Lung lymphangioleiomyomatosis

Summary

Lung lymphangioleiomyomatosis (MONDO:0006277) is a disease caused by TSC1 (GenCC Strong), with 2 cohort genes and 41 clinical trials. Top therapeutic interventions include doxycycline anhydrous, glutamine, and loratadine.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TSC1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 7
• Phenotypes (HPO): 36
• Clinical trials: 41

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.0135	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.15	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.25	Europe	Validated
Annual incidence	<1 / 1 000 000	0.015	United States	Validated
Annual incidence	<1 / 1 000 000	0.01	France	Validated
Point prevalence	1-9 / 1 000 000	0.17	United States	Validated
Point prevalence	1-9 / 1 000 000	0.19	Germany	Validated
Point prevalence	1-9 / 1 000 000	0.21	Canada	Validated
Point prevalence	1-9 / 1 000 000	0.25	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.32	Switzerland	Validated
Point prevalence	1-9 / 1 000 000	0.39	New Zealand	Validated
Point prevalence	1-9 / 1 000 000	0.26	Australia	Validated
Point prevalence	1-9 / 1 000 000	0.25	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0002091	Restrictive ventilatory defect	Very frequent (80-99%)
HP:0002094	Dyspnea	Very frequent (80-99%)
HP:0002113	Pulmonary infiltrates	Very frequent (80-99%)
HP:0012735	Cough	Very frequent (80-99%)
HP:0100749	Chest pain	Very frequent (80-99%)
HP:0100763	Abnormality of the lymphatic system	Very frequent (80-99%)
HP:0000008	Abnormal morphology of female internal genitalia	Frequent (30-79%)
HP:0000790	Hematuria	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002097	Emphysema	Frequent (30-79%)
HP:0002107	Pneumothorax	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0006772	Renal angiomyolipoma	Frequent (30-79%)
HP:0010310	Chylothorax	Frequent (30-79%)
HP:0012798	Pulmonary lymphangiomyomatosis	Frequent (30-79%)
HP:0100750	Atelectasis	Frequent (30-79%)
HP:0100804	Ungual fibroma	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0001000	Abnormality of skin pigmentation	Occasional (5-29%)
HP:0001004	Lymphedema	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001541	Ascites	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002105	Hemoptysis	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0005562	Multiple renal cysts	Occasional (5-29%)
HP:0009594	Retinal hamartoma	Occasional (5-29%)
HP:0009721	Shagreen patch	Occasional (5-29%)
HP:0009726	Renal neoplasm	Occasional (5-29%)
HP:0011852	Chylopericardium	Occasional (5-29%)
HP:0012086	Abnormal urinary color	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0012733	Macule	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lung lymphangioleiomyomatosis
Mondo ID	MONDO:0006277
EFO	EFO:1000334
Orphanet	538
DOID	DOID:3319
NCIT	C38153
SNOMED CT	277844007
UMLS	C0349649
MedGen	91161
GARD	0003319
MedDRA	10049459
Anatomy (UBERON)	UBERON:0002048
Is cancer (heuristic)	no

Also known as: lung lymphangioleiomyomatosis · lung lymphangiomyomatosis · Lymphangioleiomyomatosis · lymphangioleiomyomatosis · pulmonary lymphangiomyomatosis

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record · 23 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › connective and soft tissue neoplasm › soft tissue neoplasm › neoplasm with perivascular epithelioid cell differentiation › lymphangioleiomyomatosis › lung lymphangioleiomyomatosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

4 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
49302	NM_000548.5(TSC2):c.4524CTT[1] (p.Phe1510del)	TSC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
49963	NM_000548.5(TSC2):c.4849+12C>T	TSC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365518	NM_000368.5(TSC1):c.1002G>A (p.Ser334=)	TSC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
5099	NM_000368.5(TSC1):c.1760A>G (p.Lys587Arg)	TSC1	Benign	criteria provided, multiple submitters, no conflicts
49504	NM_000548.5(TSC2):c.4536C>T (p.Asp1512=)	TSC2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
49616	NM_000548.5(TSC2):c.2031C>T (p.Pro677=)	TSC2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
50023	NM_000548.5(TSC2):c.3815-15G>A	TSC2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TSC1	Strong	Autosomal dominant	lung lymphangioleiomyomatosis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	gencc,clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSC1	Other/Unknown	no		Hamartin
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC1	5,445
TSC2	4,135

