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:
categories:
Small molecules
small molecules
2025-11-27 | Danon Disease Presenting as Refractory Chronic Lymphocytic Myocarditis: A Case Report
Introduction: Myocarditis is a challenging diagnosis that can progress to severe cardiomyopathy and sudden cardiac death. In refractory cases, an underlying genetic etiology should be strongly suspected. This report highlights a rare presentation of Danon disease mimicking chronic lymphocytic myocarditis. Case Presentation: A 26-year-old female presented with progressive fatigue, dyspnea, and non-specific chest discomfort, suggesting heart failure (HF). Initial investigations revealed an irregular pulse, hypotension (80/50 mmHg), elevated high-sensitivity Troponin I, and severe electrical abnormalities (atrial fibrillation, complete heart block). Transthoracic echocardiography (TTE) showed biventricular hypertrophic cardiomyopathy (HCM) with a severely reduced left ventricular ejection fraction (LVEF 15%). An endomyocardial biopsy (EMB) confirmed chronic lymphocytic myocarditis. Diagnosis and Treatment: The patient’s symptoms worsened following discontinuation of initial empirical immunosuppressive therapy, necessitating a comprehensive work-up. The combination of refractory myocarditis and HCM prompted genetic testing. This revealed defective splicing of the lysosome-associated membrane protein 2 (LAMP2) gene, confirming the diagnosis of Danon disease, an X-linked lysosomal storage disorder. The patient was re-initiated on a tailored regimen of immunosuppressives (corticosteroids) and immunomodulators (Tacrolimus and Mycophenolate). Outcome and Conclusion: The combined therapeutic approach led to a favourable clinical outcome, with the patient remaining stable and TTE demonstrating an improved LVEF of 25% after six months. This case underscores the importance of considering rare inherited cardiomyopathies, such as Danon disease, in young patients presenting with unexplained, refractory chronic myocarditis, especially those with hypertrophic features, to guide appropriate disease-specific management.
2025-11-04 | DREAMS: Drug REpurposing with Artificial Intelligence for Muscular Disorders
Rare diseases affect over 300 million people worldwide, yet only 6% currently have an approved treatment option. Given these numbers, and the pharmaceutical industry’s traditional “one drug, one disease” paradigm, it is crucial to develop disruptive approaches that accelerate drug discovery while reducing development time and costs. To address this challenge, the DREAMS project aims to identify repurposable treatments for multiple rare diseases by targeting shared pathological phenotypes. Our approach is built on four key pillars: (i) disease modeling using patient-derived pluripotent stem cells to identify common pathological phenotypes; (ii) phenotypic screening to identify compounds that rescue these molecular and cellular dysfunctions; (iii) artificial intelligence-based target deconvolution to understand mechanisms of action, predict therapeutic targets, and propose new disease indications; and (iv) innovative clinical trial methodologies designed to address groups of diseases rather than single conditions. Importantly, DREAMS is deeply patient-centric, with patient representatives actively involved in the design of the clinical trial to ensure that the research aligns with patients’ needs and priorities. To develop this approach, DREAMS specifically focuses on rare neuromuscular disorders that share a key pathological mechanism: impaired autophagy in striated muscle tissue. Five genetic diseases were selected based on their clinical relevance and preclinical evidence demonstrating that autophagy rescue can be beneficial: dynamin 2-related centronuclear myopathy, Duchenne muscular dystrophy, LMNA-related Emery–Dreifuss muscular dystrophy type 2, glycogen storage disease type II (Pompe disease), and Danon disease. By focusing on shared mechanisms rather than disease-specific mutations, DREAMS establishes a scalable and reusable platform for drug discovery that can be applied to additional rare diseases with overlapping pathophysiological features.
2025-01-27 | VEXAS, Chediak-Higashi syndrome and Danon disease: myeloid cell endo-lysosomal pathway dysfunction as a common denominator?
Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak-Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy. Furthermore, all three genes are highly expressed in the more mature myeloid cells pointing out their likely important function in these cells. LAMP2 deficiency for instance is known to be associated with alterations of lysosome architecture and function. It is thus well established that different cell types from Danon disease patients that harbor invalidating mutations in LAMP2 exhibit giant lysosomes containing undigested materials characteristic of defects in the fusion of lysosomes with autophagosomes, a feature also found in VEXAS and CHS. Other similarities regarding these three diseases include granulocyte and monocyte dysfunctions and a recurrent inflammatory climate. In the present review we discuss the possibility that some common clinical manifestations of these diseases, notably the hematopoietic ones are consecutive to a dysfunction of the endo-lysosomal pathway in myeloid/erythroid progenitors and in mature myeloid cells including neutrophiles, monocytes and macrophages. Finally, we propose reacidification as a way of reinducing lysosome functionalities and autophagy as a potential approach for a better management of these diseases.
