Disruption of the human cone photoreceptor mosaic from a defect in NR2E3 transcription factor function in young adults

Abstract

Background Enhanced S-cone syndrome is an orphan disease caused by mutations in the NR2E3 gene which result in an increased number of S-cones overpopulating the retina. Although the characteristic onset of enhanced S-cone syndrome can be well-documented by current ophthalmic imaging modalities, techniques such as spectral-domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) fail to provide sufficient details regarding the microstructure of photoreceptors in retinal diseases. Adaptive optics (AO) provides a unique opportunity to analyze the effects of genetic mutations on photoreceptors by compensating aberrations of human eyes. Methods Three eyes of three young adults with enhanced Scone syndrome were studied by clinical examination, genetic screening, fundus autofluorescence (FAF) imaging, SD-OCT, and electroretinography (ERG). Cone mosaic imaging was accomplished by an AO-SLO equipped with a dual crystal on silicon spatial light modulator. Qualitative image analyses and genetic findings were investigated in each patient. Results The diagnosis of patients was confirmed by ERG finding. Genetic screening confirmed the presence of two disease-causing mutations in the NR2E3 gene in each study patient, as well as identified a novel mutation (202 A > G, S68G). Fundus photograph, FAF, and SD-OCT found rosette-like lesion within the mid-periphery along the vascular arcades of the retina. In all AO-SLO images of patients, sparse distribution and asymmetric size of cone mosaic pattern were found within central retina. There were regions of dark space between groups of photoreceptors, distinguishable from shadowing and artifacts. Conclusions AO-SLO provided an in-depth window into the retina of live enhanced S-cone syndrome patients beyond the ability of other current imaging modalities. Dark lesions within the central retina in each patient contain structurally dysfunctional cones which account for retinal mosaic disorganization, and may predispose affected areas to other abnormalities such as rosette lesions. AO-SLO can be an efficient diagnostic tool in clinics for examining cellular-level pathologies in various retinal dystrophies.

Electroretinography and optical coherence tomography reveal abnormal post-photoreceptoral activity and altered retinal lamination in patients with enhanced S-cone syndrome

“…Other OCT studies have described cystic changes in the macula as the most common finding in ESCS [8,11,18,31,32]. Disorganized retinal lamination with splitting at the level of the outer retinal layers [18] or normal overall retinal structure within thinner retina have also been described [19]. In the present study, there were cystic changes in only half of the patients; the retina was thicker than normal in three patients, and the retinal lamination in the central regions was in generally preserved, while profound thickening of the ONL was common in all four of these patients.…”

“…In later stages, retinal lamination was coarse, with a thick and bulging appearance of the retina, localized to an annulus encircling the central fovea [17]. Cases with normal overall retinal structure and thinner retina have also been described [19].…”

Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping

“…It is expressed only in the retina and is known to cause several retinal diseases, including enhanced S-cone syndrome (ESCS), ARRP, ADRP, clumped pigmentary retinal degeneration (CPRD), and Goldmann-Favre syndrome (GFS). [55][56][57][58][59] Family MOL0481. The index case of this large consanguineous Arab-Muslim family (Fig.…”

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

“…Optical coherence tomography (OCT) findings are variable and may include a thickened outer nuclear layer (ONL), cystic macular changes, disorganized retinal structure with splitting of the outer retinal layers, ONL rosette formation, or thin retinas with normal structure. 9,14,[18][19][20] Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset myopathy, characterized by early selective involvement of the eyelids and pharyngeal muscles, producing ptosis and dysphagia, followed by proximal limb weakness. 21 Oculopharyngeal muscular dystrophy is caused by an expansion of a trinucleotide repeat, (GCN)10 to (GCN)12-17, within the PABPN1 gene.…”