👪

Inheritance

2

Autosomal dominant HP:0000006

TSC is inherited in an autosomal dominant manner, with heterozygous pathogenic variants in either TSC1 or TSC2. About one third of affected individuals have an affected parent; the remaining two thirds result from a de novo pathogenic variant, and each child of an affected individual has a 50% chance of inheriting the variant. Penetrance is essentially complete but expressivity is highly variable, so clinical severity differs markedly even within a family carrying the same variant. Low-level somatic mosaicism accounts for a substantial share of cases in which no germline variant is identified.

Autosomal dominant inheritance Penetrance: COMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:20301399 SUPPORT Human Clinical

"TSC is inherited in an autosomal dominant manner. About one third of individuals diagnosed with TSC have an affected parent; two thirds of individuals with TSC have the disorder as the result of a de novo pathogenic variant. Each child of an individual with TSC has a 50% chance of inheriting the..."

GeneReviews establishes the autosomal dominant mode of inheritance, the one-third inherited / two-thirds de novo split, and the 50% recurrence risk to offspring.

PMID:41361250 SUPPORT Human Clinical

"Penetrance is nearly complete, but symptoms can differ significantly within families"

Supports essentially complete penetrance alongside highly variable expressivity within families.

Somatic mosaicism (conventionally mutation-negative cases) HP:0001442

A minority of clinically definite TSC is caused not by a germline TSC1/TSC2 variant but by low-level post-zygotic mosaicism for one. These individuals have no variant on conventional blood testing, tend to a milder phenotype, and carry a recurrence risk for offspring that depends on whether the mosaic clone includes the germline. This block records the mosaic arm alongside the predominant autosomal dominant inheritance above; it does not replace it.

Somatic mosaicism

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."

Quantifies the mutation-negative fraction and attributes most of it to somatic mosaicism.

◆

Subtypes

4

TSC2-related TSC MONDO:0013199

~70-83% of molecularly solved cases TSC2 hgnc:12363

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 MONDO:0008612

~15-20% of molecularly solved cases TSC1 hgnc:12362

Pathogenic variants in TSC1 on chromosome 9q34 (encoding hamartin) account for ~15-20% of molecularly solved TSC cases across independent genotype-phenotype cohorts. TSC1-related disease is on average milder than TSC2-related disease: sporadic TSC1 patients have a lower frequency of seizures and moderate-to-severe intellectual disability, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, and less-severe facial angiofibroma than TSC2 patients. Grade 2-4 renal cysts/angiomyolipomas, forehead (fibrous cephalic) plaques, and retinal hamartomas are very rare or not seen at all in isolated TSC1 disease. TSC1 pathogenic variants are almost uniformly predicted truncating (nonsense, frameshift, splice-site, or large deletion), in contrast to TSC2's broader spectrum that also includes missense variants clustered in functional domains, and are significantly enriched in familial versus sporadic TSC — consistent with a milder phenotype compatible with reproduction, and the main reason TSC1 accounts for a disproportionate share of familial (vs. de novo) TSC cases.

Show evidence (9 references)

PMID:11112665 SUPPORT Human Clinical

"Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe..."

Landmark 224-patient genotype-phenotype cohort establishing that sporadic TSC1 disease is milder than TSC2 disease across seizures, intellectual disability, brain lesion burden, kidney involvement, retinal hamartoma, and facial angiofibroma severity.

PMID:11112665 SUPPORT Human Clinical

"some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"

Identifies specific phenotypes that are very rare or absent in TSC1-related disease, distinguishing it from TSC2-related disease.

PMID:10205261 SUPPORT Human Clinical

"TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185)."

Establishes that TSC1 variants are significantly enriched in familial (versus sporadic/de novo) TSC, a key genotype-driven feature distinguishing TSC1 from TSC2 disease.

+ 6 more references

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

1

Canonical TSC1 / TSC2 / mTORC1 Hyperactivation Model

canonical_tsc1_tsc2_mtorc1_hyperactivation_model CANONICAL

Evidence balance 1 support 2 refute

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 (3 references)

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.

PMID:31217257 REFUTE Human Clinical

"Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC."

Refutes the pharmacologic-validation corollary of this hypothesis - that mTOR inhibitors "definitively confirm" the mTORC1 axis - for the neuropsychiatric arm specifically. In a 12-month double-blind placebo-controlled trial of 32 children aged 4-17 titrated to trough levels of 5-10 ng/mL, everolimus produced no benefit on full-scale IQ (treatment effect -5.6 points, 95% CI -12.3 to 1.0) and no effect on any secondary neuropsychological, behavioural, or quality-of-life outcome; the paper carries a Class I evidence classification. The tumour and seizure arms of the pharmacologic validation are unaffected, so this narrows the hypothesis rather than displacing it.

PMID:26837766 REFUTE Model Organism

"the mTOR pathway was not activated in all TSC2(+/-) tumors and was elevated in only 50% of human mesenchymal tumors"

Refutes this hypothesis's claim that mTORC1 hyperactivation produces the characteristic lesions in "nearly every organ system", for the mesenchymal tumour class. Half of the human mesenchymal tumours assayed showed no mTOR pathway activation at all, and the corresponding mouse tumours required HMGA2 rather than a second hit, so at least one TSC lesion class arises through a pathway this hypothesis does not describe.

?

Discussions and Knowledge Gaps

2

Why does correcting mTORC1 activity fail to correct the neuropsychiatric manifestations of TSC, and is there a developmental window before which it would still work?

KNOWLEDGE GAP OPEN gap_tsc_tand_not_reversible_by_mtorc1_inhibition

Attached to

mechanistic_hypotheses#canonical_tsc1_tsc2_mtorc1_hyperactivation_model pathophysiology#Neuroglial Dysplasia and Cortical Network Disorganization phenotypes#Intellectual Disability phenotypes#Autism Spectrum Disorder treatments#mTOR Inhibitor Therapy (Everolimus)

Every other arm of this entry's causal chain is closed by a drug: mTOR inhibitors shrink SEGAs and angiomyolipomas and reduce seizure frequency, and that pharmacologic reversal is the strongest single argument for the canonical mechanism. The neuropsychiatric arm is the exception. A Class I randomised trial found no effect of everolimus on IQ, autism, or any neuropsychological outcome in children aged 4-17, and two independent trials of pre-emptive vigabatrin found no effect on developmental or autism outcomes in infants. So the entry asserts a causal edge from mTORC1 hyperactivation to TAND that no intervention has yet been able to move, and it is not known whether the edge is wrong, whether it operates only during a developmental window that has closed by the age at which these trials enrol, or whether TAND is driven by parallel mTORC1-independent mechanisms. The distinction matters clinically: the first reading says stop looking at mTOR for TAND, the second says treat earlier, the third says treat something else as well. Human iPSC neuron work supplies a candidate mechanism for the second reading - impaired activity-dependent transcription tied to maturation-dependent DNA demethylation, with late mTORC1 inhibition unable to reverse neuronal hyperactivity - but the loci, cell types, and timing of any such window are unmeasured, and no human in vivo evidence exists.

Proposed experiments

Pre-emptive mTOR inhibition before seizure onset in infants with TSC

exp_tsc_preemptive_mtor_inhibition_infants

Randomise infants with a genetic or cardiac-rhabdomyoma diagnosis of TSC, before seizure onset and before four months of age, to an mTOR inhibitor or placebo, stratified by TSC1 versus TSC2 genotype and by EEG status at enrolment, with developmental and autism outcomes at 24-36 months as the primary endpoints. This is the design that separates "mTORC1 does not drive TAND" from "mTORC1 drives TAND only inside a developmental window that has closed by school age", which no trial run to date can distinguish because all enrolled after that putative window.

Would support

mechanistic_hypotheses#canonical_tsc1_tsc2_mtorc1_hyperactivation_model pathophysiology#Neuroglial Dysplasia and Cortical Network Disorganization

Supporting outcome

Better developmental and autism-specific outcomes at 24-36 months in the treated arm would show the mTORC1-to-TAND edge is real and timing-dependent, and would make age at initiation, not drug choice, the operative variable.

Refuting outcome

No difference despite treatment beginning before seizure onset would leave the mTORC1-to-TAND edge unsupported by any interventional evidence at any age, and would move the neuropsychiatric arm toward the mTORC1-independent mechanisms discussed separately.

Show evidence (2 references)

PMID:31217257 SUPPORT Human Clinical

"Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0)."

Establishes the gap as a measured null rather than an untested assumption: the point estimate is slightly negative and the confidence interval excludes any clinically meaningful benefit at this age range.

PMID:41379617 SUPPORT In Vitro

"mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC"

Supplies the leading candidate explanation for the clinical null - that the neuronal phenotype becomes mTORC1-independent as neurons mature - and simultaneously shows why it is unresolved: the result is in human iPSC-derived neurons, the window is not bounded, and the demethylation loci are not identified.

Which TSC manifestations are driven by mechanisms downstream of TSC1/TSC2 loss but outside mTORC1 - haploinsufficiency-level RHOA signalling, HMGA2-dependent mesenchymal tumorigenesis, and the mTORC2-dependent estradiol-COX-2 arm in LAM - and how much of the residual disease burden do they account for?

KNOWLEDGE GAP OPEN gap_tsc_mtorc1_independent_arms

Attached to

mechanistic_hypotheses#canonical_tsc1_tsc2_mtorc1_hyperactivation_model pathophysiology#Somatic Second Hit at TSC Locus pathophysiology#Pulmonary Lymphangioleiomyomatosis Growth

Three separate lines of work now place part of TSC pathology outside the mTORC1 axis this entry is built on, and they share a structural feature that makes them awkward for the canonical model: two of them operate at haploinsufficiency, i.e. without a second hit, so they are present in every cell of the patient rather than confined to lesion clones. TSC2+/- human iPSC neurons fail to respond to axon guidance cues through diminished RHOA signalling, with normal mTOR activity and no rescue by mTORC1 or mTORC2 inhibitors; TSC2+/- mesenchymal tumours require HMGA2 and show mTOR activation in only half of the human cases; and COX-2 induction in TSC2-null LAM cells is rapamycin-insensitive but mTORC2-dependent. What is not known is how much each contributes in patients. None has a human quantitative estimate, none has been targeted therapeutically in TSC, and the alternative that they are minor accompaniments of a predominantly mTORC1-driven disease has not been excluded.

Proposed experiments

Attribution of TSC lesion burden to mTORC1-independent arms

exp_tsc_mtorc1_independent_arm_attribution

Across matched lesion classes from the same patients - cortical tuber, angiomyolipoma, mesenchymal tumour, and LAM tissue - assay TSC1/TSC2 allele status alongside mTORC1 output (phospho-S6, phospho-4E-BP1), mTORC2 output (phospho-Akt S473, COX-2), HMGA2, and RHOA pathway activity, so that each lesion class is assigned to an arm rather than assumed to be mTORC1-driven. Pair with dual mTORC1/2 versus mTORC1-selective inhibition in the LAM arm, reading out VEGF-D and prostaglandins.

Would support

pathophysiology#Pulmonary Lymphangioleiomyomatosis Growth pathophysiology#Somatic Second Hit at TSC Locus

Supporting outcome

Lesion classes segregating by arm - retained heterozygosity with HMGA2 and no mTORC1 output in mesenchymal tumours, mTORC2 output surviving mTORC1-selective inhibition in LAM - would establish the mTORC1-independent arms as distinct pathways requiring their own pathophysiology nodes and their own drugs.

Refuting outcome

Uniform biallelic loss and mTORC1 output across lesion classes would indicate the published exceptions are model-system or sampling artefacts, and the single-axis account should stand unqualified.

Show evidence (1 reference)

PMID:33972524 SUPPORT In Vitro

"we find that TSC2 signaled through MTOR-independent RHOA in growth cones"

Documents a TSC2-dependent, mTOR-independent signalling route in human neurons: basal mTOR activity and cue-driven protein synthesis were normal in TSC2+/- neurons, mTORC1 and mTORC2 inhibitors did not rescue the guidance defect, and basal and cue-activated RHOA was diminished. Derived from one patient line plus engineered isogenic controls, so the effect size in patients is unknown.

⚙

Pathophysiology

15

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.

TSC2 GAP Domain Catalytic Loss Within the TSC1/TSC2/TBC1D7 complex, only TSC2 contributes the catalytically active GAP domain; loss-of-function variants in TSC2 directly abolish RHEB-GAP catalysis, whereas TSC1 has no intrinsic catalytic activity and instead scaffolds/stabilizes the complex.

Show evidence (4 references)

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."

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

TSC2 GAP Domain Catalytic Loss

Cryo-EM structural studies of the human TSC complex show it assembles as an arch-shaped 2:2:1 (TSC1:TSC2:TBC1D7) heteropentamer in which a parallel TSC1 coiled-coil dimer packs against a tail-to-tail TSC2 dimer, with a single TBC1D7 bound to the TSC1 C-terminal helices (TBC1D7 makes no direct contact with TSC2 and sits far from the central core, consistent with an auxiliary role). The two TSC2 GAP domains are cradled within the core module formed by the TSC2 dimerization domain and the TSC1 central coiled-coil, and directly contact RHEB: an asparagine "thumb" (N1643) in the TSC2 GAP domain stabilizes the gamma-phosphate of GTP-bound RHEB and accelerates RHEB GTP hydrolysis. TSC1 contributes no catalytic residues to this reaction; its coiled-coil region instead scaffolds and stabilizes the complex. Pathogenic variants disrupting the TSC2 GAP domain or its RHEB-contacting residues therefore abolish RHEB-GAP catalysis directly. Note this is a candidate structural contribution to — not a complete explanation of — the observed TSC2-over-TSC1 severity gradient, which is also shaped by TSC2's larger mutational target size, its higher burden of truncating alleles, the rarity of pathogenic TSC1 missense variants, and ascertainment differences; TSC1 loss also destabilizes TSC2 and abolishes complex GAP activity in vivo.

TSC2 hgnc:12363

GTPase activator activity GO:0005096

Downstream

Constitutive mTORC1 Hyperactivation Loss of TSC2 GAP catalysis removes the complex's ability to drive RHEB GTP hydrolysis, leaving RHEB GTP-loaded and mTORC1 constitutively active. Full constitutive activation in a lesion clone additionally requires biallelic loss via a somatic second hit.

Show evidence (3 references)

PMID:33436626 SUPPORT In Vitro

"The two TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1. Structural and biochemical analyses reveal TSC2 GAP-Rheb complimentary interactions and suggest a catalytic mechanism, by which an asparagine thumb..."

Cryo-EM structure of the human TSC complex localizes the catalytic GAP-RHEB interaction to the TSC2 subunit (asparagine-1643 thumb), with TSC1 forming the surrounding coiled-coil scaffold rather than contributing catalytic residues.

PMID:33436626 SUPPORT In Vitro

"The TBC1D7 associates with and stabilizes the C-terminal helices (residues 937–971) of TSC1a/1b but has no direct contact with TSC2."

Establishes that the auxiliary TBC1D7 subunit binds only TSC1, not TSC2, constraining how the 2:2:1 complex is described.

PMID:38540392 SUPPORT Human Clinical

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

Supports the within-complex claim that variants in critical/catalytic TSC2 domains correlate with greater severity. Marked PARTIAL because it does not itself establish the broader TSC2-vs-TSC1 between-gene severity gradient, which this node treats as a candidate contribution only.

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. The requirement for a second hit is well established for the classic hamartomas but is not universal across lesion classes: mesenchymal tumorigenesis in the TSC2+/- mouse proceeds from haploinsufficiency alone and is HMGA2- rather than mTOR-dependent, with mTOR pathway activation detectable in only half of the corresponding human tumours.

TSC1 hgnc:12362 TSC2 hgnc:12363

Experimental models

CRISPR-engineered TSC2 conditional-biallelic human cortical spheroids ORGANOID The conditional allele lets biallelic TSC2 loss be triggered in a mosaic of neural progenitors, and only that second hit produces dysplastic cells and excess glia, which is the somatic second-hit node.

TSC human cerebral organoids with caudal late interneuron progenitor (CLIP) over-proliferation ORGANOID Giant cells in TSC2+/- patient organoids retain wild-type TSC2 protein, so tuber-like cells form here without the somatic second hit this node requires; the authors conclude bi-allelic inactivation is dispensable for disease initiation in human tissue.

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 (4 references)

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.

PMID:25432535 SUPPORT Human Clinical

"Molecular studies indicate that tumors developed independently due to various second hit events"

Targeted sequencing of renal tumors from two patients with the germline TSC2 variant p.R905Q identified a distinct, independent second-hit TSC2 event in most tumors that were sequenced (5/5 in the first patient, 1/2 in the second), indicating that multiple lesions within one organ of one TSC2 patient arise from separate stochastic second-hit events rather than clonal spread. Note that only 1 of 11 further tumors available from the first patient carried one of the identified second hits, so the per-tumor yield outside the sequenced set is lower.

PMID:27494029 SUPPORT Human Clinical

"Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1."

Quantifies the second hit in human lesions rather than asserting it: whole-exome sequencing of 32 resected angiomyolipoma/LAM samples found biallelic TSC1/TSC2 loss in 94%, most often by copy-neutral loss of heterozygosity. The same study reports a median of only 4 other somatic non-synonymous coding mutations per tumour, so biallelic TSC loss is not merely present but is the essential driver event.

+ 1 more reference

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.

mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction Beyond the neuron-centred dysplasia arm, mTORC1 hyperactivity biases neural precursors toward gliogenesis and dysregulates astrocyte, oligodendrocyte, NG2 glia and microglial maturation and function, extending to the astrocyte-supported neurovascular unit. The glial lineage effect is a differentiation consequence of mTORC1 signalling rather than of hamartoma growth, so it is placed on the mTORC1 hub.

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

"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. "

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

Experimental models

CRISPR-engineered TSC2 conditional-biallelic human cortical spheroids ORGANOID Spheroids reproduce the dysmorphic cells and glial excess of a tuber but not cortical lamination, network activity or epileptogenesis.

TSC human cerebral organoids with caudal late interneuron progenitor (CLIP) over-proliferation ORGANOID Excess interneurons and cortical malformations arise from the same progenitor expansion, reproducing the malformation side of the node without its network or seizure readouts.

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 (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, which can include autism spectrum disorder and cognitive disability. "

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.

PMID:38714540 SUPPORT Human Clinical

"Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC."

Resolves the "disorganized cortical network" claim of this node to a specific cell type. Single-nuclei RNA sequencing of TSC patient tissue identifies somatostatin-expressing interneurons as developmentally immature, carrying an abnormal NKCC1/KCC2 ratio, downregulated GABRA1 and upregulated GABRA2, and an altered deep-layer distribution consistent with cortical dyslamination. The authors are explicit that the resulting failure of the excitatory-to-inhibitory GABA switch is inferred from these markers rather than measured, and how the cell-autonomous defect produces circuit-level epileptogenesis is not established.

mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction

Alongside the neuron-centred account of TSC brain disease, mTORC1 hyperactivation produces a distinct, non-neuronal "gliopathy" arm. mTORC1 hyperactivity biases neural precursors toward gliogenesis (contributing to the glial excess within tubers); astrocytes become reactive, proliferative and proinflammatory while losing homeostatic ion- and neurotransmitter-handling functions; oligodendrocyte lineage cells mature abnormally, giving hypomyelination and impaired remyelination; NG2 glia and microglia are also altered. The same mTOR-dependent lesion extends to the neurovascular unit: a human iPSC-derived, microfluidic blood-brain-barrier model built from TSC-mutant cells is abnormally permeable, and the defect is corrected either by supplying wild-type astrocytes or by rapamycin, showing the barrier phenotype is astrocyte-dependent and mTOR-dependent rather than a fixed structural consequence of the mutation. This node captures the glial and neurovascular contribution to epileptogenesis and to the cognitive/behavioural comorbidities of TAND, which the dysplasia node above does not.

astrocyte CL:0000127 oligodendrocyte CL:0000128 NG2 glia (oligodendrocyte precursor cell) CL:0002453 microglial cell CL:0000129 brain microvascular endothelial cell CL:2000044

gliogenesis GO:0042063 ↑ INCREASED myelination GO:0042552 ↓ DECREASED maintenance of blood-brain barrier GO:0035633 ↓ DECREASED

brain UBERON:0000955

Experimental models

TSC patient-derived neurovascular unit (iPSC blood-brain-barrier chip) ORGAN ON CHIP The chip reproduces the increased barrier permeability of the TSC neurovascular unit and shows it is reversible by astrocyte replacement or mTOR inhibition.

