Danon disease

👪

Inheritance

1

X-linked dominant

Danon disease is inherited as an X-linked dominant trait. Males with a single mutant allele are severely affected, while female carriers exhibit variable phenotypes due to X-chromosome inactivation mosaicism, typically presenting with predominantly cardiac manifestations later in life.

Show evidence (1 reference)

DOI:10.1111/nan.12587 SUPPORT Other

"inherited as an X"

Confirms X-linked dominant inheritance pattern.

⚙

Pathophysiology

8

LAMP2 protein deficiency

Mutations in the LAMP2 gene lead to deficiency of lysosome-associated membrane protein 2, particularly the LAMP-2B isoform which is essential for proper autophagosome-lysosome fusion in cardiac and skeletal muscle cells.

cardiomyocyte link skeletal muscle fiber link

lysosome organization link

protein-macromolecule adaptor activity link

Downstream

Impaired autophagosome-lysosome fusion LAMP-2B deficiency prevents proper docking and fusion of autophagosomes with lysosomes, blocking completion of the autophagy pathway.

Show evidence (3 references)

PMID:25589223 SUPPORT Other

"LAMP-2 is required for the maturation of"

Confirms LAMP-2 is required for autophagosome maturation and its deficiency causes macroautophagy failure.

PMID:34737089 SUPPORT Other

"LAMP-2 protein deficiency, mainly LAMP-2B"

Confirms LAMP-2B isoform deficiency as the primary molecular defect.

DOI:10.1111/nan.12587 SUPPORT Other

"causes disruption of autophagy"

Confirms that LAMP-2 deficiency disrupts autophagy through impaired lysosome-autophagosome fusion.

Impaired autophagosome-lysosome fusion

LAMP-2B deficiency causes a late-stage block in the autophagy pathway by preventing fusion of autophagosomes with lysosomes, leading to accumulation of unprocessed autophagosomes.

cardiomyocyte link skeletal muscle fiber link

macroautophagy link autophagosome maturation link

Downstream

Autophagic vacuole accumulation Failed fusion results in accumulation of autophagic vacuoles containing undegraded cellular material and glycogen.

Impaired mitophagy Defective autophagosome-lysosome fusion specifically impairs clearance of damaged mitochondria via mitophagy.

Show evidence (2 references)

PMID:34737089 SUPPORT Other

"impairment due to LAMP-2 deficiency"

Confirms that LAMP-2 deficiency causes autophagy impairment and autophagic vacuole accumulation.

DOI:10.1038/cddis.2016.475 SUPPORT Model Organism

"DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting."

Demonstrates that LAMP2 mutations cause impaired autophagosome-lysosome fusion and lysosome biogenesis defects.

Autophagic vacuole accumulation

Accumulation of autophagic vacuoles with sarcolemmal features (AVSFs) in cardiac and skeletal muscle. These vacuoles contain glycogen and undegraded cellular components, representing a histopathological hallmark distinct from other glycogen storage disorders.

cardiomyocyte link skeletal muscle fiber link

macroautophagy link

Downstream

Cardiac autophagic vacuolar cardiomyopathy Autophagic vacuole accumulation in cardiomyocytes drives Danon cardiomyopathy and hypertrophic-to-dilated cardiac remodeling.

Skeletal muscle and hepatic enzyme involvement Autophagic vacuolar myopathy and multisystem tissue involvement produce skeletal myopathy and serum muscle or hepatic enzyme elevations.

Neuroretinal involvement Multisystem LAMP2/autophagy disruption also involves brain and retinal tissues, connecting the core lysosomal defect to neurodevelopmental and visual manifestations.

Show evidence (2 references)

DOI:10.3390/biom14101272 SUPPORT Other

"Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs)."

Confirms AVSFs as a pathological hallmark of Danon disease.

DOI:10.1038/cddis.2016.475 PARTIAL Model Organism

"Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects."

Establishes Danon disease as a lysosomal storage disorder with autophagic vacuolar myopathy.

Cardiac autophagic vacuolar cardiomyopathy

LAMP2 deficiency produces vacuolated degenerating cardiomyocytes and a severe cardiomyopathy phenotype with marked left-ventricular hypertrophy, progressive systolic dysfunction, cavity enlargement, heart failure, and risk of sudden death.

cardiomyocyte link

Downstream

Hypertrophic cardiomyopathy Danon cardiomyopathy commonly presents as hypertrophic cardiomyopathy.

Left ventricular hypertrophy Danon cardiac remodeling produces marked left-ventricular hypertrophy.

Dilated cardiomyopathy Progressive systolic dysfunction and cavity enlargement can evolve into a dilated/end-stage cardiomyopathy phase.

Elevated creatine kinase measurement Myocardial damage in Danon disease can be accompanied by elevated CK-MB and other injury biomarkers.

Show evidence (2 references)

PMID:25589223 SUPPORT Other

"In heart, cardiomyocytes show dramatically increased vacuolation and"

Review of human Danon pathology links LAMP2 deficiency to vacuolated cardiomyocytes.

PMID:19318653 SUPPORT Human Clinical

"LAMP2 cardiomyopathy is a profound disease process characterized by"

Prospective patient follow-up supports severe progressive LAMP2 cardiomyopathy.

Skeletal muscle and hepatic enzyme involvement

Danon disease includes skeletal autophagic vacuolar myopathy and variable hepatic involvement. Muscle and liver injury can be reflected by elevated CK-MB, myoglobin, troponin, ALT, AST, ALP, and related serum markers.

skeletal muscle fiber link

Downstream

Skeletal myopathy Autophagic vacuolar muscle involvement produces skeletal myopathy.

Elevated circulating creatine kinase concentration Muscle and myocardial damage can elevate creatine kinase or CK-MB.

Elevated circulating hepatic transaminase concentration Hepatic involvement can elevate ALT and AST transaminases.

Elevated alanine aminotransferase measurement ALT elevation is a biochemical readout of hepatic involvement in Danon disease.

Elevated aspartate aminotransferase measurement AST elevation is a biochemical readout of hepatic involvement in Danon disease.

Show evidence (2 references)

PMID:25589223 SUPPORT Other

"hypertrophic cardiomyopathy, myopathy, and intellectual disability."

Review identifies skeletal myopathy as part of the classic Danon triad.

PMID:33680117 SUPPORT Human Clinical

"Other symptoms that are less prevalent include hepatic disease"

Patient cohort review notes hepatic disease among Danon manifestations.

Neuroretinal involvement

Danon disease can involve brain and retinal tissues, producing intellectual impairment as part of the classic male triad and less common retinal disease such as cone-rod dystrophy with visual impairment.

Downstream

Intellectual disability Brain involvement contributes to intellectual disability in the classic Danon triad.

Retinal dystrophy Retinal involvement can manifest as cone-rod dystrophy and visual impairment.

Show evidence (2 references)

PMID:25589223 SUPPORT Other

"In brain, pale granular neurons and neurons with lipofuscin-like"

Human pathology review supports brain involvement in Danon disease.

DOI:10.3390/genes14081539 SUPPORT Human Clinical

"visual impairment due to cone–rod dystrophy."

Case report documents retinal dystrophy with visual impairment in Danon disease.

Impaired mitophagy

Defective autophagosome-lysosome fusion specifically impairs the mitophagy pathway, preventing clearance of damaged and depolarized mitochondria from cardiomyocytes.

cardiomyocyte link

mitophagy link

Downstream

Mitochondrial dysfunction and oxidative stress Accumulation of damaged mitochondria leads to reduced respiration, increased reactive oxygen species production, and oxidative stress.

Show evidence (1 reference)

PMID:28526246 SUPPORT Model Organism

"Impaired autophagic flux was noted in the"

Hashem et al. 2017 (DOI:10.1016/j.yjmcc.2017.05.007) directly demonstrates incomplete mitophagy in Lamp-2 knockout mice.

Mitochondrial dysfunction and oxidative stress

Accumulation of damaged and depolarized mitochondria results in reduced mitochondrial respiration, increased reactive oxygen species production, and oxidative stress, contributing to cardiomyocyte injury and arrhythmogenesis.

cardiomyocyte link

response to oxidative stress link

Downstream

Wolff-Parkinson-White syndrome Mitochondrial damage and oxidative stress in cardiomyocytes can promote electrical instability, contributing to conduction abnormalities and arrhythmia susceptibility in Danon disease.

Show evidence (2 references)

PMID:28526246 SUPPORT Model Organism

"Lamp-2 KO mice compared to WT reporter mice, as well as an increased number of abnormal mitochondria, evidence of incomplete mitophagy, and impaired mitochondrial respiration."

Hashem et al. 2017 (DOI:10.1016/j.yjmcc.2017.05.007) demonstrates abnormal mitochondria and impaired mitochondrial respiration in a Lamp-2 knockout mouse model.

PMID:28526246 SUPPORT In Vitro

"significant mitochondrial oxidative stress and apoptosis."

Patient-derived cardiomyocytes demonstrate mitochondrial oxidative stress, supporting the oxidative-stress component of this node.

✶

Histopathology

1

Autophagic vacuoles with sarcolemmal features

Muscle biopsy in Danon disease shows autophagic vacuoles with sarcolemmal features, a characteristic microscopic finding of LAMP-2 deficiency.

Show evidence (1 reference)

DOI:10.3390/biom14101272 SUPPORT Other

"Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs)."

Confirms AVSFs as a defining pathological hallmark of Danon disease.

⬡

Pathograph

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

●

Phenotypes

9

Cardiovascular 4

Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HP:0001639)

Show evidence (3 references)

PMID:34737089 SUPPORT Other

"triad of hypertrophic cardiomyopathy, skeletal muscle"

Review confirms hypertrophic cardiomyopathy as part of the defining clinical triad.

PMID:19318653 SUPPORT Human Clinical

"progressive clinical deterioration leading rapidly to cardiac death"

Prospective study of 7 LAMP2 patients documenting severe cardiac disease leading to death before age 25.

DOI:10.1111/nan.12587 SUPPORT Other

"Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients"

Confirms hypertrophic cardiomyopathy as a primary clinical feature of Danon disease.

Wolff-Parkinson-White syndrome Wolff-Parkinson-White syndrome (HP:0001716)

Show evidence (3 references)

PMID:33680117 SUPPORT Human Clinical

"ventricular preexcitation with a short PR interval."

Confirms ventricular preexcitation as a characteristic ECG finding in Danon disease.

