Phenotypic Transition From Danon Disease to Arrhythmogenic Cardiomyopathy: Multimodality and Histopathologic Evidence.

Background

Pathogenic variants in lysosome-associated membrane protein 2 (LAMP2) gene cause X-linked Danon disease, associated with hypertrophic cardiomyopathy. Arrhythmogenic cardiomyopathy is characterized by myocardial fibrofatty replacement and ventricular arrhythmias. CASE SUMMARY A 30-year-old woman presented with a hypertrophic phenotype and a short PR interval. At 40 years of age, she developed progressive diffuse low QRS complex voltages and recurrent ventricular arrhythmias. Cardiac magnetic resonance showed extensive ring-like late gadolinium enhancement and biventricular systolic dysfunction, consistent with biventricular arrhythmogenic cardiomyopathy. Genetic testing identified a pathogenic LAMP2 variant (LAMP2:c.928G>A; p.Val310Ile) associated with Danon disease. Despite optimized medical therapy, she progressed to advanced heart failure requiring heart transplantation. The explanted heart demonstrated severe fibrofatty myocardial replacement, with thinning of the right ventricular wall and vacuolated cardiomyocyte, which were strongly stained by periodic acid-Schiff.

Discussion

Danon disease is characterized by myocardial hypertrophy, but not by fibrofatty replacement, which is a hallmark of arrhythmogenic cardiomyopathy. This case demonstrates a rare phenotypic evolution in LAMP2 cardiomyopathy.