RARE DISEASE
Danon disease
Danon disease
Danon disease
Synonyms: GSD due to LAMP-2 deficiency, GSD, type 2B, GSD, type IIb, Glycogen storage disease due to LAMP-2 deficiency, Glycogen storage disease, type 2B, Glycogen storage disease, type IIb, Glycogenosis due to LAMP-2 deficiency, Lysosomal glycogen storage disease with normal acid maltase activity
Synonyms: GSD due to LAMP-2 deficiency, GSD, type 2B, GSD, type IIb, Glycogen storage disease due to LAMP-2 deficiency, Glycogen storage disease, type 2B, Glycogen storage disease, type IIb, Glycogenosis due to LAMP-2 deficiency, Lysosomal glycogen storage disease with normal acid maltase activity
Synonyms: GSD due to LAMP-2 deficiency, GSD, type 2B, GSD, type IIb, Glycogen storage disease due to LAMP-2 deficiency, Glycogen storage disease, type 2B, Glycogen storage disease, type IIb, Glycogenosis due to LAMP-2 deficiency, Lysosomal glycogen storage disease with normal acid maltase activity
Drug discovery
4
drugs
With orphan designations
Overview
Danon Disease Overview
Danon disease is a rare X-linked dominant disorder caused by LAMP2 gene mutations, leading to lysosomal dysfunction and impaired autophagy [1][5][9]. It primarily manifests as cardiomyopathy (hypertrophic or dilated), skeletal myopathy, and intellectual disability, with males exhibiting earlier and more severe symptoms (onset in childhood/adolescence) than females (onset in adulthood) [1][6][17]. Cardiac complications, including heart failure and arrhythmias, are the leading cause of mortality [6][10].
Categories: rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
88 drug discovery papers about Danon disease, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
88 drug discovery papers about Danon disease, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-10 | Cardiomyopathy in glycogen storage diseases: diagnosis, prognosis, and advanced management.
Glycogen storage diseases (GSDs) are a heterogeneous group of rare and often under-recognized causes of inherited cardiomyopathy characterized by pathological glycogen or autophagic vacuole accumulation of debris within various tissues, including the heart. These diseases often present as phenocopies of sarcomeric hypertrophic cardiomyopathy, though they may also manifest with dilated or mixed phenotypes. Key GSDs with cardiomyopathy include Pompe disease (GSD IIa), Danon disease (IIb), Cori/Forbes disease (GSD III), Andersen disease (GSD IV), Tarui disease (GSD VII), phosphorylase kinase deficiency (GSD IX), glycogenin-1 deficiency (GSD XV), and PRKAG2 syndrome, each presenting unique clinical trajectories. Accurate diagnosis requires integration of clinical red flags, multimodality cardiac imaging, and electrocardiography, alongside definitive diagnostic tools like enzyme screening, genetic testing, and endomyocardial biopsy. There is a dearth of evidence regarding specific treatment of each unique GSD cardiomyopathy, but emerging therapeutics across the spectrum of GSDs aim to address this need. This review covers current knowledge on the spectrum of GSD-related cardiomyopathies, discussing pathophysiology, diagnosis, and evolving treatment strategies.
2026-07-01 | Cardiac characteristics of Chinese patients with Danon disease associated with LAMP2 p.Leu325fs variants.
This study characterized the clinical and genetic features of Danon disease (DD), focusing on participants harboring LAMP2 frameshift variants at the 325th amino acid position (p.Leu325fs), and explored their cardiac implications. These frameshift variants result in loss of functional LAMP2 protein through premature termination, thereby impairing lysosomal function. Although the association between LAMP2 variants and DD is established, the cardiac phenotype specifically associated with p.Leu325fs variants remains incompletely characterized. We conducted a retrospective analysis of nine patients with DD diagnosed at the Fuwai Hospital of the Chinese Academy of Medical Sciences, Beijing, China. Comprehensive clinical data, including biochemical markers, electrocardiographic findings, and imaging studies (echocardiography and cardiac magnetic resonance imaging), were collected. Pathogenic LAMP2 variants were confirmed through exome sequencing or clinical genetic testing. All participants carried pathogenic frameshift variants at p.Leu325fs, presenting with prominent cardiac manifestations including myocardial hypertrophy or dilation, impaired systolic function, and arrhythmias. Electrocardiographic abnormalities, notably intraventricular conduction block and ST-T segment changes, were observed in all participants. Elevated N-terminal prohormone of brain natriuretic peptide and lactate dehydrogenase levels were observed in all participants, consistent with advanced heart failure and myocardial injury. Our findings suggest that p.Leu325fs pathogenic variants in DD are associated with a predominantly cardiac phenotype, characterized by universal intraventricular conduction block, ST-T segment changes, progressive myocardial fibrosis, and impaired systolic function. These results support the clinical value of integrating LAMP2 genetic testing, cardiac MRI, and electrocardiographic monitoring into the early diagnosis, risk stratification, and management of patients with DD.