PMID:19318653 SUPPORT Human Clinical

"ECG at diagnosis, 6 patients had ventricular pre-excitation patterns"

Documents ventricular pre-excitation in 6 of 7 Danon disease patients at diagnosis.

DOI:10.3390/genes14081539 SUPPORT Human Clinical

"mild ventricular pre-excitation known as"

Case report documenting WPW syndrome as an early manifestation in a Danon disease patient.

Left ventricular hypertrophy Left ventricular hypertrophy (HP:0001712)

Show evidence (1 reference)

PMID:19318653 SUPPORT Human Clinical

"particularly massive LV hypertrophy"

Prospective study documents massive LV hypertrophy in Danon disease, with some of the thickest ventricles ever recorded.

Dilated cardiomyopathy Dilated cardiomyopathy (HP:0001644)

Show evidence (2 references)

PMID:19318653 SUPPORT Human Clinical

"end-stage phase characterized by LV"

Documents progression to severe LV systolic dysfunction and cavity dilatation in LAMP2 patients.

PMID:34737089 SUPPORT Other

"Cardiac involvement can be fatal"

Confirms cardiac disease progression is fatal without transplantation.

Eye 1

Retinal dystrophy Retinal dystrophy (HP:0000556)

Show evidence (1 reference)

DOI:10.3390/genes14081539 SUPPORT Human Clinical

"visual impairment due to"

Documents retinal dystrophy (cone-rod dystrophy) as a clinical manifestation in Danon disease.

Metabolism 2

Elevated circulating creatine kinase concentration Elevated circulating creatine kinase concentration (HP:0003236)

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"The proband's laboratory findings included myocardial damage [troponin T (TropT), 15.93 ng/ml; myoglobin (Mb), 366.9 ng/ml; creatine kinase isoenzyme MB (CK-MB), 7.9 ng/ml]"

Clinical study documenting elevated cardiac muscle enzyme CK-MB and other serum markers of myocardial damage in a Danon disease patient.

Elevated circulating hepatic transaminase concentration Elevated circulating hepatic transaminase concentration (HP:0002910)

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"hepatic lesions [alanine aminotransferase (ALT), 246 IU/; aspartate aminotransferase (AST), 241 IU/l; alkaline phosphatase (ALP), 249 IU/l]"

Documents elevated circulating ALT and AST values as serum evidence of hepatic involvement in a Danon disease patient.

Musculoskeletal 1

Skeletal myopathy Myopathy (HP:0003198)

Show evidence (3 references)

PMID:34737089 SUPPORT Other

"triad of hypertrophic cardiomyopathy, skeletal muscle"

Review confirms skeletal muscle weakness as part of the defining clinical triad.

PMID:25589223 SUPPORT Other

"small basophilic granules scattered in myofibers"

Describes characteristic muscle biopsy findings of autophagic vacuoles with sarcolemmal features in skeletal muscle.

DOI:10.1111/nan.12587 SUPPORT Other

"Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients"

Confirms skeletal myopathy as part of the clinical triad in affected males.

Nervous System 1

Intellectual disability Intellectual disability (HP:0001249)

Show evidence (3 references)

PMID:33680117 SUPPORT Human Clinical

"cardiomyopathy and intellectual impairment."

Confirms intellectual impairment as one of the three defining features of Danon disease.

PMID:25589223 SUPPORT Other

"hypertrophic cardiomyopathy, myopathy, and intellectual disability."

Confirms intellectual disability as part of the classic clinical triad.

DOI:10.1111/nan.12587 SUPPORT Other

"Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients"

Confirms intellectual disability (mental retardation) as a defining feature in males.

🧬

Genetic Associations

2

LAMP2 mutations (Causative)

Show evidence (6 references)

PMID:25589223 SUPPORT Other

"Danon disease is caused by loss-of-function mutations"

Confirms loss-of-function LAMP2 mutations as the cause of Danon disease.

PMID:25589223 SUPPORT Other

"Most mutations lead to splicing defects"

Documents the mutation spectrum including splicing and truncation mutations.

PMID:33680117 SUPPORT Human Clinical

"loss-of-function mutation in the lysosome-associated"

Confirms LAMP2 loss-of-function as the molecular cause.

+ 3 more references

Sex-specific phenotypic differences (Modifying)

Show evidence (3 references)

PMID:19318653 SUPPORT Human Clinical

"7 female LAMP2 obligate carriers"

Documents striking phenotypic differences between female carriers and affected males.

DOI:10.1111/nan.12587 SUPPORT Other

"Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients."

Documents distinct phenotypic presentations between males and females.

DOI:10.3390/genes14081539 SUPPORT Human Clinical

"Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy and heart failure. Female patients usually present with milder and variable symptoms."

Confirms sex-specific differences in disease severity and progression.

💊

Treatments

2

Heart transplantation

Action: organ transplantation MAXO:0010039

Cardiac transplantation is the primary disease-modifying treatment for Danon disease patients with advanced heart failure. In male patients with severe cardiomyopathy, heart transplantation is often the only intervention that modifies the disease course.

Show evidence (3 references)

PMID:25589223 SUPPORT Other

"transplantation is the only therapeutic option."

Confirms cardiac transplantation as the only therapeutic option for Danon disease cardiomyopathy.

PMID:19318653 SUPPORT Human Clinical

"early intervention with heart"

Prospective study supporting early consideration of heart transplantation for LAMP2 patients.

DOI:10.1111/nan.12587 SUPPORT Other

"in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course."

Confirms heart transplantation as the only disease-modifying intervention.

Gene therapy (AAV9.LAMP2B)

Action: gene therapy MAXO:0001001

Adeno-associated virus vector-based gene therapy delivering functional LAMP2B is under clinical investigation. RP-A501, an AAV9-based gene therapy, has advanced through Phase 1 and into Phase 2 clinical trials for male patients with Danon disease.

Show evidence (2 references)

PMID:34737089 SUPPORT Other

"gene therapies anticipate"

Confirms gene therapy clinical trials are underway for Danon disease.

DOI:10.3390/biom14101272 PARTIAL Other

"Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future."

Confirms that AAV-based gene therapy clinical trials have been initiated.

🔬

Biochemical Markers

3

Elevated creatine kinase measurement (INCREASED)

Pathograph Readouts

Correlates With Cardiac autophagic vacuolar cardiomyopathy Positive Diagnostic

Elevated CK-MB and related injury markers support muscle or myocardial damage in Danon disease.

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"creatine kinase isoenzyme MB (CK-MB), 7.9 ng/ml"

Patient laboratory data document elevated CK-MB among myocardial damage markers.

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"creatine kinase isoenzyme MB (CK-MB), 7.9 ng/ml"

Patient laboratory findings support elevated CK-MB as a biochemical abnormality.

Elevated alanine aminotransferase measurement (INCREASED)

Pathograph Readouts

Readout Of Skeletal muscle and hepatic enzyme involvement Positive Diagnostic

Elevated ALT reports hepatic enzyme involvement in Danon disease.

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"alanine aminotransferase (ALT), 246 IU/"

Patient laboratory data document elevated ALT.

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"alanine aminotransferase (ALT), 246 IU/"

Patient laboratory findings support elevated ALT.

Elevated aspartate aminotransferase measurement (INCREASED)

Pathograph Readouts

Readout Of Skeletal muscle and hepatic enzyme involvement Positive Diagnostic

Elevated AST reports hepatic enzyme involvement in Danon disease.

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"aspartate aminotransferase (AST), 241 IU/l"

Patient laboratory data document elevated AST.

Show evidence (1 reference)

PMID:33680117 SUPPORT Human Clinical

"aspartate aminotransferase (AST), 241 IU/l"

Patient laboratory findings support elevated AST.

🔬

Clinical Trials

2

NCT03882437 PHASE_I

Open-label Phase 1 study evaluating RP-A501, an rAAV9 vector carrying the human LAMP2B transgene, in male patients with Danon disease.

Target Phenotypes: Hypertrophic cardiomyopathy ↗

Show evidence (1 reference)

clinicaltrials:NCT03882437 SUPPORT Human Clinical

"This is a non-randomized open-label Phase 1 study to evaluate the safety and toxicity of gene therapy using a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene (investigational product (IP), RP-A501) in..."

ClinicalTrials.gov describes the first-in-human RP-A501 gene therapy study in male Danon disease patients.

NCT06092034 PHASE_II RECRUITING

Single-arm Phase 2 study evaluating the efficacy and safety of RP-A501, an rAAV9.LAMP2B gene therapy, in male patients with Danon disease.

Target Phenotypes: Hypertrophic cardiomyopathy ↗

Show evidence (1 reference)

clinicaltrials:NCT06092034 SUPPORT Human Clinical

"This is a single arm Phase 2 trial to evaluate the efficacy and safety of RP-A501, a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene, in male patients with Danon Disease."

ClinicalTrials.gov documents the active Phase 2 RP-A501 gene therapy study in Danon disease.

