Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene

Abstract

Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the lifethreatening condition of Danon disease.

Review: Danon disease: Review of natural history and recent advances

“…Other central neurological symptoms, such as generalized seizures, autism, psychosis, suicidal ideation and depression were rarely reported . Brain PET and MRI imaging showed either decreased glucose metabolism in the cortex (possibly underlying cognitive involvement ) or involvement of the central nervous system .…”

“…Peripheral pigmentary retinal dystrophy (with subsequent thinning of the photoreceptor layers), maculopathy, choriocapillary atrophy and serious colour vision disturbances were found in 60–70% of patients . Since LAMP2 is only expressed in the retinal pigmented epithelium (where it is thought to play an important role in autophagosome formation ), LAMP‐2 deficiency is likely to cause the loss of photoreceptors.…”

“…Complete LAMP‐2 deficiency was demonstrated in explanted heart and in endomyocardial biopsies either by immunoblot or immunohistochemistry , suggesting that the latter should be performed on every endomyocardial biopsy. Muscle immunoblot analysis showed either trace amounts of normal‐sized LAMP‐2 in patients with null, splicing or exon 9b mutations or no significant protein reduction .…”

Pigmentary retinopathy can indicate the presence of pathogenic LAMP2 variants even in somatic mosaic carriers with no additional signs of Danon disease

“…Although a number of individual case reports demonstrate impaired vision in patients with DD, detailed ocular findings have been, to the best of our knowledge, reported in less than 20 patients, and of these only 10 underwent imaging with spectral‐domain optical coherence tomography (SD‐OCT) and 7 had fundus autofluorescence imaging (Prall et al 2006; Schorderet et al 2007; Thiadens et al 2012; Mack 2014; Thompson et al 2016; Fukushima et al 2020; Majer et al 2019; Meinert et al 2019).…”

“…A growing number of reports suggest that females, who are somatic (and possibly also germinal) mosaics for LAMP2 variants represent a specific and under‐detected patient/carrier group. Some of these carrier females have been reported to express the phenotype (Meinert et al 2019) but others remain free of clinical DD symptoms (Chen et al 2012; Majer et al 2014).…”