal epilepsy.
  phenotype_term:
    preferred_term: Cortical tubers
    term:
      id: HP:0009717
      label: Cortical tubers
  evidence:
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability"
    explanation: Identifies cortical tubers as a defining TSC manifestation.
- category: Neurologic
  name: Subependymal Nodules
  frequency: VERY_FREQUENT
  description: >
    Subependymal nodules are small (often calcified) hamartomatous masses
    along the lateral ventricle walls, present in approximately 80% of TSC
    patients and a major diagnostic feature.
  phenotype_term:
    preferred_term: Subependymal nodules
    term:
      id: HP:0009716
      label: Subependymal nodules
- category: Neurologic
  name: Subependymal Giant Cell Astrocytoma
  frequency: OCCASIONAL
  description: >
    SEGAs develop from subependymal nodules near the foramen of Monro and can
    cause obstructive hydrocephalus. They occur in up to ~20% of TSC patients
    and respond to mTOR inhibitor therapy with substantial tumour shrinkage.
  phenotype_term:
    preferred_term: Subependymal giant-cell astrocytoma
    term:
      id: HP:0009718
      label: Subependymal giant-cell astrocytoma
  evidence:
  - reference: PMID:38042867
    reference_title: "Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months."
    explanation: Real-world data showing substantial mTOR inhibitor-driven SEGA volume reductions, supporting SEGA as an mTOR-pathway-driven phenotype.
- category: Neurologic
  name: Sudden Unexpected Death in Epilepsy
  frequency: VERY_RARE
  description: >
    Sudden unexpected death in epilepsy (SUDEP) is one of the leading causes
    of mortality in TSC, in the context of drug-resistant epilepsy.
  phenotype_term:
    preferred_term: Sudden death
    term:
      id: HP:0001699
      label: Sudden death
  evidence:
  - reference: PMID:39334956
    reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality."
    explanation: Identifies sudden unexpected death from epilepsy as a leading cause of TSC mortality.
- category: Ocular
  name: Retinal Hamartoma
  frequency: OCCASIONAL
  description: >
    Multiple retinal nodular hamartomas (or retinal achromic patches) are
    typically asymptomatic but contribute to TSC's clinical diagnostic
    criteria as a major feature.
  phenotype_term:
    preferred_term: Retinal hamartoma
    term:
      id: HP:0009594
      label: Retinal hamartoma
- category: Renal
  name: Renal Angiomyolipoma
  frequency: VERY_FREQUENT
  description: >
    Renal angiomyolipomas occur in approximately 80% of TSC patients and are
    benign tumours composed of dysplastic vascular, smooth-muscle-like, and
    adipocytic components. They are a major cause of morbidity due to risk of
    haemorrhage in lesions >4 cm. Lesion shrinkage with mTOR inhibitor therapy
    is well established.
  phenotype_term:
    preferred_term: Renal angiomyolipoma
    term:
      id: HP:0006772
      label: Renal angiomyolipoma
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders"
    explanation: Kidney tumors including angiomyolipomas are listed as a major feature of TSC.
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function."
    explanation: Confirms renal angiomyolipomas as a major TSC kidney manifestation, with morbidity from progression, bleeding, and loss of kidney function.
  - reference: PMID:38042867
    reference_title: "Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months."
    explanation: Real-world quantification of mTOR inhibitor-induced AML lesion size reduction.
- category: Renal
  name: Renal Cyst
  frequency: FREQUENT
  description: >
    Multiple bilateral renal cysts arise in TSC and are particularly numerous
    and early-onset in TSC2-PKD1 contiguous deletion syndrome where they
    progress to early kidney failure.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas"
    explanation: Confirms cystic renal lesions as a TSC kidney manifestation.
- category: Renal
  name: Renal Hemorrhage
  frequency: OCCASIONAL
  description: >
    Spontaneous haemorrhage from large angiomyolipomas (>4 cm) is the most
    serious renal complication of TSC and is a leading kidney-related cause
    of morbidity. Embolization or partial nephrectomy is reserved for
    haemorrhage unresponsive to mTOR inhibitor therapy.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage."
    explanation: Identifies severe renal hemorrhage as a complication of TSC kidney lesions and its management.
