An International Longitudinal Natural History Study of Patients With Danon Disease: Unique Cardiac Trajectories Identified Based on Sex and Heart Failure Outcomes.

Abstract

Background: Danon disease is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 gene. Though the severe morbidity of disease in men is well established, longitudinal studies describing the trajectory of cardiovascular disease in both sexes are lacking.

Methods and results: Data were from the International Danon Disease Registry and includes retrospective data on 116 patients who provided informed consent between 2005 and 2022. The analysis included 116 patients with Danon disease with a median age of diagnosis of 15.2 years (10.0-25.2 years). Trends in echocardiographic parameters over time indicate decreased left ventricular ejection fraction and increased left ventricular end diastolic dimension regardless of sex and heart failure (HF) outcome; however, rate of change was increased in patients who experienced a HF outcome in both sexes. Left ventricular wall hypertrophy continues in men who have not yet experienced a HF outcome and stabilizes before HF outcome, while females have progressive left ventricular thinning regardless of HF outcome. Stratified analysis demonstrated 2 distinct groups of females: one who experienced HF outcome before 26 years of age and another group with this HF outcome after.

Conclusions: In this largest longitudinal natural history study of Danon disease to date, we confirmed that males present on average a decade earlier and demonstrate more progressive cardiac hypertrophy and HF than females. Notably, there may be a subset of females who are phenotypically similar to males with profound left ventricular hypertrophy that appears to stabilize or regress before HF outcome. Correlations between structural cardiac dysfunction and disease progression may permit risk stratification, refinement of treatment algorithms, and inform therapeutic trial design.

Registration: URL: https://clinicaltrials.gov/; Unique Identifier: NCT03766386.