Giovanna Napolitano Pereira Ribeiro et al. Layara Fernanda Vicente Pereira Lipari Paula Mendonça Senra Lucas Vieira Lacerda Pires … Marjorie Hayashida Mizuta Natália Quintella Sangiorgi Olivetti Vera Demarchi Aiello José Eduardo Krieger
Abstract
Danon disease (DD) is a rare X-linked disorder caused by pathogenic or likely pathogenic variants in the lysosome-associated membrane protein 2 (LAMP2) gene. It primarily manifests as hypertrophic cardiomyopathy, myopathy, intellectual disability, and retinopathy, with males typically experiencing a more severe and early-onset phenotype. The pathophysiology of DD is linked to defective autophagy due to LAMP2 deficiency, leading to the accumulation of glycogen-filled vacuoles within cardiomyocytes and other tissues. This results in progressive cardiac hypertrophy, conduction abnormalities, and eventual heart failure, often necessitating heart transplantation. Skeletal muscle involvement is common in males, while cognitive impairments are observed in both genders, though more prevalent in males. Diagnosis is challenging due to the condition’s rarity and variable presentation, highlighting the need for a multidisciplinary approach, including genetic testing for definitive diagnosis. Genetic testing must be performed only after proper genetic counseling is done. Differential diagnosis must be considered when DD is suspected, depending on the signs and symptoms, such as Fabry disease, PRKAG2, Pompe disease, and others. Management strategies currently focus on symptomatic treatment, with cardiac transplantation as a critical intervention for advanced cases. Emerging therapies, such as gene therapy targeting LAMP2, could help in altering disease progression. This review provides a comprehensive overview of DD, discussing its clinical manifestations, underlying mechanisms, diagnostic challenges, and potential therapeutic approaches in improving outcomes. Our goal is to increase the recognition of DD so that the prevention of possible complications and early diagnosis becomes feasible, ultimately leading to more favorable patient outcomes.