- category: Pulmonary
  name: Pulmonary Lymphangioleiomyomatosis
  frequency: FREQUENT
  description: >
    Pulmonary lymphangioleiomyomatosis is an mTOR inhibitor-responsive lung
    manifestation of TSC caused by proliferation of abnormal smooth-muscle-like
    cells and cystic lung remodeling.
  phenotype_term:
    preferred_term: Pulmonary lymphangioleiomyomatosis
    term:
      id: HP:0005948
      label: Multiple pulmonary cysts
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >
      Remarkable progress in basic and translational research, in addition to
      several randomized controlled trials worldwide, has led to regulatory
      approval of the use of mTOR inhibitors for the treatment of renal
      angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary
      lymphangioleiomyomatosis
    explanation: >
      Supports pulmonary lymphangioleiomyomatosis as a TSC manifestation with
      mTOR inhibitor-responsive biology.
  - reference: PMID:23539171
    reference_title: "Lymphangioleiomyomatosis screening in women with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Forty-eight (47.5%) met criteria for TSC-LAM on the initial CT scan."
    explanation: >
      This female TSC clinic cohort supports a FREQUENT frequency band for LAM
      in women with TSC.
- category: Cardiac
  name: Cardiac Rhabdomyoma
  frequency: FREQUENT
  description: >
    Cardiac rhabdomyomas are typically the earliest detectable lesion in TSC,
    often identified prenatally on fetal echocardiography. They occur in
    approximately 50-65% of patients overall and were the highest-incidence
    manifestation (54.8%) in a Japanese claims cohort diagnosed under 2 years
    of age. Most regress spontaneously during childhood; large or multiple
    lesions can cause hydrops fetalis or arrhythmias.
  phenotype_term:
    preferred_term: Cardiac rhabdomyoma
    term:
      id: HP:0009729
      label: Cardiac rhabdomyoma
  evidence:
  - reference: PMID:39617898
    reference_title: "Diagnostic flow analysis of tuberous sclerosis complex in Japan: a retrospective claims database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac rhabdomyoma had the highest incidence (54.8%) among Cohort 2 patients."
    explanation: Real-world claims data showing cardiac rhabdomyoma as the most frequent early-life (under 2 years) TSC manifestation.
  - reference: PMID:39518472
    reference_title: "Prenatal mTOR Inhibitors in Tuberous Sclerosis Complex: Current Insights and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberous sclerosis complex (TSC) can present prenatally, often with cardiac rhabdomyomas, which, if large, may cause complications such as hydrops fetalis and reduced cardiac output."
    explanation: Confirms prenatal cardiac rhabdomyoma as an early TSC presentation with potential complications.
genetic:
- name: TSC1
  association: Pathogenic Mutations
  presence: Positive
  notes: >
    TSC1 on chromosome 9q34 encodes hamartin. Loss-of-function variants account
    for ~17-30% of molecularly solved TSC cases. Pathogenic alterations are
    inactivating (nonsense, frameshift, splice-site, missense, intragenic
    deletions). TSC1-related disease is on average milder than TSC2-related
    disease.
  evidence:
  - reference: PMID:29478616
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are over 2000 known allelic variants for TSC, including nonsense and misssense mutation, and all pathogenic mutations are inactivating, leading to loss-of-function effects on the encoded proteins, TSC1 and TSC2."
    explanation: Confirms TSC1 inactivating mutations as causative.
  - reference: PMID:39596632
    reference_title: "Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2."
    explanation: Quantitative cohort data on TSC1 vs TSC2 contribution among molecularly solved cases.
  - reference: CGGV:assertion_61b07bb0-1385-4344-8b6c-571f6a271000-2019-01-23T170000.000Z
    reference_title: "TSC1 / tuberous sclerosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TSC1 | HGNC:12362 | tuberous sclerosis | MONDO:0001734 | AD | Definitive"
    explanation: ClinGen classifies the TSC1-tuberous sclerosis gene-disease relationship as definitive with autosomal dominant inheritance.
- name: TSC2
  association: Pathogenic Mutations
  presence: Positive
  notes: >
    TSC2 on chromosome 16p13.3 encodes tuberin. Loss-of-function variants
    account for ~70-83% of molecularly solved TSC cases. TSC2 mutations are
