Danon disease: From genetic origins and molecular defects to therapeutic advances.

Abstract

Danon disease (DD) represents a rare and complex X-linked disorder, characterized by hypertrophic cardiomyopathy, skeletal muscle deterioration, and cognitive deficits. At its core, the disease stems from mutations in the LAMP2 (lysosome-associated membrane protein 2) gene, which result in a critical deficiency of LAMP-2, particularly the LAMP-2B isoform. This loss destabilizes normal autophagic clearance, leading to the buildup of dysfunctional autophagic vacuoles that ultimately disrupt cellular homeostasis. Although accurately modeling the full range of DD symptoms remains challenging, patient-specific induced pluripotent stem cells and innovative LAMP-2-deficient animal models have provided valuable insights into the disease's molecular and cellular basis. Recent research points decisively to mitochondrial dysfunction and fragmentation as pivotal contributors to disease progression, shifting our understanding of DD beyond lysosomal defects alone. These mechanistic revelations have inspired new therapeutic directions, with gene therapy emerging as a particularly promising candidate based on encouraging preclinical results and ongoing clinical studies. Moving forward, a deeper integration of molecular insights with therapeutic innovation will be essential to developing effective strategies that address the multifaceted pathology of DD and improve outcomes for affected individuals. In this review, we provide a comprehensive analysis of DD, focusing on its genetic and molecular underpinnings, particularly the role of LAMP-2 deficiency in disrupting autophagy and mitochondrial integrity. We critically evaluate experimental models that have advanced our understanding of DD pathogenesis. Additionally, we discuss emerging therapeutic strategies, with an emphasis on gene therapy and other innovative approaches aimed at restoring cellular homeostasis and mitigating cardiomyopathy and neuromuscular symptoms.