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

Abstract

Purpose Danon disease (DD) is a rare X‐linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD. Methods Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45‐year‐old asymptomatic female somatic mosaic carrier of a LAMP2 disease‐causing variant. Results All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone‐rod involvement overtime. Spectral‐domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full‐field electroretinography was normal. Conclusions Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life‐threatening disease.

Danon Disease: A Model of Photoreceptor Degeneration Secondary to Primary Retinal Pigment Epithelium Disease

“…3 Photoreceptor and RPE abnormalities have been documented clinically and with multimodal imaging with SW-FAF and SD-OCT in DD. 6,[8][9][10][11][12] The pattern of SW-FAF abnormalities described herein is similar to previous descriptions in DD and with the appearance of carriers of X-linked retinal degenerations, such as X-linked retinitis pigmentosa and choroideremia. 16 In this work, we found a disproportionate loss of the NIR-FAF as compared with the SW-FAF signals, not only supportive of the RPE as the primary site of the disease but also consistent with a primary defect directly or indirectly affecting RPE melanization, and thus reduced NIR-FAF signals that perhaps precedes RPE cell loss and the expected loss of SW-FAF signals.…”

“…As in previous reports, the cross-sectional abnormalities were most severe within the central retina. 6,8–12 The most severely affected DD patient in our small cohort showed a pattern reminiscent of the earliest abnormalities in CHM, a disease model or primary RPE or parallel RPE and photoreceptor degeneration in which abnormalities at the level of the photoreceptor outer segment and apical RPE interface are associated with locally severe rod photoreceptor dysfunction. 14,17 Further characterizations of the retinal disease in DD using similar methodology will help determine to what extent the abnormalities reported herein occur in DD and if the pattern of structural and functional changes are indeed specific of a primary RPE disease with secondary photoreceptor loss.…”

“…1 The reported disease predominantly involves the central retina, particularly the parafovea, causing a bull's eye pattern that usually spares the fovea and visual acuities. 2,[4][5][6][7][8][9][10][11][12][13] There are associated mild peripheral pigmentary changes that can elude detection in minimally symptomatic patients. 2,7 However, abnormalities in both rodmediated and cone-mediated responses are clearly detectable with ERGs.…”

“…1 Despite the reported high frequency of associated ophthalmic abnormalities, the focus, understandably, has been on the serious cardiovascular manifestations with only a few case reports in existence detailing the ocular phenotype. 2,4–13 Overall, the reported pattern is of a peripheral pigmentary retinopathy with central, sometimes asymmetric, involvement. 7 With the goal of gaining a better understanding of the pathophysiology of this disease, we studied the retinal phenotype of three patients from two unrelated families carrying mutations in LAMP2 .…”

Case series: Fundus autofluorescence abnormalities in a family of ocular albinism carriers

“…Danon disease is a rare x-linked disorder characterized by cardiomyopathy, skeletal myopathy, and intellectual disability 8 . Ophthalmic manifestations in female carriers of this disease are variable but generally include pigmentary retinal abnormalities with associated rod and cone dysfunction, which are less severe than those in affected male patients 9 . Fundus autofluorescence imaging shows areas of hypoautofluorescence and hyperautofluorescence, which correlate with pigmentary mottling visible on funduscopy.…”