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Background <p>Danon disease (DD) is a rare X-linked cardioskeletal myopathy caused by pathogenic mutations in lysosomal-associated membrane protein-2 (<i>LAMP2</i>). It is a multisystemic disease that affects the heart, skeletal, neurologic and ophthalmic systems. With an early age of onset especially in males and no treatment for the cardiomyopathy outside of heart transplant, natural history studies have been paramount to providing clinical data for the development and advancement of disease-focused therapies. Herein we present a comprehensive, prospective study detailing both cardiac and extracardiac features of DD.</p> Methods <p>The cohort was comprised of 8 male pediatric and 1 male young adult patient, enrolled at the University of California, San Diego. Diagnosis of DD was confirmed with a pathogenic or likely pathogenic <i>LAMP2</i> variants. The patients underwent serial quality of life, neuropsychological, cognitive, ophthalmological, cardiac, pulmonary, and neuromuscular assessments every 6 months for 3 years.</p> Results <p>The mean age of the cohort at study enrollment was 11.6 ± 4.5 years. The mean age of the cohort at diagnosis was 6.5 ± 5.2 years. Quality of life: assessed through the Pediatric Cardiac Quality of Life Inventory (PCQLI) and Pediatric Quality of Life Inventory (PQLQ) reveals perceptions of poor quality of life by both patients and parents. Cognitive: Differential Ability Scales-II (DAS-II) and Vineland Adaptive Behavior Scales-3 (VABS-3) showed marked intellectual disability at baseline. Cardiac: over time, ejection fraction decreased, myocardial walls thickened, and left ventricular mass increased. Pulmonary: FVC increased over time; cardiopulmonary exercise testing (CPET) revealed decreased exercise capacity as measured by peak oxygen uptake (peak VO<sub>2</sub> max) and 6-minute walk test (6MWT). Neuromuscular: most patients in the cohort achieved maximum scores on North Star Ambulatory Assessment (NSAA), with minimal changes over 6-month follow-up; they were faster than a study of normal children during the 10-meter walk test (10MWT); they were slower than a study of normal children during time to rise and the 4-stair climb test.</p> Conclusion <p>Natural history studies provide an important opportunity to study rare diseases, especially when longitudinal data is available to characterize clinical changes and disease course. In the case of DD, young, male patients were found to have general deficits across quality-of-life indices and cognitive, cardiac, neuromuscular, ophthalmologic, and pulmonary functions. Stabilization or improvements in these domains may be appropriate outcomes for clinical trials to consider.</p>

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Danon disease in male patients: a prospective natural history study to augment understanding of the phenotype

  • 期刊论文

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  • 发表日期：

    2025年10月21日

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  • Tarek Khedro,
  • Jennifer Attias,
  • Emily Eshraghian,
  • Melina Tsotras,
  • Emily Margolin,
  • Shaden Yassin,
  • Elizabeth Silver,
  • Quan Bui,
  • Shyamanga Borooah,
  • Chamindra G. Laverty,
  • Matthew R. G. Taylor,
  • Eric D. Adler,
  • Kimberly N. Hong

摘要

Background

Danon disease (DD) is a rare X-linked cardioskeletal myopathy caused by pathogenic mutations in lysosomal-associated membrane protein-2 (LAMP2). It is a multisystemic disease that affects the heart, skeletal, neurologic and ophthalmic systems. With an early age of onset especially in males and no treatment for the cardiomyopathy outside of heart transplant, natural history studies have been paramount to providing clinical data for the development and advancement of disease-focused therapies. Herein we present a comprehensive, prospective study detailing both cardiac and extracardiac features of DD.

Methods

The cohort was comprised of 8 male pediatric and 1 male young adult patient, enrolled at the University of California, San Diego. Diagnosis of DD was confirmed with a pathogenic or likely pathogenic LAMP2 variants. The patients underwent serial quality of life, neuropsychological, cognitive, ophthalmological, cardiac, pulmonary, and neuromuscular assessments every 6 months for 3 years.

Results

The mean age of the cohort at study enrollment was 11.6 ± 4.5 years. The mean age of the cohort at diagnosis was 6.5 ± 5.2 years. Quality of life: assessed through the Pediatric Cardiac Quality of Life Inventory (PCQLI) and Pediatric Quality of Life Inventory (PQLQ) reveals perceptions of poor quality of life by both patients and parents. Cognitive: Differential Ability Scales-II (DAS-II) and Vineland Adaptive Behavior Scales-3 (VABS-3) showed marked intellectual disability at baseline. Cardiac: over time, ejection fraction decreased, myocardial walls thickened, and left ventricular mass increased. Pulmonary: FVC increased over time; cardiopulmonary exercise testing (CPET) revealed decreased exercise capacity as measured by peak oxygen uptake (peak VO2 max) and 6-minute walk test (6MWT). Neuromuscular: most patients in the cohort achieved maximum scores on North Star Ambulatory Assessment (NSAA), with minimal changes over 6-month follow-up; they were faster than a study of normal children during the 10-meter walk test (10MWT); they were slower than a study of normal children during time to rise and the 4-stair climb test.

Conclusion

Natural history studies provide an important opportunity to study rare diseases, especially when longitudinal data is available to characterize clinical changes and disease course. In the case of DD, young, male patients were found to have general deficits across quality-of-life indices and cognitive, cardiac, neuromuscular, ophthalmologic, and pulmonary functions. Stabilization or improvements in these domains may be appropriate outcomes for clinical trials to consider.