2024-08-29 | Post-COVID Myocarditis in Patients with Primary Cardiomyopathies: Diagnosis, Clinical Course and Outcomes.
The aim of this study was to evaluate the clinical course and outcomes of post-COVID myocarditis in patients with cardiomyopathies (CMP). This case series includes 10 patients with different CMPs who had COVID-19 (seven men; 48.4 ± 11.4 yr.): left ventricular non-compaction (n = 2), arrhythmogenic right ventricular CMP in combination with a heterozygous form of hemochromatosis (n = 1, HFE), restrictive CMP (n = 1, MyBPC3), laminopathy (n = 1, LMNA), dilated cardiomyopathy (n = 1, MYH7 + MyBPC3), Danon's disease (n = 1, LAMP2) and AL cardiac amyloidosis (n = 3). Myocardial morphological examination with immunohistochemical staining and PCR for SARS-CoV-2 and cardiotropic viruses was performed in six patients, while cardiac MRI and anti-cardiac antibody titres were evaluated in all patients. Post-COVID lymphocytic myocarditis was confirmed morphologically in six patients (with LVNC, RCM, ARCV, Danon's disease, and AL amyloidosis). Spike and nucleocapsid coronavirus proteins were detected in cell infiltrates, endothelium and cardiomyocytes in all biopsies; SARS-CoV-2 RNA was found in five out of six. In four patients, the diagnosis of myocarditis was based on MRI, high titres of anti-cardiac antibodies and clinical data. The mean time from COVID-19 to the diagnosis of myocarditis was 7 (5; 10.5) months. Myocarditis manifested with the onset/increase of arrhythmias and heart failure. Immunosuppressive therapy with corticosteroids was administered to six patients and led to an increase in ejection fraction and improvement of heart failure symptoms in five of them. CMPs are a favourable background for the development of post-COVID myocarditis. The onset or deterioration of heart failure and/or arrhythmias in patients with CMPs after COVID-19 requires the exclusion of myocarditis and, if present, the administration of immunosuppressive therapy.
2024-06-05 | DREAMS - Drug REpurposing with Artificial intelligence for Muscular disorderS
The World Health Organization highlights a critical need for treatments in rare diseases, with less than 6% currently having approved therapies. The EU-funded DREAMS project aims to discover therapies for five rare neuromuscular disorders with similar pathophysiological traits. To do so we will generate a collection of induced pluripotent stem cells from patients affected with Duchenne muscular dystrophy, Pompe disease, DNM2 centronuclear myopathy, Danon disease and Emery-Dreifuss muscular dystrophy. Following differentiation into skeletal muscle cells, these iPS cells will be used to discover common biomarkers across these disorders. A particular interest will be given to autophagic dysregulations that have previously been reported as a target of interest in those diseases. In DREAMS, we will also develop phenotypic and mechanism based screening approaches to test a library of 4000 drugs. Hits mechanism of action will be investigated using AI based target deconvolution algorithms and the best candidates will be evaluated in preclinical animal models of these diseases. Beyond the identification of repurposable drugs for these five diseases, DREAMS propose an innovative platform combining pluripotent stem cells, drug screening and AI usable to find treatments to other groups of diseases of genetic origin.
