Clinical Trajectories and Cardiac Phenotypes in Danon Disease.

Danon disease is a rare X-linked lysosomal cardioskeletal myopathy caused by loss-of-function variants in LAMP2, which impair autophagosome-lysosome fusion and lead to accumulation of autophagic vacuoles in cardiomyocytes. Although cardiac penetrance is high in both sexes, the natural history differs markedly by sex. Males typically present in childhood or adolescence with hypertrophic cardiomyopathy, skeletal myopathy, and intellectual disability, and often progress to heart failure or ventricular arrhythmias by early adulthood. Females typically present later in life with a cardiac-predominant phenotype that more often evolves to dilated cardiomyopathy, although a subset develops an early onset, severe phenotype reminiscent of male hemizygotes. Pooled case data suggest that cumulative rates of death, heart transplantation, or ventricular assist device implantation are similar between sexes but occur approximately 2 decades later in females, indicating that women may be delayed rather than spared. Ventricular preexcitation, mediated by fasciculoventricular or extranodal accessory pathways, and a characteristic cardiac magnetic resonance pattern of late gadolinium enhancement with mid-basal septal sparing can support the diagnosis, although septal sparing is less frequent in females. Heart transplantation remains the established treatment, and a phase 1 trial of AAV9-LAMP2B gene therapy has provided early proof-of-concept in males.