Cone-rod dystrophy can be a manifestation of Danon disease

Abstract

Background: Danon disease is a neuromuscular disorder with variable expression in the eye. We describe a family with Danon disease and cone-rod dystrophy (CRD).

Methods: Affected males of one family with Danon were invited for an extensive ophthalmologic examination, including color vision testing, fundus photography, Goldmann perimetry, full-field electroretinogram (ERG), and SD-OCT. Previous ophthalmologic data were retrieved from medical charts. The LAMP2 and RPGR gene were analyzed by direct sequencing.

Results: Two siblings had no ocular phenotype. The third sibling and a cousin developed CRD leading to legal blindness. Visual acuity deteriorated progressively over time, color vision was severely disturbed, and ERG showed reduced photopic and scotopic responses. SD-OCT revealed thinning of the photoreceptor and RPE layer. Visual fields demonstrated central scotoma. The causal mutation was p.Gly384Arg in LAMP2; no mutations were found in RPGR.

Conclusions: This is the first description of CRD in Danon disease. The retinal phenotype was a late onset but severe dystrophy characterized by loss of photoreceptors and RPE cells. With this report, we highlight the importance of a comprehensive ophthalmologic examination in the clinical work-up of Danon disease.

Fig. 1

The pedigree, fundus photographs, spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG) and a schematic representation of the localization of the LAMP2 protein in the retinal pigment epithelium (RPE) of the X-linked family with Danon disease and cone-rod dystrophy (CRD). a The pedigree shows two affected siblings with CRD and the mutation p.Gly384Arg in the LAMP2 gene; no mutations in the RPGR gene. Open square: unaffected male; black square: affected males with Danon disease and CRD; half-open square: affected males with Danon disease but without CRD; dashed symbols denote deceased individuals. b Fundus photograph of the left eye of the proband III-1, performed at age 69, showing RPE clumping and atrophy in the macula. The arrow denotes the position of the SD-OCT image, showing thinning of the outer segments and RPE, pigment clumping at the RPE layer and in the photoreceptor cell layer, and window defects due to atrophy of the RPE. c Fundus photograph of the right eye of the affected cousin III-5, performed at age 64, showing RPE atrophy in the macula. The arrow denotes the position of the SD-OCT image, showing a thinner but intact photoreceptor layer and thinning of the RPE cell layer. The SD-OCT cross section is not fully perpendicular. d Fundus photograph of the left eye of the unaffected cousin III-2, performed at age 68, showing a normal macular appearance. e Fundus photograph of the left eye of the unaffected cousin III-4, performed at age 66, showing a normal macular appearance. f Electroretinogram of proband III-1 (69 years) performed with the standard International Society for Clinical Electrophysiology of Vision (ISCEV) protocol. Replications of the responses are shown as thin traces, the average as solid. ERGs of 17 age-related normal subjects (63 ± 5 years) were analyzed in terms of amplitudes and peak latencies of the relevant components, of which the two SD criteria are mentioned below. In the dark-adapted state, the b-onset amplitudes were reduced to 80 μV and 39 μV for right and left eye respectively (normal: ≥105 μV), and the b-latencies were increased to 125 ms and 128 ms for right and left eye respectively (normal: ≤115 ms) (0.001 cd.s/m²). The b-a amplitudes for the 3 cd.s/m² were 190 μV and 162 μV for the right and left eye respectively (normal: ≥172 μV). The a-latencies were 25 ms and 29 ms (normal ≤19 ms), and the b-latencies were 72 ms and 67 ms for the right and left eye respectively (normal: ≤62 ms). Note the reduced rod-specific response is more severely reduced in the left eye. In the light-adapted state, the b-a amplitudes were reduced to 64 μV and 43 μV for right and left eye respectively (normal ≥68 μV), and the b-latencies were increased to 41 ms and 40 ms for right and left eye respectively (normal: ≤34 ms). The diminished cone-specific function was also proven by the mildly reduced amplitudes of the cone-specific response to 30 Hz flicker stimulation (45 μV and 35 μV, for right and left eye respectively (normal ≥37 μV), and increased peak latencies to 37 ms and 38 ms for right and left eye respectively (normal: ≤33 ms). g Schematic drawing showing the presumed localization of the LAMP2 protein in the RPE lysosome, and the accumulation of outer segment remnants in the RPE cell in Danon disease. Abbreviation: OS: outer segments of photoreceptor cells.

Fig. 1

The pedigree, fundus photographs, spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG) and a schematic representation of the localization of the LAMP2 protein in the retinal pigment epithelium (RPE) of the X-linked family with Danon disease and cone-rod dystrophy (CRD). a The pedigree shows two affected siblings with CRD and the mutation p.Gly384Arg in the LAMP2 gene; no mutations in the RPGR gene. Open square: unaffected male; black square: affected males with Danon disease and CRD; half-open square: affected males with Danon disease but without CRD; dashed symbols denote deceased individuals. b Fundus photograph of the left eye of the proband III-1, performed at age 69, showing RPE clumping and atrophy in the macula. The arrow denotes the position of the SD-OCT image, showing thinning of the outer segments and RPE, pigment clumping at the RPE layer and in the photoreceptor cell layer, and window defects due to atrophy of the RPE. c Fundus photograph of the right eye of the affected cousin III-5, performed at age 64, showing RPE atrophy in the macula. The arrow denotes the position of the SD-OCT image, showing a thinner but intact photoreceptor layer and thinning of the RPE cell layer. The SD-OCT cross section is not fully perpendicular. d Fundus photograph of the left eye of the unaffected cousin III-2, performed at age 68, showing a normal macular appearance. e Fundus photograph of the left eye of the unaffected cousin III-4, performed at age 66, showing a normal macular appearance. f Electroretinogram of proband III-1 (69 years) performed with the standard International Society for Clinical Electrophysiology of Vision (ISCEV) protocol. Replications of the responses are shown as thin traces, the average as solid. ERGs of 17 age-related normal subjects (63 ± 5 years) were analyzed in terms of amplitudes and peak latencies of the relevant components, of which the two SD criteria are mentioned below. In the dark-adapted state, the b-onset amplitudes were reduced to 80 μV and 39 μV for right and left eye respectively (normal: ≥105 μV), and the b-latencies were increased to 125 ms and 128 ms for right and left eye respectively (normal: ≤115 ms) (0.001 cd.s/m²). The b-a amplitudes for the 3 cd.s/m² were 190 μV and 162 μV for the right and left eye respectively (normal: ≥172 μV). The a-latencies were 25 ms and 29 ms (normal ≤19 ms), and the b-latencies were 72 ms and 67 ms for the right and left eye respectively (normal: ≤62 ms). Note the reduced rod-specific response is more severely reduced in the left eye. In the light-adapted state, the b-a amplitudes were reduced to 64 μV and 43 μV for right and left eye respectively (normal ≥68 μV), and the b-latencies were increased to 41 ms and 40 ms for right and left eye respectively (normal: ≤34 ms). The diminished cone-specific function was also proven by the mildly reduced amplitudes of the cone-specific response to 30 Hz flicker stimulation (45 μV and 35 μV, for right and left eye respectively (normal ≥37 μV), and increased peak latencies to 37 ms and 38 ms for right and left eye respectively (normal: ≤33 ms). g Schematic drawing showing the presumed localization of the LAMP2 protein in the RPE lysosome, and the accumulation of outer segment remnants in the RPE cell in Danon disease. Abbreviation: OS: outer segments of photoreceptor cells.