Key result
Pathogenic LAMP2 variant drives rare progression from HCM to arrhythmogenic cardiomyopathy requiring heart transplantation.
Why the study?
Danon disease caused by LAMP2 variants is associated with hypertrophic cardiomyopathy, but its phenotypic evolution to arrhythmogenic cardiomyopathy is not well described.
Case Report (n=1)
This case highlights that Danon disease (LAMP2 mutation) can rarely evolve from a hypertrophic phenotype into arrhythmogenic cardiomyopathy characterized by myocardial fibrofatty replacement and ventricular arrhythmias.
Case suggests possible progression to arrhythmogenic cardiomyopathy in female LAMP2 carriers; extends Danon disease phenotype but remains hypothesis-generating.
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.
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Olivetti et al. (2026) conducted a case report in Danon Disease / Arrhythmogenic Cardiomyopathy (n=1). Pathogenic LAMP2 variant (LAMP2:c.928G>A) was evaluated. A patient with a pathogenic LAMP2 variant exhibited a rare phenotypic transition from hypertrophic cardiomyopathy to arrhythmogenic cardiomyopathy, eventually requiring heart transplantation.
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