Danon disease

Summary

Danon disease (MONDO:0010281) is a disease caused by LAMP2 (GenCC Definitive), with 3 cohort genes and 7 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LAMP2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 656
• Phenotypes (HPO): 6
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		84	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	<1 / 1 000 000	0.05	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0001644	Dilated cardiomyopathy	Very frequent (80-99%)
HP:0006543	Cardiorespiratory arrest	Very frequent (80-99%)
HP:0010547	Muscle flaccidity	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Danon disease
Mondo ID	MONDO:0010281
EFO	EFO:1001333
MeSH	D052120
OMIM	300257
Orphanet	34587
DOID	DOID:0050437
ICD-11	1233188442
NCIT	C84735
SNOMED CT	419097006
UMLS	C0878677
MedGen	209235
GARD	0009730
NORD	1033
Is cancer (heuristic)	no

Also known as: ANTOPOL disease · Danon disease · Danon disease, X-linked dominant · glycogen storage cardiomyopathy · glycogen storage disease limited to the heart · glycogen storage disease type 2b (formerly) · glycogen storage disease type IIb · glycogenosis due to LAMP-2 deficiency · GSD due to LAMP-2 deficiency · GSD IIb · GSD2B (formerly) · LAMP2 lysosomal glycogen storage disease · lysosomal glycogen storage disease caused by mutation in LAMP2 · lysosomal glycogen storage disease with normal acid maltase activity · lysosomal glycogen storage disease without acid maltase deficiency · lysosomal glycogen storage disease without acid maltase deficiency (formerly) · vacuolar cardiomyopathy and myopathy X-linked · X-linked vacuolar cardiomyopathy and myopathy

Data availability: 656 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › Danon disease

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, glycogen storage disease IXd, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

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

600 retrieved; paginated sample, class counts are floors:

209 uncertain significance, 161 likely benign, 89 pathogenic, 53 conflicting classifications of pathogenicity, 31 benign, 30 benign/likely benign, 18 likely pathogenic, 9 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012342	NM_002294.3(LAMP2):c.139C>T (p.Gln47Ter)	LAMP2	Pathogenic	criteria provided, single submitter
1029437	NM_002294.3(LAMP2):c.614_615del (p.Val205fs)	LAMP2	Pathogenic	criteria provided, single submitter
1064624	NM_002294.3(LAMP2):c.928+3A>T	LAMP2	Pathogenic	criteria provided, single submitter
1072236	NC_000023.10:g.(?119565168)(119603034_?)del	LAMP2	Pathogenic	criteria provided, single submitter
1074071	NM_002294.3(LAMP2):c.646G>T (p.Glu216Ter)	LAMP2	Pathogenic	criteria provided, single submitter
1075078	NM_002294.3(LAMP2):c.929-197_1070del	LAMP2	Pathogenic	criteria provided, single submitter
1300025	NM_002294.3(LAMP2):c.864+4A>G	LAMP2	Pathogenic	no assertion criteria provided
1323186	NM_002294.3(LAMP2):c.64G>T (p.Gly22Ter)	LAMP2	Pathogenic	criteria provided, single submitter
1323190	NM_002294.3(LAMP2):c.1057C>T (p.Gln353Ter)	LAMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323203	NM_002294.3(LAMP2):c.467T>G (p.Leu156Ter)	LAMP2	Pathogenic	criteria provided, single submitter
1323222	NM_002294.3(LAMP2):c.183+2T>C	LAMP2	Pathogenic	criteria provided, single submitter
1323223	NM_002294.3(LAMP2):c.327T>A (p.Tyr109Ter)	LAMP2	Pathogenic	criteria provided, single submitter
1369085	NM_002294.3(LAMP2):c.955del (p.Ser319fs)	LAMP2	Pathogenic	criteria provided, single submitter
1398614	NM_002294.3(LAMP2):c.54C>A (p.Cys18Ter)	LAMP2	Pathogenic	criteria provided, single submitter
1451509	NM_002294.3(LAMP2):c.1041del (p.Phe348fs)	LAMP2	Pathogenic	criteria provided, single submitter
1452436	NM_002294.3(LAMP2):c.928G>C (p.Val310Leu)	LAMP2	Pathogenic	criteria provided, single submitter
1459080	NM_002294.3(LAMP2):c.391del (p.Asp131fs)	LAMP2	Pathogenic	criteria provided, single submitter
1514744	NM_002294.3(LAMP2):c.741+2T>A	LAMP2	Pathogenic	criteria provided, single submitter
1523103	NM_002294.3(LAMP2):c.1A>C (p.Met1Leu)	LAMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
163812	NM_002294.3(LAMP2):c.877C>T (p.Arg293Ter)	LAMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
163813	NM_002294.3(LAMP2):c.864+1G>T	LAMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
163816	NM_002294.3(LAMP2):c.183+1G>A	LAMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685922	NM_002294.3(LAMP2):c.436_440dup (p.Leu147fs)	LAMP2	Pathogenic	criteria provided, single submitter
1698512	NC_000023.10:g.(?119560002)(119603205_?)del	LAMP2	Pathogenic	criteria provided, single submitter
177994	NM_002294.3(LAMP2):c.128_129dup (p.Ala44fs)	LAMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
178999	NM_002294.3(LAMP2):c.1020del (p.Gly341fs)	LAMP2	Pathogenic	criteria provided, single submitter
179062	NM_002294.3(LAMP2):c.121del (p.Cys41fs)	LAMP2	Pathogenic	criteria provided, single submitter
179126	NM_002294.3(LAMP2):c.851_852del (p.Phe284fs)	LAMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
179254	NM_002294.3(LAMP2):c.1093+1G>A	LAMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1806359	NM_002294.3(LAMP2):c.584_585insGC (p.Thr196fs)	LAMP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
LAMP2	Definitive	X-linked	Danon disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMP2	Orphanet:34587	Danon disease
CUL4B	Orphanet:85293	X-linked intellectual disability, Cabezas type

