Abstract
Purpose :
Danon Disease is a rare X-linked dominant disorder caused by variants in the LAMP2 gene, which predominantly affects the heart, muscles and brain. It can cause retinal degeneration, but this is poorly characterised. Here we describe a late presentation of mild retinal phenotype, initially diagnosed as choroideremia carrier phenotype, associated with a novel variant in the LAMP2 gene.
Methods :
Retrospective analysis included medical history, ophthalmic examination and retinal imaging (fundus autofluorescence(FAF), optical coherence tomography (OCT) and fundus photography). Microperimetry was performed to measure central retinal sensitivity. Molecular genetic testing was conducted using next generation sequencing (NGS), followed by whole genome sequencing (WGS) and targeted analysis of LAMP2. Literature review of reported LAMP2 pathogenic variants was undertaken.
Results :
In a non-consanguineous family, the 54-year-old proband presented with worsening night vision. No significant ocular family history was reported. VA was 6/6 (20/20) in both eyes. Fundus examination showed bilateral light peripheral pigmentary changes. FAF demonstrated widespread speckled pattern and OCT revealed hyperreflective spots in the outer nuclear layer. Differentials included non-genetic (rubella retinitis,drug toxicity) and genetic (choroideremia carrier) causes. Initial NGS testing did not detect a pathogenic variant. Further exploration of the retinal phenotype (microperimetry showed mild reduction in retinal sensitivity) and systems review revealed that the patient had a heart transplant for dilated cardiomyopathy in her 20s. Due to a potential link to Danon Disease, WGS testing, with targeted sequencing of LAMP2, was initiated after cardiology input. This identified a novel heterozygous variant (c.925del,p.Ser309fs) in LAMP2, confirming the diagnosis of X-linked Danon Disease.
Conclusions :
Our study reinforces the importance of recording previous medical history in patients healthy at time of presentation. Despite childhood-onset cardiomyopathy with heart transplant in early adulthood, the unifying diagnosis of Danon disease was only confirmed after ophthalmic input at 54. The similarity of choroideremia carrier and Danon Disease retinal phenotypes suggests a possible common pathway in lysosomal trafficking of these two genes where pathogenic variants impair phagocytosis and cause retinal pigment epithelium degeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.