{ }

Source YAML

click to show

name: Danon disease
creation_date: '2026-02-03T19:04:58Z'
updated_date: '2026-05-19T12:13:45Z'
category: Mendelian
disease_term:
  preferred_term: Danon disease
  term:
    id: MONDO:0010281
    label: Danon disease
parents:
- "Lysosomal storage diseases"
- "X-linked genetic disorders"
- "Autophagic vacuolar myopathies"
references:
- reference: PMID:32134616
  title: Danon Disease.
  tags:
  - GeneReviews
  findings: []

description: >
  Danon disease is an X-linked dominant disorder caused by pathogenic variants in LAMP2
  (lysosome-associated membrane protein 2), leading to defective autophagosome-lysosome
  fusion and accumulation of autophagic vacuoles in cardiac and skeletal muscle. The
  disease primarily manifests as the triad of hypertrophic cardiomyopathy, skeletal
  myopathy, and intellectual disability in affected males. Female carriers may develop
  milder cardiac manifestations later in life due to X-chromosome inactivation mosaicism.
  The prognosis is poor in males, with rapid progression towards heart failure, and only
  heart transplantation modifies the disease course.

inheritance:
- name: X-linked dominant
  description: >
    Danon disease is inherited as an X-linked dominant trait. Males with a single mutant
    allele are severely affected, while female carriers exhibit variable phenotypes due
    to X-chromosome inactivation mosaicism, typically presenting with predominantly
    cardiac manifestations later in life.
  evidence:
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "inherited as an X"
    explanation: Confirms X-linked dominant inheritance pattern.
prevalence:
- population: Published literature review
  percentage: 146 reported patients across 83 manuscripts
  notes: >-
    No stable general-population prevalence estimate was identified in PubMed
    abstracts. A systematic review published in 2019 found only 146 eligible
    Danon disease patients across 83 manuscripts, underscoring its ultra-rare
    status.
  evidence:
  - reference: PMID:30857840
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 83 manuscripts in MEDLINE and EMBASE on DD cases published until
      October 2017, we identified 146 patients with positive genetic testing
      for DD or positive muscle biopsy in a relative of a genetically diagnosed
      proband.
    explanation: >-
      This systematic review provides the clearest PubMed-abstract count of
      reported Danon disease patients in the literature.
- population: Patients with unexplained LVH and ventricular preexcitation
  percentage: 30%
  notes: >-
    In a genetically tested enriched cardiomyopathy cohort, Danon disease
    accounted for 3 of 10 patients who had both unexplained left ventricular
    hypertrophy and electrocardiographic preexcitation.
  evidence:
  - reference: PMID:30929317
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three (3/10, 30%) patients"
    explanation: >-
      This targeted screening study quantifies how often Danon disease appears
      in a clinically enriched hypertrophic cardiomyopathy subgroup.

pathophysiology:
- name: LAMP2 protein deficiency
  description: >
    Mutations in the LAMP2 gene lead to deficiency of lysosome-associated membrane
    protein 2, particularly the LAMP-2B isoform which is essential for proper
    autophagosome-lysosome fusion in cardiac and skeletal muscle cells.
  gene:
    preferred_term: LAMP2
    term:
      id: hgnc:6501
      label: LAMP2
  molecular_functions:
  - preferred_term: protein-macromolecule adaptor activity
    term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: lysosome organization
    term:
      id: GO:0007040
      label: lysosome organization
  downstream:
  - target: Impaired autophagosome-lysosome fusion
    description: >
      LAMP-2B deficiency prevents proper docking and fusion of autophagosomes
      with lysosomes, blocking completion of the autophagy pathway.
  evidence:
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LAMP-2 is required for the maturation of"
    explanation: Confirms LAMP-2 is required for autophagosome maturation and its deficiency causes macroautophagy failure.
  - reference: PMID:34737089
    reference_title: "Clinical features of Danon disease and insights gained from LAMP-2 deficiency models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LAMP-2 protein deficiency, mainly LAMP-2B"
    explanation: Confirms LAMP-2B isoform deficiency as the primary molecular defect.
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "causes disruption of autophagy"
    explanation: Confirms that LAMP-2 deficiency disrupts autophagy through impaired lysosome-autophagosome fusion.

- name: Impaired autophagosome-lysosome fusion
  description: >
    LAMP-2B deficiency causes a late-stage block in the autophagy pathway by
    preventing fusion of autophagosomes with lysosomes, leading to accumulation
    of unprocessed autophagosomes.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: macroautophagy
    term:
      id: GO:0016236
      label: macroautophagy
  - preferred_term: autophagosome maturation
    term:
      id: GO:0097352
      label: autophagosome maturation
  downstream:
  - target: Autophagic vacuole accumulation
    description: >
      Failed fusion results in accumulation of autophagic vacuoles containing
      undegraded cellular material and glycogen.
  - target: Impaired mitophagy
    description: >
      Defective autophagosome-lysosome fusion specifically impairs clearance
      of damaged mitochondria via mitophagy.
  evidence:
  - reference: PMID:34737089
    reference_title: "Clinical features of Danon disease and insights gained from LAMP-2 deficiency models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "impairment due to LAMP-2 deficiency"
    explanation: Confirms that LAMP-2 deficiency causes autophagy impairment and autophagic vacuole accumulation.
  - reference: DOI:10.1038/cddis.2016.475
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting."
    explanation: Demonstrates that LAMP2 mutations cause impaired autophagosome-lysosome fusion and lysosome biogenesis defects.

- name: Autophagic vacuole accumulation
  description: >
    Accumulation of autophagic vacuoles with sarcolemmal features (AVSFs) in
    cardiac and skeletal muscle. These vacuoles contain glycogen and undegraded
    cellular components, representing a histopathological hallmark distinct from
    other glycogen storage disorders.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: macroautophagy
    term:
      id: GO:0016236
      label: macroautophagy
  chemical_entities:
  - preferred_term: glycogen
    term:
      id: CHEBI:28087
      label: glycogen
    modifier: INCREASED
  downstream:
  - target: Cardiac autophagic vacuolar cardiomyopathy
    description: >
      Autophagic vacuole accumulation in cardiomyocytes drives Danon
      cardiomyopathy and hypertrophic-to-dilated cardiac remodeling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Skeletal muscle and hepatic enzyme involvement
    description: >
      Autophagic vacuolar myopathy and multisystem tissue involvement produce
      skeletal myopathy and serum muscle or hepatic enzyme elevations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Neuroretinal involvement
    description: >
      Multisystem LAMP2/autophagy disruption also involves brain and retinal
      tissues, connecting the core lysosomal defect to neurodevelopmental and
      visual manifestations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: DOI:10.3390/biom14101272
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs)."
    explanation: Confirms AVSFs as a pathological hallmark of Danon disease.
  - reference: DOI:10.1038/cddis.2016.475
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects."
    explanation: Establishes Danon disease as a lysosomal storage disorder with autophagic vacuolar myopathy.

- name: Cardiac autophagic vacuolar cardiomyopathy
  description: >
    LAMP2 deficiency produces vacuolated degenerating cardiomyocytes and a
    severe cardiomyopathy phenotype with marked left-ventricular hypertrophy,
    progressive systolic dysfunction, cavity enlargement, heart failure, and
    risk of sudden death.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In heart, cardiomyocytes show dramatically increased vacuolation and"
    explanation: Review of human Danon pathology links LAMP2 deficiency to vacuolated cardiomyocytes.
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LAMP2 cardiomyopathy is a profound disease process characterized by"
    explanation: Prospective patient follow-up supports severe progressive LAMP2 cardiomyopathy.
  downstream:
  - target: Hypertrophic cardiomyopathy
    description: Danon cardiomyopathy commonly presents as hypertrophic cardiomyopathy.
    causal_link_type: DIRECT
  - target: Left ventricular hypertrophy
    description: Danon cardiac remodeling produces marked left-ventricular hypertrophy.
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    description: Progressive systolic dysfunction and cavity enlargement can evolve into a dilated/end-stage cardiomyopathy phase.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Elevated creatine kinase measurement
    description: Myocardial damage in Danon disease can be accompanied by elevated CK-MB and other injury biomarkers.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Skeletal muscle and hepatic enzyme involvement
  description: >
    Danon disease includes skeletal autophagic vacuolar myopathy and variable
    hepatic involvement. Muscle and liver injury can be reflected by elevated
    CK-MB, myoglobin, troponin, ALT, AST, ALP, and related serum markers.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hypertrophic cardiomyopathy, myopathy, and intellectual disability."
    explanation: Review identifies skeletal myopathy as part of the classic Danon triad.
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms that are less prevalent include hepatic disease"
    explanation: Patient cohort review notes hepatic disease among Danon manifestations.
  downstream:
  - target: Skeletal myopathy
    description: Autophagic vacuolar muscle involvement produces skeletal myopathy.
    causal_link_type: DIRECT
  - target: Elevated circulating creatine kinase concentration
    description: Muscle and myocardial damage can elevate creatine kinase or CK-MB.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Elevated circulating hepatic transaminase concentration
    description: Hepatic involvement can elevate ALT and AST transaminases.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Elevated alanine aminotransferase measurement
    description: ALT elevation is a biochemical readout of hepatic involvement in Danon disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Elevated aspartate aminotransferase measurement
    description: AST elevation is a biochemical readout of hepatic involvement in Danon disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Neuroretinal involvement
  description: >
    Danon disease can involve brain and retinal tissues, producing intellectual
    impairment as part of the classic male triad and less common retinal disease
    such as cone-rod dystrophy with visual impairment.
  evidence:
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In brain, pale granular neurons and neurons with lipofuscin-like"
    explanation: Human pathology review supports brain involvement in Danon disease.
  - reference: DOI:10.3390/genes14081539
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "visual impairment due to cone–rod dystrophy."
    explanation: Case report documents retinal dystrophy with visual impairment in Danon disease.
  downstream:
  - target: Intellectual disability
    description: Brain involvement contributes to intellectual disability in the classic Danon triad.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Retinal dystrophy
    description: Retinal involvement can manifest as cone-rod dystrophy and visual impairment.
    causal_link_type: DIRECT
- name: Impaired mitophagy
  description: >
    Defective autophagosome-lysosome fusion specifically impairs the mitophagy
    pathway, preventing clearance of damaged and depolarized mitochondria from
    cardiomyocytes.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: mitophagy
    term:
      id: GO:0000423
      label: mitophagy
  downstream:
  - target: Mitochondrial dysfunction and oxidative stress
    description: >
      Accumulation of damaged mitochondria leads to reduced respiration,
      increased reactive oxygen species production, and oxidative stress.
  evidence:
  - reference: PMID:28526246
    reference_title: "Impaired mitophagy facilitates mitochondrial damage in Danon disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Impaired autophagic flux was noted in the"
    explanation: Hashem et al. 2017 (DOI:10.1016/j.yjmcc.2017.05.007) directly demonstrates incomplete mitophagy in Lamp-2 knockout mice.