proteins
2024-11-12 | Abstract 4139615: X-linked LAMP2B p.Val397Ile variant leads to late-onset Danon disease in females with hypertrophic cardiomyopathy
Introduction: Danon disease is an X-linked dominant disorder in lysosome-associated membrane protein 2B (LAMP2B) that presents with cardiomyopathy and in males, intellectual disability. Dysfunction of LAMP2B, a lysosomal transmembrane protein in muscle, prevents macroautophagy and causes intracytoplasmic accumulation of cellular debris. Loss-of-function mutations in LAMP2B manifest as full Danon disease while missense mutations drive milder phenotypes. There is currently no effective therapy. Existing literature reports two transmembrane missense mutations, which presented as late-onset cardiac hypertrophy, but do not explore mutation pathogenicity. In our work, we investigate the mechanism of a novel transmembrane missense variant p.Val397Ile in two unrelated females who presented with late-onset hypertrophic obstructive cardiomyopathy with patient myectomy sample. Methods: Myectomy heart tissue was analyzed via Western blot and RT-qPCR for protein and RNA levels. In vitro overexpression of reference and alternate missense alleles was conducted in HEK293 cells, then analyzed by Western blot, RT-qPCR, and immunofluorescence. Immunofluorescence image analysis compared LAMP2B signal intensity and distribution between variant and wild-type proteins. Results: Patient heart tissue showed increased LAMP2 degradation and decreased autophagy markers by Western blot. EndoH treatment to investigate N- linked glycosylation patterns further revealed decreased total LAMP2 in patient samples. RT-qPCR showed increased RNA expression in the variant allele. LAMP2 overexpression in HEK293 cells resulted in reduced LAMP2B molecular weight and subcellular mislocalization. Fluorescent image segmentation revealed increased aggregation of variant LAMP2B around nuclei and surrounding structures compared to wild-type. Collectively, these results suggest arrested protein maturation in the Golgi apparatus and increased RNA expression to compensate for reduced functional protein. Conclusion: Our study demonstrated that the LAMP2B missense variant c.1189G>A p.Val397Ile is implicated with increased degradation of LAMP2B protein, reduced protein levels of autophagy markers, and elevated LAMP2B RNA expression in cardiomyocytes. Our in vitro studies suggest that missense mutations may cause myocardial dysfunction via abnormal LAMP2B maturation and localization. Our work enhances mechanistic understanding of LAMP2B-related pathogenicity and may inform future therapeutic strategies for Danon disease.
2019-05-06 | Lysosomal storage disorders affecting the heart: a review.
Lysosomal storage disorders (LSD) comprise a group of diseases caused by a deficiency of lysosomal enzymes, membrane transporters or other proteins involved in lysosomal biology. Lysosomal storage disorders result from an accumulation of specific substrates, due to the inability to break them down. The diseases are classified according to the type of material that is accumulated; for example, lipid storage disorders, mucopolysaccharidoses and glycoproteinoses. Cardiac disease is particularly important in lysosomal glycogen storage diseases (Pompe and Danon disease), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease). Various disease manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular diseases. Endomyocardial biopsies can play an important role in the diagnosis of these diseases. Microscopic features along with ancillary tests like special stains and ultrastructural studies help in the diagnosis of these disorders. Diagnosis is further confirmed based upon enzymatic and molecular genetic analysis. Emerging evidence suggests that Enzyme replacement therapy (ERT) substantially improves many of the features of the disease, including some aspects of cardiac involvement. The identification of these disorders is important due to the availability of ERT, the need for family screening, as well as appropriate patient management and counseling.
2013-11-05 | Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease.
The complex of Vacuolar Protein Sorting 34 and 15 (Vps34 and Vps15) has Class III phosphatidylinositol 3-kinase activity and putative roles in nutrient sensing, mammalian Target Of Rapamycin (mTOR) activation by amino acids, cell growth, vesicular trafficking and autophagy. Contrary to expectations, here we show that Vps15-deficient mouse tissues are competent for LC3-positive autophagosome formation and maintain mTOR activation. However, an impaired lysosomal function in mutant cells is traced by accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles, which can be reverted to normal levels after ectopic overexpression of Vps15. Mice lacking Vps15 in skeletal muscles, develop a severe myopathy. Distinct from the autophagy deficient Atg7(-/-) mutants, pathognomonic morphological hallmarks of autophagic vacuolar myopathy (AVM) are observed in Vps15(-/-) mutants, including elevated creatine kinase plasma levels, accumulation of autophagosomes, glycogen and sarcolemmal features within the fibres. Importantly, Vps34/Vps15 overexpression in myoblasts of Danon AVM disease patients alleviates the glycogen accumulation. Thus, the activity of the Vps34/Vps15 complex is critical in disease conditions such as AVMs, and possibly a variety of other lysosomal storage diseases.
2010-09-05 | P2.22 Lamp-1 overexpression rescues cardiomyopathy in Lamp-2 deficient cells by correcting cellular lysosomal function
Danon disease is a rare disorder characterized by a clinical triad of hypertrophic cardiomyopathy, skeletal myopathy and mental retardation, which is caused by a mutation in the gene encoding lysosome-associated membrane protein 2 (Lamp-2). Lamp2 KO mice, the mouse model of Danon disease, have massive hypertrophic cardiomyopathy and mild myopathy. In hepatocytes, reduced lysosomal protein degradation and retarded autophagic process were reported. In this study, we examined whether the phenotype of Lamp-2 deficiency can be rescued by overexpression of Lamp-1, which is a homolog molecule with 37% identity in amino acid to Lamp-2. We generated Lamp1-Tg mice, in which Lamp-1 was overexpressed in various organs and crossed with Lamp2 KO mice (Lamp2KOLamp1-Tg). In our results, cardiomyocyte hypertrophy and fibrosis was observed in Lamp2 KO mice. In contrast, Lamp2KOLamp1-Tg showed remarkable improvement in these phenotypes. These results indicate that overexpression of Lamp1 can rescue cardiomyopathy in Lamp2 KO mice.
gene therapies
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.
