A detailed phenotypic study of "cone dystrophy with supernormal rod ERG"

Abstract

Aims: To characterise the detailed phenotype of ''cone dystrophy with supernormal rod ERG'' in a case series of 10 patients. Methods: 10 affected patients were examined clinically and underwent colour fundus photography, with nine undergoing detailed electrophysiological testing. Five patients were assessed further with fundus autofluorescence (AF) imaging, automated photopic and dark adapted perimetry, and dark adaptometry. Detailed colour vision assessment was performed in six subjects. Blood samples were taken from four patients for DNA extraction and mutation screening of NR2E3 was undertaken. Results: The onset of symptoms was in the first and second decades of life. Subjects presented with reduced central vision and marked photophobia. All individuals were myopic and colour vision testing revealed severely reduced colour discrimination predominantly along the red-green axes; tritan colour vision was relatively well preserved. Nyctalopia is a later feature of the disorder. Funduscopy and AF imaging revealed a range of macular appearances. There was electrophysiological evidence of marked macular dysfunction, reduced and delayed cone responses, and supernormal and delayed rod responses. Photopic and dark adapted perimetry revealed central scotomata with widespread peripheral sensitivity loss. No disease causing sequence variants in NR2E3 were identified. Conclusions: The largest case series to date has been described of the clinical, psychophysical and electrophysiological characteristics of this unusual cone dystrophy with supernormal rod responses. Electrophysiological data were consistent with a post-phototransduction, but pre-inner nuclear layer, site of dysfunction. While the definitive diagnosis can only be made with electrophysiological testing, several characteristics that may increase suspicion of this diagnosis are presented.T he cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of retinal disorders. 1 2 A range of different phenotypes have been described including an unusual cone disorder associated with supernormal and delayed rod ERG b-waves. [3][4][5][6][7][8] This retinal dystrophy was first described by Gouras et al in two siblings with generalised loss of cone vision, clinical evidence of progression, and nyctalopia.3 Cone ERGs were markedly reduced while the rod b-wave was supernormal in amplitude in response to intense flashes, but smaller than normal and delayed over the lower intensity series. Alexander and Fishman reported two similar cases with supernormal rod ERGs without nyctalopia, suggestive of good rod function despite an abnormal scotopic ERG.

Phenotypic Characteristics Including In Vivo Cone Photoreceptor Mosaic inKCNV2-Related “Cone Dystrophy with Supernormal Rod Electroretinogram”

“…[3][4][5][6][7][8]10,36 Nyctalopia and early onset photophobia were common at presentation as previously reported. 2,5,8 Nystagmus was more common in this series as all subjects presented at a young age. Spontaneous improvement in head shaking was observed in two cases; one of them showed simultaneous improvement in nystagmus.…”

“…1 Affected individuals usually present within the first two decades of life with symptoms of diminution of distant vision and photophobia; a history of nyctalopia is present in about 50% of cases. [2][3][4][5] Nystagmus is observed in a subset of cases, but is more common in children. 6 Color vision deficits, myopia, and central scotoma are commonly described.…”

“…6 Color vision deficits, myopia, and central scotoma are commonly described. 2,4,5,7 Fundus findings are usually unremarkable in children, but adults frequently show macular retinal pigment epithelial (RPE) changes or atrophy. [1][2][3][4][5][6][7][8] The nomenclature ''CDSR'' has its origin from the unique full-field electroretinogram (ERG) characteristics found in the disease 1 and is summarized here.…”

Retinal function and PKC alpha expression after focal laser photocoagulation

“…To understand the possible relationship between retinal function and morphological events, we in figure 6 we have compiled temporal data concerning changes in ERG and GFAP/PKC alfa expression. ERG supernormality has not previously been described after laser phoRetinal function after focal laser photocoagulation Page 15 tocoagulation, but the abnormal response has been found in a relatively unusual form of cone dystrophy, and also early in uveitis [18,25,36]. In the experimental situation, a disturbed phototransduction in the form of elevated levels of cyclic GMP by direct injection into outer segments or inhibition of phosphodiesterase (PDE) has been reported to amplify rod b-wave amplitudes substantially [26,31].…”

The Retinal Clock Drives the Expression ofKcnv2, a Channel Essential for Visual Function and Cone Survival

“…12,13 Affected individuals are often myopic and have a normal peripheral retinal appearance and a range of macular abnormalities. Early diagnosis is possible due to the unique electrophysiologic characteristics.…”