2026-06-25 | Autophagy–Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy
Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy–lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome–lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy—particularly AAV9-LAMP2B for Danon disease—together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
2026-04-18 | Uncovering the gene variants in a global cohort of patients with unexplained increased left ventricular wall thickness using next-generation sequencing.
BACKGROUND: Genetic analysis using massive parallel sequencing is crucial for the accurate and early diagnosis of hereditary hypertrophic cardiomyopathies and their phenocopies, especially transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD). This study extends the cardio next-generation sequencing (NGS) pilot study by investigating the detection rate of gene variants causing increased left ventricular wall thickness (LVWT) using an expanded 19-gene NGS panel in a larger global cohort. METHODS: This study included 2068 patients with unexplained increased LVWT enrolled at cardiological clinics across 22 countries/regions between 2020 and 2022. The NGS panel comprised 19 genes associated with hypertrophic cardiomyopathy (HCM) and its phenocopies. Sequencing was performed using the Illumina NextSeq 500 and NovaSeq 6000 systems, with variant interpretation performed according to the American College of Medical Genetics and Genomics guidelines. Novel variants were analyzed using the Human Gene Mutation Database (HGMD®), Franklin, and VarSome. RESULTS: Among the 2068 patients, 453 patients were positive for pathogenic/likely pathogenic variants (21.9%). The diagnostic yield for HCM was 18.4%, while that of HCM phenocopies was 3.5%, including ATTR-CA (1.5%), and FD (0.9%). In patients with a positive test (HCM or HCM phenocopies), the most prevalent HCM-related variants were MYBPC3 and MYH7 (36.4% and 34.4% of all positive samples, respectively), whereas TTR (7.1%) and GLA (4.0%) were the most common phenocopy variants. Other classical phenocopies, Noonan syndrome, Danon disease, and PRKAG2, comprised another 2.0%, 0.9%, and 0.7% of the cohort, respectively. The mean ages for patients with HCM sarcomeric gene variants, HCM phenocopy variants, FD, and ATTR-CA were 45.1 ± 17.6, 50.9 ± 23.7, 51.1 ± 19.4, and 64.6 ± 19.0 years, respectively. CONCLUSION: This study demonstrates the need to include GLA and TTR in NGS panels for patients with increased unexplained LVWT. NGS effectively identifies phenocopies often missed by imaging. Using a large, diverse cohort, this study reveals the prevalence of FD and ATTR-CA in patients with unexplained increased LVWT, reinforcing the importance of NGS for early diagnosis and targeted therapy.
2026-03-14 | Advancing Gene Therapies and Novel Treatment Strategies for Infiltrative Cardiomyopathies: A Comprehensive Review of Targeted Interventions.
Recent progress in unraveling the molecular mechanisms of infiltrative Cardiomyopathies (CMPs) has created exciting opportunities for targeted therapies. These conditions, which include cardiac amyloidosis, sarcoidosis, Danon disease, Fabry disease, Mucopolysaccharidoses (MPS), and cardiac oxalosis, significantly impair cardiac function through complex pathogenic mechanisms. In cardiac amyloidosis, the accumulation of misfolded proteins into fibrillary amyloids disrupts myocardial structure, leading to inflammation, oxidative stress, and apoptosis. New treatments such as Antisense Oligonucleotides [ASOs], small interfering RNA [siRNA], and monoclonal antibodies have shown promising results in preclinical and clinical settings for managing amyloid deposition. Gene editing technologies, particularly CRISPR-Cas9, also have significant potential to deliver lasting therapeutic benefits by precisely correcting pathogenic mutations. Furthermore, managing Fabry disease with Enzyme Replacement Therapies [ERT] and chaperone molecules has improved cardiac outcomes; however, challenges remain in advanced stages due to ongoing myocardial involvement. Immunomodulatory strategies and innovative antibody-based therapies targeting pathological protein aggregates represent groundbreaking approaches that have shown efficacy in preclinical and earlyphase clinical trials. Despite these advancements, challenges remain, including the efficiency of drug delivery, possible off-target effects, and inconsistent clinical responses among different patient groups. Future research should focus on improving these therapies to increase their specificity and safety, ultimately enhancing patient outcomes and quality of life in infiltrative cardiomyopathies.