Downstream

Epileptic Seizures Reactive astrogliosis with loss of potassium and glutamate homeostasis, inflammatory glial signalling, and impaired myelination alter network excitability and contribute to epileptogenesis independently of the dysplastic neuronal population.

Cerebral Hypomyelination Oligodendrocyte-lineage mTORC1 dysregulation reduces oligodendrocyte proliferation and maturation, producing hypomyelination and impaired remyelination in TSC brain lesions.

Intellectual Disability Altered myelination and glial support of cortical networks contribute to the cognitive component of TSC-associated neuropsychiatric disorders.

Show evidence (6 references)

PMID:33041976 SUPPORT Human Clinical

"the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia"

Establishes that the neuropathology of TSC is not neuron-restricted and names the four glial populations that define the gliopathy arm modelled by this node.

PMID:33041976 SUPPORT Human Clinical

"These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders."

Links the glial changes and interglial crosstalk to the two downstream clinical outcomes this node feeds - epilepsy and the cognitive and behavioural comorbidities of TAND.

PMID:33041976 SUPPORT Human Clinical

"mTOR hyperactivity promotes development of often multifocal brain lesions characterized by aberrant glioneuronal proliferation, cortical dyslamination, and hypomyelination"

Places hypomyelination alongside glioneuronal proliferation and cortical dyslamination as a direct consequence of mTOR hyperactivity in the TSC brain, supporting the DECREASED myelination annotation.

+ 3 more references

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

Experimental models

TSC human cerebral organoids with caudal late interneuron progenitor (CLIP) over-proliferation ORGANOID CLIP cell over-proliferation in TSC organoids produces brain tumours, matching the subependymal tumour growth node and proposing its human-specific cell of origin.

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 (3 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.

PMID:41361250 SUPPORT Human Clinical

"TSC2 mutations were associated with a higher rate (42.9%) and velocity (18.7% per year) of tumor regression compared to TSC1 mutations (25% and 12.4% per year, respectively)."

A 22-patient single-center cohort with confirmed cardiac rhabdomyomas found TSC2-mutant patients regressed their tumors both more often and faster than TSC1-mutant patients, an unusual instance where the TSC2 genotype tracks with a more favorable course for this specific lesion (contrasting with the generally more severe TSC2 phenotype overall). The authors describe this as a trend requiring confirmation in larger prospective studies, not an established correlation.

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. Not all of the relevant mTOR signalling runs through mTORC1: in TSC2-deficient LAM cells an estradiol-driven COX-2/prostaglandin arm is regulated by mTORC2 and is not suppressed by rapamycin, which is one candidate explanation for the striking female predominance of LAM and for the incompleteness of the rapalogue response.

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 (4 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 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.

PMID:19419980 SUPPORT Human Clinical

"TSC2 women with LAM had a significantly greater number of cysts than did TSC1 patients (p = 0.010)."

A CT cohort of TSC women found LAM-consistent cysts in a similar proportion of TSC1 (40%) and TSC2 (48%) patients, i.e. LAM is not TSC2-exclusive, but TSC2 patients who develop LAM have a significantly greater cyst burden than TSC1 patients, indicating a genotype-severity (not genotype-presence) difference for this manifestation.

+ 1 more reference

⬡

Pathograph

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

●

Phenotypes

38

Cardiovascular 3

Cardiac Rhabdomyoma FREQUENT 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.

Cardiac Arrhythmia OCCASIONAL HP:0011675

Show evidence (1 reference)

PMID:24053983 SUPPORT Human Clinical

"echocardiogram and electrocardiogram (ECG) should be obtained to evaluate for rhabdomyomas and arrhythmia, respectively"

The 2012 International TSC Consensus guidelines explicitly mandate ECG at diagnosis in pediatric patients to evaluate for arrhythmia, establishing cardiac arrhythmia as a recognized surveillance target in TSC. The snippet supports the disease-phenotype association but not a specific frequency band; the OCCASIONAL assignment is a clinical estimate (no quantitative frequency is reported in the guideline and no Orphanet frequency is available for this phenotype).

Hypertension OCCASIONAL HP:0000822

The 2012 International TSC Consensus carries a clinically important drug-interaction caveat for first-line antihypertensive choice: angiotensin-converting enzyme (ACE) inhibitors should be avoided in patients concurrently treated with an mTOR inhibitor (e.g. everolimus, sirolimus), because of an increased risk of angioedema with that combination. A non-ACE renin-angiotensin-aldosterone system inhibitor is preferred in mTOR-inhibitor-treated patients.

Show evidence (2 references)

PMID:24053983 SUPPORT Human Clinical

"accurate blood pressure assessment is important because of increased risk of secondary hypertension"

The 2012 International TSC Consensus guidelines identify secondary hypertension as an increased-risk complication warranting dedicated blood pressure assessment at time of TSC diagnosis.

PMID:24053983 SUPPORT Human Clinical

"Annual clinical assessment of renal function and hypertension is required"

Ongoing annual hypertension surveillance is mandated by the 2012 International TSC Consensus, reflecting the chronic risk of secondary hypertension from progressive renal disease in TSC.

Digestive 1

Hepatic Cysts OCCASIONAL HP:0001407

Show evidence (1 reference)

ORPHA:805 SUPPORT Other

"HP:0001407 | Hepatic cysts | Occasional (29-5%)"

Orphanet's curated HPO frequency annotation classifies hepatic cysts as occasional (29-5%) in tuberous sclerosis complex.

Eye 1

Retinal Hamartoma OCCASIONAL HP:0009594

Genotype-phenotype cohorts find retinal hamartomas very rare or absent in sporadic TSC1-related disease; this phenotype is disproportionately TSC2-driven.

Show evidence (1 reference)

PMID:11112665 SUPPORT Human Clinical

"Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe..."

Directly reports that sporadic TSC1 patients had no retinal hamartomas, in contrast to TSC2 patients.

Genitourinary 6

Renal Angiomyolipoma VERY_FREQUENT HP:0006772

Renal angiomyolipoma still occurs in TSC1-related disease, but kidney involvement is on average less severe than in TSC2-related disease; grade 2-4 angiomyolipomas are very rare or absent in isolated TSC1 disease.

Show evidence (7 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

"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 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.

+ 4 more references

Renal Cyst FREQUENT HP:0000107

Grade 2-4 (higher-severity) renal cysts are very rare or absent in isolated TSC1-related disease; this severe end of the spectrum is disproportionately TSC2-driven.

Show evidence (2 references)

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.

PMID:11112665 SUPPORT Human Clinical

"some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"

Grade 2-4 kidney cysts are identified as very rare or absent specifically in TSC1-related disease.

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.

Renal Cell Carcinoma VERY_RARE HP:0005584

Show evidence (4 references)

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."

Identifies renal cell carcinoma as one of the three major kidney manifestations of TSC alongside cystic lesions and angiomyolipomas.

PMID:24053983 SUPPORT Human Clinical

"Imaging to diagnose polycystic disease, renal cell carcinoma or other tumors"

The 2012 International TSC Consensus guidelines include renal cell carcinoma as an explicit surveillance target requiring periodic renal MRI.

ORPHA:805 SUPPORT Other

"HP:0005584 | Renal cell carcinoma | Very rare (<4-1%)"

Orphanet's curated HPO frequency annotation classifies renal cell carcinoma as very rare in tuberous sclerosis complex.

+ 1 more reference

Renal Oncocytoma HP:0011798

Show evidence (1 reference)

PMID:20301399 SUPPORT Human Clinical

"kidneys (benign renal angiomyolipomas, epithelial cysts, oncocytoma, renal cell carcinoma)"

GeneReviews lists oncocytoma among the kidney manifestations of TSC alongside angiomyolipomas, epithelial cysts, and renal cell carcinoma.

Chronic Kidney Disease FREQUENT HP:0012622

Course: PROGRESSIVE

Show evidence (3 references)

ORPHA:805 SUPPORT Other

"HP:0012622 | Chronic kidney disease | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies chronic kidney disease as frequent (79-30%) in tuberous sclerosis complex.

ORPHA:805 SUPPORT Other

"HP:0003774 | Stage 5 chronic kidney disease | Very rare (<4-1%)"

Orphanet separately annotates end-stage (stage 5) chronic kidney disease as very rare, indicating that while reduced renal function is common, progression to kidney failure is not the usual outcome.

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."

Identifies loss of kidney function as the shared downstream consequence of the cystic and angiomyolipomatous renal lesions of TSC.

Head and Neck 1

Dental Enamel Pits VERY_FREQUENT HP:0009722

Integument 4

Hypomelanotic Macules VERY_FREQUENT HP:0009719

Confetti-like Hypopigmented Macules OCCASIONAL HP:0007449

Subungual Fibromas FREQUENT 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 HP:0009721

Musculoskeletal 1

Sclerotic Bone Lesions OCCASIONAL Patchy osteosclerosis HP:0005686

Show evidence (1 reference)

PMID:34399110 SUPPORT Human Clinical

"sclerotic bone lesions were reinstated as a minor criterion"

The 2021 International TSC Consensus reinstated sclerotic bone lesions as a minor diagnostic criterion for TSC, acknowledging their role as a recognized manifestation of the disease.

Nervous System 12

Epileptic Seizures VERY_FREQUENT HP:0001250

Sequelae: Sudden Unexpected Death in Epilepsy

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, which can include autism spectrum disorder and cognitive disability."

Seizures are listed as a major feature of TSC.

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."

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.

Infantile Spasms FREQUENT HP:0012469

Focal-Onset Seizures FREQUENT HP:0007359

Show evidence (2 references)

ORPHA:805 SUPPORT Other

"HP:0007359 | Focal-onset seizure | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies focal-onset seizure as frequent (79-30%) in tuberous sclerosis complex.

PMID:40579409 SUPPORT Human Clinical

"More in detail, two patients (6.4%) presented infantile spasms, 12 (38.7%) had focal seizures (three with impaired awareness), six (19.3%) patients experienced generalized tonic clonic seizures"

Seizure-type breakdown of the 31-patient TSC1 arm of the Sicilian cohort: focal seizures were the single most common type (12/31, 38.7%), well ahead of infantile spasms (2/31) in this predominantly adult TSC1 group.

Cerebral Hypomyelination HP:0006808

No `frequency:` band is asserted. Neither Orphanet's HPO annotation set for ORPHA:805 nor the cited gliopathy review states a proportion of patients with hypomyelination, and imaging-based white-matter abnormality rates in TSC vary with modality and definition. Omitted rather than estimated.

Show evidence (3 references)

PMID:33041976 SUPPORT Human Clinical

"mTOR hyperactivity promotes development of often multifocal brain lesions characterized by aberrant glioneuronal proliferation, cortical dyslamination, and hypomyelination"

Names hypomyelination as a defining component of the multifocal brain lesions produced by mTOR hyperactivity in TSC.

PMID:33041976 SUPPORT Human Clinical

"Oligodendrocyte dysfunction leads to hypomyelination and disturbed remyelination, and their proliferation is reduced."

Attributes the hypomyelination specifically to oligodendrocyte-lineage dysfunction, linking this phenotype to the gliopathy pathophysiology node rather than to neuronal dysplasia alone.

PMID:32954437 SUPPORT Human Clinical

"Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder."

Supplies the human evidence for the description's claim that altered myelination is a substrate for the cognitive and autism-spectrum components of TAND. Quantitative image analysis of resected cortical tubers from 46 patients found reduced oligodendroglia and altered myelin basic protein in both grey and white matter relative to matched controls, with the two clinical correlations quoted. These are cross-sectional associations in surgical specimens from patients selected for drug-resistant epilepsy, so they establish the link, not its direction.

Intellectual Disability FREQUENT 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 HP:0001263

Autism Spectrum Disorder FREQUENT 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 HP:0007018

Anxiety FREQUENT HP:0000739

Depression FREQUENT HP:0000716

Show evidence (2 references)

ORPHA:805 SUPPORT Other

"HP:0000716 | Depression | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies depression as frequent (79-30%) in tuberous sclerosis complex.

PMID:32982929 SUPPORT Human Clinical

"the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population"

TOSCA quality-of-life substudy corroborating a substantial burden of mood symptoms. Classified PARTIAL because the EQ-5D dimension pools anxiety and depression and is a self- or proxy-rated symptom score, not a clinical diagnosis of depressive disorder.

Aggressive Behavior FREQUENT HP:0000718

Show evidence (1 reference)

ORPHA:805 SUPPORT Other

"HP:0000718 | Aggressive behavior | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies aggressive behaviour as frequent (79-30%) in tuberous sclerosis complex.

Sleep Abnormality FREQUENT Sleep disturbance HP:0002360

Show evidence (1 reference)

ORPHA:805 SUPPORT Other

"HP:0002360 | Sleep abnormality | Frequent (79-30%)"

Orphanet's curated HPO frequency annotation classifies HP:0002360 as frequent (79-30%) in tuberous sclerosis complex. Orphanet's record renders the term with the exact synonym "Sleep abnormality"; the canonical HPO label for HP:0002360 is "Sleep disturbance", which is what `term.label` carries.

Respiratory 2

Pulmonary Lymphangioleiomyomatosis FREQUENT Multiple pulmonary cysts HP:0005948

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 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.

Multifocal Micronodular Pneumocyte Hyperplasia Type II pneumocyte hyperplasia HP:0033328

Show evidence (1 reference)

PMID:20301399 SUPPORT Human Clinical

"multifocal micronodular pneumonocyte hyperplasia"

GeneReviews lists multifocal micronodular pneumonocyte hyperplasia among the lung manifestations of TSC, alongside lymphangioleiomyomatosis.

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 6

Facial Angiofibromas VERY_FREQUENT HP:0010615

Fibrous Cephalic Plaque Cutaneous hamartoma HP:0031111

Genotype-phenotype cohorts find forehead plaques very rare or absent in TSC1-related disease.

Show evidence (2 references)

PMID:24053983 SUPPORT Human Clinical

"facial angiofibromas, fibrous cephalic plaques, hypomelanotic macules or confetti lesions, ungual fibromas, shagreen patch, defects in tooth enamel, and intraoral fibroma"

The 2012 International TSC Consensus recommendations explicitly list fibrous cephalic plaques among the dermatologic features requiring evaluation at time of TSC diagnosis, establishing them as a recognized major diagnostic criterion.

PMID:11112665 SUPPORT Human Clinical

"some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"

Forehead (fibrous cephalic) plaques are identified as very rare or absent specifically in TSC1-related disease, unlike TSC2-related disease.

Intraoral Fibroma OCCASIONAL HP:0010614

Show evidence (1 reference)

PMID:24053983 SUPPORT Human Clinical

"Oral fibromas should be excised surgically if symptomatic or if interfering with oral hygiene. Oral fibromas may recur once excised; therefore, periodic oral evaluation is encouraged."

The 2012 International TSC Consensus guidelines include oral fibromas as a dental/oral feature requiring evaluation and periodic surveillance, with surgical management guidance for symptomatic cases.

Cortical Tubers VERY_FREQUENT 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 HP:0009716

Subependymal Giant Cell Astrocytoma OCCASIONAL HP:0009718

Show evidence (2 references)

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.

PMID:28057044 SUPPORT Human Clinical

"SEGA were bilateral in 18% and growing in 4.5% of patients with mutations in TSC1 versus in 34 and 16% of patients with mutations in TSC2."

Among the 207 TOSCA SEGA patients with an identified pathogenic variant, SEGAs in TSC2-mutant patients were more often bilateral (34% vs 18%) and more often actively growing (16% vs 4.5%) than in TSC1-mutant patients, consistent with a TSC2 genotype-severity gradient for this manifestation. Interpret cautiously: the TSC1 arm is small (n=22, vs n=185 for TSC2), so "4.5% growing" represents a single patient, and TOSCA reports no significance test for this comparison.

🧬

Genetic Associations

3

TSC1 (Pathogenic Mutations)

Gene: TSC1 hgnc:12362

Show evidence (7 references)

PMID:32555378 SUPPORT Human Clinical

"TSC1 is located on chromosome 9q34 and consists of 23 exons, which encode the 130 kDa TSC1 protein, hamartin."

Locus, exon count, and protein product for TSC1, anchoring the gene description above to a primary source.

PMID:32555378 SUPPORT Human Clinical

"To assist in the classification of 11 TSC2 variants, we investigated the effects of these variants in an in vitro functional assay. Based on the functional results, as well as population and genetic data, we classified 8 variants as likely to be pathogenic and 3 as likely to be benign."

Demonstrates the in vitro TSC-complex functional assay as a practical adjunct to sequence-only ACMG/AMP classification. The 11 assayed variants in this study were TSC2, not TSC1; the assay platform is shared, and the same group applied it to TSC1 variants in the 2024 Brazilian cohort (PMID:39596632), but this particular result does not itself demonstrate TSC1 variant reclassification.

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.

+ 4 more references

TSC2 (Pathogenic Mutations)

Gene: TSC2 hgnc:12363

Show evidence (5 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%).

+ 2 more references

Somatic Mosaicism (Mosaic Pathogenic Variants)

variant_origin: SOMATIC

Show evidence (2 references)

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."

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

PMID:39352229 SUPPORT Human Clinical

"A diagnostic yield of 72% (13/18) was achieved, with the majority (10/13) being mosaic variants and the remainder heterozygous variants missed on previous testing."

Converts the mosaicism hypothesis into a measured yield. Massively parallel sequencing across the whole genomic regions of TSC1 and TSC2, run on two to four tissues per participant (blood, buccal swab, and where available lesional skin), resolved 13 of 18 clinically definite no-mutation-identified cases, 10 of them mosaic. Note the remaining five stayed unsolved even at 4000x depth, so mosaic detection does not account for every negative case.

💊

Medical Actions

10

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

"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."

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

"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 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 (6 references)

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."

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.

PMID:38042867 SUPPORT Human Clinical

"Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common."

Real-world tolerability denominator for chronic everolimus therapy: essentially all treated patients (61/64) experienced at least one adverse effect over a median 31 months, with oral ulceration/stomatitis the dominant treatment-limiting toxicity.

+ 3 more references

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

Show evidence (4 references)

PMID:37041855 SUPPORT Human Clinical

"An increasing body of research suggests that early, effective treatment of TSC-associated epilepsy during critical neurodevelopmental periods can potentially improve cognitive outcomes."

States the rationale for treating TSC-associated epilepsy early and aggressively - the intervention window is developmental, not merely symptomatic - which is the basis for first-line vigabatrin and for the pre-symptomatic prevention trials.

PMID:37041855 SUPPORT Human Clinical

"Refractory TSC-associated epilepsy is associated with increased risk of neurodevelopmental comorbidities, including developmental delay, intellectual disability, autism spectrum disorder, and attention hyperactivity disorder."

Establishes the outcome that early seizure control is intended to prevent, linking refractory epilepsy to the TAND comorbidity cluster already curated in this entry.

PMID:41061327 REFUTE Human Clinical

"No significant differences in developmental or autism-specific outcomes were seen between treatment groups"

Tests the neurodevelopmental rationale above and does not find it. PREVeNT was a Phase IIb multicentre double-blind placebo-controlled trial of pre-emptive vigabatrin in 84 infants with TSC across 13 US clinics; 65 completed assessments to 36 months, 31% were rated as having autism spectrum disorder, and that rate did not differ by treatment assignment. This refutes the prevention rationale, not vigabatrin's established efficacy against infantile spasms, which is a separate claim. The investigators note the null may partly reflect early seizure detection and closer developmental monitoring across every arm of the trial.

+ 1 more reference

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. Agents/circumstances to avoid (GeneReviews): smoking and estrogen use are both listed among the circumstances to avoid in TSC and are of particular relevance to women with, or at risk of, lymphangioleiomyomatosis.

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 (2 references)

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.

PMID:20301399 SUPPORT Human Clinical

"Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy."

GeneReviews lists smoking and estrogen use among the circumstances to avoid in TSC, supporting the counselling note recorded in this treatment's description.