Intra-cohort edges

A	B	Sources
TSC1	TSC2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSC1	Q92574	5
TSC2	P49815	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of TSC complex formation by AKT (PKB)	2	2284.0×	1e-06	TSC1, TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	2	393.8×	2e-05	TSC1, TSC2
TBC/RABGAPs	2	259.6×	3e-05	TSC1, TSC2
TP53 Regulates Metabolic Genes	2	129.8×	1e-04	TSC1, TSC2
Macroautophagy	2	115.3×	1e-04	TSC1, TSC2
AKT phosphorylates targets in the cytosol	1	407.9×	0.003	TSC2
Constitutive Signaling by AKT1 E17K in Cancer	1	211.5×	0.005	TSC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of TOR signaling	2	561.7×	1e-04	TSC1, TSC2
negative regulation of TORC1 signaling	2	324.1×	2e-04	TSC1, TSC2
cellular response to starvation	2	193.7×	3e-04	TSC1, TSC2
neural tube closure	2	187.2×	3e-04	TSC1, TSC2
regulation of cell cycle	2	74.6×	0.002	TSC1, TSC2
memory T cell differentiation	1	2808.7×	0.003	TSC1
cellular response to decreased oxygen levels	1	2106.5×	0.003	TSC1
negative regulation of cell population proliferation	2	42.1×	0.003	TSC1, TSC2
negative regulation of ATP-dependent activity	1	842.6×	0.005	TSC1
negative regulation of cell size	1	842.6×	0.005	TSC1
regulation of insulin receptor signaling pathway	1	842.6×	0.005	TSC2
negative regulation of mitophagy	1	766.0×	0.005	TSC2
regulation of cell-matrix adhesion	1	648.1×	0.005	TSC1
anoikis	1	648.1×	0.005	TSC2
negative regulation of macroautophagy	1	561.7×	0.005	TSC1
regulation of stress fiber assembly	1	495.6×	0.006	TSC1
obsolete D-glucose import	1	421.3×	0.006	TSC1
positive chemotaxis	1	401.2×	0.006	TSC2
activation of GTPase activity	1	366.4×	0.007	TSC1
cardiac muscle cell differentiation	1	337.0×	0.007	TSC1
positive regulation of focal adhesion assembly	1	324.1×	0.007	TSC1
positive regulation of macroautophagy	1	263.3×	0.008	TSC2
associative learning	1	240.7×	0.008	TSC1
regulation of endocytosis	1	240.7×	0.008	TSC2
cell projection organization	1	187.2×	0.009	TSC1
negative regulation of insulin receptor signaling pathway	1	187.2×	0.009	TSC2
negative regulation of Wnt signaling pathway	1	172.0×	0.010	TSC2
adult locomotory behavior	1	150.5×	0.011	TSC1
synapse organization	1	140.4×	0.011	TSC1
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	131.7×	0.012	TSC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSC1	0	0
TSC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TSC2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TSC1, TSC2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TSC1	0	—
TSC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 41.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	17
PHASE2	10
PHASE1/PHASE2	5
PHASE1	4
PHASE3	3
PHASE4	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00989742	PHASE4	COMPLETED	Doxycycline In Lymphangioleiomyomatosis (LAM)
NCT03150914	PHASE3	ACTIVE_NOT_RECRUITING	Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
NCT00414648	PHASE3	COMPLETED	Efficacy and Safety of Sirolimus in LAM
NCT00790400	PHASE3	COMPLETED	Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
NCT01799538	PHASE1/PHASE2	RECRUITING	Nebulized or Inhaled Albuterol for Lymphangioleiomyomatosis
NCT05467397	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Feasibility of [11C]Acetate-PET in LAM and TSC
NCT00005906	PHASE2	COMPLETED	Treatment With Octreotide in Patients With Lymphangioleiomyomatosis
