A novel frameshift variant in LAMP2 gene mimicking choroideremia carrier retinopathy

• Published in: Ophthalmic genetics 2024-12, Vol.45 (6), p.668-675
• Main Authors: Narayan, Akshay, Taylor, Laura J, Sperring, Sian, Shanks, Morag, Clouston, Penny, MacLaren, Robert E, Cehajic-Kapetanovic, Jasmina
• Format: Article
• Language: English
• Subjects: Choroideremia - diagnosis; Choroideremia - genetics; Diagnosis, Differential; Female; Frameshift Mutation; Glycogen Storage Disease Type IIb - diagnosis; Glycogen Storage Disease Type IIb - genetics; Heterozygote; Humans; Lysosomal-Associated Membrane Protein 2 - genetics; Middle Aged; Retrospective Studies; Tomography, Optical Coherence
• ISSN: 1381-6810; 1744-5094; 1744-5094
• DOI: 10.1080/13816810.2024.2404148

Danon disease is a rare, multisystemic X-linked dominant disorder caused by variants in the gene. It can be associated with retinal degeneration, but this is not well characterized. Here we describe a late presentation of a mild retinal phenotype, initially diagnosed as choroideremia carrier, associated with a novel variant in the gene. Retrospective analysis of the case included medical history, ophthalmic examination, multimodal retinal imaging, and microperimetry. Genetic testing was conducted to establish the molecular diagnosis. A 54-year-old female presented with worsening night vision, without any family history. BCVA was 6/6 bilaterally and fundus examination showed light peripheral pigmentary changes bilaterally. FAF demonstrated a widespread speckled pattern and OCT revealed hyper-reflective spots in the outer nuclear layer. Differentials included non-genetic and genetic causes, suspected of being a manifesting choroideremia carrier. However, initial genetic testing by targeted analysis of retinal disorders did not detect a pathogenic variant. Further systems review revealed that the patient had previously been diagnosed with dilated cardiomyopathy, mini-stroke and partial deafness. Subsequent whole mitochondrial genome sequencing analysis did not detect any pathogenic variants too. Finally, whole exome sequencing with targeted analysis of a panel of hypertrophic cardiomyopathy genes identified a novel pathogenic heterozygous variant (c.925del, p.(Ser309fs)) in the gene, confirming the diagnosis of X-linked Danon disease. Recording previous medical history and extraocular symptoms is crucial. The similarity in choroideremia carrier and Danon disease retinal phenotypes suggests a possible common pathway in these two genes where pathogenic variants lead to retinal pigment epithelium degeneration.