    generally associated with more severe disease, with critical-domain
    variants correlating with the highest disease severity.
  evidence:
  - reference: PMID:27226234
    reference_title: "Tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2."
    explanation: Confirms TSC1 and TSC2 as the causative genes.
  - reference: PMID:38540392
    reference_title: "The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity."
    explanation: Establishes the TSC2 genotype-phenotype severity correlation.
  - reference: PMID:39596632
    reference_title: "Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2."
    explanation: Quantitative cohort data showing TSC2 as the predominant causal gene among molecularly solved cases (~83%).
  - reference: CGGV:assertion_0b0a33ff-44ca-497c-8499-cc1f50cead93-2019-01-23T170000.000Z
    reference_title: "TSC2 / tuberous sclerosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TSC2 | HGNC:12363 | tuberous sclerosis | MONDO:0001734 | AD | Definitive"
    explanation: ClinGen classifies the TSC2-tuberous sclerosis gene-disease relationship as definitive with autosomal dominant inheritance.
- name: Somatic Mosaicism
  association: Mosaic Pathogenic Variants
  presence: Positive
  notes: >
    Approximately 10-15% of clinically definite TSC cases have no germline
    pathogenic variant detected by conventional sequencing. Most are
    postulated to result from low-level somatic mosaicism for TSC1 or TSC2
    variants and may show milder phenotypes.
  evidence:
  - reference: PMID:38540392
    reference_title: "The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges."
    explanation: Quantifies the prevalence and likely mosaic origin of conventionally negative TSC cases.
treatments:
- name: mTOR Inhibitor Therapy (Everolimus)
  description: >
    Everolimus is an mTOR inhibitor with FDA approval for TSC-associated
    subependymal giant cell astrocytomas, renal angiomyolipomas, and as
    adjunctive treatment for refractory seizures. Real-world data show ≥50%
    seizure reduction in ~31% of patients (46% in those <18 years), AML
    longest-diameter reduction in 38% with stabilization in 59%, and
    substantial SEGA volume reductions.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: everolimus
      term:
        id: CHEBI:68478
        label: everolimus
  target_phenotypes:
  - preferred_term: Subependymal giant-cell astrocytoma
    term:
      id: HP:0009718
      label: Subependymal giant-cell astrocytoma
  - preferred_term: Renal angiomyolipoma
    term:
      id: HP:0006772
      label: Renal angiomyolipoma
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Constitutive mTORC1 Hyperactivation
    treatment_effect: INHIBITS
    description: >
      Everolimus directly inhibits mTORC1 kinase activity by allosteric binding
      to FKBP12, counteracting the central pathobiological hub of TSC.
    evidence:
    - reference: PMID:39334956
      reference_title: "Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC."
      explanation: Identifies mTORC1 hyperactivation as the central drug target counteracted by mTOR inhibitors in TSC.
  - target: mTOR-Driven Multisystem Hamartoma Growth
    treatment_effect: INHIBITS
    description: >
      Everolimus inhibits mTORC1 signalling, counteracting the shared
      lesion-growth mechanism downstream of TSC1/TSC2 loss.
    evidence:
    - reference: PMID:29478616
      reference_title: "Tuberous sclerosis complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        The mTOR inhibitors rapamycin (sirolimus) and everolimus have been shown
        to reduce renal and brain lesion size, and improve pulmonary function in
        TSC, and these compounds may also decrease seizure frequency.
      explanation: >
        Supports mTOR inhibition as a pathway-directed treatment for multiple
        downstream TSC manifestations.
  - target: Renal Angiomyolipoma Growth
    treatment_effect: INHIBITS
    description: >
      Everolimus reduces renal angiomyolipoma size and stabilises lesions in
      most treated patients.
    evidence:
    - reference: PMID:38042867
      reference_title: "Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months."
      explanation: Real-world quantification of mTOR-inhibitor effect on AML.
  - target: Subependymal Glioneuronal Tumor Growth
    treatment_effect: INHIBITS
    description: >
      Everolimus reduces SEGA volume substantially with long-term treatment.