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LAMP2	HGNC:6501	ENSG00000005893	P13473	Lysosome-associated membrane glycoprotein 2	gencc,clinvar
CUL4B	HGNC:2555	ENSG00000158290	Q13620	Cullin-4B	clinvar
RHOXF2B	HGNC:33519	ENSG00000203989	P0C7M4	Rhox homeobox family member 2B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMP2	Lysosome-associated membrane glycoprotein 2	Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, lysosomal pH regulation and autophagy.
CUL4B	Cullin-4B	Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
RHOXF2B	Rhox homeobox family member 2B	Transcription factor maybe involved in reproductive processes.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAMP2	Other/Unknown	no		Lysosome-assoc_membr_glycop, LAMP_CS, Lamp2-like_TM
CUL4B	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology
RHOXF2B	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
lateral globus pallidus	1
nephron tubule	1
corpus epididymis	1
male germ cell	1
sperm	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMP2	301	ubiquitous	marker	corpus callosum, lateral globus pallidus, nephron tubule
CUL4B	291	ubiquitous	marker	sperm, male germ cell, corpus epididymis
RHOXF2B	55	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL4B	4,342
LAMP2	3,838
RHOXF2B	301

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CUL4B	Q13620	5
LAMP2	P13473	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHOXF2B	P0C7M4	63.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 3 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
Chaperone Mediated Autophagy	1	248.3×	0.022	LAMP2
Recognition of DNA damage by PCNA-containing replication complex	1	190.3×	0.022	CUL4B
DNA Damage Recognition in GG-NER	1	142.8×	0.022	CUL4B
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	132.8×	0.022	CUL4B
Dual Incision in GG-NER	1	129.8×	0.022	CUL4B
Formation of Incision Complex in GG-NER	1	126.9×	0.022	CUL4B
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.022	CUL4B
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.022	CUL4B
Dual incision in TC-NER	1	86.5×	0.022	CUL4B
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.022	LAMP2
Autophagy	1	74.2×	0.022	LAMP2
Platelet activation, signaling and aggregation	1	52.9×	0.028	LAMP2
Platelet degranulation	1	43.9×	0.031	LAMP2
Neddylation	1	23.7×	0.054	CUL4B
Hemostasis	1	18.0×	0.066	LAMP2
Innate Immune System	1	12.8×	0.087	LAMP2
Neutrophil degranulation	1	11.5×	0.090	LAMP2
Immune System	1	6.5×	0.148	LAMP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein targeting to lysosome involved in chaperone-mediated autophagy	1	1872.4×	0.012	LAMP2
chaperone-mediated autophagy	1	936.2×	0.012	LAMP2
protein import	1	561.7×	0.012	LAMP2
positive regulation of ferroptosis	1	510.7×	0.012	LAMP2
UV-damage excision repair	1	432.1×	0.012	CUL4B
lysosomal protein catabolic process	1	351.1×	0.012	LAMP2
negative regulation of NLRP3 inflammasome complex assembly	1	330.4×	0.012	LAMP2
proteasomal protein catabolic process	1	255.3×	0.012	CUL4B
astrocyte differentiation	1	255.3×	0.012	CUL4B
lysosomal lumen acidification	1	224.7×	0.012	LAMP2
muscle cell cellular homeostasis	1	216.1×	0.012	LAMP2
ribosome biogenesis	1	208.1×	0.012	CUL4B
negative regulation of protein-containing complex assembly	1	151.8×	0.016	LAMP2
positive regulation of G1/S transition of mitotic cell cycle	1	133.8×	0.017	CUL4B
protein targeting	1	122.1×	0.017	LAMP2
autophagosome maturation	1	117.0×	0.017	LAMP2
cellular response to UV	1	98.5×	0.018	CUL4B
neuron development	1	85.1×	0.020	RHOXF2B
protein catabolic process	1	79.1×	0.021	LAMP2
positive regulation of protein catabolic process	1	67.7×	0.022	CUL4B
G1/S transition of mitotic cell cycle	1	66.9×	0.022	CUL4B
cellular response to starvation	1	64.6×	0.022	LAMP2
regulation of protein stability	1	41.9×	0.032	LAMP2
protein polyubiquitination	1	38.5×	0.033	CUL4B
gene expression	1	26.6×	0.046	CUL4B
ubiquitin-dependent protein catabolic process	1	24.8×	0.048	CUL4B
protein stabilization	1	22.3×	0.051	LAMP2
DNA damage response	1	17.8×	0.061	CUL4B
protein ubiquitination	1	13.8×	0.076	CUL4B
positive regulation of gene expression	1	12.9×	0.078	RHOXF2B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LAMP2	0	0
CUL4B	0	0
RHOXF2B	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
CUL4B	5	Binding:5
LAMP2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	LAMP2, CUL4B, RHOXF2B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LAMP2	2	—
CUL4B	5	—
RHOXF2B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06092034	PHASE2	RECRUITING	A Gene Therapy Study of RP-A501 in Male Patients With Danon Disease
NCT03882437	PHASE1	UNKNOWN	Gene Therapy for Male Patients With Danon Disease (DD) Using RP-A501; AAV9.LAMP2B
NCT06214507	Not specified	RECRUITING	Danon Disease Natural History Study
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT03766386	Not specified	UNKNOWN	The Natural History of Danon Disease
NCT05548855	Not specified	COMPLETED	Natural History of Danon Disease