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 Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

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 Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Selective renal artery embolization or partial/total nephrectomy is reserved for complications of large angiomyolipomas (especially severe haemorrhage) unresponsive to mTOR inhibitor therapy. Agents/circumstances to avoid (GeneReviews): nephrectomy is explicitly listed among the circumstances to avoid in TSC — because renal lesions are typically bilateral and multifocal, kidney-sparing approaches (embolization, kidney-sparing resection, ablation) are preferred over nephrectomy to preserve long-term renal function. GeneReviews also lists smoking and estrogen use as circumstances to avoid; those two are recorded on the pulmonary/LAM-directed treatment rather than here.

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 (2 references)

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.

PMID:20301399 SUPPORT Human Clinical

"Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy."

GeneReviews explicitly lists nephrectomy (alongside smoking and estrogen use) as a circumstance to avoid in TSC, supporting the kidney-sparing preference recorded in this treatment's description.

Multidisciplinary TSC Clinic Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

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 NCIT:C15240

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.

Multisystem Surveillance and Screening (2012 International TSC Consensus, updated 2021)

Action: multisystem disease surveillance and screening Ontology label: Supportive Care NCIT:C15747

Lifelong, age-appropriate multisystem surveillance and screening per the evidence-based recommendations of the International TSC Consensus Group, first issued by the 2012 Consensus Conference (Krueger & Northrup 2013) and revised by the 2021 update (Northrup et al. 2021), which is the current authoritative standard. Core elements include serial brain MRI for subependymal giant cell astrocytoma, annual renal function and blood-pressure assessment with periodic renal MRI for angiomyolipomata, at-least-annual TAND (TSC-associated neuropsychiatric disorders) screening, an annual skin survey, periodic echocardiography and ECG until cardiac rhabdomyoma regression, and HRCT plus pulmonary function testing for lymphangioleiomyomatosis risk in females from age 18. The 2021 revision largely retained the 2013 schedules while adding increased emphasis on early screening for electroencephalographic abnormalities, enhanced TAND surveillance and management, and new medication approvals. Because the dominant pathology shifts across the lifespan, coordinated multidisciplinary surveillance enables early detection and treatment of complications, the factor most associated with optimal outcome.

Target Phenotypes: Subependymal giant-cell astrocytoma HP:0009718 Renal angiomyolipoma HP:0006772 Pulmonary lymphangioleiomyomatosis HP:0005948

Show evidence (10 references)

PMID:24053983 SUPPORT Human Clinical

"All individuals suspected of having TSC, regardless of age, should undergo magnetic resonance imaging (MRI) of the brain with and without gadolinium"

2012 International TSC Consensus baseline brain-MRI recommendation (Category 1) at the time of diagnosis to assess for tubers, subependymal nodules, and SEGA.

PMID:24053983 SUPPORT Human Clinical

"surveillance by MRI should be performed every 1–3 years in all individuals with TSC until the age of 25 years."

Consensus SEGA surveillance schedule (Category 2A); optimal outcome is associated with early detection and treatment.

PMID:24053983 SUPPORT Human Clinical

"Annual clinical assessment of renal function and hypertension is required."

Consensus renal-surveillance recommendation (Category 1); periodic renal MRI monitors angiomyolipomata, which require more intervention in adulthood.

+ 7 more references

🔬

Diagnosis

1

Molecular Genetic Testing for TSC1/TSC2

The molecular diagnosis is established by identifying a heterozygous pathogenic variant in TSC1 or TSC2. Because TSC2 accounts for the large majority of molecularly solved cases, a positive result most often identifies the TSC2 (tuberous sclerosis 2) subtype. Molecular testing complements, rather than replaces, the clinical diagnostic criteria: a clinical diagnosis can be established from two major features, or one major plus two or more minor features, and 10-15% of clinically definite cases have no variant identified on conventional sequencing, often reflecting low-level somatic mosaicism.

molecular genetic testing NCIT:C19770

Show evidence (2 references)

PMID:20301399 SUPPORT Human Clinical

"The molecular diagnosis can be established in a proband with a heterozygous pathogenic variant in TSC1 or TSC2 identified by molecular genetic testing."

GeneReviews defines molecular genetic testing of TSC1/TSC2 as the basis of the molecular diagnosis of TSC.

PMID:20301399 SUPPORT Human Clinical

"The clinical diagnosis of TSC can be established in a proband based on clinical diagnostic criteria"

Confirms that a clinical diagnosis is established independently of molecular testing, supporting the complementary framing above.

📈

Progression

3

Onset

Age: Prenatal to infancy

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.

Childhood

Age: 1-12 years

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).

Adolescence and adulthood

Age: ≥12 years

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.

📊

Prevalence

2

Global

Birth Prevalence 12.0 per 100,000 1–9 per 10,000 (births)

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).

Japan (Shizuoka Prefecture)

Point Prevalence 10.2 per 100,000 1–9 per 10,000

Adjusted population prevalence of 10.2 per 100,000 in a 2012-2020 retrospective cohort using ICD-10 Q85.1 ascertainment (Kishida 2025).

⚖️

Clinical Burden

High

TSC imposes lifelong, multiorgan, multidisciplinary burden that is not captured by lesion counts. Beyond drug-resistant epilepsy and TAND, the TOSCA quality-of-life substudy (143 participants drawn from the international registry) documented substantial psychosocial and economic impact on both patients and caregivers, alongside poorly coordinated care and a largely unsuccessful paediatric-to-adult transition. Expressivity is highly variable, so a disease-level HIGH rating does not imply uniformly severe expression: mosaic and some TSC1-related presentations can be clinically subtle.

Denominators differ by question within the TOSCA substudy: the 42.1% education/career figure is 16 of 38 self-reporting adults, the 76.5% caregiver relationship-impact figure is 13 of 17 caregiver-reported adults, and the 35% / 43.4% EQ-5D rates are out of all 143 participants. The abstract states them without those denominators; do not re-use them as whole-cohort rates.

Show evidence (3 references)

PMID:32982929 SUPPORT Human Clinical

"Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed)."

Quantifies education/career impact on patients and employment impact on caregivers in the 143-participant TOSCA quality-of-life substudy.

PMID:32982929 SUPPORT Human Clinical

"the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population"

EQ-5D dimension rates across all 143 participants, supporting a disease-level assessment of high burden of illness and low quality of life independent of organ-lesion severity.

PMID:32982929 SUPPORT Human Clinical

"a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients"

Care-coordination failure is itself a component of disease burden; only about a third of adult respondents reported a smooth transition from paediatric to adult services.

📊

Related Datasets

5

Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment ega:EGAS00001002485

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Tuberous Sclerosis Complex"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex ega:EGAS00001004586

Although the intricate and prolonged development of the human brain critically distinguishes it from other mammals, our current understanding of neurodevelopmental diseases is largely based on work using animal models. Recent studies revealed that neural progenitors in the human brain are profoundly different from those found in rodent animal models. Moreover, post-mortem studies revealed extensive migration of interneurons into the late-gestational and post-natal human prefrontal cortex that does not occur in rodents.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Tuberous Sclerosis Complex"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Molecular EPISTOP: Comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years ega:EGAS00001007264

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Tuberous Sclerosis Complex"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Pilot Study Evaluating Everolimus Molecular Mechanisms in Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) massive:MSV000088551

Treatment resistant epilepsy in tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mammalian target of rapamycin (mTOR) signaling. This can upregulate cell growth and proliferation, with increased downstream ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors are used in TSC, the archetypal mTORopathy, to reduce tumor growth or seizure frequency. Preclinical studies in FCD support a potential role in suppressing seizures.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberous Sclerosis Complex"). Retrieved 2026-08-02.

The Genomic Landscape of Tuberous Sclerosis Complex (TSC) dbgap:phs001357

In this study, we characterized the genomic landscape of tuberous sclerosis complex (TSC), a rare genetic disease causing multisystem growth of benign tumors and other hamartomatous lesions. We analyzed 127 human tissues, including 111 TSC-associated samples and 16 non-TSC negative controls, using multiple genomic platforms including whole exome sequencing, targeted sequencing of known disease-causative loci ( TSC1 and TSC2 ), mRNA sequencing, high-density SNP arrays, and DNA methylation arrays.

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberous Sclerosis Complex"). Retrieved 2026-08-02.

🔬

Clinical Trials

8

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

NCT05104983 PHASE_II RECRUITING

TSC-STEPS (Stopping TSC Onset and Progression 2B): randomised, placebo-controlled trial of sirolimus for prevention of TSC-associated epilepsy in 64 seizure-free infants. Tests pre-symptomatic mTOR inhibition inside the early developmental window, complementing the vigabatrin-based prevention approach in NCT04987463.

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

NCT05323734 PHASE_III COMPLETED

TrustTSC: completed placebo-controlled trial of adjunctive ganaxolone (a neuroactive-steroid GABA-A positive allosteric modulator) in 129 children and adults with TSC-related epilepsy. Represents a non-mTOR-directed adjunctive antiseizure strategy.

Target Phenotypes: Seizures HP:0001250

NCT05059327 PHASE_II COMPLETED

Completed placebo-controlled crossover study of basimglurant (NOE-101), an mGluR5 negative allosteric modulator, in 61 children, adolescents and young adults with TSC. Targets glutamatergic signalling rather than the mTORC1 axis.

Target Phenotypes: Seizures HP:0001250

NCT02962414 PHASE_III ACTIVE_NOT_RECRUITING

Open-label roll-over study collecting long-term safety of everolimus in 206 patients with TSC and refractory seizures who completed EXIST-3 and continued to benefit. The principal source of multi-year everolimus exposure data in this population.

Target Phenotypes: Seizures HP:0001250

NCT05495425 PHASE_III COMPLETED

Completed placebo-controlled study of NPC-12Y (topical sirolimus) gel in 43 patients with TSC-associated skin lesions, extending the topical mTOR-inhibitor evidence base beyond NCT01526356.

Target Phenotypes: Angiofibromas HP:0010615

🧫

Experimental Models

3

TSC patient-derived neurovascular unit (iPSC blood-brain-barrier chip) ORGAN_ON_CHIP

A human microphysiological blood-brain-barrier model assembled from TSC-patient iPSC-derived endothelium and astrocytes. It provides a human, lineage-resolvable readout of neurovascular dysfunction in TSC that neither rodent models nor two-dimensional culture supply, and it supports lineage-swap experiments (mutant endothelium with wild-type astrocytes) that separate cell-autonomous from non-cell-autonomous contributions to the barrier defect.

Organism

human NCBITaxon:9606

Cell source

Patient-derived induced pluripotent stem cells carrying a heterozygous TSC2 variant, differentiated to brain microvascular endothelial cells and astrocytes.

Culture

Microfluidic multi-compartment neurovascular-unit chip

Pathograph links

mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction The chip reproduces the increased barrier permeability of the TSC neurovascular unit and shows it is reversible by astrocyte replacement or mTOR inhibition.

Show evidence (1 reference)

PMID:38783199 SUPPORT In Vitro

"Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor."

Directly demonstrates the modelled mechanism and its astrocyte-dependence and mTOR-dependence.

The published model uses TSC2 heterozygous patient cells. An equivalent TSC1-mutant neurovascular-unit model was not identified in this curation pass; the mechanism is expected to be shared because both proteins act through the same TSC complex, but that expectation is untested here.

Show evidence (1 reference)

PMID:38783199 SUPPORT In Vitro

"We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies."

Describes the construction of the model system - iPSC-derived cells in a microfluidic culture platform.

CRISPR-engineered TSC2 conditional-biallelic human cortical spheroids ORGANOID

Isogenic cortical spheroids in which the timing of biallelic TSC2 loss can be controlled. Mosaic second-hit loss during progenitor expansion is necessary for dysplastic cells and excess glia, supporting the second-hit model of tuber formation.

Organism

human NCBITaxon:9606

Cell source

Human pluripotent stem cells with CRISPR-Cas9-edited TSC1 or TSC2, including heterozygous TSC2 lines carrying a conditional mutation in the remaining allele, differentiated to three-dimensional cortical spheroids

Publication

PMID:30127391

Pathograph links

Somatic Second Hit at TSC Locus recapitulates fidelity: moderate observes: cellular The conditional allele lets biallelic TSC2 loss be triggered in a mosaic of neural progenitors, and only that second hit produces dysplastic cells and excess glia, which is the somatic second-hit node.

Limitations: The second hit is induced experimentally rather than arising spontaneously, and the spheroids lack vasculature, microglia and the in-vivo developmental timeline.

Divergences from the human mechanism

contested assumption qualifying

The spheroid result assumes the second hit is required for tuber cells, but the patient-derived cerebral organoids in PMID:35084981, added in the same pass, find wild-type TSC2 protein in over 98% of giant cells in TSC2+/- organoids and conclude that bi-allelic inactivation is dispensable for disease initiation in human tissue. The two human models therefore disagree on whether this node is necessary for tuber formation, which is why the link is not graded HIGH.

Readouts

Dysplastic cell formation after mosaic biallelic TSC2 loss

Direction: INCREASED

Interpretation: Dysplastic cells form only when both alleles are lost during progenitor expansion.

Show evidence (1 reference)

PMID:30127391 SUPPORT In Vitro

"mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids"

Reports the dysplasia measurement.

Glia production after mosaic biallelic TSC2 loss

Direction: INCREASED

Interpretation: Glial output increases with biallelic loss.

Show evidence (1 reference)

PMID:30127391 SUPPORT In Vitro

"increased glia production in three-dimensional cortical spheroids"

Reports the glia measurement.

Show evidence (1 reference)

PMID:30127391 SUPPORT In Vitro

"Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids. Our findings..."

A human model in which the second hit is necessary for the dysplastic phenotype directly tests the node.

Neuroglial Dysplasia and Cortical Network Disorganization partially recapitulates fidelity: moderate observes: tissue Spheroids reproduce the dysmorphic cells and glial excess of a tuber but not cortical lamination, network activity or epileptogenesis.

Limitations: No layered cortex, no electrophysiological network readout and no seizure phenotype; the tuber is represented by its cellular composition only.

Readouts

Dysplastic cells and glia in cortical spheroids

Direction: INCREASED

Interpretation: Tuber-like cellular composition arises after the second hit.

Show evidence (1 reference)

PMID:30127391 SUPPORT In Vitro

"the formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids"

Reports the cellular composition measurement.

Show evidence (1 reference)

PMID:30127391 SUPPORT In Vitro

"Hallmark pathologies of TSC are cortical tubers-regions of dysmorphic, disorganized neurons and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC"

The model is built to reproduce tuber cell composition, which is part of what this node describes.

Show evidence (1 reference)

PMID:30127391 SUPPORT In Vitro

"we established human cellular models of TSC by CRISPR-Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs)."

Establishes the engineered human model.

TSC human cerebral organoids with caudal late interneuron progenitor (CLIP) over-proliferation ORGANOID

Cerebral organoids identify a human-specific interneuron progenitor population that over-proliferates in TSC, generating excess interneurons, tumours and cortical malformations; EGFR inhibition reduces tumour burden.

Organism

human NCBITaxon:9606

Cell source

Induced pluripotent stem cells derived from patients carrying TSC2 mutations, with isogenic TSC2+/+ control lines, grown as cerebral organoids

Publication

PMID:35084981

Pathograph links

Somatic Second Hit at TSC Locus fails to recapitulate observes: cellular Giant cells in TSC2+/- patient organoids retain wild-type TSC2 protein, so tuber-like cells form here without the somatic second hit this node requires; the authors conclude bi-allelic inactivation is dispensable for disease initiation in human tissue.

Limitations: The antibody readout reports presence of wild-type protein, not absence of a second hit by sequencing, and organoids at 230 days do not reach the timescale over which subependymal tumours acquire bi-allelic loss in patients. This directly conflicts with the conditional-biallelic spheroid model above.

Readouts

Wild-type TSC2 protein in giant cells

Direction: UNCHANGED

Interpretation: Over 98% of giant cells retain wild-type TSC2, so no loss of the second allele is seen.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"TSC2 protein expression was detected in over 98% of giant cells using an antibody recognizing only the wild type TSC2 variant"

Reports the giant-cell TSC2 immunostaining measurement.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"TSC2 protein expression was detected in over 98% of giant cells using an antibody recognizing only the wild type TSC2 variant (patient 1, 98.4%; patient 2, 98.7%: Fig. S7A-C). TSC2 protein was also expressed in giant cells in fetal cortical tubers (Fig. S7D), consistent with previous data (26,..."

Wild-type TSC2 in nearly all giant cells means the model produces tuber cells without the second hit, which is a failure to recapitulate the node rather than a low-fidelity version of it.

Subependymal Glioneuronal Tumor Growth recapitulates fidelity: moderate observes: tissue CLIP cell over-proliferation in TSC organoids produces brain tumours, matching the subependymal tumour growth node and proposing its human-specific cell of origin.

Limitations: Organoid tumours lack the ventricular location, vasculature and growth timescale of a subependymal giant cell astrocytoma.

Readouts

CLIP cell proliferation

Direction: INCREASED

Interpretation: The interneuron progenitor population over-proliferates in TSC organoids.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations."

Reports the proliferation measurement.

Tumour burden under EGFR inhibition

Direction: DECREASED

Interpretation: EGFR inhibition reduces organoid tumour burden.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"Epidermal growth factor receptor inhibition reduces tumor burden"

Reports the treatment-arm measurement.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders."

Tumour formation from an over-proliferating progenitor in a human model supports the tumour-growth node.

Neuroglial Dysplasia and Cortical Network Disorganization partially recapitulates fidelity: moderate observes: tissue Excess interneurons and cortical malformations arise from the same progenitor expansion, reproducing the malformation side of the node without its network or seizure readouts.

Limitations: Organoids have no functional cortical network and no seizure phenotype; the malformation is scored structurally.

Readouts

Interneuron output and cortical malformation

Direction: INCREASED

Interpretation: Excess interneurons and malformed cortex follow CLIP over-proliferation.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"generating excessive interneurons, brain tumors, and cortical malformations"

Reports the structural measurement.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations."

Cortical malformation in the organoid is part of what this node describes.

Show evidence (1 reference)

PMID:35084981 SUPPORT In Vitro

"We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells."

Establishes the organoid model and the cell population it identifies.