    evidence:
    - reference: PMID:38042867
      reference_title: "Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months."
      explanation: Real-world example SEGA shrinkage on everolimus.
  - target: Pulmonary Lymphangioleiomyomatosis Growth
    treatment_effect: INHIBITS
    description: mTOR inhibitor therapy improves pulmonary function in TSC-associated lung disease.
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor."
    explanation: Confirms FDA approval of everolimus for three TSC indications.
  - reference: PMID:38042867
    reference_title: "Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment."
    explanation: Real-world seizure response rate to adjunctive everolimus in TSC.
- name: Vigabatrin for Infantile Spasms
  description: >
    Vigabatrin is the first-line treatment for TSC-associated infantile
    spasms, with high response rates specific to this population. Vigabatrin
    is also being evaluated for pre-symptomatic prevention of TSC seizures
    in infants with epileptiform EEG (e.g., NCT04987463 — rapamycin vs
    vigabatrin prevention).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Neuroglial Dysplasia and Cortical Network Disorganization
    treatment_effect: MODULATES
    description: >-
      Vigabatrin irreversibly inhibits GABA transaminase, elevating synaptic
      GABA levels and reducing the hyperexcitability of dysplastic cortical
      tubers that drives infantile spasms and seizures in TSC.
- name: mTOR Inhibitor Therapy (Sirolimus/Rapamycin)
  description: >
    Sirolimus (rapamycin) is an mTOR inhibitor FDA-approved for
    lymphangioleiomyomatosis. Topical sirolimus formulations are also
    effective for facial angiofibromas.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_phenotypes:
  - preferred_term: Pulmonary lymphangioleiomyomatosis
    term:
      id: HP:0005948
      label: Multiple pulmonary cysts
  target_mechanisms:
  - target: Constitutive mTORC1 Hyperactivation
    treatment_effect: INHIBITS
    description: >
      Sirolimus directly inhibits mTORC1 by FKBP12-mediated allosteric
      binding, the same mechanism as everolimus.
  - target: Pulmonary Lymphangioleiomyomatosis Growth
    treatment_effect: INHIBITS
    description: >
      Sirolimus inhibits mTOR signaling in the LAM branch downstream of TSC1/TSC2
      loss.
  evidence:
  - reference: PMID:32222129
    reference_title: "Tuberous sclerosis: a review of the past, present, and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rapamycin has been FDA approved for lymphangioleiomyomatosis."
    explanation: >
      Supports rapamycin/sirolimus as a distinct FDA-approved treatment for
      lymphangioleiomyomatosis in TSC.
- name: Topical Sirolimus for Facial Angiofibromas
  description: >
    Topical sirolimus formulations applied to facial skin reduce the size
    and erythema of TSC-associated facial angiofibromas with minimal systemic
    exposure. Multiple clinical trials have demonstrated efficacy
    (NCT01526356, NCT03140449).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_phenotypes:
  - preferred_term: Angiofibromas
    term:
      id: HP:0010615
      label: Angiofibromas
  target_mechanisms:
  - target: Cutaneous Fibrovascular Hamartoma Formation
    treatment_effect: INHIBITS
    description: >
      Topical mTOR inhibition reduces dermal fibroblast/vascular proliferation
      driving angiofibroma growth.
- name: Cannabidiol for Drug-Resistant TSC Epilepsy
  description: >
    Plant-derived cannabidiol (Epidiolex) is FDA-approved as adjunctive
    therapy for drug-resistant TSC-associated seizures based on randomized
    controlled trial evidence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cannabidiol
      term:
        id: CHEBI:69478
        label: cannabidiol
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Neuroglial Dysplasia and Cortical Network Disorganization
    treatment_effect: MODULATES
    description: >-
      Cannabidiol suppresses seizure activity in TSC-associated drug-resistant
      epilepsy, modulating the hyperexcitable cortical network formed by
      neuroglial dysplastic tubers.
- name: Epilepsy Surgery
  description: >
    Surgical resection of an epileptogenic tuber may be considered for
    drug-resistant focal seizures when a dominant epileptogenic lesion can be
    localised by imaging and electrophysiology.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Neuroglial Dysplasia and Cortical Network Disorganization
