ENOrphanet Journal of Rare Diseases | Prospective Natural History Study of Danon Disease in Male Patients Reveals Multisystem Phenotypic Changes
Date: April 05, 2025
Classification: Frontiers
Recommend:
This study provides the first systematic description of the natural course of Danon disease (DD) in male patients, covering multiple dimensions including cardiac, neurocognitive, pulmonary function, and quality of life. Through a three-year longitudinal assessment, it reveals functional decline across multiple systems in DD patients, offering critical baseline data for future clinical trials. The study emphasizes the significant impact of LAMP2 mutations on cardiac structure and suggests that ejection fraction and left ventricular mass may serve as potential biomarkers for disease progression.
Literature Overview
This article, titled Danon disease in male patients: a prospective natural history study to augment understanding of the phenotype, published in the Orphanet Journal of Rare Diseases, reviews and summarizes the multisystem clinical features and natural history progression of Danon disease (DD) in male patients. Through long-term follow-up assessments of multiple parameters including cardiac function, neurocognition, pulmonary function, and quality of life, the study reveals phenotypic changes in pediatric and early-adult DD patients, offering systematic data support for rare disease research.
Background Knowledge
Danon disease is an X-linked dominant genetic disorder caused by pathogenic variants in the LAMP2 gene, primarily characterized by cardiomyopathy, skeletal muscle involvement, intellectual disability, and retinal abnormalities. Males tend to present with more severe symptoms, often developing cardiac manifestations during adolescence, while female carriers typically exhibit milder phenotypes. Due to its rarity, previous studies have largely been cross-sectional with limited longitudinal data. Although existing studies suggest that DD accounts for 4–6% of pediatric hypertrophic cardiomyopathy (HCM) cases, the natural progression and multisystem involvement of the disease have not been clearly defined. This prospective cohort study enrolled nine genetically confirmed male DD patients (eight children and one young adult) and conducted a three-year follow-up using various assessment tools (PCQLI, PQLQ, DAS-II, VABS-3, NSAA, CPET, etc.), systematically uncovering dynamic changes in cardiac, pulmonary, cognitive, and quality-of-life domains. It was also found that all patients experienced a decline in left ventricular ejection fraction (LVEF) and an increase in left ventricular mass, suggesting that cardiac structural changes can serve as potential indicators of disease progression. Additionally, both patient and caregiver reports indicated lower quality-of-life scores compared to healthy controls, further supporting the profound impact of DD on patients and their families. This study provides a critical data foundation for future clinical trials, including outcome measures, disease biomarkers, and therapeutic endpoints.
Study Methods and Experiments
This study employed a single-center prospective cohort design, enrolling nine genetically confirmed male DD patients (eight pediatric and one young adult) at the University of California, San Diego, for a three-year follow-up. All participants underwent comprehensive assessments every six months, including quality-of-life questionnaires (PCQLI, PQLQ), cognitive testing (DAS-II, VABS-3), neuromuscular assessments (NSAA, 10MWT, 4SC, 6MWT), pulmonary function tests (PFTs), cardiac evaluations (LVEF, LVMWT, LVEDD), genotype analysis, and laboratory testing (NT-proBNP, hs-cTnT, CPK, etc.). Due to the small sample size, paired comparisons were performed using the Wilcoxon signed-rank test, and data from patients who underwent heart transplantation or enrolled in gene therapy trials were censored.
Key Findings and Insights
Significance and Future Directions
This study is the first to systematically describe the natural history of DD in male patients, providing critical baseline clinical data for future gene therapy or enzyme replacement trials. It recommends using LVEF, LV mass, and VO2 max as primary endpoints in clinical trials and suggests incorporating both patient self-reports and caregiver assessments to more accurately capture quality-of-life changes. Furthermore, the study highlights early deficits in neurocognition, retinal function, and motor capacity in DD patients, suggesting the need for early intervention strategies such as gene therapy, neuroprotection, or visual rehabilitation. Due to the limited sample size, future multicenter and long-term follow-up studies are needed to validate these findings and explore genetic and environmental factors contributing to inter-individual variability.
Conclusion
This three-year prospective follow-up study systematically characterizes the natural history of Danon disease in male patients, revealing broad impacts on cardiac, cognitive, pulmonary, motor, and quality-of-life domains. It was found that all patients exhibited decreased left ventricular ejection fraction (LVEF), increased left ventricular mass, and thickened myocardial walls, indicating that cardiac structural changes are key indicators of disease progression. Both patient self-reports and caregiver assessments showed significantly lower quality-of-life scores compared to healthy controls, with notable discrepancies between the two, underscoring the need for both subjective and objective assessments to accurately measure disease burden. Cognitive testing revealed substantial intellectual disability in DD patients, averaging two standard deviations below the normal population, further supporting the neurodevelopmental impact of the disease. Retinal abnormalities, including hyperreflective foci in the outer nuclear layer and increased macular autofluorescence, were universally present, indicating the necessity of routine ophthalmologic monitoring. Pulmonary function tests (FVC, FEV1) remained stable or slightly increased, possibly due to relative preservation of respiratory muscle function. Cardiopulmonary exercise testing (CPET) showed significantly reduced VO2 max, suggesting impaired cardiopulmonary function. The study underscores the importance of multidimensional assessments involving cardiac, cognitive, motor, and quality-of-life domains in DD and recommends incorporating these metrics in future clinical trials to evaluate therapeutic efficacy. Additionally, the observed differences between patient and caregiver reports highlight the need for cautious interpretation of quality-of-life data. Overall, this study provides a solid foundation for the clinical management and therapeutic development of Danon disease, particularly in terms of natural history documentation, assessment tools, and endpoint selection.