2026-07-10 | Cardiomyopathy in glycogen storage diseases: diagnosis, prognosis, and advanced management.
Glycogen storage diseases (GSDs) are a heterogeneous group of rare and often under-recognized causes of inherited cardiomyopathy characterized by pathological glycogen or autophagic vacuole accumulation of debris within various tissues, including the heart. These diseases often present as phenocopies of sarcomeric hypertrophic cardiomyopathy, though they may also manifest with dilated or mixed phenotypes. Key GSDs with cardiomyopathy include Pompe disease (GSD IIa), Danon disease (IIb), Cori/Forbes disease (GSD III), Andersen disease (GSD IV), Tarui disease (GSD VII), phosphorylase kinase deficiency (GSD IX), glycogenin-1 deficiency (GSD XV), and PRKAG2 syndrome, each presenting unique clinical trajectories. Accurate diagnosis requires integration of clinical red flags, multimodality cardiac imaging, and electrocardiography, alongside definitive diagnostic tools like enzyme screening, genetic testing, and endomyocardial biopsy. There is a dearth of evidence regarding specific treatment of each unique GSD cardiomyopathy, but emerging therapeutics across the spectrum of GSDs aim to address this need. This review covers current knowledge on the spectrum of GSD-related cardiomyopathies, discussing pathophysiology, diagnosis, and evolving treatment strategies.
2026-07-01 | Cardiac characteristics of Chinese patients with Danon disease associated with LAMP2 p.Leu325fs variants.
This study characterized the clinical and genetic features of Danon disease (DD), focusing on participants harboring LAMP2 frameshift variants at the 325th amino acid position (p.Leu325fs), and explored their cardiac implications. These frameshift variants result in loss of functional LAMP2 protein through premature termination, thereby impairing lysosomal function. Although the association between LAMP2 variants and DD is established, the cardiac phenotype specifically associated with p.Leu325fs variants remains incompletely characterized. We conducted a retrospective analysis of nine patients with DD diagnosed at the Fuwai Hospital of the Chinese Academy of Medical Sciences, Beijing, China. Comprehensive clinical data, including biochemical markers, electrocardiographic findings, and imaging studies (echocardiography and cardiac magnetic resonance imaging), were collected. Pathogenic LAMP2 variants were confirmed through exome sequencing or clinical genetic testing. All participants carried pathogenic frameshift variants at p.Leu325fs, presenting with prominent cardiac manifestations including myocardial hypertrophy or dilation, impaired systolic function, and arrhythmias. Electrocardiographic abnormalities, notably intraventricular conduction block and ST-T segment changes, were observed in all participants. Elevated N-terminal prohormone of brain natriuretic peptide and lactate dehydrogenase levels were observed in all participants, consistent with advanced heart failure and myocardial injury. Our findings suggest that p.Leu325fs pathogenic variants in DD are associated with a predominantly cardiac phenotype, characterized by universal intraventricular conduction block, ST-T segment changes, progressive myocardial fibrosis, and impaired systolic function. These results support the clinical value of integrating LAMP2 genetic testing, cardiac MRI, and electrocardiographic monitoring into the early diagnosis, risk stratification, and management of patients with DD.
2026-06-25 | Autophagy–Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy
Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy–lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome–lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy—particularly AAV9-LAMP2B for Danon disease—together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
2026-04-18 | Uncovering the gene variants in a global cohort of patients with unexplained increased left ventricular wall thickness using next-generation sequencing.