{ }

Source YAML

click to show

name: Tuberous Sclerosis Complex
creation_date: "2026-03-06T00:00:00Z"
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
  subtype_term:
    preferred_term: Tuberous sclerosis 2
    term:
      id: MONDO:0013199
      label: tuberous sclerosis 2
  subtype_frequency: "~70-83% of molecularly solved cases"
  genes:
  - preferred_term: TSC2
    term:
      id: hgnc:12363
      label: TSC2
  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
  subtype_term:
    preferred_term: Tuberous sclerosis 1
    term:
      id: MONDO:0008612
      label: tuberous sclerosis 1
  subtype_frequency: "~15-20% of molecularly solved cases"
  description: >
    Pathogenic variants in TSC1 on chromosome 9q34 (encoding hamartin) account
    for ~15-20% of molecularly solved TSC cases across independent
    genotype-phenotype cohorts. TSC1-related disease is on average milder than
    TSC2-related disease: sporadic TSC1 patients have a lower frequency of
    seizures and moderate-to-severe intellectual disability, fewer
    subependymal nodules and cortical tubers, less-severe kidney involvement,
    and less-severe facial angiofibroma than TSC2 patients. Grade 2-4 renal
    cysts/angiomyolipomas, forehead (fibrous cephalic) plaques, and retinal
    hamartomas are very rare or not seen at all in isolated TSC1 disease.
    TSC1 pathogenic variants are almost uniformly predicted truncating
    (nonsense, frameshift, splice-site, or large deletion), in contrast to
    TSC2's broader spectrum that also includes missense variants clustered in
    functional domains, and are significantly enriched in familial versus
    sporadic TSC — consistent with a milder phenotype compatible with
    reproduction, and the main reason TSC1 accounts for a disproportionate
    share of familial (vs. de novo) TSC cases.
  genes:
  - preferred_term: TSC1
    term:
      id: hgnc:12362
      label: TSC1
  evidence:
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma."
    explanation: >
      Landmark 224-patient genotype-phenotype cohort establishing that
      sporadic TSC1 disease is milder than TSC2 disease across seizures,
      intellectual disability, brain lesion burden, kidney involvement,
      retinal hamartoma, and facial angiofibroma severity.
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"
    explanation: >
      Identifies specific phenotypes that are very rare or absent in
      TSC1-related disease, distinguishing it from TSC2-related disease.
  - reference: PMID:10205261
    reference_title: "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185)."
    explanation: >
      Establishes that TSC1 variants are significantly enriched in familial
      (versus sporadic/de novo) TSC, a key genotype-driven feature
      distinguishing TSC1 from TSC2 disease.
  - reference: PMID:10205261
    reference_title: "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein."
    explanation: >
      Establishes that TSC1 pathogenic variants are almost uniformly
      truncating, distinct from TSC2's broader spectrum that also includes
      missense variants clustered in functional domains.
  - reference: PMID:10205261
    reference_title: "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P=.0145)."
    explanation: >
      Independent cohort corroborating lower intellectual disability
      frequency in TSC1 versus TSC2 sporadic disease.
  - reference: PMID:33041968
    reference_title: "Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention."
    explanation: >
      The 2,211-patient TOSCA international registry confirms the milder
      average renal course of TSC1 disease (later onset, smaller, less often
      growing angiomyolipomas) but explicitly qualifies it: by age 40 the
      proportion of patients requiring intervention is indistinguishable
      between TSC1 and TSC2. Classified PARTIAL because it supports the
      "milder on average" framing while refuting any inference that a TSC1
      genotype justifies relaxed lifelong renal surveillance.
  - reference: PMID:40579409
    reference_title: "Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with pathogenic TSC2 variants tended to exhibit a higher frequency of weekly seizures, a higher prevalence of infantile spasms and hypsarrhythmia compared to those with pathogenic TSC1 variants, consistent with a more severe phenotype."
    explanation: >
      Independent 81-patient Sicilian cohort (31 TSC1, 50 TSC2) reproducing
      the milder TSC1 epilepsy phenotype on seizure frequency, infantile
      spasms, and hypsarrhythmia.
  - reference: PMID:40579409
    reference_title: "Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive and behavioral disorders were similarly distributed, although TSC1 patients had higher rates of normal or borderline cognitive function, while TSC2 patients had more severe neuropsychiatric profiles compared to TSC1."
    explanation: >
      Corroborates the higher rate of preserved cognition in TSC1 disease
      while noting that cognitive and behavioural disorders as a class are
      similarly distributed between the two genotypes.
  - reference: PMID:40579409
    reference_title: "Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, TSC1 patients exhibited a higher incidence of radial bands, while TSC2 patients harbored a larger average size of tubers and subependymal nodules."
    explanation: >
      Identifies a brain-imaging feature that runs counter to the general
      TSC1-is-milder gradient: radial migration bands were MORE frequent in
      TSC1, whereas the TSC2 advantage in lesion burden is one of tuber and
      subependymal nodule size rather than of every structural feature.
- 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.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >
    TSC is inherited in an autosomal dominant manner, with heterozygous
    pathogenic variants in either TSC1 or TSC2. About one third of affected
    individuals have an affected parent; the remaining two thirds result from
    a de novo pathogenic variant, and each child of an affected individual has
    a 50% chance of inheriting the variant. Penetrance is essentially complete
    but expressivity is highly variable, so clinical severity differs markedly
    even within a family carrying the same variant. Low-level somatic
    mosaicism accounts for a substantial share of cases in which no germline
    variant is identified.
  evidence:
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC is inherited in an autosomal dominant manner. About one third of individuals diagnosed with TSC have an affected parent; two thirds of individuals with TSC have the disorder as the result of a de novo pathogenic variant. Each child of an individual with TSC has a 50% chance of inheriting the TSC-related pathogenic variant."
    explanation: >
      GeneReviews establishes the autosomal dominant mode of inheritance, the
      one-third inherited / two-thirds de novo split, and the 50% recurrence
      risk to offspring.
  - reference: PMID:41361250
    reference_title: "Cardiac rhabdomyomas in tuberous sclerosis complex: clinical manifestations and genotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Penetrance is nearly complete, but symptoms can differ significantly within families"
    explanation: Supports essentially complete penetrance alongside highly variable expressivity within families.
- name: Somatic mosaicism (conventionally mutation-negative cases)
  inheritance_term:
    preferred_term: Somatic mosaicism
    term:
      id: HP:0001442
      label: Typified by somatic mosaicism
  description: >-
    A minority of clinically definite TSC is caused not by a germline TSC1/TSC2 variant but by
    low-level post-zygotic mosaicism for one. These individuals have no variant on conventional
    blood testing, tend to a milder phenotype, and carry a recurrence risk for offspring that
    depends on whether the mosaic clone includes the germline. This block records the mosaic
    arm alongside the predominant autosomal dominant inheritance above; it does not replace it.
  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 mutation-negative fraction and attributes most of it to somatic mosaicism.
diagnosis:
- name: Molecular Genetic Testing for TSC1/TSC2
  description: >
    The molecular diagnosis is established by identifying a heterozygous
    pathogenic variant in TSC1 or TSC2. Because TSC2 accounts for the large
    majority of molecularly solved cases, a positive result most often
    identifies the TSC2 (tuberous sclerosis 2) subtype. Molecular testing
    complements, rather than replaces, the clinical diagnostic criteria: a
    clinical diagnosis can be established from two major features, or one
    major plus two or more minor features, and 10-15% of clinically definite
    cases have no variant identified on conventional sequencing, often
    reflecting low-level somatic mosaicism.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis can be established in a proband with a heterozygous pathogenic variant in TSC1 or TSC2 identified by molecular genetic testing."
    explanation: >
      GeneReviews defines molecular genetic testing of TSC1/TSC2 as the basis
      of the molecular diagnosis of TSC.
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of TSC can be established in a proband based on clinical diagnostic criteria"
    explanation: >
      Confirms that a clinical diagnosis is established independently of
      molecular testing, supporting the complementary framing above.
prevalence:
- population: Global
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 12.0
  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)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 10.2
  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.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    TSC imposes lifelong, multiorgan, multidisciplinary burden that is not
    captured by lesion counts. Beyond drug-resistant epilepsy and TAND, the
    TOSCA quality-of-life substudy (143 participants drawn from the
    international registry) documented substantial psychosocial and economic
    impact on both patients and caregivers, alongside poorly coordinated care
    and a largely unsuccessful paediatric-to-adult transition. Expressivity is
    highly variable, so a disease-level HIGH rating does not imply uniformly
    severe expression: mosaic and some TSC1-related presentations can be
    clinically subtle.
  evidence:
  - reference: PMID:32982929
    reference_title: "Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed)."
    explanation: >
      Quantifies education/career impact on patients and employment impact on
      caregivers in the 143-participant TOSCA quality-of-life substudy.
  - reference: PMID:32982929
    reference_title: "Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population"
    explanation: >
      EQ-5D dimension rates across all 143 participants, supporting a
      disease-level assessment of high burden of illness and low
      quality of life independent of organ-lesion severity.
  - reference: PMID:32982929
    reference_title: "Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients"
    explanation: >
      Care-coordination failure is itself a component of disease burden;
      only about a third of adult respondents reported a smooth transition
      from paediatric to adult services.
  notes: >-
    Denominators differ by question within the TOSCA substudy: the 42.1%
    education/career figure is 16 of 38 self-reporting adults, the 76.5%
    caregiver relationship-impact figure is 13 of 17 caregiver-reported
    adults, and the 35% / 43.4% EQ-5D rates are out of all 143 participants.
    The abstract states them without those denominators; do not re-use them
    as whole-cohort rates.
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.
  - reference: PMID:31217257
    reference_title: "A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC."
    explanation: >
      Refutes the pharmacologic-validation corollary of this hypothesis - that
      mTOR inhibitors "definitively confirm" the mTORC1 axis - for the
      neuropsychiatric arm specifically. In a 12-month double-blind
      placebo-controlled trial of 32 children aged 4-17 titrated to trough
      levels of 5-10 ng/mL, everolimus produced no benefit on full-scale IQ
      (treatment effect -5.6 points, 95% CI -12.3 to 1.0) and no effect on any
      secondary neuropsychological, behavioural, or quality-of-life outcome;
      the paper carries a Class I evidence classification. The tumour and
      seizure arms of the pharmacologic validation are unaffected, so this
      narrows the hypothesis rather than displacing it.
  - reference: PMID:26837766
    reference_title: "Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "the mTOR pathway was not activated in all TSC2(+/-) tumors and was elevated in only 50% of human mesenchymal tumors"
    explanation: >
      Refutes this hypothesis's claim that mTORC1 hyperactivation produces the
      characteristic lesions in "nearly every organ system", for the
      mesenchymal tumour class. Half of the human mesenchymal tumours assayed
      showed no mTOR pathway activation at all, and the corresponding mouse
      tumours required HMGA2 rather than a second hit, so at least one TSC
      lesion class arises through a pathway this hypothesis does not describe.
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
  - target: TSC2 GAP Domain Catalytic Loss
    description: >
      Within the TSC1/TSC2/TBC1D7 complex, only TSC2 contributes the
      catalytically active GAP domain; loss-of-function variants in TSC2
      directly abolish RHEB-GAP catalysis, whereas TSC1 has no intrinsic
      catalytic activity and instead scaffolds/stabilizes the complex.
    causal_link_type: DIRECT
- name: TSC2 GAP Domain Catalytic Loss
  biological_scale: MOLECULAR
  subtypes:
  - TSC2
  description: >
    Cryo-EM structural studies of the human TSC complex show it assembles as
    an arch-shaped 2:2:1 (TSC1:TSC2:TBC1D7) heteropentamer in which a parallel
    TSC1 coiled-coil dimer packs against a tail-to-tail TSC2 dimer, with a
    single TBC1D7 bound to the TSC1 C-terminal helices (TBC1D7 makes no direct
    contact with TSC2 and sits far from the central core, consistent with an
    auxiliary role). The two TSC2 GAP domains are cradled within the core
    module formed by the TSC2 dimerization domain and the TSC1 central
    coiled-coil, and directly contact RHEB: an asparagine "thumb" (N1643) in
    the TSC2 GAP domain stabilizes the gamma-phosphate of GTP-bound RHEB and
    accelerates RHEB GTP hydrolysis. TSC1 contributes no catalytic residues to
    this reaction; its coiled-coil region instead scaffolds and stabilizes the
    complex. Pathogenic variants disrupting the TSC2 GAP domain or its
    RHEB-contacting residues therefore abolish RHEB-GAP catalysis directly.
    Note this is a candidate structural contribution to — not a complete
    explanation of — the observed TSC2-over-TSC1 severity gradient, which is
    also shaped by TSC2's larger mutational target size, its higher burden of
    truncating alleles, the rarity of pathogenic TSC1 missense variants, and
    ascertainment differences; TSC1 loss also destabilizes TSC2 and abolishes
    complex GAP activity in vivo.
  genes:
  - preferred_term: TSC2
    term:
      id: hgnc:12363
      label: TSC2
  molecular_functions:
  - preferred_term: GTPase activator activity
    term:
      id: GO:0005096
      label: GTPase activator activity
  evidence:
  - reference: PMID:33436626
    reference_title: "Structural insights into TSC complex assembly and GAP activity on Rheb."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1. Structural and biochemical analyses reveal TSC2 GAP-Rheb complimentary interactions and suggest a catalytic mechanism, by which an asparagine thumb (N1643) stabilizes γ-phosphate of GTP and accelerate GTP hydrolysis of Rheb."
    explanation: Cryo-EM structure of the human TSC complex localizes the catalytic GAP-RHEB interaction to the TSC2 subunit (asparagine-1643 thumb), with TSC1 forming the surrounding coiled-coil scaffold rather than contributing catalytic residues.
  - reference: PMID:33436626
    reference_title: "Structural insights into TSC complex assembly and GAP activity on Rheb."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The TBC1D7 associates with and stabilizes the C-terminal helices (residues 937–971) of TSC1a/1b but has no direct contact with TSC2."
    explanation: Establishes that the auxiliary TBC1D7 subunit binds only TSC1, not TSC2, constraining how the 2:2:1 complex is described.
  - 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: >
      Supports the within-complex claim that variants in critical/catalytic
      TSC2 domains correlate with greater severity. Marked PARTIAL because it
      does not itself establish the broader TSC2-vs-TSC1 between-gene severity
      gradient, which this node treats as a candidate contribution only.
  downstream:
  - target: Constitutive mTORC1 Hyperactivation
    description: >
      Loss of TSC2 GAP catalysis removes the complex's ability to drive RHEB
      GTP hydrolysis, leaving RHEB GTP-loaded and mTORC1 constitutively
      active. Full constitutive activation in a lesion clone additionally
      requires biallelic loss via a somatic second hit.
    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. The requirement
    for a second hit is well established for the classic hamartomas but is not
    universal across lesion classes: mesenchymal tumorigenesis in the TSC2+/-
    mouse proceeds from haploinsufficiency alone and is HMGA2- rather than
    mTOR-dependent, with mTOR pathway activation detectable in only half of the
    corresponding human tumours.
  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.
  - reference: PMID:25432535
    reference_title: "A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular studies indicate that tumors developed independently due to various second hit events"
    explanation: >
      Targeted sequencing of renal tumors from two patients with the germline
      TSC2 variant p.R905Q identified a distinct, independent second-hit TSC2
      event in most tumors that were sequenced (5/5 in the first patient, 1/2
      in the second), indicating that multiple lesions within one organ of one
      TSC2 patient arise from separate stochastic second-hit events rather
      than clonal spread. Note that only 1 of 11 further tumors available from
      the first patient carried one of the identified second hits, so the
      per-tumor yield outside the sequenced set is lower.
  - reference: PMID:27494029
    reference_title: "Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1."
    explanation: >
      Quantifies the second hit in human lesions rather than asserting it:
      whole-exome sequencing of 32 resected angiomyolipoma/LAM samples found
      biallelic TSC1/TSC2 loss in 94%, most often by copy-neutral loss of
      heterozygosity. The same study reports a median of only 4 other somatic
      non-synonymous coding mutations per tumour, so biallelic TSC loss is not
      merely present but is the essential driver event.
  - reference: PMID:26837766
    reference_title: "Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "haploinsufficiency of one TSC tumor suppressor gene was required for tumor initiation, but further tumorigenesis did not require the second hit, as previously postulated"
    explanation: >
      Bounds the two-hit model rather than overturning it. In the TSC2+/- mouse,
      mesenchymal tumours initiate and progress from haploinsufficiency alone,
      require HMGA2, and retain tuberin expression; the companion human tumour
      series in the same paper found mTOR pathway activation in only 50% of
      mesenchymal tumours. Cited as REFUTE against this node's claim that
      biallelic inactivation is required for lesion formation, scoped to the
      mesenchymal tumour class - the hamartoma classes above are unaffected.
  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
  conforms_to: "deregulated_nutrient_sensing#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.
  - target: mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction
    description: >
      Beyond the neuron-centred dysplasia arm, mTORC1 hyperactivity biases
      neural precursors toward gliogenesis and dysregulates astrocyte,
      oligodendrocyte, NG2 glia and microglial maturation and function,
      extending to the astrocyte-supported neurovascular unit. The glial
      lineage effect is a differentiation consequence of mTORC1 signalling
      rather than of hamartoma growth, so it is placed on the mTORC1 hub.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - mTORC1-driven gliogenic lineage bias in neural precursors
    - dysregulated glial maturation and reactive astrogliosis
    evidence:
    - reference: PMID:33041976
      reference_title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "mTOR hyperactivity promotes development of often multifocal brain lesions characterized by aberrant glioneuronal proliferation, cortical dyslamination, and hypomyelination"
      explanation: >
        Attributes the glial/myelination arm of TSC brain pathology directly
        to mTOR hyperactivity, supporting this causal edge from the mTORC1
        hub to the gliopathy node.
- 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
  conforms_to: "deregulated_nutrient_sensing#Autophagy Suppression and Anabolic Bias"
  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.
  - reference: PMID:38714540
    reference_title: "Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC."
    explanation: >
      Resolves the "disorganized cortical network" claim of this node to a
      specific cell type. Single-nuclei RNA sequencing of TSC patient tissue
      identifies somatostatin-expressing interneurons as developmentally
      immature, carrying an abnormal NKCC1/KCC2 ratio, downregulated GABRA1 and
      upregulated GABRA2, and an altered deep-layer distribution consistent with
      cortical dyslamination. The authors are explicit that the resulting
      failure of the excitatory-to-inhibitory GABA switch is inferred from these
      markers rather than measured, and how the cell-autonomous defect produces
      circuit-level epileptogenesis is not established.
  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: mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction
  biological_scale: CELLULAR
  description: >
    Alongside the neuron-centred account of TSC brain disease, mTORC1
    hyperactivation produces a distinct, non-neuronal "gliopathy" arm.
    mTORC1 hyperactivity biases neural precursors toward gliogenesis
    (contributing to the glial excess within tubers); astrocytes become
    reactive, proliferative and proinflammatory while losing homeostatic
    ion- and neurotransmitter-handling functions; oligodendrocyte lineage
    cells mature abnormally, giving hypomyelination and impaired
    remyelination; NG2 glia and microglia are also altered. The same
    mTOR-dependent lesion extends to the neurovascular unit: a human
    iPSC-derived, microfluidic blood-brain-barrier model built from
    TSC-mutant cells is abnormally permeable, and the defect is corrected
    either by supplying wild-type astrocytes or by rapamycin, showing the
    barrier phenotype is astrocyte-dependent and mTOR-dependent rather than
    a fixed structural consequence of the mutation. This node captures the
    glial and neurovascular contribution to epileptogenesis and to the
    cognitive/behavioural comorbidities of TAND, which the dysplasia node
    above does not.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: NG2 glia (oligodendrocyte precursor cell)
    term:
      id: CL:0002453
      label: oligodendrocyte precursor cell
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  biological_processes:
  - preferred_term: gliogenesis
    modifier: INCREASED
    term:
      id: GO:0042063
      label: gliogenesis
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  - preferred_term: maintenance of blood-brain barrier
    modifier: DECREASED
    term:
      id: GO:0035633
      label: maintenance of blood-brain barrier
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:33041976
    reference_title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia"
    explanation: >
      Establishes that the neuropathology of TSC is not neuron-restricted and
      names the four glial populations that define the gliopathy arm modelled
      by this node.
  - reference: PMID:33041976
    reference_title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders."
    explanation: >
      Links the glial changes and interglial crosstalk to the two downstream
      clinical outcomes this node feeds - epilepsy and the cognitive and
      behavioural comorbidities of TAND.
  - reference: PMID:33041976
    reference_title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mTOR hyperactivity promotes development of often multifocal brain lesions characterized by aberrant glioneuronal proliferation, cortical dyslamination, and hypomyelination"
    explanation: >
      Places hypomyelination alongside glioneuronal proliferation and cortical
      dyslamination as a direct consequence of mTOR hyperactivity in the TSC
      brain, supporting the DECREASED myelination annotation.
  - reference: PMID:38783199
    reference_title: "Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor."
    explanation: >
      Direct experimental support for an mTOR-dependent, astrocyte-dependent
      blood-brain-barrier defect in TSC. Note the model is TSC2 heterozygous;
      the mechanism is shared TSC-complex/mTORC1 biology, but this specific
      demonstration has not been repeated in TSC1-mutant cells.
  - reference: PMID:26003087
    reference_title: "Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the increase in inflammatory markers was also observed in astrocyte culture in vitro and at 2 weeks of age in Tsc1(GFAP)CKO mice before the onset of epilepsy in vivo, indicating that the inflammatory changes were not secondary to seizures"
    explanation: >
      Establishes the temporal ordering behind the "proinflammatory astrocyte"
      component of this node. IL-1beta and CXCL10 rise in Tsc1(GFAP)CKO
      neocortex and hippocampus, localise primarily to astrocytes, and are
      reversed by an mTORC1 inhibitor - and they are already elevated at two
      weeks of age, before seizure onset, so the glial inflammation is not a
      consequence of seizing. Blocking IL-1beta and CXCL10 reduced seizure
      frequency and prolonged survival, making this a perturbation result
      rather than an association. The ordering is established in the mouse; no
      equivalent pre-seizure human timepoint exists.
  - reference: PMID:24948799
    reference_title: "Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that also oligodendrocyte-specific overactivation of mTORC1, via ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregulation of Akt signaling and lipogenic pathways."
    explanation: >
      Supplies the causal, cell-type-specific basis for the DECREASED
      myelination annotation on this node: deleting Tsc1 in oligodendrocytes
      alone is sufficient to produce hypomyelination, so the myelin deficit is
      an oligodendrocyte-autonomous consequence of mTORC1 overactivation rather
      than a downstream effect of tuber burden or seizures. The same study
      shows that deleting Rptor also impairs myelination, i.e. myelination
      requires balanced rather than merely reduced mTORC1 activity - which is
      why mTOR inhibition cannot be assumed to correct the white-matter arm.
  downstream:
  - target: Epileptic Seizures
    description: >
      Reactive astrogliosis with loss of potassium and glutamate homeostasis,
      inflammatory glial signalling, and impaired myelination alter network
      excitability and contribute to epileptogenesis independently of the
      dysplastic neuronal population.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of astrocytic ion and neurotransmitter homeostasis
    - glial proinflammatory signalling
  - target: Cerebral Hypomyelination
    description: >
      Oligodendrocyte-lineage mTORC1 dysregulation reduces oligodendrocyte
      proliferation and maturation, producing hypomyelination and impaired
      remyelination in TSC brain lesions.
    causal_link_type: DIRECT
  - target: Intellectual Disability
    description: >
      Altered myelination and glial support of cortical networks contribute to
      the cognitive component of TSC-associated neuropsychiatric disorders.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hypomyelination and altered connectivity
    - glial contribution to network dysfunction
- 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.
  - reference: PMID:41361250
    reference_title: "Cardiac rhabdomyomas in tuberous sclerosis complex: clinical manifestations and genotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC2 mutations were associated with a higher rate (42.9%) and velocity (18.7% per year) of tumor regression compared to TSC1 mutations (25% and 12.4% per year, respectively)."
    explanation: >
      A 22-patient single-center cohort with confirmed cardiac rhabdomyomas
      found TSC2-mutant patients regressed their tumors both more often and
      faster than TSC1-mutant patients, an unusual instance where the TSC2
      genotype tracks with a more favorable course for this specific lesion
      (contrasting with the generally more severe TSC2 phenotype overall). The
      authors describe this as a trend requiring confirmation in larger
      prospective studies, not an established correlation.
  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. Not all of the
    relevant mTOR signalling runs through mTORC1: in TSC2-deficient LAM cells
    an estradiol-driven COX-2/prostaglandin arm is regulated by mTORC2 and is
    not suppressed by rapamycin, which is one candidate explanation for the
    striking female predominance of LAM and for the incompleteness of the
    rapalogue response.
  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.
  - reference: PMID:19419980
    reference_title: "TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC2 women with LAM had a significantly greater number of cysts than did TSC1 patients (p = 0.010)."
    explanation: >
      A CT cohort of TSC women found LAM-consistent cysts in a similar
      proportion of TSC1 (40%) and TSC2 (48%) patients, i.e. LAM is not
      TSC2-exclusive, but TSC2 patients who develop LAM have a significantly
      greater cyst burden than TSC1 patients, indicating a genotype-severity
      (not genotype-presence) difference for this manifestation.
  - reference: PMID:24395886
    reference_title: "Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was also increased at baseline in TSC-deficient cells and was not affected by rapamycin treatment."
    explanation: >
      Identifies an arm of LAM cell biology that mTORC1-selective inhibition
      does not reach. COX-2 induction by estradiol in TSC2-deficient cells was
      unaffected by rapamycin but was reduced by Torin 1 and by Rictor
      knockdown, placing it downstream of mTORC2 rather than mTORC1; LAM
      patients had higher serum prostaglandins than healthy women, and COX
      inhibitors reduced tumour development in preclinical models. Scope: the
      rapamycin insensitivity demonstrated here is of COX-2 expression in
      cultured cells and xenografts, not of LAM disease progression - sirolimus
      does stabilise lung function in LAM - so this is a parallel contributor,
      not a competing account of the disease.
  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: Focal-Onset Seizures
  frequency: FREQUENT
  description: >
    Focal-onset seizures are the predominant seizure type in TSC outside the
    infantile-spasms window and are the seizure class that most often becomes
    drug resistant, driving epilepsy-surgery evaluation. The 2021 diagnostic
    criteria's emphasis on multiple cortical tubers reflects the focal,
    multifocal and asymmetric nature of the epileptogenic substrate.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007359 | Focal-onset seizure | Frequent (79-30%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies focal-onset
      seizure as frequent (79-30%) in tuberous sclerosis complex.
  - reference: PMID:40579409
    reference_title: "Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More in detail, two patients (6.4%) presented infantile spasms, 12 (38.7%) had focal seizures (three with impaired awareness), six (19.3%) patients experienced generalized tonic clonic seizures"
    explanation: >
      Seizure-type breakdown of the 31-patient TSC1 arm of the Sicilian
      cohort: focal seizures were the single most common type (12/31, 38.7%),
      well ahead of infantile spasms (2/31) in this predominantly adult
      TSC1 group.
- category: Neurologic
  name: Cerebral Hypomyelination
  description: >
    Hypomyelination and abnormal white-matter microstructure are part of the
    TSC brain phenotype and are increasingly attributed to
    oligodendrocyte-lineage mTORC1 dysregulation rather than being a purely
    secondary consequence of tuber burden or seizures. Altered myelination is
    associated with abnormal connectivity and is one proposed substrate for
    the cognitive and autism-spectrum components of TAND.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: PMID:33041976
    reference_title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mTOR hyperactivity promotes development of often multifocal brain lesions characterized by aberrant glioneuronal proliferation, cortical dyslamination, and hypomyelination"
    explanation: >
      Names hypomyelination as a defining component of the multifocal brain
      lesions produced by mTOR hyperactivity in TSC.
  - reference: PMID:33041976