NCT00457808	PHASE2	COMPLETED	Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM
NCT00457964	PHASE1/PHASE2	COMPLETED	RAD001 Therapy of Angiomyolipomata in Patients With TS Complex and Sporadic LAM
NCT00490789	PHASE2	UNKNOWN	Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
NCT01059318	PHASE2	COMPLETED	A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis
NCT01353209	PHASE2	COMPLETED	Letrozole for Lymphangioleiomyomatosis
NCT02061397	PHASE1/PHASE2	COMPLETED	Safety of Simvastatin in LAM and TSC
NCT02484664	PHASE2	COMPLETED	COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
NCT03062943	PHASE2	COMPLETED	A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)
NCT03131999	PHASE1/PHASE2	COMPLETED	LAM Pilot Study With Imatinib Mesylate
NCT03253913	PHASE2	COMPLETED	Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial
NCT03304678	PHASE2	COMPLETED	Discovery of Sirolimus Sensitive Biomarkers in Blood
NCT05190627	PHASE2	UNKNOWN	Effect of Loratadine in Lymphangioleiomyomatosis
NCT06889168	PHASE1	RECRUITING	Evaluating the Long-term Safety and Tolerability of Imatinib in Patients With Lymphangioleiomyomatosis (LAM)
NCT01552434	PHASE1	TERMINATED	Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease
NCT01687179	PHASE1	COMPLETED	Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
NCT04388371	PHASE1	COMPLETED	Glutamine PET Imaging in LAM
NCT05087134	EARLY_PHASE1	UNKNOWN	Characterizing LAM With 11C-Choline PET/CT
NCT00001465	Not specified	RECRUITING	Study of the Disease Process of Lymphangioleiomyomatosis
NCT01484236	Not specified	RECRUITING	National Lymphangioleiomyomatosis Registry, France
NCT02432560	Not specified	RECRUITING	Safety and Durability of Sirolimus for Treatment of LAM
NCT05676099	Not specified	RECRUITING	TSC Biosample Repository and Natural History Database
NCT05727852	Not specified	ENROLLING_BY_INVITATION	Breath Analysis and Arterial Stiffness in Patients With Respiratory Diseases
NCT06160310	Not specified	RECRUITING	Tuberous Sclerosis Complex and Lymphangioleiomyomatosis Pregnancy Registry (TSC-LAM Registry)
NCT07304856	Not specified	RECRUITING	Role of Extracellular Vesicles as Biomarkers of Pulmonary Involvement in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex
NCT00366509	Not specified	COMPLETED	Role of Helicobacter Pylori and Its Toxins in Lung and Digestive System Diseases
NCT00552955	Not specified	COMPLETED	Effect of Fasting on the Size of Abdominal Lymphatic Tumors in Women
NCT00960895	Not specified	COMPLETED	Pulmonary Hypertension in Lymphangioleiomyomatosis
NCT02009241	Not specified	COMPLETED	Pulmonary Rehabilitation in Lymphangioleiomyomatosis
NCT02325505	Not specified	COMPLETED	Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma
NCT02654340	Not specified	TERMINATED	Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)
NCT02859194	Not specified	COMPLETED	The Effect of Lt to Rt Shunt Using Veno-veno-arterial Extracorporeal Membrane Oxygenation (ECMO) on Coronary Oxygenation in Lung Transplantation Patients
NCT04184193	Not specified	COMPLETED	Benefits of Pulmonary Rehabilitation in Patients With Severe Lymphangioleiomyomatosis (LAM)
NCT04577937	Not specified	UNKNOWN	Sleep Patterns in Patients Affected by Lymphangioleiomiomatosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXYCYCLINE ANHYDROUS	4	3
GLUTAMINE	4	1
LORATADINE	4	1
NINTEDANIB	4	1
OCTREOTIDE	4	1
SIROLIMUS	4	1
RESVERATROL	3	1
CHEMBL3350037	0	1