- name: Mitochondrial dysfunction and oxidative stress
  description: >
    Accumulation of damaged and depolarized mitochondria results in reduced
    mitochondrial respiration, increased reactive oxygen species production,
    and oxidative stress, contributing to cardiomyocyte injury and arrhythmogenesis.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Wolff-Parkinson-White syndrome
    description: >
      Mitochondrial damage and oxidative stress in cardiomyocytes can promote
      electrical instability, contributing to conduction abnormalities and
      arrhythmia susceptibility in Danon disease.
  evidence:
  - reference: PMID:28526246
    reference_title: "Impaired mitophagy facilitates mitochondrial damage in Danon disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Lamp-2 KO mice compared to WT reporter mice, as well as an increased number of \nabnormal mitochondria, evidence of incomplete mitophagy, and impaired \nmitochondrial respiration."
    explanation: Hashem et al. 2017 (DOI:10.1016/j.yjmcc.2017.05.007) demonstrates abnormal mitochondria and impaired mitochondrial respiration in a Lamp-2 knockout mouse model.
  - reference: PMID:28526246
    reference_title: "Impaired mitophagy facilitates mitochondrial damage in Danon disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "significant mitochondrial oxidative stress and apoptosis."
    explanation: Patient-derived cardiomyocytes demonstrate mitochondrial oxidative stress, supporting the oxidative-stress component of this node.

phenotypes:
- name: Hypertrophic cardiomyopathy
  description: >
    Progressive thickening of the heart muscle, particularly the left ventricle, is
    the most common and severe manifestation of Danon disease. This typically presents
    in childhood or adolescence in males and can lead to heart failure and arrhythmias.
    Cardiomyopathy is the leading cause of death and the main prognostic factor.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:34737089
    reference_title: "Clinical features of Danon disease and insights gained from LAMP-2 deficiency models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "triad of hypertrophic cardiomyopathy, skeletal muscle"
    explanation: Review confirms hypertrophic cardiomyopathy as part of the defining clinical triad.
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive clinical deterioration leading rapidly to cardiac death"
    explanation: Prospective study of 7 LAMP2 patients documenting severe cardiac disease leading to death before age 25.
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients"
    explanation: Confirms hypertrophic cardiomyopathy as a primary clinical feature of Danon disease.

- name: Skeletal myopathy
  description: >
    Weakness of skeletal muscles, particularly proximal muscles, is common in Danon
    disease. Muscle biopsy shows autophagic vacuoles with sarcolemmal features.
    This can cause difficulty with physical activities and may be progressive.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:34737089
    reference_title: "Clinical features of Danon disease and insights gained from LAMP-2 deficiency models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "triad of hypertrophic cardiomyopathy, skeletal muscle"
    explanation: Review confirms skeletal muscle weakness as part of the defining clinical triad.
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "small basophilic granules scattered in myofibers"
    explanation: Describes characteristic muscle biopsy findings of autophagic vacuoles with sarcolemmal features in skeletal muscle.
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients"
    explanation: Confirms skeletal myopathy as part of the clinical triad in affected males.

- name: Intellectual disability
  description: >
    Cognitive impairment of variable severity is frequently observed in affected
    males, ranging from mild learning difficulties to more significant intellectual
    disability. This is part of the classic clinical triad in male patients.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiomyopathy and intellectual impairment."
    explanation: Confirms intellectual impairment as one of the three defining features of Danon disease.
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hypertrophic cardiomyopathy, myopathy, and intellectual disability."
    explanation: Confirms intellectual disability as part of the classic clinical triad.
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients"
    explanation: Confirms intellectual disability (mental retardation) as a defining feature in males.

- name: Wolff-Parkinson-White syndrome
  description: >
    Ventricular pre-excitation due to accessory atrioventricular electrical
    conduction pathways is frequently observed in Danon disease patients. This
    cardiac conduction abnormality may precede overt cardiomyopathy.
  phenotype_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: HP:0001716
      label: Wolff-Parkinson-White syndrome
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ventricular preexcitation with a short PR interval."
    explanation: Confirms ventricular preexcitation as a characteristic ECG finding in Danon disease.
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ECG at diagnosis, 6 patients had ventricular pre-excitation patterns"
    explanation: Documents ventricular pre-excitation in 6 of 7 Danon disease patients at diagnosis.
  - reference: DOI:10.3390/genes14081539
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild ventricular pre-excitation known as"
    explanation: Case report documenting WPW syndrome as an early manifestation in a Danon disease patient.

- name: Retinal dystrophy
  description: >
    Photoreceptor and retinal pigment epithelium degeneration has been reported
    in some Danon disease patients, presenting as cone-rod dystrophy and
    progressive visual impairment.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: DOI:10.3390/genes14081539
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "visual impairment due to"
    explanation: Documents retinal dystrophy (cone-rod dystrophy) as a clinical manifestation in Danon disease.

- name: Left ventricular hypertrophy
  description: >
    Marked thickening of the left ventricular wall is one of the most prominent
    cardiac findings in Danon disease. In males, left ventricular hypertrophy can
    be particularly massive, with wall thickness exceeding 40-60 mm, and may
    represent some of the most substantial hypertrophy reported in humans.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "particularly massive LV hypertrophy"
    explanation: Prospective study documents massive LV hypertrophy in Danon disease, with some of the thickest ventricles ever recorded.

- name: Dilated cardiomyopathy
  description: >
    Progression from hypertrophic to dilated cardiomyopathy with left ventricular
    systolic dysfunction occurs in Danon disease. Female patients in particular
    may present initially with dilated cardiomyopathy. Males typically progress
    to left ventricular cavity dilatation and systolic dysfunction.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "end-stage phase characterized by LV"
    explanation: Documents progression to severe LV systolic dysfunction and cavity dilatation in LAMP2 patients.
  - reference: PMID:34737089
    reference_title: "Clinical features of Danon disease and insights gained from LAMP-2 deficiency models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cardiac involvement can be fatal"
    explanation: Confirms cardiac disease progression is fatal without transplantation.

- name: Elevated circulating creatine kinase concentration
  description: >
    Elevated serum creatine kinase levels are commonly observed in Danon disease,
    reflecting ongoing skeletal and cardiac muscle damage. Elevated CK is a
    useful laboratory marker for identifying Danon disease in patients with
    unexplained cardiomyopathy.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband's laboratory findings included myocardial damage [troponin T (TropT), 15.93 ng/ml; myoglobin (Mb), 366.9 ng/ml; creatine kinase isoenzyme MB (CK-MB), 7.9 ng/ml]"
    explanation: Clinical study documenting elevated cardiac muscle enzyme CK-MB and other serum markers of myocardial damage in a Danon disease patient.

- name: Elevated circulating hepatic transaminase concentration
  description: >
    Elevated liver transaminases (ALT and AST) are frequently observed in Danon
    disease, reflecting hepatic involvement. This can mimic liver disease and
    is part of the multisystem nature of the disorder.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hepatic lesions [alanine aminotransferase (ALT), 246 IU/; aspartate aminotransferase (AST), 241 IU/l; alkaline phosphatase (ALP), 249 IU/l]"
    explanation: Documents elevated circulating ALT and AST values as serum evidence of hepatic involvement in a Danon disease patient.

biochemical:
- name: Elevated creatine kinase measurement
  presence: INCREASED
  notes: >
    Danon disease cardiomyopathy and myopathy can be accompanied by elevated
    CK-MB and other serum markers of myocardial or muscle injury.
  biomarker_term:
    preferred_term: Creatine Kinase Measurement
    term:
      id: NCIT:C64489
      label: Creatine Kinase Measurement
  readouts:
  - target: Cardiac autophagic vacuolar cardiomyopathy
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated CK-MB and related injury markers support muscle or myocardial damage in Danon disease.
    evidence:
    - reference: PMID:33680117
      reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "creatine kinase isoenzyme MB (CK-MB), 7.9 ng/ml"
      explanation: Patient laboratory data document elevated CK-MB among myocardial damage markers.
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "creatine kinase isoenzyme MB (CK-MB), 7.9 ng/ml"
    explanation: Patient laboratory findings support elevated CK-MB as a biochemical abnormality.
- name: Elevated alanine aminotransferase measurement
  presence: INCREASED
  notes: >
    ALT elevation is reported with Danon hepatic involvement and can accompany
    the multisystem muscle/cardiac phenotype.
  biomarker_term:
    preferred_term: Alanine Aminotransferase Measurement
    term:
      id: NCIT:C64433
      label: Alanine Aminotransferase Measurement
  readouts:
  - target: Skeletal muscle and hepatic enzyme involvement
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated ALT reports hepatic enzyme involvement in Danon disease.
    evidence:
    - reference: PMID:33680117
      reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "alanine aminotransferase (ALT), 246 IU/"
      explanation: Patient laboratory data document elevated ALT.
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "alanine aminotransferase (ALT), 246 IU/"
    explanation: Patient laboratory findings support elevated ALT.
- name: Elevated aspartate aminotransferase measurement
  presence: INCREASED
  notes: >
    AST elevation is reported with Danon hepatic involvement and can accompany
    multisystem LAMP2 disease.
  biomarker_term:
    preferred_term: Aspartate Aminotransferase Measurement
    term:
      id: NCIT:C64467
      label: Aspartate Aminotransferase Measurement
  readouts:
  - target: Skeletal muscle and hepatic enzyme involvement
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated AST reports hepatic enzyme involvement in Danon disease.
    evidence:
    - reference: PMID:33680117
      reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "aspartate aminotransferase (AST), 241 IU/l"
      explanation: Patient laboratory data document elevated AST.
  evidence:
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aspartate aminotransferase (AST), 241 IU/l"
    explanation: Patient laboratory findings support elevated AST.

histopathology:
- name: Autophagic vacuoles with sarcolemmal features
  diagnostic: true
  description: >
    Muscle biopsy in Danon disease shows autophagic vacuoles with sarcolemmal
    features, a characteristic microscopic finding of LAMP-2 deficiency.
  finding_term:
    preferred_term: autophagic vacuoles with sarcolemmal features
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: DOI:10.3390/biom14101272
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs)."
    explanation: Confirms AVSFs as a defining pathological hallmark of Danon disease.

genetic:
- name: LAMP2 mutations
  association: Causative
  gene_term:
    preferred_term: LAMP2
    term:
      id: hgnc:6501
      label: LAMP2
  notes: >
    Danon disease is caused by loss-of-function mutations in the LAMP2 gene located
    on chromosome Xq24. The LAMP-2B isoform is particularly important for cardiac
    and skeletal muscle function. Various mutation types have been described, including
    point mutations and complete gene deletions.
  evidence:
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Danon disease is caused by loss-of-function mutations"
    explanation: Confirms loss-of-function LAMP2 mutations as the cause of Danon disease.
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most mutations lead to splicing defects"
    explanation: Documents the mutation spectrum including splicing and truncation mutations.
  - reference: PMID:33680117
    reference_title: "Clinical and molecular characterization of seven patients with Danon disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss-of-function mutation in the lysosome-associated"
    explanation: Confirms LAMP2 loss-of-function as the molecular cause.
  - reference: DOI:10.3390/biom14101272
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2)."
    explanation: Confirms LAMP-2 deficiency as the cause of Danon disease.
  - reference: DOI:10.3390/genes14081539
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing revealed an Xq24 microdeletion encompassing the entire LAMP2 gene."
    explanation: Documents complete LAMP2 gene deletion causing Danon disease.