2026-01-12 | A Rare Cause of Cardiac Hypertrophy: Danon Disease
Cardiac hypertrophy is a common clinical finding and may appear as a cardiac manifestation of numerous diseases. In addition to frequently encountered causes such as hypertension and valvular heart disease, clinicians must also consider cardiac amyloidosis, hypertrophic cardiomyopathies, and various rare genetic conditions. Danon disease is a rare X-linked dominant multisystem disorder characterized by cardiomyopathy, skeletal myopathy, and intellectual disability. It results from defects in the lysosome-associated membrane protein-2 (LAMP2) gene, and numerous pathogenic mutations have been described. Here, we present the case of a 64-year-old woman who was evaluated for suspected cardiac amyloidosis due to marked left ventricular hypertrophy and was subsequently diagnosed with Danon disease. The coexistence of Danon disease and cardiac amyloidosis is exceedingly uncommon and highlights the importance of considering rare etiologies in patients presenting with hypertrophic phenotypes.
cell therapies
2026-02-14 | [A 14-year management of an early-onset female Danon disease carrier: analysis of family clinical phenotype and transplant efficacy].
Objective: To investigate the clinical characteristics, disease progression pattern, genetic variant features, and therapeutic effect of heart transplantation in a family with Danon disease. Methods: This study is a single-center retrospective case analysis. A proband with Danon disease who was diagnosed and treated at Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2009 and July 2024 and underwent heart transplantation was selected. Retrospective data were collected, including medical history, imaging findings (echocardiography, cardiac magnetic resonance), electrocardiogram, laboratory indicators, pathological examination results, and genetic testing results of the proband and her family members. Regular follow-up was conducted to evaluate the patient's disease progression and post-transplant recovery. Results: The proband was a 23-year-old female with an onset age of 7 years. Initially, the patient presented with non-obstructive hypertrophic cardiomyopathy (maximum left ventricular wall thickness: 29 mm) accompanied by reduced diastolic function. At 19 years old, the disease progressed to dilated cardiomyopathy (left ventricular end-diastolic diameter: 61 mm; left ventricular ejection fraction: 35%). At 22 years old, she was diagnosed with end-stage heart failure (cardiac index: 2.4 L·min-1·m-2). Genetic testing revealed that the patient carried a pathogenic heterozygous variant of the LAMP2 gene c.459C>A (p.Cys153Ter). She underwent orthotopic heart transplantation at 22 years old, and during 3 years of post-transplant follow-up, her cardiac function remained normal (left ventricular ejection fraction >60%). The patient's mother carried the same genetic variant and underwent heart transplantation at 29 years old. Conclusion: Despite being female, the Danon disease patient in this case exhibited clinical features of rapidly progressive cardiomyopathy. Heart transplantation is an effective treatment for patients with end-stage Danon disease, with significant long-term therapeutic effects confirmed by post-transplant follow-up. Clinicians should be alert to the possibility of Danon disease in young patients with hypertrophic cardiomyopathy. Early genetic testing helps confirm the diagnosis and provides a basis for clinical intervention.
2026-01-21 | Danon disease: Two case reports and literature review.
Danon disease (DD) is an X-linked lysosomal storage disorder caused by LAMP2 variants, with males presenting more severe phenotypes. However, evidence for genotype-phenotype correlation remains limited. This study reports 2 male DD patients with distinct LAMP2 mutations to clarify mutation-specific prognostic differences. A 15-year-old male: chest tightness and palpitations, creatine kinase (CK) 3867 U/L, and hypertrophic cardiomyopathy. A 12-year-old male: exertional dyspnea and syncope, left ventricular ejection fraction 36%, left ventricular thrombus, and CK 5210 U/L. Both were diagnosed with DD via genetic testing: the 15-year-old had a LAMP2 IVS6 + 1G > T splice mutation, and the 12-year-old carried a LAMP2 exon 1 deletion. The 15-year-old underwent heart transplantation followed by immunosuppressive therapy. The 12-year-old received only symptomatic treatment without transplantation. The 15-year-old had normal cardiac function and normalized CK levels during 24-month posttransplant follow-up. The 12-year-old died of heart failure 8 months after diagnosis. LAMP2 mutation types correlate with DD severity. Heart transplantation improves prognosis in severe cases, emphasizing the importance of early diagnosis and intervention.