    treatment_effect: MODULATES
    description: >-
      Resection of epileptogenic tubers removes the dysplastic cortical tissue
      that anchors reentrant seizure circuits, directly eliminating the
      neuroglial dysplasia substrate responsible for focal drug-resistant
      epilepsy.
- name: Renal AML Embolization or Nephrectomy
  description: >
    Selective renal artery embolization or partial/total nephrectomy is
    reserved for complications of large angiomyolipomas (especially severe
    haemorrhage) unresponsive to mTOR inhibitor therapy.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  target_phenotypes:
  - preferred_term: Renal angiomyolipoma
    term:
      id: HP:0006772
      label: Renal angiomyolipoma
  evidence:
  - reference: PMID:38991206
    reference_title: "Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage."
    explanation: Establishes embolization and nephrectomy as second-line for AML complications unresponsive to mTOR inhibitors.
  target_mechanisms:
  - target: Renal Angiomyolipoma Growth
    treatment_effect: MODULATES
    description: >-
      Embolization devascularizes and shrinks bleeding AMLs; nephrectomy
      removes the growth entirely. Both procedures eliminate the acute
      hemorrhagic complication of mTOR-driven renal angiomyolipoma growth
      without affecting the upstream mTORC1 dysregulation.
- name: Multidisciplinary TSC Clinic Care
  description: >
    Care at a dedicated multidisciplinary TSC clinic is associated with
    earlier diagnosis (median 11.5 vs 19.0 months for epilepsy presentations,
    p=0.0379) and better surveillance and management of multisystem
    manifestations.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:39617898
    reference_title: "Diagnostic flow analysis of tuberous sclerosis complex in Japan: a retrospective claims database study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "those attending facilities with a TSC clinic were diagnosed with TSC more quickly than those attending facilities without a TSC clinic (median: 11.5 and 19.0 months, respectively; p = 0.0379)."
    explanation: Quantifies the diagnostic-time benefit of dedicated TSC clinics.
- name: Genetic Counseling
  description: >
    Genetic counseling is recommended for TSC families given the autosomal
    dominant inheritance pattern, variable expressivity, and reproductive
    options (preimplantation/prenatal testing) when the familial variant is
    known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
clinical_trials:
- name: NCT05534672
  phase: PHASE_III
  status: RECRUITING
  description: >
    Placebo-controlled randomized trial of rapamycin (sirolimus) for
    drug-resistant epilepsy associated with TSC.
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- name: NCT04987463
  phase: PHASE_III
  status: RECRUITING
  description: >
    Trial comparing rapamycin (sirolimus) vs vigabatrin for prevention of
    TSC-related seizures and neurodevelopmental impairment in infants
    identified before seizure onset.
  target_phenotypes:
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- name: NCT01526356
  phase: PHASE_II
  status: COMPLETED
  description: >
    Trial of topical sirolimus formulations for TSC-associated facial
    angiofibromas demonstrating reduction in lesion size and erythema.
  target_phenotypes:
  - preferred_term: Angiofibromas
    term:
      id: HP:0010615
      label: Angiofibromas
notes: |
  Quantitative evidence highlights from recent literature integrated into this
  entry:
  - Adjusted prevalence: 10.2 per 100,000 in Shizuoka, Japan, 2012-2020
    (Kishida 2025; PMID:40410908).
  - Diagnostic yield of conventional sequencing: 91% (TSC2 83%, TSC1 17%);
    NMI ~10-15% likely due to mosaicism (Dufner-Almeida 2024 PMID:39596632;
    Man 2024 PMID:38540392).
  - Real-world everolimus outcomes (Cockerell 2023 PMID:38042867):
    seizure reduction ≥50% in 31% (46% under 18 years), AML response 38% with
    stabilization in 59%, SEGA volume reductions of 43-71%, AEs in 95%.
  - QoL burden in TSC-related epilepsy: EQ-5D-3L TTO 0.705, VAS 0.577;
    unemployment 60% (Lappe 2024 PMID:38812055).
  - Diagnostic delay reduced at TSC clinics: 11.5 vs 19.0 months for epilepsy
    (Okanishi 2024 PMID:39617898).
  - SUDEP, brain tumours, and respiratory complications are the leading
    causes of TSC mortality (Conte 2024 PMID:39334956).
datasets:

📚

References & Deep Research

Deep Research

Falcon ▸

Tuberous Sclerosis Complex (TSC) — Disease Characteristics Research Report

Edison Scientific Literature 43 citations 2026-04-25T22:27:54.938854

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.

Domain	Metric	Value(s)	Population/Study	Year (publication)	DOI/URL
Epidemiology	Incidence at birth/live births	1:5,800 to 1:13,520 live births	Review of TSC genetics and epidemiology	2024	https://doi.org/10.3390/genes15030332 (man2024thegeneticsof pages 1-2)
Epidemiology	Incidence at birth/live births	1:6,000 to 1:10,000 live births	Therapeutic review of TSC	2024	https://doi.org/10.3390/biom14091190 (conte2024therapeuticapproachesto pages 1-2)
Epidemiology	Prevalence	~1 in 6,000 live births	Prenatal mTOR inhibitor review	2024	https://doi.org/10.3390/jcm13216335 (racioppi2024prenatalmtorinhibitors pages 1-2)
Epidemiology	Adjusted prevalence	10.2 per 100,000	Shizuoka Kokuho Database; 125 TSC patients; ICD-10 Q85.1 ascertainment	2025	https://doi.org/10.1186/s13023-025-03799-w (kishida2025epidemiologicalinsightsand pages 1-2, kishida2025epidemiologicalinsightsand pages 2-4)
Epidemiology	Crude annual prevalence (2019)	85 cases among 1,401,399 registrants; ~6.1 per 100,000	Shizuoka Kokuho Database	2025	https://doi.org/10.1186/s13023-025-03799-w (kishida2025epidemiologicalinsightsand pages 2-4)
Epidemiology	Age-specific prevalence, males	0–19 y: 18.29/100,000; 20–64 y: 8.53/100,000; 65+ y: 2.37/100,000	Shizuoka, 2019	2025	https://doi.org/10.1186/s13023-025-03799-w (kishida2025epidemiologicalinsightsand pages 2-4)
Epidemiology	Age-specific prevalence, females	0–19 y: 15.38/100,000; 20–64 y: 8.56/100,000; 65+ y: 2.24/100,000	Shizuoka, 2019	2025	https://doi.org/10.1186/s13023-025-03799-w (kishida2025epidemiologicalinsightsand pages 2-4)
Epidemiology	Prevalence trend	5.4/100,000 (2014) to 6.1/100,000 (2015)	Shizuoka prevalence trend after criteria/treatment changes	2025	https://doi.org/10.1186/s13023-025-03799-w (kishida2025epidemiologicalinsightsand pages 5-6)
Genetics	No mutation identified (NMI) by conventional testing	~15%	Genetics review	2024	https://doi.org/10.3390/genes15030332 (man2024thegeneticsof pages 1-2)
Genetics	Molecular diagnostic yield	106/116 (91%) definite clinical TSC cases had pathogenic TSC1/TSC2 alteration	Molecular and functional assessment cohort	2024	https://doi.org/10.3390/genes15111432 (dufneralmeida2024molecularandfunctional pages 1-2)
Genetics	Gene distribution in molecularly solved cohort	TSC1: 18/106 (17%); TSC2: 88/106 (83%); 35 novel variants	Molecular and functional assessment cohort	2024	https://doi.org/10.3390/genes15111432 (dufneralmeida2024molecularandfunctional pages 1-2)
Phenotypes	Epilepsy frequency	62% to 93%	Therapeutic review	2024	https://doi.org/10.3390/biom14091190 (conte2024therapeuticapproachesto pages 1-2)
Phenotypes	Drug-resistant/pharmacoresistant epilepsy	~two-thirds affected	Prenatal mTOR inhibitor review	2024	https://doi.org/10.3390/jcm13216335 (racioppi2024prenatalmtorinhibitors pages 1-2)
Phenotypes	Intellectual disability	~50%	Prenatal mTOR inhibitor review	2024	https://doi.org/10.3390/jcm13216335 (racioppi2024prenatalmtorinhibitors pages 1-2)
Phenotypes	Autism spectrum disorder	~50%; TAND affects ~90% lifetime	Prenatal mTOR inhibitor review	2024	https://doi.org/10.3390/jcm13216335 (racioppi2024prenatalmtorinhibitors pages 1-2, racioppi2024prenatalmtorinhibitors pages 2-3)
Phenotypes	SEGA prevalence	Up to 20%	Therapeutic review	2024	https://doi.org/10.3390/biom14091190 (conte2024therapeuticapproachesto pages 1-2)
Phenotypes	TSC-LAM incidence	About 30%	Therapeutic review	2024	https://doi.org/10.3390/biom14091190 (conte2024therapeuticapproachesto pages 1-2)
Diagnostics	Current clinical diagnostic rule	Definite TSC: 2 major, or 1 major + ≥2 minor, or pathogenic TSC1/TSC2 variant	Clinical criteria table image/summary	2023	https://doi.org/10.3390/genes14020433 (jurca2023tuberoussclerosistype media b5f360a7)
Diagnostics	Median time-to-diagnosis (TTD), TSC-specific vs non-specific manifestations	1 month (range 1–27) vs 11 months (range 1–84); p=0.0035	Japan JMDC claims database, Cohort 1	2024	https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 4-5)
Diagnostics	Longest TTD by presentation	Renal tumor median 23 months (up to 91 months)	Japan JMDC claims database	2024	https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 1-2, okanishi2024diagnosticflowanalysis pages 7-9)
Diagnostics	TTD with vs without TSC clinic (all manifestations)	3.0 months (range 1–49) vs 13.0 months (range 1–91); p=0.0966	Japan JMDC claims database	2024	https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 5-7)