    reference_title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oligodendrocyte dysfunction leads to hypomyelination and disturbed remyelination, and their proliferation is reduced."
    explanation: >
      Attributes the hypomyelination specifically to oligodendrocyte-lineage
      dysfunction, linking this phenotype to the gliopathy pathophysiology
      node rather than to neuronal dysplasia alone.
  - reference: PMID:32954437
    reference_title: "Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder."
    explanation: >
      Supplies the human evidence for the description's claim that altered
      myelination is a substrate for the cognitive and autism-spectrum
      components of TAND. Quantitative image analysis of resected cortical
      tubers from 46 patients found reduced oligodendroglia and altered myelin
      basic protein in both grey and white matter relative to matched controls,
      with the two clinical correlations quoted. These are cross-sectional
      associations in surgical specimens from patients selected for
      drug-resistant epilepsy, so they establish the link, not its direction.
  notes: >-
    No `frequency:` band is asserted. Neither Orphanet's HPO annotation set for
    ORPHA:805 nor the cited gliopathy review states a proportion of patients
    with hypomyelination, and imaging-based white-matter abnormality rates in
    TSC vary with modality and definition. Omitted rather than estimated.
- 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: Behavioral
  name: Depression
  frequency: FREQUENT
  description: >
    Depressive disorder is part of the psychiatric domain of TSC-associated
    neuropsychiatric disorders (TAND) and is a recognised contributor to the
    quality-of-life burden reported by adults with TSC and their caregivers.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000716 | Depression | Frequent (79-30%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies depression as
      frequent (79-30%) in tuberous sclerosis complex.
  - reference: PMID:32982929
    reference_title: "Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population"
    explanation: >
      TOSCA quality-of-life substudy corroborating a substantial burden of
      mood symptoms. Classified PARTIAL because the EQ-5D dimension pools
      anxiety and depression and is a self- or proxy-rated symptom score, not
      a clinical diagnosis of depressive disorder.
- category: Behavioral
  name: Aggressive Behavior
  frequency: FREQUENT
  description: >
    Aggressive and self-injurious behaviour fall within the behavioural domain
    of TAND and are among the manifestations that drive caregiver burden and
    the need for behavioural intervention.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000718 | Aggressive behavior | Frequent (79-30%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies aggressive
      behaviour as frequent (79-30%) in tuberous sclerosis complex.
- category: Behavioral
  name: Sleep Abnormality
  frequency: FREQUENT
  description: >
    Sleep disturbance is a recognised TAND manifestation in TSC, compounded by
    nocturnal seizures, and is one of the domains the annual TAND screen is
    intended to capture.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002360 | Sleep abnormality | Frequent (79-30%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies HP:0002360 as
      frequent (79-30%) in tuberous sclerosis complex. Orphanet's record
      renders the term with the exact synonym "Sleep abnormality"; the
      canonical HPO label for HP:0002360 is "Sleep disturbance", which is what
      `term.label` carries.
- 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: Dermatologic
  name: Fibrous Cephalic Plaque
  diagnostic: true
  description: >
    Fibrous cephalic plaques (forehead fibrous plaques) are raised, firm
    connective-tissue hamartomas appearing on the forehead or scalp. They are
    a major diagnostic feature of TSC. The 2012 International TSC Consensus
    guidelines mandate evaluation for fibrous cephalic plaques at time of
    diagnosis.
  phenotype_term:
    preferred_term: Fibrous cephalic plaque
    term:
      id: HP:0031111
      label: Cutaneous hamartoma
  evidence:
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial angiofibromas, fibrous cephalic plaques, hypomelanotic macules or confetti lesions, ungual fibromas, shagreen patch, defects in tooth enamel, and intraoral fibroma"
    explanation: >
      The 2012 International TSC Consensus recommendations explicitly list
      fibrous cephalic plaques among the dermatologic features requiring
      evaluation at time of TSC diagnosis, establishing them as a recognized
      major diagnostic criterion.
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"
    explanation: >
      Forehead (fibrous cephalic) plaques are identified as very rare or
      absent specifically in TSC1-related disease, unlike TSC2-related
      disease.
  notes: >
    Genotype-phenotype cohorts find forehead plaques very rare or absent in
    TSC1-related disease.
- 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: Oral
  name: Intraoral Fibroma
  frequency: OCCASIONAL
  description: >
    Intraoral fibromas (oral mucosal fibromas, gingival fibromas) are benign
    hamartomatous growths on the oral mucosa or gingiva in TSC patients. They
    are a minor diagnostic criterion for TSC. Oral fibromas may recur after
    surgical excision and require periodic oral evaluation per the 2012
    International TSC Consensus guidelines.
  phenotype_term:
    preferred_term: Intraoral fibroma
    term:
      id: HP:0010614
      label: Fibroma
  evidence:
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral fibromas should be excised surgically if symptomatic or if interfering with oral hygiene. Oral fibromas may recur once excised; therefore, periodic oral evaluation is encouraged."
    explanation: >
      The 2012 International TSC Consensus guidelines include oral fibromas
      as a dental/oral feature requiring evaluation and periodic surveillance,
      with surgical management guidance for symptomatic cases.
- 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.
  - reference: PMID:28057044
    reference_title: "TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SEGA were bilateral in 18% and growing in 4.5% of patients with mutations in TSC1 versus in 34 and 16% of patients with mutations in TSC2."
    explanation: >
      Among the 207 TOSCA SEGA patients with an identified pathogenic variant,
      SEGAs in TSC2-mutant patients were more often bilateral (34% vs 18%) and
      more often actively growing (16% vs 4.5%) than in TSC1-mutant patients,
      consistent with a TSC2 genotype-severity gradient for this manifestation.
      Interpret cautiously: the TSC1 arm is small (n=22, vs n=185 for TSC2), so
      "4.5% growing" represents a single patient, and TOSCA reports no
      significance test for this comparison.
- 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
  notes: >
    Genotype-phenotype cohorts find retinal hamartomas very rare or absent in
    sporadic TSC1-related disease; this phenotype is disproportionately
    TSC2-driven.
  evidence:
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma."
    explanation: >
      Directly reports that sporadic TSC1 patients had no retinal
      hamartomas, in contrast to TSC2 patients.
- 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.
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sporadic patients with TSC1 mutations had, on average, milder disease in comparison with patients with TSC2 mutations, despite being of similar age. They had a lower frequency of seizures and moderate-to-severe mental retardation, fewer subependymal nodules and cortical tubers, less-severe kidney involvement, no retinal hamartomas, and less-severe facial angiofibroma."
    explanation: >
      Sporadic TSC1 patients had less-severe kidney involvement overall than
      TSC2 patients.
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"
    explanation: >
      Grade 2-4 (higher-severity) angiomyolipomas are identified as very rare
      or absent specifically in TSC1-related disease.
  - reference: PMID:33041968
    reference_title: "Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years."
    explanation: >
      Median age at angiomyolipoma diagnosis in the largest international TSC
      registry cohort (1,062 patients with a history of angiomyolipoma out of
      2,211 enrolled), anchoring the adolescent onset of this phenotype.
  - reference: PMID:33041968
    reference_title: "Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary."
    explanation: >
      Establishes 18-40 years as the peak window for new angiomyolipoma
      appearance and the rationale for lifelong rather than time-limited
      abdominal imaging surveillance.
  notes: >
    Renal angiomyolipoma still occurs in TSC1-related disease, but kidney
    involvement is on average less severe than in TSC2-related disease;
    grade 2-4 angiomyolipomas are very rare or absent in isolated TSC1
    disease.
- 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
  notes: >
    Grade 2-4 (higher-severity) renal cysts are very rare or absent in
    isolated TSC1-related disease; this severe end of the spectrum is
    disproportionately TSC2-driven.
  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.
  - reference: PMID:11112665
    reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some features (grade 2-4 kidney cysts or angiomyolipomas, forehead plaques, retinal hamartomas, and liver angiomyolipomas) were very rare or not seen at all in TSC1 patients"
    explanation: >
      Grade 2-4 kidney cysts are identified as very rare or absent
      specifically in TSC1-related disease.
- 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: Pulmonary
  name: Multifocal Micronodular Pneumocyte Hyperplasia
  description: >
    Multifocal micronodular pneumocyte hyperplasia (MMPH) is a distinct
    pulmonary manifestation of TSC characterized by multiple small nodular
    proliferations of type II pneumocytes. Unlike LAM it affects both sexes
    and is usually asymptomatic and non-progressive, but it is a recognized
    TSC lung finding separate from the cystic LAM phenotype.
  phenotype_term:
    preferred_term: Multifocal micronodular pneumocyte hyperplasia
    term:
      id: HP:0033328
      label: Type II pneumocyte hyperplasia
  evidence:
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multifocal micronodular pneumonocyte hyperplasia"
    explanation: >
      GeneReviews lists multifocal micronodular pneumonocyte hyperplasia among
      the lung manifestations of TSC, alongside lymphangioleiomyomatosis.
- 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.
- category: Musculoskeletal
  name: Sclerotic Bone Lesions
  frequency: OCCASIONAL
  description: >
    Sclerotic bone lesions are focal areas of increased bone density in TSC
    patients, detectable on radiographs, and are a minor diagnostic criterion
    reinstated in the 2021 International TSC Consensus update. These
    osteosclerotic hamartomas are typically asymptomatic and represent
    disordered bone formation driven by mTORC1 dysregulation.
  phenotype_term:
    preferred_term: Sclerotic bone lesions
    term:
      id: HP:0005686
      label: Patchy osteosclerosis
  evidence:
  - reference: PMID:34399110
    reference_title: "Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sclerotic bone lesions were reinstated as a minor criterion"
    explanation: >
      The 2021 International TSC Consensus reinstated sclerotic bone lesions
      as a minor diagnostic criterion for TSC, acknowledging their role as a
      recognized manifestation of the disease.
- category: Cardiac
  name: Cardiac Arrhythmia
  frequency: OCCASIONAL
  description: >
    Cardiac arrhythmias and conduction defects are recognized cardiovascular
    features of TSC, particularly in pediatric patients. The 2012 International
    TSC Consensus guidelines mandate electrocardiogram (ECG) at diagnosis in
    young children to evaluate for arrhythmia, and recommend follow-up ECG
    monitoring every 3-5 years in asymptomatic adults because conduction defects
    may persist throughout life. Arrhythmias are mechanistically linked to the
    presence of cardiac rhabdomyomas that can disrupt the conduction system.
  phenotype_term:
    preferred_term: Cardiac arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "echocardiogram and electrocardiogram (ECG) should be obtained to evaluate for rhabdomyomas and arrhythmia, respectively"
    explanation: >
      The 2012 International TSC Consensus guidelines explicitly mandate ECG
      at diagnosis in pediatric patients to evaluate for arrhythmia, establishing
      cardiac arrhythmia as a recognized surveillance target in TSC. The snippet
      supports the disease-phenotype association but not a specific frequency band;
      the OCCASIONAL assignment is a clinical estimate (no quantitative frequency
      is reported in the guideline and no Orphanet frequency is available for this
      phenotype).
- category: Renal
  name: Hypertension
  frequency: OCCASIONAL
  description: >
    Secondary hypertension is a recognized complication of renal tuberous sclerosis
    complex manifestations, particularly from renal angiomyolipomas and cysts
    impairing normal renal architecture and renin-angiotensin regulation. The 2012
    International TSC Consensus guidelines require annual blood pressure assessment
    and recommend renin-angiotensin system inhibitors as first-line therapy when
    hypertension is identified.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  notes: >
    The 2012 International TSC Consensus carries a clinically important drug-interaction
    caveat for first-line antihypertensive choice: angiotensin-converting enzyme (ACE)
    inhibitors should be avoided in patients concurrently treated with an mTOR inhibitor
    (e.g. everolimus, sirolimus), because of an increased risk of angioedema with that
    combination. A non-ACE renin-angiotensin-aldosterone system inhibitor is preferred
    in mTOR-inhibitor-treated patients.
  evidence:
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accurate blood pressure assessment is important because of increased risk of secondary hypertension"
    explanation: >
      The 2012 International TSC Consensus guidelines identify secondary hypertension
      as an increased-risk complication warranting dedicated blood pressure assessment
      at time of TSC diagnosis.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual clinical assessment of renal function and hypertension is required"
    explanation: >
      Ongoing annual hypertension surveillance is mandated by the 2012 International
      TSC Consensus, reflecting the chronic risk of secondary hypertension from
      progressive renal disease in TSC.
- category: Renal
  name: Renal Cell Carcinoma
  frequency: VERY_RARE
  description: >
    TSC patients have an elevated risk of renal cell carcinoma (RCC) compared with
    the general population. RCC arises in the context of the broader renal involvement
    of TSC alongside angiomyolipomas and cysts, and is included as an explicit
    surveillance target in the 2012 International TSC Consensus guidelines, which
    mandate periodic renal MRI to detect RCC and other tumors.
  phenotype_term:
    preferred_term: Renal cell carcinoma
    term:
      id: HP:0005584
      label: Renal cell carcinoma
  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, which may progress and cause pain, bleeding, and loss of kidney function."
    explanation: >
      Identifies renal cell carcinoma as one of the three major kidney manifestations
      of TSC alongside cystic lesions and angiomyolipomas.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Imaging to diagnose polycystic disease, renal cell carcinoma or other tumors"
    explanation: >
      The 2012 International TSC Consensus guidelines include renal cell carcinoma
      as an explicit surveillance target requiring periodic renal MRI.
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005584 | Renal cell carcinoma | Very rare (<4-1%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies renal cell carcinoma
      as very rare in tuberous sclerosis complex.
  - reference: PMID:25432535
    reference_title: "A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal cell carcinoma (RCC) occurs in ∼3% of TSC patients, and typically develops at age <50."
    explanation: >
      Quantifies RCC frequency (~3%) and typical age of onset (<50 years) in TSC.
      Both reported cases carried the germline TSC2 variant p.R905Q and had
      multifocal papillary RCC; among the tumors that underwent targeted
      sequencing, most harbored an independent somatic TSC2 second hit,
      illustrating subtype-relevant renal tumor multifocality.
- category: Renal
  name: Renal Oncocytoma
  description: >
    Renal oncocytoma is a benign renal epithelial tumour composed of
    mitochondria-rich oncocytes. It is a recognised but uncommon renal
    manifestation of TSC, distinct from the far more frequent angiomyolipomas
    and epithelial cysts, and is relevant to the differential diagnosis of a
    solid renal mass detected on TSC surveillance imaging.
  phenotype_term:
    preferred_term: Renal oncocytoma
    term:
      id: HP:0011798
      label: Renal oncocytoma
  evidence:
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "kidneys (benign renal angiomyolipomas, epithelial cysts, oncocytoma, renal cell carcinoma)"
    explanation: >
      GeneReviews lists oncocytoma among the kidney manifestations of TSC
      alongside angiomyolipomas, epithelial cysts, and renal cell carcinoma.
- category: Renal
  name: Chronic Kidney Disease
  frequency: FREQUENT
  description: >
    Progressive loss of kidney function is a major long-term complication of
    TSC, arising from cumulative parenchymal replacement by angiomyolipomas
    and cysts, from haemorrhage, and from the cumulative nephron loss of
    repeated embolisation or nephrectomy. It is the reason the consensus
    surveillance schedule pairs abdominal imaging with at least annual blood
    pressure and renal-function measurement, and the reason nephron-sparing
    management is preferred over nephrectomy.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  evidence:
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012622 | Chronic kidney disease | Frequent (79-30%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies chronic kidney
      disease as frequent (79-30%) in tuberous sclerosis complex.
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003774 | Stage 5 chronic kidney disease | Very rare (<4-1%)"
    explanation: >
      Orphanet separately annotates end-stage (stage 5) chronic kidney disease
      as very rare, indicating that while reduced renal function is common,
      progression to kidney failure is not the usual outcome.
  - 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: >
      Identifies loss of kidney function as the shared downstream consequence
      of the cystic and angiomyolipomatous renal lesions of TSC.
- category: Hepatic
  name: Hepatic Cysts
  frequency: OCCASIONAL
  description: >
    Hepatic cysts and extrarenal hamartomas of the liver can occur in TSC as part
    of the generalized multisystem hamartoma phenotype. They are typically detected
    incidentally on abdominal MRI performed for renal surveillance and are usually
    asymptomatic.
  phenotype_term:
    preferred_term: Hepatic cysts
    term:
      id: HP:0001407
      label: Hepatic cysts
  evidence:
  - reference: ORPHA:805
    reference_title: "Tuberous sclerosis complex"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001407 | Hepatic cysts | Occasional (29-5%)"
    explanation: >
      Orphanet's curated HPO frequency annotation classifies hepatic cysts as
      occasional (29-5%) in tuberous sclerosis complex.
genetic:
- name: TSC1
  gene_term:
    preferred_term: TSC1
    term:
      id: hgnc:12362
      label: TSC1
  association: Pathogenic Mutations
  presence: Positive
  notes: >
    TSC1 on chromosome 9q34 encodes hamartin. Loss-of-function variants account
    for ~15-20% of molecularly solved TSC cases across independent cohorts.
    Pathogenic alterations are predominantly protein-truncating (nonsense,
    frameshift, splice-site, or large intragenic deletion/duplication);
    missense variants are comparatively rare in TSC1, in contrast to TSC2
    where they cluster in functional domains. TSC1-related disease is on
    average milder than TSC2-related disease and is significantly enriched
    in familial (versus sporadic) TSC.
  case_fractions:
  - population: US/Poland TSC cohort (Dabora et al. 2001)
    case_fraction_percent: 15.1
    cohort_size: 186
    notes: >-
      28 of 186 mutation-positive index patients (out of 224 screened) had
      small TSC1 mutations.
    evidence:
    - reference: PMID:11112665
      reference_title: "Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutations were identified in 186 (83%) of 224 of cases, comprising 138 small TSC2 mutations, 20 large TSC2 mutations, and 28 small TSC1 mutations."
      explanation: Source cohort counts for the TSC1 case-fraction estimate.
  - population: UK/Cardiff TSC cohort (Jones et al. 1999)
    case_fraction_percent: 18.3
    cohort_size: 120
    notes: >-
      22 of 120 mutation-positive patients (out of 150 screened families) had
      TSC1 mutations.
    evidence:
    - reference: PMID:10205261
      reference_title: "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 98 cases."
      explanation: Source cohort counts for the TSC1 case-fraction estimate.
  - population: Molecularly solved TSC cohort (Dufner-Almeida et al. 2024)
    case_fraction_percent: 17.0
    cohort_size: 106
    notes: 18 of 106 molecularly solved cases carried a TSC1 pathogenic variant.
    evidence:
    - 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: Quantifies the TSC1 share of pathogenic variants among molecularly solved cases.
  - population: TOSCA international registry, molecularly tested patients (n=902)
    case_fraction_percent: 19.7
    cohort_size: 902
    notes: >
      Denominator is patients who underwent molecular testing (902 of 2,093
      enrolled), not molecularly solved cases; the TSC1 19.7% + TSC2 63.3%
      shares leave the remainder as no-mutation-identified.
    evidence:
    - reference: PMID:28057044
      reference_title: "TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TSC1 mutations were identified in 19.7% of the patients and TSC2 in 63.3%"
      explanation: Quantifies the TSC1 share among molecularly tested patients in the 2,093-patient international TOSCA registry.
  - population: Danish TSC cohort (Rosengren et al. 2020)
    case_fraction_percent: 25.0
    cohort_size: 168
    notes: >-
      42 of 168 individuals with a predicted pathogenic or likely pathogenic
      variant carried a TSC1 variant (33 distinct TSC1 variants), out of 327
      individuals screened for suspected TSC.
    evidence:
    - reference: PMID:32555378
      reference_title: "Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A total of 137 predicted pathogenic or likely pathogenic variants were identified: 33 different TSC1 variants in 42 patients, and 104 different TSC2 variants in 126 patients."
      explanation: Source cohort counts for the TSC1 case-fraction estimate.
  - population: Sicilian TSC cohort (Praticò et al. 2025)
    case_fraction_percent: 38.3
    cohort_size: 81
    notes: >-
      31 of 81 genotyped Sicilian patients carried a pathogenic TSC1 variant.
      This is a marked regional outlier - well above the 15-25% TSC1 share
      seen in the US/UK/Brazilian/Danish cohorts and the TOSCA registry - and
      is inflated in part by six related patients from a single family
      carrying the same c.1498C>T p.(Arg500Ter) allele. Treat it as evidence
      of ascertainment and founder effects in a small regional series, not as
      a revised global estimate.
    evidence:
    - reference: PMID:40579409
      reference_title: "Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pathogenic TSC2 variants were more common than pathogenic TSC1 variants (61.7% vs. 38.3%)."
      explanation: Source cohort proportions for the TSC1 case-fraction estimate.
  evidence:
  - reference: PMID:32555378
    reference_title: "Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC1 is located on chromosome 9q34 and consists of 23 exons, which encode the 130 kDa TSC1 protein, hamartin."
    explanation: >
      Locus, exon count, and protein product for TSC1, anchoring the gene
      description above to a primary source.
  - reference: PMID:32555378
    reference_title: "Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To assist in the classification of 11 TSC2 variants, we investigated the effects of these variants in an in vitro functional assay. Based on the functional results, as well as population and genetic data, we classified 8 variants as likely to be pathogenic and 3 as likely to be benign."
    explanation: >
      Demonstrates the in vitro TSC-complex functional assay as a practical
      adjunct to sequence-only ACMG/AMP classification. The 11 assayed
      variants in this study were TSC2, not TSC1; the assay platform is
      shared, and the same group applied it to TSC1 variants in the 2024
      Brazilian cohort (PMID:39596632), but this particular result does not
      itself demonstrate TSC1 variant reclassification.
  - 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: PMID:10205261
    reference_title: "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein."
    explanation: >
      Establishes that TSC1 pathogenic variants are almost uniformly
      truncating, distinct from TSC2's broader spectrum that also includes
      missense variants clustered in functional domains.
  - reference: PMID:10205261
    reference_title: "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC1 mutations were significantly underrepresented in sporadic cases (P=. 000185)."
    explanation: >
      Establishes that TSC1 variants are significantly enriched in familial
      (versus sporadic/de novo) TSC relative to TSC2.
  - 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
  gene_term:
    preferred_term: TSC2
    term:
      id: hgnc:12363
      label: 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. Within TSC2 itself,
    variant class and location further stratify severity: protein-truncating
    variants and variants in the hamartin (TSC1)-interaction domain are
    associated with lower intellectual outcomes, whereas TSC2 missense variants
    and small in-frame deletions are associated with higher IQ/DQ.
  case_fractions:
  - population: Molecularly solved TSC cohort (Molecular and Functional Assessment study)
    case_fraction_percent: 83.0
    cohort_size: 106
    notes: 88 of 106 molecularly solved cases carried a TSC2 pathogenic variant.
    evidence:
    - 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: Quantifies the TSC2 share of pathogenic variants among molecularly solved cases (the majority gene).
  - population: TOSCA international registry, molecularly tested patients (n=902)
    case_fraction_percent: 63.3
    cohort_size: 902
    notes: >
      Denominator is patients who underwent molecular testing (902 of 2,093
      enrolled), not molecularly solved cases; the TSC1 19.7% + TSC2 63.3%
      shares leave the remainder as no-mutation-identified.
    evidence:
    - reference: PMID:28057044
      reference_title: "TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TSC1 mutations were identified in 19.7% of the patients and TSC2 in 63.3%"
      explanation: Quantifies the TSC2 share among molecularly tested patients in the 2,093-patient international TOSCA registry, independently corroborating TSC2 as the predominant gene.
  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.
  - reference: PMID:22189265
    reference_title: "Genotype and cognitive phenotype of patients with tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSC2 protein-truncating mutations and small in-frame mutations are associated with distinctly different intelligence profiles"
    explanation: A 137-patient genotype-neurocognitive-phenotype cohort shows TSC2 variant class (truncating/hamartin-interaction-domain vs missense/small in-frame) stratifies intellectual outcome, refining the general TSC2-severity correlation.
- name: Somatic Mosaicism
  association: Mosaic Pathogenic Variants
  presence: Positive
  variant_origin: SOMATIC
  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. The postulate has since been
    tested directly: deep sequencing of two to four tissues per participant in
    an 18-patient "no mutation identified" cohort solved 13 (72%), of which 10
    were mosaic, so mosaicism is a demonstrated rather than an assumed
    explanation for the majority of conventionally negative cases.
  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.
  - reference: PMID:39352229
    reference_title: 'Deep Sequencing and Phenotyping in an Australian Tuberous Sclerosis Complex "No Mutations Identified" Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A diagnostic yield of 72% (13/18) was achieved, with the majority (10/13) being mosaic variants and the remainder heterozygous variants missed on previous testing."
    explanation: >
      Converts the mosaicism hypothesis into a measured yield. Massively
      parallel sequencing across the whole genomic regions of TSC1 and TSC2, run
      on two to four tissues per participant (blood, buccal swab, and where
      available lesional skin), resolved 13 of 18 clinically definite
      no-mutation-identified cases, 10 of them mosaic. Note the remaining five
      stayed unsolved even at 4000x depth, so mosaic detection does not account
      for every negative case.
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.
  - 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: "Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common."
    explanation: >
      Real-world tolerability denominator for chronic everolimus therapy:
      essentially all treated patients (61/64) experienced at least one
      adverse effect over a median 31 months, with oral
      ulceration/stomatitis the dominant treatment-limiting toxicity.
  - 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: "The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients."
    explanation: >
      Defines the laboratory-monitoring requirement (lipids, haemoglobin,
      white-cell count) and quantifies serious toxicity, supporting the
      surveillance burden that accompanies pathway-directed mTOR inhibition.
  - 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: "Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects."
    explanation: >
      The authors' own management conclusion: adverse-effect ascertainment is
      unreliable in patients with intellectual disability or limited
      communication, so monitoring must be clinician-driven.
  - reference: PMID:30192751
    reference_title: "Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth."
    explanation: >
      Substantiates the cytostatic-not-curative characterisation in the notes
      below, with the authors' own limit on it. In the EXIST-2 non-interventional
      follow-up, median angiomyolipoma volume relative to baseline moved from
      -70.6% at the point of everolimus discontinuation to -50.6% one year off
      drug, and 5 of 16 evaluable patients progressed relative to their volume at
      discontinuation - but the paper explicitly declines to call this rapid
      regrowth. Only 16 of the 112 patients who discontinued were evaluable, so
      the rebound estimate is imprecise.
  notes: >-
    Everolimus is cytostatic rather than curative in TSC: lesions regress
    during treatment and can regrow after withdrawal, so the tolerability
    profile above is a chronic-exposure profile, not a course-of-treatment
    one. The real-world Norwegian/Danish series (n=64) reports a lower
    epilepsy response rate than the EXIST-3 trial and an age gradient
    (46% responders under 18 years vs 14% at or above 18 years).
- 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.
  evidence:
  - reference: PMID:37041855
    reference_title: "Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An increasing body of research suggests that early, effective treatment of TSC-associated epilepsy during critical neurodevelopmental periods can potentially improve cognitive outcomes."
    explanation: >
      States the rationale for treating TSC-associated epilepsy early and
      aggressively - the intervention window is developmental, not merely
      symptomatic - which is the basis for first-line vigabatrin and for the
      pre-symptomatic prevention trials.
  - reference: PMID:37041855
    reference_title: "Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Refractory TSC-associated epilepsy is associated with increased risk of neurodevelopmental comorbidities, including developmental delay, intellectual disability, autism spectrum disorder, and attention hyperactivity disorder."
    explanation: >
      Establishes the outcome that early seizure control is intended to
      prevent, linking refractory epilepsy to the TAND comorbidity cluster
      already curated in this entry.
  - reference: PMID:41061327
    reference_title: "Neurodevelopmental Outcomes From the PREVeNT Trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No significant differences in developmental or autism-specific outcomes were seen between treatment groups"
    explanation: >
      Tests the neurodevelopmental rationale above and does not find it. PREVeNT
      was a Phase IIb multicentre double-blind placebo-controlled trial of
      pre-emptive vigabatrin in 84 infants with TSC across 13 US clinics; 65
      completed assessments to 36 months, 31% were rated as having autism