other
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.
small molecules
2025-11-27 | Danon Disease Presenting as Refractory Chronic Lymphocytic Myocarditis: A Case Report
Introduction: Myocarditis is a challenging diagnosis that can progress to severe cardiomyopathy and sudden cardiac death. In refractory cases, an underlying genetic etiology should be strongly suspected. This report highlights a rare presentation of Danon disease mimicking chronic lymphocytic myocarditis. Case Presentation: A 26-year-old female presented with progressive fatigue, dyspnea, and non-specific chest discomfort, suggesting heart failure (HF). Initial investigations revealed an irregular pulse, hypotension (80/50 mmHg), elevated high-sensitivity Troponin I, and severe electrical abnormalities (atrial fibrillation, complete heart block). Transthoracic echocardiography (TTE) showed biventricular hypertrophic cardiomyopathy (HCM) with a severely reduced left ventricular ejection fraction (LVEF 15%). An endomyocardial biopsy (EMB) confirmed chronic lymphocytic myocarditis. Diagnosis and Treatment: The patient’s symptoms worsened following discontinuation of initial empirical immunosuppressive therapy, necessitating a comprehensive work-up. The combination of refractory myocarditis and HCM prompted genetic testing. This revealed defective splicing of the lysosome-associated membrane protein 2 (LAMP2) gene, confirming the diagnosis of Danon disease, an X-linked lysosomal storage disorder. The patient was re-initiated on a tailored regimen of immunosuppressives (corticosteroids) and immunomodulators (Tacrolimus and Mycophenolate). Outcome and Conclusion: The combined therapeutic approach led to a favourable clinical outcome, with the patient remaining stable and TTE demonstrating an improved LVEF of 25% after six months. This case underscores the importance of considering rare inherited cardiomyopathies, such as Danon disease, in young patients presenting with unexplained, refractory chronic myocarditis, especially those with hypertrophic features, to guide appropriate disease-specific management.
2025-11-04 | DREAMS: Drug REpurposing with Artificial Intelligence for Muscular Disorders
Rare diseases affect over 300 million people worldwide, yet only 6% currently have an approved treatment option. Given these numbers, and the pharmaceutical industry’s traditional “one drug, one disease” paradigm, it is crucial to develop disruptive approaches that accelerate drug discovery while reducing development time and costs. To address this challenge, the DREAMS project aims to identify repurposable treatments for multiple rare diseases by targeting shared pathological phenotypes. Our approach is built on four key pillars: (i) disease modeling using patient-derived pluripotent stem cells to identify common pathological phenotypes; (ii) phenotypic screening to identify compounds that rescue these molecular and cellular dysfunctions; (iii) artificial intelligence-based target deconvolution to understand mechanisms of action, predict therapeutic targets, and propose new disease indications; and (iv) innovative clinical trial methodologies designed to address groups of diseases rather than single conditions. Importantly, DREAMS is deeply patient-centric, with patient representatives actively involved in the design of the clinical trial to ensure that the research aligns with patients’ needs and priorities. To develop this approach, DREAMS specifically focuses on rare neuromuscular disorders that share a key pathological mechanism: impaired autophagy in striated muscle tissue. Five genetic diseases were selected based on their clinical relevance and preclinical evidence demonstrating that autophagy rescue can be beneficial: dynamin 2-related centronuclear myopathy, Duchenne muscular dystrophy, LMNA-related Emery–Dreifuss muscular dystrophy type 2, glycogen storage disease type II (Pompe disease), and Danon disease. By focusing on shared mechanisms rather than disease-specific mutations, DREAMS establishes a scalable and reusable platform for drug discovery that can be applied to additional rare diseases with overlapping pathophysiological features.
2025-01-27 | VEXAS, Chediak-Higashi syndrome and Danon disease: myeloid cell endo-lysosomal pathway dysfunction as a common denominator?
Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak-Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy. Furthermore, all three genes are highly expressed in the more mature myeloid cells pointing out their likely important function in these cells. LAMP2 deficiency for instance is known to be associated with alterations of lysosome architecture and function. It is thus well established that different cell types from Danon disease patients that harbor invalidating mutations in LAMP2 exhibit giant lysosomes containing undigested materials characteristic of defects in the fusion of lysosomes with autophagosomes, a feature also found in VEXAS and CHS. Other similarities regarding these three diseases include granulocyte and monocyte dysfunctions and a recurrent inflammatory climate. In the present review we discuss the possibility that some common clinical manifestations of these diseases, notably the hematopoietic ones are consecutive to a dysfunction of the endo-lysosomal pathway in myeloid/erythroid progenitors and in mature myeloid cells including neutrophiles, monocytes and macrophages. Finally, we propose reacidification as a way of reinducing lysosome functionalities and autophagy as a potential approach for a better management of these diseases.
