The Natural History of Danon Disease: Lesson Learned from a Global Registry

Abstract

Introduction Danon Disease (DD) is a rare X-linked autophagic vacuolar myopathy due to LAMP-2 mutation. DD is characterized by high penetrance, severe predominantly hypertrophic cardiomyopathy, cognitive and skeletal muscle as well as vision impairment. Due to its rarity, the natural history (NH) is still uncertain and delay in diagnosis is common. Methods Individuals and families from the United Kingdom, Australia, and North America completed a survey about symptoms and medical history and shared their medical records with the research team. Results A total of 46 patients (18 families, 43.5% males) with positive genetic testing for DD were included. The majority of patients were Caucasian (93.5%) and from the United States (80.4%). Among the 46 mutations, 23 were described as “pathogenic,” 10 as “likely pathogenic,” 3 as “variant of uncertain significance” and unknown in 10 cases. De novo mutations occurred in 30% of cases. Cardiomyopathy occurred in 85% of patients (19/26 females, 20/20 males) at a median age of 7.3 years for males and 19.4 years for females (p=0.001). Females presented with either hypertrophic cardiomyopathy (HCM, 69%) or dilated cardiomyopathy (DCM, 2.2%) whereas males presented with HCM 100% of the time. Left ventricular outflow tract (LVOT) obstruction was reported in 4.3% of patients. 34.2% of patients were diagnosed with Wolff-Parkinson-White syndrome. Twelve patients (7 females, 5 males) underwent cardiac magnetic resonance (CMR) Out of the 9 cases in whom contrast was used, 8 (89%) exhibited extensive patchy late gadolinium-enhancement (LGE) in multiple segments of the left ventricle; 3 cases also had right ventricular LGE. The median cardiac mass index was 155 g/m2 (Q1-Q3: 70-237; v.n. 31-79 g/m2). Cognitive impairment, mainly described as learning disabilities, was assessed in 90% of males (18/20) and 73.1% (19/26) of females. Symptomatic skeletal myopathy was present in 28 (60.1%) of patients, with a higher prevalence in males (85% vs 45.8%; p Conclusions DD causes significant cardiac morbidity with the need for Htx at a young age in both sexes. While in males DD is more frequently multisystemic with a more rapid clinical deterioration, females may present with isolated cardiac disease. These findings increase understanding of the natural history of DD and highlight the importance of a timely diagnosis regardless of sex.