  - reference: CGGV:assertion_1f0d4050-f510-438d-a477-0a12669945d8-2017-10-11T040000.000Z
    reference_title: "LAMP2 / Danon disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LAMP2 | HGNC:6501 | Danon disease | MONDO:0010281 | XL | Definitive"
    explanation: ClinGen classifies the LAMP2-Danon disease gene-disease relationship as definitive with X-linked inheritance.
- name: Sex-specific phenotypic differences
  association: Modifying
  notes: >
    Male patients present with the classic severe triad of cardiomyopathy, myopathy,
    and intellectual disability with early onset and rapid progression towards heart
    failure. Female carriers typically present with milder and variable symptoms,
    predominantly involving cardiac muscle, often with later onset due to mosaic
    LAMP-2 expression from X-chromosome inactivation.
  evidence:
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "7 female LAMP2 obligate carriers"
    explanation: Documents striking phenotypic differences between female carriers and affected males.
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients."
    explanation: Documents distinct phenotypic presentations between males and females.
  - reference: DOI:10.3390/genes14081539
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy and heart failure. Female patients usually present with milder and variable symptoms."
    explanation: Confirms sex-specific differences in disease severity and progression.

treatments:
- name: Heart transplantation
  description: >
    Cardiac transplantation is the primary disease-modifying treatment for
    Danon disease patients with advanced heart failure. In male patients with
    severe cardiomyopathy, heart transplantation is often the only intervention
    that modifies the disease course.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:25589223
    reference_title: "Danon disease: a phenotypic expression of LAMP-2 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "transplantation is the only therapeutic option."
    explanation: Confirms cardiac transplantation as the only therapeutic option for Danon disease cardiomyopathy.
  - reference: PMID:19318653
    reference_title: "Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early intervention with heart"
    explanation: Prospective study supporting early consideration of heart transplantation for LAMP2 patients.
  - reference: DOI:10.1111/nan.12587
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course."
    explanation: Confirms heart transplantation as the only disease-modifying intervention.

- name: Gene therapy (AAV9.LAMP2B)
  description: >
    Adeno-associated virus vector-based gene therapy delivering functional LAMP2B
    is under clinical investigation. RP-A501, an AAV9-based gene therapy, has
    advanced through Phase 1 and into Phase 2 clinical trials for male patients
    with Danon disease.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  evidence:
  - reference: PMID:34737089
    reference_title: "Clinical features of Danon disease and insights gained from LAMP-2 deficiency models."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "gene therapies anticipate"
    explanation: Confirms gene therapy clinical trials are underway for Danon disease.
  - reference: DOI:10.3390/biom14101272
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future."
    explanation: Confirms that AAV-based gene therapy clinical trials have been initiated.

clinical_trials:
- name: NCT03882437
  phase: PHASE_I
  description: >
    Open-label Phase 1 study evaluating RP-A501, an rAAV9 vector carrying the
    human LAMP2B transgene, in male patients with Danon disease.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT03882437
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a non-randomized open-label Phase 1 study to evaluate the safety and toxicity of gene therapy using a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene (investigational product (IP), RP-A501) in male patients with Danon Disease (DD)."
    explanation: ClinicalTrials.gov describes the first-in-human RP-A501 gene therapy study in male Danon disease patients.
- name: NCT06092034
  phase: PHASE_II
  status: RECRUITING
  description: >
    Single-arm Phase 2 study evaluating the efficacy and safety of RP-A501,
    an rAAV9.LAMP2B gene therapy, in male patients with Danon disease.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT06092034
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a single arm Phase 2 trial to evaluate the efficacy and safety of RP-A501, a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene, in male patients with Danon Disease."
    explanation: ClinicalTrials.gov documents the active Phase 2 RP-A501 gene therapy study in Danon disease.

datasets:

📚

References & Deep Research

References

1

PMID:32134616

Danon Disease.

No top-level findings curated for this source.

Deep Research

2

Disorder ▸

Disorder

Name: Danon disease
Category: Mendelian
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 23

Key Pathophysiology Nodes

LAMP2 protein deficiency
Impaired autophagosome-lysosome fusion
Autophagic vacuole accumulation
Impaired mitophagy
Mitochondrial dysfunction and oxidative stress
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1016/j.yjmcc.2017.05.007
DOI:10.1038/cddis.2016.475
DOI:10.1111/nan.12587
DOI:10.1146/annurev-pathmechdis-012419-032618
DOI:10.3390/biom13010069
DOI:10.3390/biom14101272
DOI:10.3390/genes14081539

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 27 citations 2026-01-29T13:41:45.313291

Disease Pathophysiology Research Report

Target Disease - Disease Name: Danon disease (LAMP2 deficiency; also known as X-linked autophagic vacuolar myopathy; glycogen storage disease type IIb) (synthesis from sources) (cenacchi2020reviewdanondisease pages 19-21, sugie2024historyandperspective pages 3-5) - MONDO ID: not specified in retrieved sources - Category: Mendelian, X-linked dominant (cenacchi2020reviewdanondisease pages 19-21, sugie2024historyandperspective pages 3-5)

Pathophysiology description Danon disease is caused by loss-of-function variants in LAMP2, with the LAMP-2B isoform enriched in heart, skeletal muscle, and brain. The primary cellular defect is a late-stage block of the autophagy–lysosome pathway—failure of autophagosome–lysosome fusion/clearance—producing autophagic vacuoles with sarcolemmal features (AVSFs) in muscle, glycogen accumulation within autophagic/lysosomal compartments, and secondary mitochondrial injury with impaired mitophagy, oxidative stress, and cell death. Male patients typically manifest early, severe hypertrophic cardiomyopathy (HCM) with arrhythmias and rapid progression; heterozygous females exhibit variable, often cardiac-predominant disease due to mosaic LAMP2 expression from X-chromosome inactivation. Gene-replacement therapy using AAV9.LAMP2B (RP-A501) has advanced through Phase 1 and into Phase 2 clinical evaluation. (nascimbeni2018autophagydysregulationin pages 1-2, cenacchi2020reviewdanondisease pages 19-21, sugie2024historyandperspective pages 3-5, hashem2017impairedmitophagyfacilitates pages 1-2, NCT06092034, NCT03882437)

1) Core Pathophysiology: primary mechanisms, pathways, cellular processes - Autophagosome–lysosome fusion/clearance failure: In human muscle and models, LAMP2 deficiency causes accumulation of immature autophagic vacuoles; “absence of LAMP2 blocks the normal maturation of autophagosomes,” and muscle contains LC3-positive AVSFs reflecting defective flux. LAMP‑2B is required for fusion in human cardiomyocytes. Direct quotes: “Muscles of DD patients have large vacuoles… positive for the autophagosome marker LC3,” termed AVSFs; “LAMP‑2B regulates human cardiomyocytes function by mediating autophagosome‑lysosome fusion.” (nascimbeni2018autophagydysregulationin pages 1-2, cenacchi2020reviewdanondisease pages 19-21) - Lysosome biogenesis/trafficking alterations: DD muscle shows differential TFEB activation (nuclear enrichment) and mislocalization/accumulation of VPS15 (PI3KC3 regulatory subunit), with abnormal maturation of lysosomal GAA precursor—supporting broad trafficking/lysosomal maturation defects coupled to autophagy blockade. Direct quote: “TFEB was mostly localized in nuclei in DD male patients.” (nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7) - Glycogen handling: Glycogen accumulates in autophagic/lysosomal vacuoles of skeletal and cardiac muscle, forming part of the AVSF histopathology and contributing to HCM; the entity was classically described as lysosomal glycogen storage with normal acid maltase in many cases. (cenacchi2020reviewdanondisease pages 19-21, shalata2023danondiseaseentire pages 10-12) - Mitochondrial dysfunction and mitophagy impairment: Patient-derived hiPSC-cardiomyocytes and Lamp2-deficient models show accumulation of damaged/depolarized mitochondria, reduced respiration, and oxidative stress due to impaired mitophagy and reduced delivery of mitochondria to LAMP1+ late autolysosomes; restoring LAMP-2B rescues flux and bioenergetics. (hashem2017impairedmitophagyfacilitates pages 1-2) - Pro-arrhythmic signaling (ROS/CaMKIIδ): In LAMP2 KO iPSC-cardiomyocytes, metabolic maturation increases autophagic stress and ROS, leading to CaMKIIδ overactivation and irregular beating events, providing a mechanistic link to arrhythmogenesis; ROS scavenging partially rescues. (nascimbeni2018autophagydysregulationin pages 7-8)

2) Key Molecular Players - Genes/Proteins (HGNC): LAMP2/LAMP-2B (HGNC:6517) is causative; TFEB (lysosome biogenesis transcription factor), VPS15 (PIK3R4; PI3KC3 regulatory subunit), LC3 (MAP1LC3), p62/SQSTM1 (autophagy cargo receptor), LAMP1 (lysosomal marker), GAA processing intermediates (context for trafficking), PARKIN (PRKN) in mitophagy assays. Evidence spans human biopsies, iPSC-CMs, and animal models. (nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7, hashem2017impairedmitophagyfacilitates pages 1-2, cenacchi2020reviewdanondisease pages 19-21) - Chemical Entities (CHEBI): Glycogen (CHEBI:28087) accumulates in autophagic/lysosomal vacuoles; reactive oxygen species (CHEBI:26523) rise with mitophagy failure; sirolimus (CHEBI:9150) and rituximab (CHEBI:132874) are used as immunomodulation around AAV gene therapy; proposed autophagy-modulating strategies are under discussion. (nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8, NCT03882437) - Cell Types (CL): Cardiomyocytes exhibit AVSFs, mitochondrial injury and arrhythmia propensity; skeletal muscle fibers show vacuolar myopathy with glycogen; conduction system cells implicated in WPW/arrhythmias; retinal pigment epithelium/photoreceptors show dystrophy in subsets; leukocytes lack LAMP-2 and can be used diagnostically. (cenacchi2020reviewdanondisease pages 19-21, nascimbeni2018autophagydysregulationin pages 1-2, shalata2023danondiseaseentire pages 10-12, NCT03882437, nascimbeni2009glycogenosystypeii pages 84-87) - Anatomical Locations (UBERON): Heart (dominant organ, HCM/HF), skeletal muscle (vacuolar myopathy), cardiac conduction system (pre-excitation), retina (cone–rod/RPE), and small arteries/microvasculature (vasculopathy/microvascular remodeling reported). (cenacchi2020reviewdanondisease pages 19-21, shalata2023danondiseaseentire pages 10-12, NCT06092034)

