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.