Clinical characteristics and outcomes of danon disease in women: a single center experience
C Nouraee, W H Swain, J N Johnson, D B Newman, S R Ommen, J B Geske, J M Bos, M J Ackerman, J R GiudicessiAbstract
Background
Danon disease is a rare, X-linked dominant disorder of autophagy caused by pathogenic/likely pathogenic (P/LP) loss-of-function variants in LAMP2-encoded lysosome-associated membrane protein-2. Classically, Danon disease results in severe cardiac hypertrophy, skeletal myopathy, and neurocognitive deficits due to the abnormal accumulation of vacuoles containing glycogen and other cellular components. In women, clinical expression is highly variable, likely due to X-linked dominant inheritance and differential X-inactivation, making diagnosis challenging.
Purpose
To describe the presentation, clinical course, and outcomes of women with P/LP variants in LAMP2 evaluated at a single tertiary center.
Methods
In this single center observational study, retrospective review of 2,184 genotype-positive cardiomyopathy patients evaluated between 01/2007-12/2025 was used to identify all patients with a P/LP variant in LAMP2. The clinical characteristics and outcomes of female patients with P/LP variants in LAMP2 were extracted.
Results
Overall, 13/2,184 (0.6%) genotype-positive cardiomyopathy patients possessed a P/LP variant in LAMP2. Of these, 10/13 (77%) were female (median age at diagnosis of 17 [IQR 11-28] years; median ejection fraction 60% (IQR 53-65); median maximum wall thickness 15 mm (IQR 12-17); and 4 (40%) with Wolff-Parkinson-White syndrome). Disease penetrance from a cardiomyopathy perspective was high (9/10; 90%) with 6/10 (60%) presenting with a non-obstructive hypertrophic cardiomyopathy (HCM) phenotype and 3/10 (30%) presenting with a non-HCM phenotype (2 with non-dilated left ventricular cardiomyopathy [NDLVC] and 1 with dilated cardiomyopathy [DCM]). The remaining patient was 13 years old at the time of her most recent evaluation and genotype-positive, but phenotype-negative. Whereas most women with clinically manifest Danon disease caused by a P/LP in-frame deletion or missense LAMP2 variant had an HCM phenotype (4/4; 100%), those with truncating variants (frameshift, splice-site, etc.) had more variable cardiomyopathy phenotypes (2 with HCM; 2 with NDLVC; and 1 with DCM). Interestingly, all patients with splice-site variants presented with a non-HCM phenotype (1 with NDLVC and 1 with DCM). One patient (10%) suffered cardiac arrest and 4 (40%) underwent heart transplantation (median age 28 [IQR 25-32]). No mortality was observed.
Conclusion
In females, LAMP2 P/LP variants demonstrate high penetrance and phenotypic pleiotropy. In addition to differential X-inactivation, variant type may influence clinical phenotype as NDLVC and DCM were more frequent in those with splice-site variants. With 40% of the cohort requiring heart transplantation at a young age, this is a patient population with unmet need. As potential disease-modifying gene therapies emerge for males with Danon disease, further studies are needed to better understand the clinical presentation(s) and course of females with Danon disease.