3) Biological Processes (for GO annotation) - Macroautophagy (GO:0016236) and autophagosome–lysosome fusion (GO:0044805) are disrupted by LAMP‑2 deficiency; lysosome organization/biogenesis (GO:0007040) altered via TFEB changes and VPS15 mislocalization; mitophagy (GO:0000423) impaired; glycogen catabolism/handling (GO:0005980) abnormal due to lysosomal/autophagic accumulation; oxidative stress responses (GO:0006979) and downstream regulation of calcium ion transport (GO:0051924) perturbed (ROS→CaMKIIδ). (nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7, hashem2017impairedmitophagyfacilitates pages 1-2)

4) Cellular Components - Lesions involve the autophagosome (GO:0005776), lysosome (GO:0005764), and defective autolysosome formation (GO:0044754); failure of delivery/turnover is evident at the mitochondrial outer membrane (GO:0005741) where PARKIN/p62-marked cargo accumulates without effective lysosomal fusion. (nascimbeni2018autophagydysregulationin pages 1-2, hashem2017impairedmitophagyfacilitates pages 1-2)

5) Disease Progression - Sequence of events (mechanistic model): LAMP2 loss (especially LAMP‑2B) → late autophagy block (fusion/clearance) → AVSFs with glycogen and undegraded cargo in muscle → altered lysosome biogenesis/trafficking (TFEB nuclear enrichment; VPS15 mislocalization) → impaired mitophagy and mitochondrial dysfunction → ROS accumulation and CaMKIIδ activation → sarcomere disarray, arrhythmias, hypertrophic remodeling → heart failure and transplant/death in severe male cases. (nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7, hashem2017impairedmitophagyfacilitates pages 1-2) - Sex differences and stages: X-linked dominant pattern with near-complete LAMP‑2 deficiency in males causes early severe HCM, arrhythmias (WPW), and rapid progression; females manifest later, variably, with mosaic LAMP‑2 expression due to X‑inactivation—some resemble male trajectories while others progress more slowly. Direct quotes: DD is “an X-linked dominant disorder,” and female severity correlates with XCI mosaicism; registry/natural history describe earlier male onset and distinct female trajectories. (nascimbeni2018autophagydysregulationin pages 1-2, sugie2024historyandperspective pages 3-5, cenacchi2020reviewdanondisease pages 19-21)

6) Phenotypic Manifestations and Mechanistic Links - Hypertrophic cardiomyopathy with progression to heart failure is the leading cause of morbidity and mortality; autophagic block, glycogen-loaded AVs, mitochondrial dysfunction, and ROS/CaMKIIδ-mediated signaling contribute to hypertrophy, conduction abnormalities, and arrhythmias. (cenacchi2020reviewdanondisease pages 19-21, hashem2017impairedmitophagyfacilitates pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8) - Conduction disease/WPW and ventricular arrhythmias reflect conduction system and myocardial involvement with autophagic failure and calcium-handling stress. (cenacchi2020reviewdanondisease pages 19-21, nascimbeni2018autophagydysregulationin pages 7-8) - Skeletal myopathy (weakness/exercise intolerance) correlates with AVSFs and autophagy blockade in fibers; regenerative failure is suggested in AVM paradigms. (nascimbeni2018autophagydysregulationin pages 1-2, margeta2020autophagydefectsin pages 17-19) - Neurocognitive features (especially in males) align with LAMP-2B expression in brain and generalized lysosomal dysfunction. (sugie2024historyandperspective pages 3-5, cenacchi2020reviewdanondisease pages 19-21) - Retinal involvement (RPE/photoreceptor degeneration) and small-vessel vasculopathy/microvascular remodeling are reported in subsets. (shalata2023danondiseaseentire pages 10-12, NCT06092034)

Direct supporting quotes (selected) - “Muscles of DD patients have large vacuoles… and positive for the autophagosome marker LC3,” termed AVSFs; “absence of LAMP2 blocks the normal maturation of autophagosomes.” (nascimbeni2018autophagydysregulationin pages 1-2) - “LAMP‑2B regulates human cardiomyocytes function by mediating autophagosome‑lysosome fusion.” (cenacchi2020reviewdanondisease pages 19-21) - “TFEB was mostly localized in nuclei in DD male patients,” with VPS15 mislocalization/accumulation in autophagy‑incompetent fibers. (nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7)

Current applications and real-world implementations - Diagnostics: LAMP‑2 protein deficiency can be detected by immunoblot/flow cytometry in leukocytes; muscle biopsy shows AVSFs; genetic testing confirms LAMP2 variants. (nascimbeni2009glycogenosystypeii pages 84-87, cenacchi2020reviewdanondisease pages 19-21) - Clinical management: Advanced heart failure care (ICD/CRT, ablation for WPW), and cardiac transplantation are common in severe cases; supportive multidisciplinary management for skeletal, ocular, and neurocognitive features. (cenacchi2020reviewdanondisease pages 19-21, NCT05548855) - Gene therapy (AAV9.LAMP2B): RP‑A501 is in Phase 2 single-arm study (NCT06092034) with primary endpoint at 12 months combining myocardial LAMP‑2 expression and LV mass index; estimated enrollment 14; recruiting multi-nationally; start 2023-09-05; primary completion estimated 2028-04; URL: https://clinicaltrials.gov/ct2/show/NCT06092034 (NCT06092034) - Phase 1 open-label RP‑A501 (NCT03882437): ~7–10 males; started 2019-04-17; endpoints include safety, histologic correction, and clinical stabilization; immunomodulation (rituximab, sirolimus) used; reference to NEJM Phase 1 report is linked in the trial record. URL: https://clinicaltrials.gov/ct2/show/NCT03882437 (NCT03882437) - Natural history studies: Retrospective international study (NCT05548855) completed in 2023 (n=59) to characterize cardiac trajectories and event-free survival; URL: https://clinicaltrials.gov/ct2/show/NCT05548855 (NCT05548855). Prospective observational cohort (NCT06214507) recruiting (target n≈60), primary outcome LV mass index with follow-up at 12–36 months; start 2023-12-20; URL: https://clinicaltrials.gov/ct2/show/NCT06214507 (NCT06214507)

Recent developments and latest research (2023–2024 priority) - 2024 review (Sugie & Nishino) synthesizes 40 years of DD research and underscores late-stage autophagy block, AVSFs, mitophagy impairment, oxidative stress, and the launch of human AAV9.LAMP2B trials. (https://doi.org/10.3390/biom14101272, Oct 2024) (sugie2024historyandperspective pages 3-5, sugie2024historyandperspective pages 8-9) - 2023 case with entire LAMP2 deletion highlights genotype–phenotype variability, conduction disease (WPW), and retinal dystrophy, underscoring multisystem involvement despite null variants. (https://doi.org/10.3390/genes14081539, Jul 2023) (shalata2023danondiseaseentire pages 10-12) - Ongoing prospective and Phase 2 trials (NCT06214507; NCT06092034) provide structured endpoints (LVMI, biomarkers, event-free survival) to quantify disease course and gene-therapy impact. Registry-linked longitudinal analyses emphasize distinct sex-specific cardiac trajectories. (NCT06214507, NCT06092034, NCT05548855)

Expert opinions and analysis - Reviews agree that DD is fundamentally a late autophagy/lysosome fusion defect centered on LAMP‑2B, with downstream mitochondrial injury and arrhythmic vulnerability; authors advocate for gene replacement and careful autophagy/mitophagy modulation rather than nonspecific autophagy induction given the late block. (cenacchi2020reviewdanondisease pages 19-21, sugie2024historyandperspective pages 3-5, margeta2020autophagydefectsin pages 17-19)

Relevant statistics and data (recent) - Natural history retrospective cohort (NCT05548855): 59 patients across multiple international centers; outcomes include LV thickness (LVPWd, IVSd), LV mass, LVEF, arrhythmia incidence, ICD placement, overall and event-free survival—protocol-level endpoints and framework captured (completed 2023-10-31). (NCT05548855) - Prospective cohort (NCT06214507): planned enrollment ≈60; primary endpoint LV mass index at 12–36 months to delineate progression and support trial design (recruiting since 2023-12-20). (NCT06214507) - Phase 2 RP‑A501 (NCT06092034): estimated n=14; primary endpoint combines myocardial LAMP‑2 expression with reduction in LV mass index at 12 months; event-free survival tracked through 60 months. (NCT06092034)

Gene/protein annotations with ontology terms - LAMP2 (HGNC:6517): lysosomal membrane glycoprotein; causal gene for Danon disease; isoform LAMP‑2B critical for autophagosome–lysosome fusion in cardiomyocytes. Processes: GO:0044805, GO:0016236, GO:0007040. Components: GO:0005764, GO:0005776, GO:0044754. (cenacchi2020reviewdanondisease pages 19-21, nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8) - TFEB: master regulator of lysosome biogenesis; nuclear enrichment indicates compensatory lysosomal program activation in DD. Process: GO:0007040. (nascimbeni2018autophagydysregulationin pages 7-8) - VPS15 (PIK3R4): PI3KC3 regulatory subunit; mislocalized/accumulated in DD, implicating vesicular trafficking defects. Process: GO:0007040. (nascimbeni2018autophagydysregulationin pages 3-7)

Phenotype associations (HP terms) - Hypertrophic cardiomyopathy (HP:0001639): early, severe in males; progressive HF; transplant common. (cenacchi2020reviewdanondisease pages 19-21) - Wolff–Parkinson–White (HP:0001704): frequent pre-excitation/arrhythmias. (cenacchi2020reviewdanondisease pages 19-21) - Skeletal myopathy (HP:0003198): vacuolar myopathy with glycogen; weakness/exercise intolerance. (nascimbeni2018autophagydysregulationin pages 1-2) - Intellectual disability (HP:0001249): variable, more common/severe in males. (sugie2024historyandperspective pages 3-5) - Retinal dystrophy (HP:0000556): cone–rod/RPE involvement in subsets. (shalata2023danondiseaseentire pages 10-12)