      spectrum disorder, and that rate did not differ by treatment assignment.
      This refutes the prevention rationale, not vigabatrin's established
      efficacy against infantile spasms, which is a separate claim. The
      investigators note the null may partly reflect early seizure detection
      and closer developmental monitoring across every arm of the trial.
  - reference: PMID:32705817
    reference_title: "Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years"
    explanation: >
      Independent replication of the same null at an earlier timepoint, in a
      prospective cohort of 80 infants enrolled at four months or younger and
      followed with monthly video EEG. The same study found abnormal
      developmental trajectories before seizure onset in 20% of children, and
      21% of those at risk of autism at 24 months had never had a seizure -
      so part of the neurodevelopmental burden is already established before
      there are seizures for vigabatrin to prevent.
  notes: >-
    The neurodevelopmental prevention rationale above has now been tested twice
    and failed twice: neither pre-emptive vigabatrin in PREVeNT (36-month
    outcomes) nor early versus conventional vigabatrin in the EPISTOP-linked
    cohort (24-month outcomes) altered developmental or autism outcomes. The
    first-line indication for TSC-associated infantile spasms is unaffected -
    that rests on seizure control, not on neurodevelopmental prevention.
- 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. Agents/circumstances to avoid
    (GeneReviews): smoking and estrogen use are both listed among the
    circumstances to avoid in TSC and are of particular relevance to women
    with, or at risk of, lymphangioleiomyomatosis.
  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.
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy."
    explanation: >
      GeneReviews lists smoking and estrogen use among the circumstances to
      avoid in TSC, supporting the counselling note recorded in this
      treatment's description.
- 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.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      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. Agents/circumstances
    to avoid (GeneReviews): nephrectomy is explicitly listed among the
    circumstances to avoid in TSC — because renal lesions are typically
    bilateral and multifocal, kidney-sparing approaches (embolization,
    kidney-sparing resection, ablation) are preferred over nephrectomy to
    preserve long-term renal function. GeneReviews also lists smoking and
    estrogen use as circumstances to avoid; those two are recorded on the
    pulmonary/LAM-directed treatment rather than here.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      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.
  - reference: PMID:20301399
    reference_title: "Tuberous Sclerosis Complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy."
    explanation: >
      GeneReviews explicitly lists nephrectomy (alongside smoking and estrogen
      use) as a circumstance to avoid in TSC, supporting the kidney-sparing
      preference recorded in this treatment's description.
  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: NCIT:C15747
      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: NCIT:C15240
      label: Genetic Counseling
- name: Multisystem Surveillance and Screening (2012 International TSC Consensus, updated 2021)
  description: >
    Lifelong, age-appropriate multisystem surveillance and screening per the
    evidence-based recommendations of the International TSC Consensus Group,
    first issued by the 2012 Consensus Conference (Krueger & Northrup 2013) and
    revised by the 2021 update (Northrup et al. 2021), which is the current
    authoritative standard. Core elements include serial brain MRI for
    subependymal giant cell astrocytoma, annual renal function and
    blood-pressure assessment with periodic renal MRI for angiomyolipomata,
    at-least-annual TAND (TSC-associated neuropsychiatric disorders) screening,
    an annual skin survey, periodic echocardiography and ECG until cardiac
    rhabdomyoma regression, and HRCT plus pulmonary function testing for
    lymphangioleiomyomatosis risk in females from age 18. The 2021 revision
    largely retained the 2013 schedules while adding increased emphasis on
    early screening for electroencephalographic abnormalities, enhanced TAND
    surveillance and management, and new medication approvals. Because the
    dominant pathology shifts across the lifespan, coordinated multidisciplinary
    surveillance enables early detection and treatment of complications, the
    factor most associated with optimal outcome.
  treatment_term:
    preferred_term: multisystem disease surveillance and screening
    term:
      id: NCIT:C15747
      label: Supportive Care
  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: Pulmonary lymphangioleiomyomatosis
    term:
      id: HP:0005948
      label: Multiple pulmonary cysts
  evidence:
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals suspected of having TSC, regardless of age, should undergo magnetic resonance imaging (MRI) of the brain with and without gadolinium"
    explanation: >
      2012 International TSC Consensus baseline brain-MRI recommendation
      (Category 1) at the time of diagnosis to assess for tubers, subependymal
      nodules, and SEGA.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surveillance by MRI should be performed every 1–3 years in all individuals with TSC until the age of 25 years."
    explanation: >
      Consensus SEGA surveillance schedule (Category 2A); optimal outcome is
      associated with early detection and treatment.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual clinical assessment of renal function and hypertension is required."
    explanation: >
      Consensus renal-surveillance recommendation (Category 1); periodic renal
      MRI monitors angiomyolipomata, which require more intervention in
      adulthood.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is imperative to continue to monitor for features of TAND and their impact on daily living through basic questioning and screening procedures at each follow-up clinic visit, with a minimum frequency of once per year."
    explanation: >
      Consensus minimum annual TAND screening at each clinic visit (Category 1),
      with comprehensive formal evaluations at scheduled developmental time
      points.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A skin survey should be performed annually, with focus on rapidly changing or symptomatic (problematic or functionally impacting) lesions"
    explanation: >
      Consensus annual dermatologic surveillance recommendation, with early
      intervention for bleeding, symptomatic, or disfiguring skin lesions.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "follow-up echocardiogram should be performed every 1–3 years in asymptomatic patients. In addition, 12-lead ECG is recommended at minimum every 3–5 years to monitor for conduction defects."
    explanation: >
      Consensus cardiac surveillance schedule (Category 1) until rhabdomyoma
      regression is documented.
  - reference: PMID:24053983
    reference_title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To evaluate for LAM, females 18 years or older should have baseline pulmonary function testing, 6-minute walk test, and high-resolution chest computed tomography (HRCT)."
    explanation: >
      Consensus baseline pulmonary evaluation for lymphangioleiomyomatosis risk
      (Category 2A) in adult females, with periodic HRCT follow-up.
  - reference: PMID:34399110
    reference_title: "Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations."
    explanation: >
      The 2021 International TSC Consensus update revises and supersedes the 2013
      (2012 Conference) surveillance and management recommendations cited above,
      reflecting new knowledge and therapy approvals since 2013.
  - reference: PMID:34399110
    reference_title: "Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals."
    explanation: >
      The substantive 2021 surveillance/management changes: earlier EEG
      screening for epileptiform abnormalities, intensified TAND surveillance,
      and incorporation of newly approved therapies into management.
  - reference: PMID:34399110
    reference_title: "Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families."
    explanation: >
      The 2021 consensus positions its updated surveillance and management
      recommendations as the current framework for optimal multidisciplinary
      TSC care.
experimental_models:
- name: TSC patient-derived neurovascular unit (iPSC blood-brain-barrier chip)
  experimental_model_type: ORGAN_ON_CHIP
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: >-
    Patient-derived induced pluripotent stem cells carrying a heterozygous TSC2
    variant, differentiated to brain microvascular endothelial cells and
    astrocytes.
  culture_system: Microfluidic multi-compartment neurovascular-unit chip
  description: >-
    A human microphysiological blood-brain-barrier model assembled from
    TSC-patient iPSC-derived endothelium and astrocytes. It provides a
    human, lineage-resolvable readout of neurovascular dysfunction in TSC
    that neither rodent models nor two-dimensional culture supply, and it
    supports lineage-swap experiments (mutant endothelium with wild-type
    astrocytes) that separate cell-autonomous from non-cell-autonomous
    contributions to the barrier defect.
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  conditions:
  - TSC2 heterozygous mutant barrier
  - TSC2 mutant barrier with wild-type astrocytes
  - TSC2 mutant barrier treated with rapamycin
  modeled_mechanisms:
  - target: mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction
    description: >-
      The chip reproduces the increased barrier permeability of the TSC
      neurovascular unit and shows it is reversible by astrocyte replacement
      or mTOR inhibition.
    evidence:
    - reference: PMID:38783199
      reference_title: "Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor."
      explanation: >
        Directly demonstrates the modelled mechanism and its
        astrocyte-dependence and mTOR-dependence.
  evidence:
  - reference: PMID:38783199
    reference_title: "Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies."
    explanation: >
      Describes the construction of the model system - iPSC-derived cells in
      a microfluidic culture platform.
  notes: >-
    The published model uses TSC2 heterozygous patient cells. An equivalent
    TSC1-mutant neurovascular-unit model was not identified in this curation
    pass; the mechanism is expected to be shared because both proteins act
    through the same TSC complex, but that expectation is untested here.
- name: CRISPR-engineered TSC2 conditional-biallelic human cortical spheroids
  experimental_model_type: ORGANOID
  organism: &id001
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human pluripotent stem cells with CRISPR-Cas9-edited TSC1 or TSC2, including heterozygous
    TSC2 lines carrying a conditional mutation in the remaining allele, differentiated to three-dimensional
    cortical spheroids
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  conditions:
  - TSC2 heterozygous with conditional loss of the functional allele
  - Mosaic biallelic TSC2 inactivation during neural progenitor expansion
  publication: PMID:30127391
  description: Isogenic cortical spheroids in which the timing of biallelic TSC2 loss can be controlled.
    Mosaic second-hit loss during progenitor expansion is necessary for dysplastic cells and excess glia,
    supporting the second-hit model of tuber formation.
  evidence:
  - reference: PMID:30127391
    reference_title: Genetically engineered human cortical spheroid models of tuberous sclerosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we established human cellular models of TSC by CRISPR-Cas9-mediated gene editing of TSC1
      or TSC2 in human pluripotent stem cells (hPSCs).
    explanation: Establishes the engineered human model.
  modeled_mechanisms:
  - target: Somatic Second Hit at TSC Locus
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The conditional allele lets biallelic TSC2 loss be triggered in a mosaic of neural progenitors,
      and only that second hit produces dysplastic cells and excess glia, which is the somatic second-hit
      node.
    limitations: The second hit is induced experimentally rather than arising spontaneously, and the spheroids
      lack vasculature, microglia and the in-vivo developmental timeline.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: >-
        The spheroid result assumes the second hit is required for tuber cells,
        but the patient-derived cerebral organoids in PMID:35084981, added in
        the same pass, find wild-type TSC2 protein in over 98% of giant cells in
        TSC2+/- organoids and conclude that bi-allelic inactivation is
        dispensable for disease initiation in human tissue. The two human
        models therefore disagree on whether this node is necessary for tuber
        formation, which is why the link is not graded HIGH.
    evidence:
    - reference: PMID:30127391
      reference_title: Genetically engineered human cortical spheroid models of tuberous sclerosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we
        show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the
        formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids.
        Our findings provide support for the second-hit model of cortical tuber formation
      explanation: A human model in which the second hit is necessary for the dysplastic phenotype directly
        tests the node.
    readouts:
    - name: Dysplastic cell formation after mosaic biallelic TSC2 loss
      target: Somatic Second Hit at TSC Locus
      direction: INCREASED
      interpretation: Dysplastic cells form only when both alleles are lost during progenitor expansion.
      evidence:
      - reference: PMID:30127391
        reference_title: Genetically engineered human cortical spheroid models of tuberous sclerosis.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: mosaic biallelic inactivation during neural progenitor expansion is necessary for the
          formation of dysplastic cells and increased glia production in three-dimensional cortical spheroids
        explanation: Reports the dysplasia measurement.
    - name: Glia production after mosaic biallelic TSC2 loss
      target: Somatic Second Hit at TSC Locus
      direction: INCREASED
      interpretation: Glial output increases with biallelic loss.
      evidence:
      - reference: PMID:30127391
        reference_title: Genetically engineered human cortical spheroid models of tuberous sclerosis.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: increased glia production in three-dimensional cortical spheroids
        explanation: Reports the glia measurement.
  - target: Neuroglial Dysplasia and Cortical Network Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Spheroids reproduce the dysmorphic cells and glial excess of a tuber but not cortical
      lamination, network activity or epileptogenesis.
    limitations: No layered cortex, no electrophysiological network readout and no seizure phenotype;
      the tuber is represented by its cellular composition only.
    evidence:
    - reference: PMID:30127391
      reference_title: Genetically engineered human cortical spheroid models of tuberous sclerosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Hallmark pathologies of TSC are cortical tubers-regions of dysmorphic, disorganized neurons
        and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin
        of tuber cells, we established human cellular models of TSC
      explanation: The model is built to reproduce tuber cell composition, which is part of what this
        node describes.
    readouts:
    - name: Dysplastic cells and glia in cortical spheroids
      target: Neuroglial Dysplasia and Cortical Network Disorganization
      direction: INCREASED
      interpretation: Tuber-like cellular composition arises after the second hit.
      evidence:
      - reference: PMID:30127391
        reference_title: Genetically engineered human cortical spheroid models of tuberous sclerosis.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: the formation of dysplastic cells and increased glia production in three-dimensional
          cortical spheroids
        explanation: Reports the cellular composition measurement.
- name: TSC human cerebral organoids with caudal late interneuron progenitor (CLIP) over-proliferation
  experimental_model_type: ORGANOID
  organism: *id001
  cell_source: Induced pluripotent stem cells derived from patients carrying TSC2 mutations, with isogenic
    TSC2+/+ control lines, grown as cerebral organoids
  cell_types:
  - preferred_term: caudal late interneuron progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  conditions:
  - TSC2 heterozygous patient-derived cerebral organoids
  - Epidermal growth factor receptor inhibition
  publication: PMID:35084981
  description: Cerebral organoids identify a human-specific interneuron progenitor population that over-proliferates
    in TSC, generating excess interneurons, tumours and cortical malformations; EGFR inhibition reduces
    tumour burden.
  evidence:
  - reference: PMID:35084981
    reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological
      defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified
      a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells.
    explanation: Establishes the organoid model and the cell population it identifies.
  modeled_mechanisms:
  - target: Somatic Second Hit at TSC Locus
    relationship: FAILS_TO_RECAPITULATE
    model_scale: CELLULAR
    description: >-
      Giant cells in TSC2+/- patient organoids retain wild-type TSC2 protein,
      so tuber-like cells form here without the somatic second hit this node
      requires; the authors conclude bi-allelic inactivation is dispensable for
      disease initiation in human tissue.
    limitations: >-
      The antibody readout reports presence of wild-type protein, not absence
      of a second hit by sequencing, and organoids at 230 days do not reach the
      timescale over which subependymal tumours acquire bi-allelic loss in
      patients. This directly conflicts with the conditional-biallelic
      spheroid model above.
    evidence:
    - reference: PMID:35084981
      reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        TSC2 protein expression was detected in over 98% of giant cells using an
        antibody recognizing only the wild type TSC2 variant (patient 1, 98.4%;
        patient 2, 98.7%: Fig. S7A-C). TSC2 protein was also expressed in giant
        cells in fetal cortical tubers (Fig. S7D), consistent with previous data
        (26, 27). This suggests that second-hit events are not a prerequisite
        for tuber formation.
      explanation: >-
        Wild-type TSC2 in nearly all giant cells means the model produces tuber
        cells without the second hit, which is a failure to recapitulate the
        node rather than a low-fidelity version of it.
    readouts:
    - name: Wild-type TSC2 protein in giant cells
      target: Somatic Second Hit at TSC Locus
      direction: UNCHANGED
      interpretation: Over 98% of giant cells retain wild-type TSC2, so no loss of the second allele is seen.
      evidence:
      - reference: PMID:35084981
        reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological defects.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: TSC2 protein expression was detected in over 98% of giant cells using an antibody recognizing only the wild type TSC2 variant
        explanation: Reports the giant-cell TSC2 immunostaining measurement.
  - target: Subependymal Glioneuronal Tumor Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: CLIP cell over-proliferation in TSC organoids produces brain tumours, matching the subependymal
      tumour growth node and proposing its human-specific cell of origin.
    limitations: Organoid tumours lack the ventricular location, vasculature and growth timescale of a
      subependymal giant cell astrocytoma.
    evidence:
    - reference: PMID:35084981
      reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological
        defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and
        cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying
        potential treatment options for TSC and related disorders.
      explanation: Tumour formation from an over-proliferating progenitor in a human model supports the
        tumour-growth node.
    readouts:
    - name: CLIP cell proliferation
      target: Subependymal Glioneuronal Tumor Growth
      direction: INCREASED
      interpretation: The interneuron progenitor population over-proliferates in TSC organoids.
      evidence:
      - reference: PMID:35084981
        reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological
          defects.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors,
          and cortical malformations.
        explanation: Reports the proliferation measurement.
    - name: Tumour burden under EGFR inhibition
      target: Subependymal Glioneuronal Tumor Growth
      direction: DECREASED
      interpretation: EGFR inhibition reduces organoid tumour burden.
      evidence:
      - reference: PMID:35084981
        reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological
          defects.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Epidermal growth factor receptor inhibition reduces tumor burden
        explanation: Reports the treatment-arm measurement.
  - target: Neuroglial Dysplasia and Cortical Network Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Excess interneurons and cortical malformations arise from the same progenitor expansion,
      reproducing the malformation side of the node without its network or seizure readouts.
    limitations: Organoids have no functional cortical network and no seizure phenotype; the malformation
      is scored structurally.
    evidence:
    - reference: PMID:35084981
      reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological
        defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and
        cortical malformations.
      explanation: Cortical malformation in the organoid is part of what this node describes.
    readouts:
    - name: Interneuron output and cortical malformation
      target: Neuroglial Dysplasia and Cortical Network Disorganization
      direction: INCREASED
      interpretation: Excess interneurons and malformed cortex follow CLIP over-proliferation.
      evidence:
      - reference: PMID:35084981
        reference_title: Amplification of human interneuron progenitors promotes brain tumors and neurological
          defects.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: generating excessive interneurons, brain tumors, and cortical malformations
        explanation: Reports the structural measurement.
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
- name: NCT05104983
  phase: PHASE_II
  status: RECRUITING
  description: >
    TSC-STEPS (Stopping TSC Onset and Progression 2B): randomised,
    placebo-controlled trial of sirolimus for prevention of TSC-associated
    epilepsy in 64 seizure-free infants. Tests pre-symptomatic mTOR
    inhibition inside the early developmental window, complementing the
    vigabatrin-based prevention approach in NCT04987463.
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
- name: NCT05323734
  phase: PHASE_III
  status: COMPLETED
  description: >
    TrustTSC: completed placebo-controlled trial of adjunctive ganaxolone
    (a neuroactive-steroid GABA-A positive allosteric modulator) in 129
    children and adults with TSC-related epilepsy. Represents a
    non-mTOR-directed adjunctive antiseizure strategy.
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- name: NCT05059327
  phase: PHASE_II
  status: COMPLETED
  description: >
    Completed placebo-controlled crossover study of basimglurant (NOE-101),
    an mGluR5 negative allosteric modulator, in 61 children, adolescents and
    young adults with TSC. Targets glutamatergic signalling rather than the
    mTORC1 axis.
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- name: NCT02962414
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >
    Open-label roll-over study collecting long-term safety of everolimus in
    206 patients with TSC and refractory seizures who completed EXIST-3 and
    continued to benefit. The principal source of multi-year everolimus
    exposure data in this population.
  target_phenotypes:
  - preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
- name: NCT05495425
  phase: PHASE_III
  status: COMPLETED
  description: >
    Completed placebo-controlled study of NPC-12Y (topical sirolimus) gel in
    43 patients with TSC-associated skin lesions, extending the topical
    mTOR-inhibitor evidence base beyond NCT01526356.
  target_phenotypes:
  - preferred_term: Angiofibromas
    term:
      id: HP:0010615
      label: Angiofibromas
discussions:
- discussion_id: gap_tsc_tand_not_reversible_by_mtorc1_inhibition
  prompt: >-
    Why does correcting mTORC1 activity fail to correct the neuropsychiatric
    manifestations of TSC, and is there a developmental window before which it
    would still work?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#canonical_tsc1_tsc2_mtorc1_hyperactivation_model
  - pathophysiology#Neuroglial Dysplasia and Cortical Network Disorganization
  - phenotypes#Intellectual Disability
  - phenotypes#Autism Spectrum Disorder
  - treatments#mTOR Inhibitor Therapy (Everolimus)
  rationale: >-
    Every other arm of this entry's causal chain is closed by a drug: mTOR
    inhibitors shrink SEGAs and angiomyolipomas and reduce seizure frequency,
    and that pharmacologic reversal is the strongest single argument for the
    canonical mechanism. The neuropsychiatric arm is the exception. A Class I
    randomised trial found no effect of everolimus on IQ, autism, or any
    neuropsychological outcome in children aged 4-17, and two independent
    trials of pre-emptive vigabatrin found no effect on developmental or
    autism outcomes in infants. So the entry asserts a causal edge from
    mTORC1 hyperactivation to TAND that no intervention has yet been able to
    move, and it is not known whether the edge is wrong, whether it operates
    only during a developmental window that has closed by the age at which
    these trials enrol, or whether TAND is driven by parallel
    mTORC1-independent mechanisms. The distinction matters clinically: the
    first reading says stop looking at mTOR for TAND, the second says treat
    earlier, the third says treat something else as well. Human iPSC neuron
    work supplies a candidate mechanism for the second reading - impaired
    activity-dependent transcription tied to maturation-dependent DNA
    demethylation, with late mTORC1 inhibition unable to reverse neuronal
    hyperactivity - but the loci, cell types, and timing of any such window
    are unmeasured, and no human in vivo evidence exists.
  evidence:
  - reference: PMID:31217257
    reference_title: "A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0)."
    explanation: >
      Establishes the gap as a measured null rather than an untested
      assumption: the point estimate is slightly negative and the confidence
      interval excludes any clinically meaningful benefit at this age range.
  - reference: PMID:41379617
    reference_title: "Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC"
    explanation: >
      Supplies the leading candidate explanation for the clinical null - that
      the neuronal phenotype becomes mTORC1-independent as neurons mature -
      and simultaneously shows why it is unresolved: the result is in
      human iPSC-derived neurons, the window is not bounded, and the
      demethylation loci are not identified.
  proposed_experiments:
  - experiment_id: exp_tsc_preemptive_mtor_inhibition_infants
    name: Pre-emptive mTOR inhibition before seizure onset in infants with TSC
    description: >-
      Randomise infants with a genetic or cardiac-rhabdomyoma diagnosis of TSC,
      before seizure onset and before four months of age, to an mTOR inhibitor
      or placebo, stratified by TSC1 versus TSC2 genotype and by EEG status at
      enrolment, with developmental and autism outcomes at 24-36 months as the
      primary endpoints. This is the design that separates "mTORC1 does not
      drive TAND" from "mTORC1 drives TAND only inside a developmental window
      that has closed by school age", which no trial run to date can
      distinguish because all enrolled after that putative window.
    would_support:
    - mechanistic_hypotheses#canonical_tsc1_tsc2_mtorc1_hyperactivation_model
    - pathophysiology#Neuroglial Dysplasia and Cortical Network Disorganization
    supporting_outcome:
    - >-
        Better developmental and autism-specific outcomes at 24-36 months in the
        treated arm would show the mTORC1-to-TAND edge is real and
        timing-dependent, and would make age at initiation, not drug choice, the
        operative variable.
    refuting_outcome:
    - >-
        No difference despite treatment beginning before seizure onset would
        leave the mTORC1-to-TAND edge unsupported by any interventional evidence
        at any age, and would move the neuropsychiatric arm toward the
        mTORC1-independent mechanisms discussed separately.
- discussion_id: gap_tsc_mtorc1_independent_arms
  prompt: >-
    Which TSC manifestations are driven by mechanisms downstream of TSC1/TSC2
    loss but outside mTORC1 - haploinsufficiency-level RHOA signalling,
    HMGA2-dependent mesenchymal tumorigenesis, and the mTORC2-dependent
    estradiol-COX-2 arm in LAM - and how much of the residual disease burden do
    they account for?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#canonical_tsc1_tsc2_mtorc1_hyperactivation_model
  - pathophysiology#Somatic Second Hit at TSC Locus
  - pathophysiology#Pulmonary Lymphangioleiomyomatosis Growth
  rationale: >-
    Three separate lines of work now place part of TSC pathology outside the
    mTORC1 axis this entry is built on, and they share a structural feature
    that makes them awkward for the canonical model: two of them operate at
    haploinsufficiency, i.e. without a second hit, so they are present in every
    cell of the patient rather than confined to lesion clones. TSC2+/- human
    iPSC neurons fail to respond to axon guidance cues through diminished RHOA
    signalling, with normal mTOR activity and no rescue by mTORC1 or mTORC2
    inhibitors; TSC2+/- mesenchymal tumours require HMGA2 and show mTOR
    activation in only half of the human cases; and COX-2 induction in
    TSC2-null LAM cells is rapamycin-insensitive but mTORC2-dependent. What is
    not known is how much each contributes in patients. None has a human
    quantitative estimate, none has been targeted therapeutically in TSC, and
    the alternative that they are minor accompaniments of a
    predominantly mTORC1-driven disease has not been excluded.
  evidence:
  - reference: PMID:33972524
    reference_title: "RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we find that TSC2 signaled through MTOR-independent RHOA in growth cones"
    explanation: >
      Documents a TSC2-dependent, mTOR-independent signalling route in human
      neurons: basal mTOR activity and cue-driven protein synthesis were normal
      in TSC2+/- neurons, mTORC1 and mTORC2 inhibitors did not rescue the
      guidance defect, and basal and cue-activated RHOA was diminished. Derived
      from one patient line plus engineered isogenic controls, so the effect
      size in patients is unknown.
  proposed_experiments:
  - experiment_id: exp_tsc_mtorc1_independent_arm_attribution
    name: Attribution of TSC lesion burden to mTORC1-independent arms
    description: >-
      Across matched lesion classes from the same patients - cortical tuber,
      angiomyolipoma, mesenchymal tumour, and LAM tissue - assay TSC1/TSC2
      allele status alongside mTORC1 output (phospho-S6, phospho-4E-BP1), mTORC2
      output (phospho-Akt S473, COX-2), HMGA2, and RHOA pathway activity, so
      that each lesion class is assigned to an arm rather than assumed to be
      mTORC1-driven. Pair with dual mTORC1/2 versus mTORC1-selective inhibition
      in the LAM arm, reading out VEGF-D and prostaglandins.
    would_support:
    - pathophysiology#Pulmonary Lymphangioleiomyomatosis Growth
    - pathophysiology#Somatic Second Hit at TSC Locus
    supporting_outcome:
    - >-
        Lesion classes segregating by arm - retained heterozygosity with HMGA2
        and no mTORC1 output in mesenchymal tumours, mTORC2 output surviving
        mTORC1-selective inhibition in LAM - would establish the
        mTORC1-independent arms as distinct pathways requiring their own
        pathophysiology nodes and their own drugs.
    refuting_outcome:
    - >-
        Uniform biallelic loss and mTORC1 output across lesion classes would
        indicate the published exceptions are model-system or sampling artefacts,
        and the single-axis account should stand unqualified.
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).
  - Foundation care guideline integrated (clinical care guidelines registry,
    issue #4878): 2012 International TSC Consensus Conference surveillance and
    management recommendations (Krueger & Northrup 2013, PMID:24053983),
    updated by the 2021 International TSC Consensus (Northrup et al. 2021,
    PMID:34399110) — together the source of the multisystem
    surveillance/screening treatment node. The 2021 revision adds earlier EEG
    screening, enhanced TAND surveillance, and new medication approvals.