2024-08-29 | Post-COVID Myocarditis in Patients with Primary Cardiomyopathies: Diagnosis, Clinical Course and Outcomes.
The aim of this study was to evaluate the clinical course and outcomes of post-COVID myocarditis in patients with cardiomyopathies (CMP). This case series includes 10 patients with different CMPs who had COVID-19 (seven men; 48.4 ± 11.4 yr.): left ventricular non-compaction (n = 2), arrhythmogenic right ventricular CMP in combination with a heterozygous form of hemochromatosis (n = 1, HFE), restrictive CMP (n = 1, MyBPC3), laminopathy (n = 1, LMNA), dilated cardiomyopathy (n = 1, MYH7 + MyBPC3), Danon's disease (n = 1, LAMP2) and AL cardiac amyloidosis (n = 3). Myocardial morphological examination with immunohistochemical staining and PCR for SARS-CoV-2 and cardiotropic viruses was performed in six patients, while cardiac MRI and anti-cardiac antibody titres were evaluated in all patients. Post-COVID lymphocytic myocarditis was confirmed morphologically in six patients (with LVNC, RCM, ARCV, Danon's disease, and AL amyloidosis). Spike and nucleocapsid coronavirus proteins were detected in cell infiltrates, endothelium and cardiomyocytes in all biopsies; SARS-CoV-2 RNA was found in five out of six. In four patients, the diagnosis of myocarditis was based on MRI, high titres of anti-cardiac antibodies and clinical data. The mean time from COVID-19 to the diagnosis of myocarditis was 7 (5; 10.5) months. Myocarditis manifested with the onset/increase of arrhythmias and heart failure. Immunosuppressive therapy with corticosteroids was administered to six patients and led to an increase in ejection fraction and improvement of heart failure symptoms in five of them. CMPs are a favourable background for the development of post-COVID myocarditis. The onset or deterioration of heart failure and/or arrhythmias in patients with CMPs after COVID-19 requires the exclusion of myocarditis and, if present, the administration of immunosuppressive therapy.
2024-06-05 | DREAMS - Drug REpurposing with Artificial intelligence for Muscular disorderS
The World Health Organization highlights a critical need for treatments in rare diseases, with less than 6% currently having approved therapies. The EU-funded DREAMS project aims to discover therapies for five rare neuromuscular disorders with similar pathophysiological traits. To do so we will generate a collection of induced pluripotent stem cells from patients affected with Duchenne muscular dystrophy, Pompe disease, DNM2 centronuclear myopathy, Danon disease and Emery-Dreifuss muscular dystrophy. Following differentiation into skeletal muscle cells, these iPS cells will be used to discover common biomarkers across these disorders. A particular interest will be given to autophagic dysregulations that have previously been reported as a target of interest in those diseases. In DREAMS, we will also develop phenotypic and mechanism based screening approaches to test a library of 4000 drugs. Hits mechanism of action will be investigated using AI based target deconvolution algorithms and the best candidates will be evaluated in preclinical animal models of these diseases. Beyond the identification of repurposable drugs for these five diseases, DREAMS propose an innovative platform combining pluripotent stem cells, drug screening and AI usable to find treatments to other groups of diseases of genetic origin.