Diagnostics	TTD for epilepsy with vs without TSC clinic	11.5 months (range 1–31) vs 19.0 months (range 1–89); p=0.0379	Japan JMDC claims database	2024	https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 5-7, okanishi2024diagnosticflowanalysis pages 1-2)
Diagnostics	Manifestation frequencies in delayed-diagnosis cohort	Epilepsy 29.2%; renal tumor 9.4%; brain/intraventricular tumor 8.5%	Japan JMDC claims database, Cohort 1	2024	https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 4-5, okanishi2024diagnosticflowanalysis pages 5-7)
Diagnostics	Early-life manifestations	Cardiac rhabdomyoma 54.8%; epilepsy 38.1%	Japan JMDC claims database, Cohort 2	2024	https://doi.org/10.1186/s13023-024-03460-y (okanishi2024diagnosticflowanalysis pages 5-7, okanishi2024diagnosticflowanalysis pages 7-9)
Treatment	Everolimus seizure response (real world)	14/45 (31%) achieved ≥50% seizure reduction; any reduction 68%; ≥30% reduction 44%	Norway/Denmark real-world cohort, 64 treated patients	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2, cockerell2023effectivenessandsafety pages 4-6, cockerell2023effectivenessandsafety pages 2-4)
Treatment	Everolimus seizure response by age	<18 y: 46% responders; ≥18 y: 14% responders	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2)
Treatment	Everolimus seizure response by country	Norway: 4/26 (15%); Denmark: 10/19 (53%)	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 4-6)
Treatment	Everolimus rAML response (real world)	Largest lesion LD response ≥30% decrease: 35%; mean bilateral diameter response: 38%; stable size 52%/59%; progression 14%/3%	Real-world cohort, 29 patients with rAML imaging	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 4-6)
Treatment	rAML burden change on everolimus (real world)	Lesions >4 cm decreased from 75% to 55%; lesions >6 cm from 31% to 24%	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 4-6)
Treatment	SEGA response (real world examples)	Volume reductions of 71%, 43%, and 48% after 39, 34, and 82 months	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2, cockerell2023effectivenessandsafety pages 6-7)
Treatment	Everolimus adverse effects (real world)	Any AE 61/64 (95%); stomatitis/oral ulceration 63%; URTI 38%; rash 27%; fatigue 22%	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2, cockerell2023effectivenessandsafety pages 6-7)
Treatment	Everolimus lab abnormalities (real world)	Hypercholesterolemia 41%; anaemia 30%; leucopoenia 25%	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2, cockerell2023effectivenessandsafety pages 7-9)
Treatment	Everolimus severe toxicity/discontinuation (real world)	Grade 3–4 AEs 36%; hospitalization/prolonged hospitalization 34%; discontinuation 9/64 (14%); two life-threatening events	Real-world cohort	2023	https://doi.org/10.1186/s13023-023-02982-1 (cockerell2023effectivenessandsafety pages 1-2, cockerell2023effectivenessandsafety pages 7-9, cockerell2023effectivenessandsafety pages 10-12)
Treatment	EXIST-2 AML response	42% response (33/79; 95% CI 31–53%) vs 0% placebo; median response time 2–9 months	EXIST-2 everolimus trial, adults with AML	2024 review summarizing prior trial	https://doi.org/10.1590/2175-8239-jbn-2024-0013en (monich2024tuberoussclerosiscomplex pages 5-7)
Treatment	EXIST-2 extension AML response	Response increased from 42% to 54%; ~97% showed some AML reduction	EXIST-2 extension	2024 review summarizing prior trial	https://doi.org/10.1590/2175-8239-jbn-2024-0013en (monich2024tuberoussclerosiscomplex pages 5-7)
Quality of life & costs	EQ-5D-3L index and VAS	TSC: TTO 0.705; VAS 0.577 vs IGE: 0.897/0.813 vs FE: 0.879/0.769	Germany matched case-control study, 92 per cohort	2024	https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2)
Quality of life & costs	QOLIE-31 and stigma	QOLIE-31: TSC 57.7 vs IGE 66.6 vs FE 57.6; rESS stigma: TSC 3.97 vs IGE 1.48 vs FE 2.45	Germany matched case-control study	2024	https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2)
Quality of life & costs	Depression/adverse-event burden	NDDI-E 13.1 vs IGE 11.2; LAEP 42.7 vs IGE 37.5	Germany matched case-control study	2024	https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2)
Quality of life & costs	Direct costs	Mean total direct costs: TSC €7,602 (median €2,620) vs IGE €1,919 vs FE €2,598	Germany matched case-control study	2024	https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2)
Quality of life & costs	Indirect productivity costs	Mean over 3 months: TSC €7,185 (median €11,925) vs IGE €3,599 vs FE €5,082	Germany matched case-control study	2024	https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2, lappe2024amulticentermatched pages 10-11)
Quality of life & costs	Unemployment	60% in TSC vs 23% in IGE vs 34% in FE	Germany matched case-control study	2024	https://doi.org/10.1186/s42466-024-00323-6 (lappe2024amulticentermatched pages 1-2, lappe2024amulticentermatched pages 10-11)