  Falcon deep-research report audit (PR #7301,
  research/Tuberous_Sclerosis_1-deep-research-falcon.md, audited 2026-08-01).
  The report is correctly scoped: subject entity is TSC1-related tuberous
  sclerosis complex (MONDO:0008612, hgnc:12362), which is the TSC1 subtype of
  this entry's MONDO:0001734; no named-entity confusion. It cites 14 literature
  sources by DOI (no PMIDs) plus 6 NCT registrations. All 11 DOIs that resolve
  to PubMed resolved to real papers matching the report's author lists, and all
  6 NCT IDs matched the described trials on ClinicalTrials.gov. Two cited
  sources have no PubMed record and were not used: a bioRxiv single-cell tuber
  preprint (doi:10.1101/2024.10.31.621014, non-peer-reviewed) and a Rutgers
  doctoral dissertation the report mislabels as "ArXiv"
  (doi:10.7282/t3-9ahy-yx47).

  Claims rejected on verification:
  - "LAM occurs in 30-40% of adult females with TSC; spontaneous pneumothorax
    in up to 70% of LAM patients", attributed to Jansen 2020 (PMID:32982929).
    That paper is the TOSCA quality-of-life substudy and contains zero
    occurrences of "lymphangioleiomyomatosis" or "pneumothorax" (searched the
    full cached text 2026-08-01). Misattribution; claim dropped. Pneumothorax
    was consequently NOT added as a phenotype: it is absent from
    references_cache for ORPHA:805, PMID:38991206, PMID:39334956,
    PMID:20301399, PMID:33041968 and PMID:38042867 as well (same search date).
  - "TAND issues affect up to ~90% across TSC literature", attributed to Singh
    2023 (PMID:37041855). No such figure appears in that abstract.
  - "TSC1 cohort: cortical tubers 67.8%, subependymal nodules 51.6%"
    (Praticò 2025, PMID:40579409). The paper says 67.8% had MORE THAN 5 tubers
    and 51.6% MORE THAN 5 subependymal nodules — a lesion-burden threshold, not
    a presence rate. Not used as a frequency.
  - Numerous quantitative claims sourced to full-text page ranges of the 2021
    consensus (Northrup, PMID:34399110) — "63-78% of infants", "11 major and 7
    minor features", "25-30% of AMLs are fat-poor", the surveillance interval
    table. The cached record for PMID:34399110 is abstract-only, so none are
    snippet-verifiable here; the surveillance content already in this entry
    derives from the 2012/2021 consensus nodes rather than from the report.
  - Report frequency bands generally: no `frequency:` value in this enrichment
    was taken from the report's prose. Bands added here come from Orphanet's
    curated HPO annotations for ORPHA:805, which state their own percentage
    range.
datasets:
- accession: ega:EGAS00001002485
  title: 'Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment'
  description: Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Tuberous Sclerosis Complex"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004586
  title: Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex
  description: Although the intricate and prolonged development of the human brain critically distinguishes it from other mammals, our current understanding of neurodevelopmental diseases is largely based on work using animal models. Recent studies revealed that neural progenitors in the human brain are profoundly different from those found in rodent animal models. Moreover, post-mortem studies revealed extensive migration of interneurons into the late-gestational and post-natal human prefrontal cortex that does not occur in rodents.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Tuberous Sclerosis Complex"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001007264
  title: 'Molecular EPISTOP: Comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Tuberous Sclerosis Complex"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000088551
  title: Pilot Study Evaluating Everolimus Molecular Mechanisms in Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD)
  description: Treatment resistant epilepsy in tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mammalian target of rapamycin (mTOR) signaling. This can upregulate cell growth and proliferation, with increased downstream ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors are used in TSC, the archetypal mTORopathy, to reduce tumor growth or seizure frequency. Preclinical studies in FCD support a potential role in suppressing seizures.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberous Sclerosis Complex"). Retrieved 2026-08-02.
- accession: dbgap:phs001357
  title: The Genomic Landscape of Tuberous Sclerosis Complex (TSC)
  description:  In this study, we characterized the genomic landscape of tuberous sclerosis complex (TSC), a rare genetic disease causing multisystem growth of benign tumors and other hamartomatous lesions. We analyzed 127 human tissues, including 111 TSC-associated samples and 16 non-TSC negative controls, using multiple genomic platforms including whole exome sequencing, targeted sequencing of known disease-causative loci ( TSC1  and  TSC2 ), mRNA sequencing, high-density SNP arrays, and DNA methylation arrays.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Tuberous Sclerosis Complex"). Retrieved 2026-08-02.
references:
- reference: PMID:24053983
  title: "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference."
  findings: []
- reference: PMID:34399110
  title: "Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations."
  findings: []
- reference: PMID:20301399
  title: "Tuberous Sclerosis Complex."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:33041968
  title: "Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas."
  findings: []
- reference: PMID:32982929
  title: "Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study."
  findings: []
- reference: PMID:40579409
  title: "Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations."
  findings: []
- reference: PMID:33041976
  title: "Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis."
  findings: []
- reference: PMID:38783199
  title: "Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit."
  findings: []
- reference: PMID:32555378
  title: "Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex."
  findings: []
- reference: PMID:37041855
  title: "Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions."
  findings: []