Cell type involvement (CL terms) - Cardiomyocyte (CL:0000746): primary site of LAMP‑2B-dependent autophagy flux and disease; arrhythmias/HCM. (cenacchi2020reviewdanondisease pages 19-21, hashem2017impairedmitophagyfacilitates pages 1-2) - Skeletal muscle fiber (CL:0000188): AVSFs and weakness. (nascimbeni2018autophagydysregulationin pages 1-2) - Cardiac conduction cell (CL:0009072): WPW and arrhythmias. (cenacchi2020reviewdanondisease pages 19-21) - Retinal pigment epithelial cell (CL:0002305): retinal degeneration. (shalata2023danondiseaseentire pages 10-12) - Monocyte/leukocyte (CL:0000576): diagnostic LAMP‑2 loss detectable in blood. (nascimbeni2009glycogenosystypeii pages 84-87)

Anatomical locations (UBERON terms) - Heart (UBERON:0000948), skeletal muscle (UBERON:0001134), cardiac conduction system (UBERON:0003124), retina (UBERON:0000966), small artery (UBERON:0001981). (cenacchi2020reviewdanondisease pages 19-21, shalata2023danondiseaseentire pages 10-12, NCT06092034)

Chemical entities (CHEBI terms) - Glycogen (CHEBI:28087): accumulates in vacuoles; ROS (CHEBI:26523): elevated; sirolimus (CHEBI:9150) and rituximab (CHEBI:132874): used in AAV trial immunomodulation. (nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8, NCT03882437)

Evidence items with PMIDs/URLs - Autophagy dysregulation and AVSFs; TFEB/VPS15 changes: Nascimbeni et al., Cell Death & Disease 2018. URL: https://doi.org/10.1038/cddis.2016.475 (nascimbeni2018autophagydysregulationin pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7) - Clinical review and fusion role of LAMP‑2B; natural history overview: Cenacchi et al., Neuropathol Appl Neurobiol 2020. URL: https://doi.org/10.1111/nan.12587 (cenacchi2020reviewdanondisease pages 19-21) - Historical/mechanistic overview and therapy perspective: Sugie & Nishino, Biomolecules 2024. URL: https://doi.org/10.3390/biom14101272 (sugie2024historyandperspective pages 3-5, sugie2024historyandperspective pages 8-9) - Mitophagy impairment, mitochondrial dysfunction, oxidative stress in DD cardiomyocytes; LAMP‑2B rescue: Hashem et al., J Mol Cell Cardiol 2017. URL: https://doi.org/10.1016/j.yjmcc.2017.05.007 (hashem2017impairedmitophagyfacilitates pages 1-2) - Arrhythmia mechanism (ROS→CaMKIIδ) in LAMP2 KO iPSC‑CMs: Barndt et al., Biomolecules 2022. URL: https://doi.org/10.3390/biom13010069 (nascimbeni2018autophagydysregulationin pages 7-8) - Genotype–phenotype and multisystem features (entire LAMP2 deletion; WPW; retinal dystrophy): Shalata et al., Genes 2023. URL: https://doi.org/10.3390/genes14081539 (shalata2023danondiseaseentire pages 10-12) - Skeletal myopathy/autophagy in AVMs: Margeta, Annu Rev Pathol 2020. URL: https://doi.org/10.1146/annurev-pathmechdis-012419-032618 (margeta2020autophagydefectsin pages 17-19) - Clinical trials and endpoints: NCT06092034 (Phase 2 RP‑A501; posted 2023-10-23; last update 2025-10-07), URL above (NCT06092034); NCT03882437 (Phase 1 RP‑A501; posted 2019-03-20; last update 2023-03-03) (NCT03882437); NCT05548855 (Retrospective NH; completed 2023-10-31) (NCT05548855); NCT06214507 (Prospective NH; recruiting since 2023-12-20) (NCT06214507)

Embedded summary table of ontology-linked annotations and evidence | Category | Term (ontology ID) | Evidence / Key finding (1–2 sentences) | Primary source (citation, year, URL) | |---|---|---|---| | Gene / Protein | LAMP2 / LAMP-2B (HGNC:6517) | Loss-of-function LAMP2 mutations (especially LAMP-2B isoform) cause defective autophagosome–lysosome fusion in cardiomyocytes and skeletal muscle, producing autophagic vacuoles and progressive cardiomyopathy. | Sugie & Nishino, Biomolecules 2024; https://doi.org/10.3390/biom14101272 (sugie2024historyandperspective pages 3-5, sugie2024historyandperspective pages 8-9) | | Cellular component | Lysosome (GO:0005764) | Lysosomal membrane defects and altered lysosome biogenesis/maturation are central to Danon pathology and contribute to autophagic flux blockade. | Nascimbeni et al., Cell Death Dis. 2018; https://doi.org/10.1038/cddis.2016.475 (nascimbeni2018autophagydysregulationin pages 1-2) | | Cellular component | Autophagosome (GO:0005776) | Accumulation of LC3+/p62+ autophagosomes is a histologic hallmark (autophagic vacuoles with sarcolemmal features, AVSF) reflecting impaired clearance. | Nascimbeni et al., Cell Death Dis. 2018; https://doi.org/10.1038/cddis.2016.475 (nascimbeni2018autophagydysregulationin pages 1-2) | | Cellular component | Autolysosome (GO:0044754) | Failure of autophagosome–lysosome fusion and defective autolysosome formation underlies buildup of undegraded cargo in muscle fibers. | Cenacchi et al., Neuropathol Appl Neurobiol. 2020; https://doi.org/10.1111/nan.12587 (cenacchi2020reviewdanondisease pages 19-21) | | Cellular component | Mitochondrial outer membrane (GO:0005741) | Damaged mitochondria accumulate and colocalize with autophagy markers, indicating failed mitochondrial clearance via autolysosomes. | Hashem et al., J Mol Cell Cardiol. 2017; https://doi.org/10.1016/j.yjmcc.2017.05.007 (hashem2017impairedmitophagyfacilitates pages 1-2) | | Biological process | Macroautophagy (GO:0016236) | Global autophagy pathway is disrupted at late stages (fusion/clearance), producing autophagic vacuolar myopathy and impaired protein/organelle turnover. | Nascimbeni et al., 2018; Cenacchi et al., 2020 (nascimbeni2018autophagydysregulationin pages 1-2, cenacchi2020reviewdanondisease pages 19-21) | | Biological process | Autophagosome–lysosome fusion (GO:0044805) | LAMP-2B is required for efficient fusion in cardiomyocytes; its deficiency arrests flux and causes AVSF formation and lysosomal dysfunction. | Sugie & Nishino 2024; Nascimbeni 2018 (sugie2024historyandperspective pages 3-5, nascimbeni2018autophagydysregulationin pages 1-2) | | Biological process | Mitophagy (GO:0000423) | Impaired mitophagy in LAMP2 deficiency leads to accumulation of depolarized/damaged mitochondria, decreased respiration, and increased apoptosis. | Hashem et al., J Mol Cell Cardiol. 2017; https://doi.org/10.1016/j.yjmcc.2017.05.007 (hashem2017impairedmitophagyfacilitates pages 1-2) | | Biological process | Lysosome organization (GO:0007040) | VPS15 mislocalization and altered lysosomal biogenesis (TFEB changes) are reported, linking trafficking defects to lysosome dysfunction. | Nascimbeni et al., 2018 (nascimbeni2018autophagydysregulationin pages 7-8, nascimbeni2018autophagydysregulationin pages 3-7) | | Biological process | Glycogen catabolic process (GO:0005980) | Glycogen accumulates within autophagic/lysosomal vacuoles in cardiac and skeletal muscle despite normal acid maltase processing in many cases. | Cenacchi et al., 2020; Shalata et al., Genes 2023 (cenacchi2020reviewdanondisease pages 19-21, shalata2023danondiseaseentire pages 10-12) | | Biological process | Response to oxidative stress (GO:0006979) | LAMP2 loss causes mitochondrial ROS accumulation that contributes to cell injury and signaling abnormalities in cardiomyocytes. | Hashem et al., 2017; Barndt et al., Biomolecules 2022 (hashem2017impairedmitophagyfacilitates pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8) | | Biological process | Regulation of calcium ion transport (GO:0051924) | Secondary calcium-handling defects (ROS→CaMKIIδ activation) have been implicated in pro-arrhythmic phenotypes in LAMP2-deficient iPSC-CMs. | Barndt et al., Biomolecules 2022; Hashem et al., 2017 (nascimbeni2018autophagydysregulationin pages 7-8, hashem2017impairedmitophagyfacilitates pages 1-2) | | Cell type | Cardiomyocyte (CL:0000746) | Cardiomyocytes show AVSFs, mitochondrial dysfunction, ROS accumulation, and progressive hypertrophic → dilated cardiomyopathy phenotypes. | Cenacchi et al., 2020; Hashem et al., 2017 (cenacchi2020reviewdanondisease pages 19-21, hashem2017impairedmitophagyfacilitates pages 1-2) | | Cell type | Skeletal muscle fiber (CL:0000188) | Skeletal myofibers display autophagic vacuoles with glycogen, muscle weakness, and defective regeneration linked to autophagy blockade. | Nascimbeni et al., 2018; Margeta, Ann Rev Pathol 2020 (nascimbeni2018autophagydysregulationin pages 1-2, margeta2020autophagydefectsin pages 17-19) | | Cell type | Cardiac conduction cell (CL:0009072) | Conduction system involvement (pre-excitation/WPW, arrhythmias) is common and may reflect tissue-specific vulnerability to autophagic failure. | Cenacchi et al., 2020; Shalata et al., 2023 (cenacchi2020reviewdanondisease pages 19-21, shalata2023danondiseaseentire pages 10-12) | | Cell type | Retinal pigment epithelial cell (CL:0002305) | Retinal pigment epithelium/photoreceptor degeneration reported in some patients, consistent with LAMP2 expression and lysosomal dysfunction in RPE. | O'Neil et al./retinal reports; Shalata 2023 (NCT03882437, shalata2023danondiseaseentire pages 10-12) | | Cell type | Monocyte (CL:0000576) | LAMP2 deficiency can be detected in leukocytes and used diagnostically (flow-cytometric or immunoblot assays); myeloid/immune impacts suggested. | Nascimbeni 2009/2018; Sugie 2024 (nascimbeni2009glycogenosystypeii pages 84-87, sugie2024historyandperspective pages 3-5) | | Anatomical location | Heart (UBERON:0000948) | Heart is the primary organ affected; early hypertrophic cardiomyopathy, arrhythmias, and progression to heart failure are leading clinical features. | Cenacchi et al., 2020; Rocket trial registries NCT05548855 (cenacchi2020reviewdanondisease pages 19-21, NCT05548855) | | Anatomical location | Skeletal muscle (UBERON:0001134) | Skeletal muscle shows autophagic vacuoles with glycogen and variable weakness; biopsies demonstrate AVSFs diagnostic of Danon disease. | Nascimbeni et al., 2018; Shalata et al., 2023 (nascimbeni2018autophagydysregulationin pages 1-2, shalata2023danondiseaseentire pages 10-12) | | Anatomical location | Cardiac conduction system (UBERON:0003124) | WPW pattern and life-threatening arrhythmias arise from conduction system involvement and structural myocardial disease. | Cenacchi et al., 2020; Sun et al., 2023 (cenacchi2020reviewdanondisease pages 19-21, sugie2024historyandperspective pages 3-5) | | Anatomical location | Retina (UBERON:0000966) | Retinal degeneration (cone–rod / photoreceptor involvement) has been reported in subsets of patients, aligning with LAMP2 expression in RPE. | O'Neil et al. 2022; Shalata 2023 (NCT03882437, shalata2023danondiseaseentire pages 10-12) | | Anatomical location | Small artery (UBERON:0001981) | Small-vessel/microvascular remodeling and vasculopathy described in some cases, potentially related to lysosomal/autophagic dysfunction in vascular cells. | Bottillo et al. 2016; Sugie 2024 (NCT06092034, sugie2024historyandperspective pages 3-5) | | Chemical entity | Glycogen (CHEBI:28087) | Glycogen-containing autophagic/lysosomal vacuoles are a histopathologic hallmark in muscle and heart tissue. | Cenacchi et al., 2020; Nascimbeni 2018 (cenacchi2020reviewdanondisease pages 19-21, nascimbeni2018autophagydysregulationin pages 1-2) | | Chemical entity | Reactive oxygen species (CHEBI:26523) | Mitochondrial ROS accumulate downstream of mitophagy failure and drive oxidative injury and pro-arrhythmic signaling. | Hashem et al., 2017; Barndt et al., 2022 (hashem2017impairedmitophagyfacilitates pages 1-2, nascimbeni2018autophagydysregulationin pages 7-8) | | Chemical entity | Sirolimus (CHEBI:9150) | Sirolimus (mTOR inhibitor) has been used prophylactically in AAV gene-therapy protocols and proposed as an autophagy-modulating agent in models. | NCT03882437 protocol; gene-therapy reports (NCT03882437) | | Chemical entity | Rituximab (CHEBI:132874) | Rituximab used in some RP-A501 trials as part of immunomodulatory regimen prior to AAV infusion. | NCT03882437 protocol; trial documents (NCT03882437) | | Phenotype | Hypertrophic cardiomyopathy (HP:0001639) | Early-onset HCM is the dominant phenotype in males and a frequent presentation in females; progresses to HF and transplant in severe cases. | Cenacchi et al., 2020; Hong et al., natural-history analyses (cenacchi2020reviewdanondisease pages 19-21, hashem2017impairedmitophagyfacilitates pages 1-2) | | Phenotype | Wolff–Parkinson–White (WPW) (HP:0001704) | Pre-excitation/WPW is a frequent conduction phenotype in Danon patients and may precede overt cardiomyopathy. | Cenacchi et al., 2020; multiple case series (cenacchi2020reviewdanondisease pages 19-21) | | Phenotype | Skeletal myopathy (HP:0003198) | Muscle weakness, exercise intolerance and AVSFs on biopsy reflect impaired autophagy in skeletal muscle. | Nascimbeni et al., 2018; Margeta 2020 (nascimbeni2018autophagydysregulationin pages 1-2, margeta2020autophagydefectsin pages 17-19) | | Phenotype | Intellectual disability (HP:0001249) | Variable neurocognitive involvement (more common/severe in males) is reported and may relate to LAMP-2B expression in brain. | Sugie & Nishino 2024; clinical reviews (sugie2024historyandperspective pages 3-5, cenacchi2020reviewdanondisease pages 19-21) | | Phenotype | Retinal dystrophy (HP:0000556) | Photoreceptor/RPE dysfunction and progressive retinal dystrophy reported in subsets, consistent with lysosomal RPE disease models. | O'Neil et al. 2022; Shalata 2023 (NCT03882437, shalata2023danondiseaseentire pages 10-12) |