proteins
2024-11-12 | Abstract 4139615: X-linked LAMP2B p.Val397Ile variant leads to late-onset Danon disease in females with hypertrophic cardiomyopathy
Introduction: Danon disease is an X-linked dominant disorder in lysosome-associated membrane protein 2B (LAMP2B) that presents with cardiomyopathy and in males, intellectual disability. Dysfunction of LAMP2B, a lysosomal transmembrane protein in muscle, prevents macroautophagy and causes intracytoplasmic accumulation of cellular debris. Loss-of-function mutations in LAMP2B manifest as full Danon disease while missense mutations drive milder phenotypes. There is currently no effective therapy. Existing literature reports two transmembrane missense mutations, which presented as late-onset cardiac hypertrophy, but do not explore mutation pathogenicity. In our work, we investigate the mechanism of a novel transmembrane missense variant p.Val397Ile in two unrelated females who presented with late-onset hypertrophic obstructive cardiomyopathy with patient myectomy sample. Methods: Myectomy heart tissue was analyzed via Western blot and RT-qPCR for protein and RNA levels. In vitro overexpression of reference and alternate missense alleles was conducted in HEK293 cells, then analyzed by Western blot, RT-qPCR, and immunofluorescence. Immunofluorescence image analysis compared LAMP2B signal intensity and distribution between variant and wild-type proteins. Results: Patient heart tissue showed increased LAMP2 degradation and decreased autophagy markers by Western blot. EndoH treatment to investigate N- linked glycosylation patterns further revealed decreased total LAMP2 in patient samples. RT-qPCR showed increased RNA expression in the variant allele. LAMP2 overexpression in HEK293 cells resulted in reduced LAMP2B molecular weight and subcellular mislocalization. Fluorescent image segmentation revealed increased aggregation of variant LAMP2B around nuclei and surrounding structures compared to wild-type. Collectively, these results suggest arrested protein maturation in the Golgi apparatus and increased RNA expression to compensate for reduced functional protein. Conclusion: Our study demonstrated that the LAMP2B missense variant c.1189G>A p.Val397Ile is implicated with increased degradation of LAMP2B protein, reduced protein levels of autophagy markers, and elevated LAMP2B RNA expression in cardiomyocytes. Our in vitro studies suggest that missense mutations may cause myocardial dysfunction via abnormal LAMP2B maturation and localization. Our work enhances mechanistic understanding of LAMP2B-related pathogenicity and may inform future therapeutic strategies for Danon disease.
2019-05-06 | Lysosomal storage disorders affecting the heart: a review.
Lysosomal storage disorders (LSD) comprise a group of diseases caused by a deficiency of lysosomal enzymes, membrane transporters or other proteins involved in lysosomal biology. Lysosomal storage disorders result from an accumulation of specific substrates, due to the inability to break them down. The diseases are classified according to the type of material that is accumulated; for example, lipid storage disorders, mucopolysaccharidoses and glycoproteinoses. Cardiac disease is particularly important in lysosomal glycogen storage diseases (Pompe and Danon disease), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease). Various disease manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular diseases. Endomyocardial biopsies can play an important role in the diagnosis of these diseases. Microscopic features along with ancillary tests like special stains and ultrastructural studies help in the diagnosis of these disorders. Diagnosis is further confirmed based upon enzymatic and molecular genetic analysis. Emerging evidence suggests that Enzyme replacement therapy (ERT) substantially improves many of the features of the disease, including some aspects of cardiac involvement. The identification of these disorders is important due to the availability of ERT, the need for family screening, as well as appropriate patient management and counseling.
2013-11-05 | Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease.
The complex of Vacuolar Protein Sorting 34 and 15 (Vps34 and Vps15) has Class III phosphatidylinositol 3-kinase activity and putative roles in nutrient sensing, mammalian Target Of Rapamycin (mTOR) activation by amino acids, cell growth, vesicular trafficking and autophagy. Contrary to expectations, here we show that Vps15-deficient mouse tissues are competent for LC3-positive autophagosome formation and maintain mTOR activation. However, an impaired lysosomal function in mutant cells is traced by accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles, which can be reverted to normal levels after ectopic overexpression of Vps15. Mice lacking Vps15 in skeletal muscles, develop a severe myopathy. Distinct from the autophagy deficient Atg7(-/-) mutants, pathognomonic morphological hallmarks of autophagic vacuolar myopathy (AVM) are observed in Vps15(-/-) mutants, including elevated creatine kinase plasma levels, accumulation of autophagosomes, glycogen and sarcolemmal features within the fibres. Importantly, Vps34/Vps15 overexpression in myoblasts of Danon AVM disease patients alleviates the glycogen accumulation. Thus, the activity of the Vps34/Vps15 complex is critical in disease conditions such as AVMs, and possibly a variety of other lysosomal storage diseases.
2010-09-05 | P2.22 Lamp-1 overexpression rescues cardiomyopathy in Lamp-2 deficient cells by correcting cellular lysosomal function
Danon disease is a rare disorder characterized by a clinical triad of hypertrophic cardiomyopathy, skeletal myopathy and mental retardation, which is caused by a mutation in the gene encoding lysosome-associated membrane protein 2 (Lamp-2). Lamp2 KO mice, the mouse model of Danon disease, have massive hypertrophic cardiomyopathy and mild myopathy. In hepatocytes, reduced lysosomal protein degradation and retarded autophagic process were reported. In this study, we examined whether the phenotype of Lamp-2 deficiency can be rescued by overexpression of Lamp-1, which is a homolog molecule with 37% identity in amino acid to Lamp-2. We generated Lamp1-Tg mice, in which Lamp-1 was overexpressed in various organs and crossed with Lamp2 KO mice (Lamp2KOLamp1-Tg). In our results, cardiomyocyte hypertrophy and fibrosis was observed in Lamp2 KO mice. In contrast, Lamp2KOLamp1-Tg showed remarkable improvement in these phenotypes. These results indicate that overexpression of Lamp1 can rescue cardiomyopathy in Lamp2 KO mice.
gene therapies
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.