📚

References & Deep Research

References

10

PMID:24053983

Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference.

No top-level findings curated for this source.

PMID:34399110

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations.

No top-level findings curated for this source.

PMID:20301399

Tuberous Sclerosis Complex.

No top-level findings curated for this source.

PMID:33041968

Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas.

No top-level findings curated for this source.

PMID:32982929

Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study.

No top-level findings curated for this source.

PMID:40579409

Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations.

No top-level findings curated for this source.

PMID:33041976

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis.

No top-level findings curated for this source.

PMID:38783199

Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit.

No top-level findings curated for this source.

PMID:32555378

Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex.

No top-level findings curated for this source.

PMID:37041855

Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (4)

Record 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). - Foundation care guideline integrated (clinical care guidelines registry, issue #4878): 2012 International TSC Consensus Conference surveillance and management recommendations (Krueger & Northrup 2013, PMID:24053983), updated by the 2021 International TSC Consensus (Northrup et al. 2021, PMID:34399110) — together the source of the multisystem surveillance/screening treatment node. The 2021 revision adds earlier EEG screening, enhanced TAND surveillance, and new medication approvals. Falcon deep-research report audit (PR #7301, research/Tuberous_Sclerosis_1-deep-research-falcon.md, audited 2026-08-01). The report is correctly scoped: subject entity is TSC1-related tuberous sclerosis complex (MONDO:0008612, hgnc:12362), which is the TSC1 subtype of this entry's MONDO:0001734; no named-entity confusion. It cites 14 literature sources by DOI (no PMIDs) plus 6 NCT registrations. All 11 DOIs that resolve to PubMed resolved to real papers matching the report's author lists, and all 6 NCT IDs matched the described trials on ClinicalTrials.gov. Two cited sources have no PubMed record and were not used: a bioRxiv single-cell tuber preprint (doi:10.1101/2024.10.31.621014, non-peer-reviewed) and a Rutgers doctoral dissertation the report mislabels as "ArXiv" (doi:10.7282/t3-9ahy-yx47). Claims rejected on verification: - "LAM occurs in 30-40% of adult females with TSC; spontaneous pneumothorax in up to 70% of LAM patients", attributed to Jansen 2020 (PMID:32982929). That paper is the TOSCA quality-of-life substudy and contains zero occurrences of "lymphangioleiomyomatosis" or "pneumothorax" (searched the full cached text 2026-08-01). Misattribution; claim dropped. Pneumothorax was consequently NOT added as a phenotype: it is absent from references_cache for ORPHA:805, PMID:38991206, PMID:39334956, PMID:20301399, PMID:33041968 and PMID:38042867 as well (same search date). - "TAND issues affect up to ~90% across TSC literature", attributed to Singh 2023 (PMID:37041855). No such figure appears in that abstract. - "TSC1 cohort: cortical tubers 67.8%, subependymal nodules 51.6%" (Praticò 2025, PMID:40579409). The paper says 67.8% had MORE THAN 5 tubers and 51.6% MORE THAN 5 subependymal nodules — a lesion-burden threshold, not a presence rate. Not used as a frequency. - Numerous quantitative claims sourced to full-text page ranges of the 2021 consensus (Northrup, PMID:34399110) — "63-78% of infants", "11 major and 7 minor features", "25-30% of AMLs are fat-poor", the surveillance interval table. The cached record for PMID:34399110 is abstract-only, so none are snippet-verifiable here; the surveillance content already in this entry derives from the 2012/2021 consensus nodes rather than from the report. - Report frequency bands generally: no `frequency:` value in this enrichment was taken from the report's prose. Bands added here come from Orphanet's curated HPO annotations for ORPHA:805, which state their own percentage range.

Enrich TSC entry from verified subset of Falcon TSC1 deep-research report (PR #7301) · 2026-08-01T22:24:49Z · View source

Acted on @cmungall's change request on PR #7301 ('incorportate deep research into main yaml'). Mined research/Tuberous_Sclerosis_1-deep-research-falcon.md and added only what survived independent verification against freshly fetched references_cache entries. NEC preflight: report subject entity is TSC1-related TSC (MONDO:0008612, hgnc:12362), the TSC1 subtype of this entry's MONDO:0001734. TSC2 content in the report is expected partner-gene context, not drift. No named-entity confusion. Provenance of report citations: the report cites sources by DOI only (no PMIDs). Resolved 13 DOIs via NCBI esearch; 11 resolved to real PubMed records whose author lists matched the report. Seven were new to this entry and were fetched with 'just fetch-reference': PMID:33041968 (TOSCA renal), PMID:32982929 (TOSCA QoL), PMID:40579409 (Sicilian TSC1/TSC2 cohort), PMID:33041976 (mTOR gliopathy review), PMID:38783199 (iPSC neurovascular-unit BBB), PMID:32555378 (Danish mutational analysis), PMID:37041855 (treatment-resistant TSC epilepsy). Two cited sources have no PubMed record and were not used (a bioRxiv preprint and a doctoral dissertation the report mislabels as ArXiv). All 6 NCT IDs were verified against the ClinicalTrials.gov v2 API and all matched. Added: 4 TSC1-vs-TSC2 genotype-phenotype evidence items on the TSC1 subtype (TOSCA renal genotype effect incl. the by-age-40 convergence, and three Sicilian-cohort findings); a new clinical_burden block (TOSCA QoL, 3 evidence items, with a notes block correcting the abstract's unstated denominators); a new pathophysiology node 'mTOR-Driven Gliopathy and Neurovascular Unit Dysfunction' (5 cell types, 3 GO processes, 4 evidence items, 3 downstream edges); 6 new phenotypes (Focal-Onset Seizures, Cerebral Hypomyelination, Depression, Aggressive Behavior, Sleep disturbance, Chronic Kidney Disease); 2 TOSCA evidence items on renal angiomyolipoma onset/peak; 4 everolimus tolerability evidence items plus a notes block; 2 early-treatment-rationale evidence items on the vigabatrin node; 2 new genetic case_fractions (Danish 25%, Sicilian 38.3% with an ascertainment caveat) and 2 TSC1 gene/functional-assay evidence items; a new experimental_models block for the iPSC BBB chip; 5 new clinical trials; and a Falcon report audit in top-level notes. Rejected and recorded in notes: the report's LAM 30-40%/pneumothorax 70% figures attributed to PMID:32982929 (that paper contains zero occurrences of either term); the ~90% TAND figure attributed to PMID:37041855 (absent from the abstract); the 'cortical tubers 67.8% / SEN 51.6%' rates from PMID:40579409 (the paper reports proportions with MORE THAN 5 lesions, not presence rates); and all quantitative claims sourced to full-text page ranges of PMID:34399110, whose cached record is abstract-only. Pneumothorax was not added as a phenotype after searching ORPHA:805 and PMIDs 38991206, 39334956, 20301399, 33041968, 38042867 on 2026-08-01 and finding no supporting text. No frequency band was taken from report prose. All new bands come from Orphanet's curated HPO annotations for ORPHA:805, which state their own percentage ranges. Cerebral Hypomyelination carries no frequency and says why. Caught and corrected one ontology label drift: Orphanet renders HP:0002360 as 'Sleep abnormality'; the canonical HPO label is 'Sleep disturbance'. Validation: just validate PASS, just validate-terms PASS, just validate-references 153/153, scripts/check_snippets_verbatim.py 153 verified 0 failed (118 before), check_folded_hyphens --check OK, validate-history-all PASS.

Deep curation of TSC1 subtype (tuberous sclerosis 1) · 2026-07-31T00:28:09Z · View source

Deep curation focused on the TSC1 subtype ("tuberous sclerosis 1") of the existing Tuberous Sclerosis Complex entry. Deep research provider: the requested Edison/Falcon provider could not be used. The EDISON_API_KEY present in the session environment was rejected with HTTP 403 Forbidden by Edison's auth endpoint (api.platform.edisonscientific.com/auth/login), reproduced by direct curl outside the client to rule out a proxy/TLS issue. A key update was made in the cloud-environment config, but per that dialog such changes apply only to new sessions and did not reach this already-running session. Deep research was therefore run with the claude_code provider instead (research/Tuberous_Sclerosis_1-deep-research-claude_code.md; 14 web searches, 16 turns, ~6 min). The report was treated as leads only, not ground truth. Ontology work: discovered and bound the dedicated MONDO subtype term MONDO:0008612 "tuberous sclerosis 1" (is_a MONDO:0001734 tuberous sclerosis; xref OMIM:191100; RO:0004003 to HGNC:12362 TSC1) as has_subtypes[TSC1].subtype_term, verified via OAK. Added the TSC1 gene descriptor (hgnc:12362) to the subtype. Content added, anchored on two verified landmark genotype-phenotype cohorts newly fetched and cached for this session (PMID:11112665 Dabora 2001, n=224; PMID:10205261 Jones 1999, n=150 families): - Expanded the TSC1 subtype description: milder phenotype across seizures, intellectual disability, subependymal nodule and cortical tuber burden, kidney involvement, and facial angiofibroma; uniformly truncating variant spectrum versus TSC2's missense-inclusive spectrum; significant enrichment in familial versus sporadic TSC. - Added 5 evidence items to the TSC1 subtype. - Added structured Genetic.case_fractions for TSC1 across three independent cohorts (15.1 percent Dabora, 18.3 percent Jones, 17.0 percent Dufner-Almeida) with cohort sizes and per-estimate evidence, complementing the coarse free-text range. Updated the TSC1 genetic notes and added 2 evidence items covering the truncating-variant spectrum and familial enrichment. - Added TSC1-versus-TSC2 genotype qualifiers plus supporting evidence to four phenotypes where these cohorts report TSC1-specific rarity, absence, or reduced severity: Retinal Hamartoma, Fibrous Cephalic Plaque, Renal Cyst, and Renal Angiomyolipoma. Deliberately NOT done: no separate kb/disorders/ file was created for TSC1. It is a subtype of the existing Tuberous_Sclerosis_Complex entry (has_subtypes), and MONDO:0008612 is_a MONDO:0001734, so splitting it out would duplicate the shared mTORC1 pathograph. The TSC2/PKD1 contiguous deletion phenomenon was explicitly kept scoped to TSC2; the deep-research report flagged the risk of conflating it with TSC1. Validation: just validate passes for the entry (schema, term, and reference validation). All 8 new and reused snippets were independently confirmed as exact whitespace-normalized substrings of their cached abstracts. The reference validator was additionally negative-tested with a deliberately fabricated snippet to confirm it was actively checking rather than silently passing; it correctly reported an error at the right location.

Deep curation of the TSC2 (tuberous sclerosis 2) subtype · 2026-07-31T00:27:51Z · View source

TSC2-focused deep curation of the existing Tuberous Sclerosis Complex entry. Scope decision: "Tuberous sclerosis 2" (MONDO:0013199) is the gene-specific Mendelian subtype of tuberous sclerosis (MONDO:0001734) and was already modelled as a has_subtypes entry in this file. Per the design-decision register (separate file only for a distinct MONDO identity AND a substantially independent mechanism), TSC2 shares the TSC1/TSC2-RHEB-mTORC1 mechanism, so it was deepened in place as a subtype rather than split into a new disorder file. Deep research: Edison Scientific (falcon provider) via deep-research-client --provider falcon, disease_name="Tuberous Sclerosis 2", mondo_id=MONDO:0013199. Output: research/Tuberous_Sclerosis_2-deep-research-falcon.md (700s runtime, 34 citations, 1 artifact). NEC preflight passed: TSC2 mentioned 86x vs TSC1 26x, and OMIM:613254 present matching the MONDO:0013199 xref. The Edison report cites by DOI rather than PMID, so DOIs were resolved to PMIDs via the PMC ID Converter and each cited abstract was fetched with `just fetch-reference` before any snippet was written; report content was treated as leads only, never as ground truth. GeneReviews baseline (mandatory step): PMID:20301399 (Northrup/Koenig/Pearson/Au, updated 2024-08-01) fetched, cached, and tagged GeneReviews in the top-level references block. Clinical Characteristics were cross-referenced against the existing phenotypes list; two documented manifestations were absent and have been added - renal oncocytoma (HP:0011798) and multifocal micronodular pneumocyte hyperplasia (HP:0033328). The GeneReviews "Agents/circumstances to avoid" (smoking, estrogen use, nephrectomy) is now captured on the Renal AML Embolization or Nephrectomy treatment. Changes: - has_subtypes: bound subtype_term for TSC2 to MONDO:0013199 and TSC1 to MONDO:0008612; both were previously unbound. - pathophysiology: new MOLECULAR-scale node "TSC2 GAP Domain Catalytic Loss (Structural Basis of Genotype Severity)", subtype-tagged to TSC2, giving the structural rationale for the TSC2-over-TSC1 severity gradient - cryo-EM shows only TSC2 contributes the catalytic GAP domain, with an asparagine thumb N1643 driving RHEB GTP hydrolysis while TSC1 acts as scaffold (PMID:33436626). Wired as a downstream edge from the germline first-hit node. - pathophysiology: added independent-second-hit evidence (PMID:25432535) to the Somatic Second Hit node; TSC1-vs-TSC2 LAM cyst-burden evidence (PMID:19419980); and cardiac rhabdomyoma genotype-regression evidence (PMID:41361250). - genetic: added structured case_fractions for both TSC1 and TSC2 across two cohorts - the 106-case molecularly-solved series at 17%/83%, and the 2093-patient TOSCA registry at 19.7%/63.3%. The two use different denominators (solved cases vs molecularly tested patients) and this is stated explicitly in each record's notes. Also added TSC2 intragenic variant-class severity stratification (PMID:22189265). - phenotypes: TOSCA SEGA genotype evidence (bilateral 34% vs 18%, growing 16% vs 4.5% for TSC2 vs TSC1, PMID:28057044); RCC frequency and onset with TSC2 p.R905Q second-hit context; plus the two new GeneReviews phenotypes above. Validation: `just validate` (schema + term + reference) passes. The reference validator was adversarially spot-checked by substituting a fabricated snippet, which correctly errored - confirming snippet checking was actually exercised rather than silently skipped by its pass-through caching. Note the validator strips square brackets, so GeneReviews quotes were chosen bracket-free.

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

Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Related Datasets

Clinical Trials

Experimental Models

Source YAML

References & Deep Research

References

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