LAUSR

Oguchi disease is a rare autosomal recessive, non-progressive retinal disorder, first described in the Japanese population. It refers to cases of congenital stationary night blindness (CSNB) in which patients have a characteristic golden-yellow fundus reflex which returns to its normal appearance after long dark adaptation. This particular finding, known as the MizuoNakamura phenomenon, is characteristic but not exclusively of Oguchi disease. In fact, it has been reported in X-linked cone-rod dystrophy and X-linked retinoschisis. Two genes are known causing Oguchi disease: arrestin gene (s-antigen; SAG) and rhodopsin kinase gene (g protein-coupled receptor kinase 1; GRK1), both are involved in rod phototransduction; however, the pathogenesis has not been elucidated. In this report, we identified a novel GRK1 mutation; in particular, this is the first report of GRK1 gene mutation in an Italian patient with Oguchi disease. In November 2014, a 28year-old female was referred to our hospital for a suspected retinal dystrophy. Her parents were consanguineous and family history was positive for inherited retinal disease: a cousin was affected with retinitis pigmentosa (RP). She complained night blindness since her childhood without other ophthalmological symptoms. At presentation, visual acuity was 20/20 in both eyes, no refractive errors were present, anterior segment and intraocular pressure were unremarkable. Fundus appearance showed characteristic golden-yellow reflex throughout the posterior pole to mid-peripheral retina and the Mizuo-Nakamura phenomenon in both eyes, in which the distinctive color of the fundus changed to normal after prolonged dark adaptation (3 hours; Figure 1). Neither vascular attenuation nor degenerative change was seen throughout the retina. Goldmann visual field was within normal limits in each eye. Optical coherece tomography (OCT) was normal in the right eye, and in the left eye it was normal except for the presence of a small subretinal drusenoid-like deposit at the posterior pole, inside the vascular arcades (Figure 1). If we consider peripheral OCT scan, where golden-yellow reflex was present, the OCT image showed a hyper-reflective alteration in correspondence of photoreceptor outer segments. After patching application (prolonged dark adaptation), in the absence of the characteristic reflex, OCT showed a normal outer retinal layer OCT segmentation in the same scan. Full-field standard electroretinogram (ERG) examination demonstrated an estinguished scotopic response, a reduction in both a-wave and b-wave amplitudes in the standard combined ERG with a predominant reduction in b-waves (“negative” configuration) and almost normal photopic amplitudes. When full-field standard ERG was repeated after patching, it was possible to record a scotopic response. Finally, fundus autofluoresence (FAF) was substantially normal in both eyes, in the left eye there was a small hyper-fluorescent dot corresponding to the small subretinal drusenoid-like deposit. Next-generation sequencing genetic screening was performed using the Illumina platform (NextSeqTM500), and a novel mutation in GRK1 gene was reported: c.470T>C (p.Leu157Pro). Sanger method was performed to validate this rare variant sequence. Our reported mutation was probably pathogenetic; in fact, it resulted in an amino acid change from leucine to proline at position 157, which was demonstrated to be in a phylogenetically conserved region (regulatory region of G protein signaling domain) by amino acid alignment analysis. Furthermore, two of the most popular bioinformatics tools [Sorting Intolerant from Tolerant (SIFT, Singapore) and Polymorphism Phenotyping version 2 (Polyphen-2, Boston, MA)], which are used to predict whether the amino acid substitution identified in the our study affected protein function, confirmed this change to be damaging. Further analysis is required in healthy populations to confirm pathogenicity. Mutations in GRK1 are mainly associated with Oguchi disease, although the association of GRK1 mutations with RP has been described. In patient family, a RP-affected relative was reported. Unfortunately, we did not visit him, so we are not sure of the RP diagnosis. However, there is evidence that Oguchi disease and RP can coexist in the same family or even in the same individual, and RP clinical findings even may mask Oguchi ophthalmic signs; furthermore, Oguchi patients can develop RP advanced stage. We have to consider that if there is significant retinal pigment epithelium (RPE) and rod degeneration, the characteristic reflex may be not seeable. Finally, the presence of single subretinal drusenoid-like deposit at the posterior pole of the left eye may represent an isolated finding as reported sometimes in young healthy subjects, or due to underlying retinal dystrophy. In fact, in many inherited conditions, it is easy to recognize different drusenoid deposits