2026-01-12 | A Rare Cause of Cardiac Hypertrophy: Danon Disease
Cardiac hypertrophy is a common clinical finding and may appear as a cardiac manifestation of numerous diseases. In addition to frequently encountered causes such as hypertension and valvular heart disease, clinicians must also consider cardiac amyloidosis, hypertrophic cardiomyopathies, and various rare genetic conditions. Danon disease is a rare X-linked dominant multisystem disorder characterized by cardiomyopathy, skeletal myopathy, and intellectual disability. It results from defects in the lysosome-associated membrane protein-2 (LAMP2) gene, and numerous pathogenic mutations have been described. Here, we present the case of a 64-year-old woman who was evaluated for suspected cardiac amyloidosis due to marked left ventricular hypertrophy and was subsequently diagnosed with Danon disease. The coexistence of Danon disease and cardiac amyloidosis is exceedingly uncommon and highlights the importance of considering rare etiologies in patients presenting with hypertrophic phenotypes.
cell therapies
2026-02-14 | [A 14-year management of an early-onset female Danon disease carrier: analysis of family clinical phenotype and transplant efficacy].
Objective: To investigate the clinical characteristics, disease progression pattern, genetic variant features, and therapeutic effect of heart transplantation in a family with Danon disease. Methods: This study is a single-center retrospective case analysis. A proband with Danon disease who was diagnosed and treated at Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2009 and July 2024 and underwent heart transplantation was selected. Retrospective data were collected, including medical history, imaging findings (echocardiography, cardiac magnetic resonance), electrocardiogram, laboratory indicators, pathological examination results, and genetic testing results of the proband and her family members. Regular follow-up was conducted to evaluate the patient's disease progression and post-transplant recovery. Results: The proband was a 23-year-old female with an onset age of 7 years. Initially, the patient presented with non-obstructive hypertrophic cardiomyopathy (maximum left ventricular wall thickness: 29 mm) accompanied by reduced diastolic function. At 19 years old, the disease progressed to dilated cardiomyopathy (left ventricular end-diastolic diameter: 61 mm; left ventricular ejection fraction: 35%). At 22 years old, she was diagnosed with end-stage heart failure (cardiac index: 2.4 L·min-1·m-2). Genetic testing revealed that the patient carried a pathogenic heterozygous variant of the LAMP2 gene c.459C>A (p.Cys153Ter). She underwent orthotopic heart transplantation at 22 years old, and during 3 years of post-transplant follow-up, her cardiac function remained normal (left ventricular ejection fraction >60%). The patient's mother carried the same genetic variant and underwent heart transplantation at 29 years old. Conclusion: Despite being female, the Danon disease patient in this case exhibited clinical features of rapidly progressive cardiomyopathy. Heart transplantation is an effective treatment for patients with end-stage Danon disease, with significant long-term therapeutic effects confirmed by post-transplant follow-up. Clinicians should be alert to the possibility of Danon disease in young patients with hypertrophic cardiomyopathy. Early genetic testing helps confirm the diagnosis and provides a basis for clinical intervention.
2026-01-21 | Danon disease: Two case reports and literature review.
Danon disease (DD) is an X-linked lysosomal storage disorder caused by LAMP2 variants, with males presenting more severe phenotypes. However, evidence for genotype-phenotype correlation remains limited. This study reports 2 male DD patients with distinct LAMP2 mutations to clarify mutation-specific prognostic differences. A 15-year-old male: chest tightness and palpitations, creatine kinase (CK) 3867 U/L, and hypertrophic cardiomyopathy. A 12-year-old male: exertional dyspnea and syncope, left ventricular ejection fraction 36%, left ventricular thrombus, and CK 5210 U/L. Both were diagnosed with DD via genetic testing: the 15-year-old had a LAMP2 IVS6 + 1G > T splice mutation, and the 12-year-old carried a LAMP2 exon 1 deletion. The 15-year-old underwent heart transplantation followed by immunosuppressive therapy. The 12-year-old received only symptomatic treatment without transplantation. The 15-year-old had normal cardiac function and normalized CK levels during 24-month posttransplant follow-up. The 12-year-old died of heart failure 8 months after diagnosis. LAMP2 mutation types correlate with DD severity. Heart transplantation improves prognosis in severe cases, emphasizing the importance of early diagnosis and intervention.
other
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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