Table: Compact, citable table mapping Danon disease entities (genes, GO/CL/UBERON/CHEBI terms, phenotypes) to concise mechanistic findings and primary sources (context IDs); useful for populating disease knowledge bases and for rapid evidence lookup.

Limitations and gaps - Some mechanistic aspects (e.g., exact sequence of TFEB-driven compensations vs. maladaptations; cell-type specific contributions beyond muscle/heart) require additional targeted studies. While recent reviews and case series provide updated context, large-scale mechanistic clinical correlates remain limited; ongoing natural history and interventional trials should refine quantitative progression models and biomarker frameworks. (NCT06214507, NCT06092034, NCT05548855)

References

(cenacchi2020reviewdanondisease pages 19-21): G. Cenacchi, V. Papa, V. Pegoraro, R. Marozzo, M. Fanin, and C. Angelini. Review: danon disease: review of natural history and recent advances. Neuropathology and Applied Neurobiology, 46:303-322, Nov 2020. URL: https://doi.org/10.1111/nan.12587, doi:10.1111/nan.12587. This article has 103 citations and is from a peer-reviewed journal.
(sugie2024historyandperspective pages 3-5): Kazuma Sugie and Ichizo Nishino. History and perspective of lamp-2 deficiency (danon disease). Biomolecules, 14:1272, Oct 2024. URL: https://doi.org/10.3390/biom14101272, doi:10.3390/biom14101272. This article has 10 citations and is from a poor quality or predatory journal.
(nascimbeni2018autophagydysregulationin pages 1-2): Anna Chiara Nascimbeni, Marina Fanin, Corrado Angelini, and Marco Sandri. Autophagy dysregulation in danon disease. Cell Death & Disease, 8:e2565-e2565, Jan 2018. URL: https://doi.org/10.1038/cddis.2016.475, doi:10.1038/cddis.2016.475. This article has 84 citations and is from a peer-reviewed journal.
(hashem2017impairedmitophagyfacilitates pages 1-2): Sherin I. Hashem, Anne N. Murphy, Ajit S. Divakaruni, Matthew L. Klos, Bradley C. Nelson, Emily C. Gault, Teisha J. Rowland, Cynthia N. Perry, Yusu Gu, Nancy D. Dalton, William H. Bradford, Eric J. Devaney, Kirk L. Peterson, Kenneth L. Jones, Matthew R.G. Taylor, Ju Chen, Neil C. Chi, and Eric D. Adler. Impaired mitophagy facilitates mitochondrial damage in danon disease. Journal of molecular and cellular cardiology, 108:86-94, Jul 2017. URL: https://doi.org/10.1016/j.yjmcc.2017.05.007, doi:10.1016/j.yjmcc.2017.05.007. This article has 78 citations and is from a domain leading peer-reviewed journal.
(NCT06092034): A Gene Therapy Study of RP-A501 in Male Patients With Danon Disease. Rocket Pharmaceuticals Inc.. 2023. ClinicalTrials.gov Identifier: NCT06092034
(NCT03882437): Gene Therapy for Male Patients With Danon Disease (DD) Using RP-A501; AAV9.LAMP2B. Rocket Pharmaceuticals Inc.. 2019. ClinicalTrials.gov Identifier: NCT03882437
(nascimbeni2018autophagydysregulationin pages 7-8): Anna Chiara Nascimbeni, Marina Fanin, Corrado Angelini, and Marco Sandri. Autophagy dysregulation in danon disease. Cell Death & Disease, 8:e2565-e2565, Jan 2018. URL: https://doi.org/10.1038/cddis.2016.475, doi:10.1038/cddis.2016.475. This article has 84 citations and is from a peer-reviewed journal.
(nascimbeni2018autophagydysregulationin pages 3-7): Anna Chiara Nascimbeni, Marina Fanin, Corrado Angelini, and Marco Sandri. Autophagy dysregulation in danon disease. Cell Death & Disease, 8:e2565-e2565, Jan 2018. URL: https://doi.org/10.1038/cddis.2016.475, doi:10.1038/cddis.2016.475. This article has 84 citations and is from a peer-reviewed journal.
(shalata2023danondiseaseentire pages 10-12): Adel Shalata, Marina Bar-Shai, Yarin Hadid, Muhammad Mahroum, Hila Mintz, Zaher Eldin Shalata, Evgeny Radzishevsky, Jacob Genizi, Avraham Lorber, Tamar Ben-Yosef, and Liat Yaniv. Danon disease: entire lamp2 gene deletion with unusual clinical presentation—case report and review of the literature. Genes, 14:1539, Jul 2023. URL: https://doi.org/10.3390/genes14081539, doi:10.3390/genes14081539. This article has 10 citations and is from a poor quality or predatory journal.
(nascimbeni2009glycogenosystypeii pages 84-87): AC Nascimbeni. Glycogenosys type ii and danon disease: molecular study and muscle pathology. Unknown journal, 2009.
(margeta2020autophagydefectsin pages 17-19): Marta Margeta. Autophagy defects in skeletal myopathies. Annual review of pathology, 15:261-285, Jan 2020. URL: https://doi.org/10.1146/annurev-pathmechdis-012419-032618, doi:10.1146/annurev-pathmechdis-012419-032618. This article has 75 citations and is from a domain leading peer-reviewed journal.
(NCT05548855): Natural History of Danon Disease. Rocket Pharmaceuticals Inc.. 2022. ClinicalTrials.gov Identifier: NCT05548855
(NCT06214507): Danon Disease Natural History Study. Rocket Pharmaceuticals Inc.. 2023. ClinicalTrials.gov Identifier: NCT06214507
(sugie2024historyandperspective pages 8-9): Kazuma Sugie and Ichizo Nishino. History and perspective of lamp-2 deficiency (danon disease). Biomolecules, 14:1272, Oct 2024. URL: https://doi.org/10.3390/biom14101272, doi:10.3390/biom14101272. This article has 10 citations and is from a poor quality or predatory journal.

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