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

Epilepsy
Type: symptom/clinical syndrome
Frequency: reported 62–93% in a 2024 therapeutic review (conte2024therapeuticapproachesto pages 1-2).
Drug-resistance: “pharmacoresistant epilepsy… affecting approximately two-thirds of patients” (2024 review) (racioppi2024prenatalmtorinhibitors pages 1-2).
HPO suggestions: HP:0001250 (Seizures); HP:0012469 (Infantile spasms) (conceptually aligned with reported early epilepsy burden) (conte2024therapeuticapproachesto pages 1-2, racioppi2024prenatalmtorinhibitors pages 2-3).
Neurodevelopmental and neuropsychiatric involvement (TAND, autism, intellectual disability)
Type: behavioral/psychiatric + developmental
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).
HPO suggestions: HP:0000717 (Autism); HP:0001249 (Intellectual disability); HP:0001263 (Global developmental delay).
CNS lesions
Type: imaging/pathology findings
Includes cortical tubers, subependymal nodules, radial migration lines, and SEGA (racioppi2024prenatalmtorinhibitors pages 1-2, conte2024therapeuticapproachesto pages 1-2).
SEGA prevalence: “up to 20% among TSC patients” (conte2024therapeuticapproachesto pages 1-2).
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)

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).
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).
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).
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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

Ask OpenScientist

OpenScientist Report

Subtypes

Mechanistic Hypotheses

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Clinical Trials

Source YAML

References & Deep Research

Deep Research

Tuberous Sclerosis Complex (TSC) — Disease Characteristics Research Report

Target disease

Executive summary (current understanding)

1. Disease information

1.1 What is the disease?

1.2 Key identifiers (available from retrieved evidence)

1.3 Synonyms / alternative names

1.4 Evidence sources

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (clinical manifestations)

3.1 Neurologic phenotypes

3.2 Renal phenotypes

3.3 Pulmonary phenotypes

3.4 Cardiac phenotypes

3.5 Skin phenotypes

Quality-of-life impact (recent quantitative evidence)

4. Genetic / molecular information

4.1 Causal genes

4.2 Pathogenic variants and molecular diagnostic yield

4.3 Somatic vs germline; two-hit model

4.4 Mechanistic pathway (current consensus)

4.5 Modifier genes, epigenetics, chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology (expanded)

6.1 Molecular pathways

6.2 Cellular processes

6.3 Cell types (CL suggestions)

6.4 Causal chain to clinical manifestations (examples)

7. Anatomical structures affected

7.1 Organ-level involvement (with UBERON suggestions)

7.2 Subcellular localization (GO cellular component suggestions)

8. Temporal development

8.1 Onset

8.2 Progression

9. Inheritance and population

9.1 Epidemiology (recent quantitative data)

9.2 Inheritance pattern and penetrance

9.3 Demographics

10. Diagnostics

10.1 Clinical criteria

10.2 Genetic testing (utility)

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

11. Outcome / prognosis (burden, morbidity)

11.1 Major morbidity/mortality themes

11.2 Quality of life and socioeconomic burden (2024)

12. Treatment

12.1 Pharmacotherapy: mTOR inhibitors (everolimus/sirolimus)

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

12.3 Surgical and interventional

12.4 Experimental / ongoing clinical trials (ClinicalTrials.gov)

13. Prevention

13.1 Primary prevention

13.2 Secondary prevention (early detection and early intervention)

13.3 Tertiary prevention

14. Other species / natural disease

15. Model organisms

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

Limitations of this tool run (data gaps)

Key source URLs (with publication dates)