BACKGROUND: Genetic analysis using massive parallel sequencing is crucial for the accurate and early diagnosis of hereditary hypertrophic cardiomyopathies and their phenocopies, especially transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD). This study extends the cardio next-generation sequencing (NGS) pilot study by investigating the detection rate of gene variants causing increased left ventricular wall thickness (LVWT) using an expanded 19-gene NGS panel in a larger global cohort. METHODS: This study included 2068 patients with unexplained increased LVWT enrolled at cardiological clinics across 22 countries/regions between 2020 and 2022. The NGS panel comprised 19 genes associated with hypertrophic cardiomyopathy (HCM) and its phenocopies. Sequencing was performed using the Illumina NextSeq 500 and NovaSeq 6000 systems, with variant interpretation performed according to the American College of Medical Genetics and Genomics guidelines. Novel variants were analyzed using the Human Gene Mutation Database (HGMD®), Franklin, and VarSome. RESULTS: Among the 2068 patients, 453 patients were positive for pathogenic/likely pathogenic variants (21.9%). The diagnostic yield for HCM was 18.4%, while that of HCM phenocopies was 3.5%, including ATTR-CA (1.5%), and FD (0.9%). In patients with a positive test (HCM or HCM phenocopies), the most prevalent HCM-related variants were MYBPC3 and MYH7 (36.4% and 34.4% of all positive samples, respectively), whereas TTR (7.1%) and GLA (4.0%) were the most common phenocopy variants. Other classical phenocopies, Noonan syndrome, Danon disease, and PRKAG2, comprised another 2.0%, 0.9%, and 0.7% of the cohort, respectively. The mean ages for patients with HCM sarcomeric gene variants, HCM phenocopy variants, FD, and ATTR-CA were 45.1 ± 17.6, 50.9 ± 23.7, 51.1 ± 19.4, and 64.6 ± 19.0 years, respectively. CONCLUSION: This study demonstrates the need to include GLA and TTR in NGS panels for patients with increased unexplained LVWT. NGS effectively identifies phenocopies often missed by imaging. Using a large, diverse cohort, this study reveals the prevalence of FD and ATTR-CA in patients with unexplained increased LVWT, reinforcing the importance of NGS for early diagnosis and targeted therapy.
2026-03-14 | Advancing Gene Therapies and Novel Treatment Strategies for Infiltrative Cardiomyopathies: A Comprehensive Review of Targeted Interventions.
Recent progress in unraveling the molecular mechanisms of infiltrative Cardiomyopathies (CMPs) has created exciting opportunities for targeted therapies. These conditions, which include cardiac amyloidosis, sarcoidosis, Danon disease, Fabry disease, Mucopolysaccharidoses (MPS), and cardiac oxalosis, significantly impair cardiac function through complex pathogenic mechanisms. In cardiac amyloidosis, the accumulation of misfolded proteins into fibrillary amyloids disrupts myocardial structure, leading to inflammation, oxidative stress, and apoptosis. New treatments such as Antisense Oligonucleotides [ASOs], small interfering RNA [siRNA], and monoclonal antibodies have shown promising results in preclinical and clinical settings for managing amyloid deposition. Gene editing technologies, particularly CRISPR-Cas9, also have significant potential to deliver lasting therapeutic benefits by precisely correcting pathogenic mutations. Furthermore, managing Fabry disease with Enzyme Replacement Therapies [ERT] and chaperone molecules has improved cardiac outcomes; however, challenges remain in advanced stages due to ongoing myocardial involvement. Immunomodulatory strategies and innovative antibody-based therapies targeting pathological protein aggregates represent groundbreaking approaches that have shown efficacy in preclinical and earlyphase clinical trials. Despite these advancements, challenges remain, including the efficiency of drug delivery, possible off-target effects, and inconsistent clinical responses among different patient groups. Future research should focus on improving these therapies to increase their specificity and safety, ultimately enhancing patient outcomes and quality of life in infiltrative cardiomyopathies.
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Drug Discovery Landscape
4 orphan drug designations for Danon disease.
4 orphan drug designations for Danon disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated viral vector serotype 2i8 containing the human LAMP2 isoform B transgene | gene therapies | EMA | 2025-05-22 | — | AskBio France |
autologous human CD34+ hematopoietic stem and progenitor cells (HSPCs), derived from G-CSF/plerixafor mobilized peripheral blood stem cells (PBSCs) of patients with Danon disease (DD) | cell therapies | FDA | 2024-04-23 | — | Papillon Therapeutics |
Adeno-associated virus serotype 9 vector containing the human LAMP2 isoform B transgene | gene therapies | EMA | 2023-08-16 | — | Rocket Pharmaceuticals B.V. |
Adeno-associated virus serotype 9 vector containing the human lysosome-associated membrane glycoprotein 2 isoform B transgene (AAV9.LAMP2B) | gene therapies | FDA | 2019-02-01 | — | Rocket Pharmaceuticals, Inc. |
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