Two cases with Fundus albipunctatus due to mutations in RPE65 gene

Purpose : Mutations in RPE65 have been primarily associated with Leber Congenital Amaurosis (LCA) and Early Onset Retinitis Pigmentosa (EORP). To extend the phenotypic spectrum associated with genetic defects in this gene, we report two cases of Fundus albipunctatus, a type of Congenital Stationary Night Blindness (CSNB), that harbor biallelic pathogenic variants in RPE65. Methods : Two unrelated Caucasian pediatric patients, born to non-consanguineous parents, underwent a complete ophthalmological assessment. Detailed physical examinations were performed to exclude systemic disease. Genetic analysis was performed by targeted Next Generation Sequencing (clinical exome). Results : An 11-year-old girl presented with night blindness from early childhood and a 15-year-old girl reported night blindness and narrowing of visual field from childhood. Both patients displayed the same clinical findings. Best corrected visual acuity was 20/20 in both eyes. Fundus examination revealed numerous white-yellow dots scattered in the mid periphery of the retina. OCT examination showed normal retinal structure, thickness and photoreceptor layer. Fundus autofluorescence displayed normal autofluorescence at the posterior pole with focal areas of hypoautofluorescence at the middle retinal periphery. Goldmann visual field showed mild reduction of visual field. Full field electroretinography (ERG) showed scotopic responses below the noise level and normal photopic responses with electronegative ERG findings. Genetic analysis identified, in the first patient, the younger one, two missense likely pathogenic variants (p.Arg347His, p.Tyr368His) in RPE65. Segregation analysis in the unaffected parents confirmed their presence in trans. While, in the other patient biallelic pathogenic variants (p.Glu254Asp, p.Leu328Phe) were identified in RPE65. Conclusions : Our study extends the phenotypic spectrum of the retinal dystrophies associated with biallelic variants in RPE65 ranging from LCA to CNSB. The findings indicate that patients harboring mutations in RPE65 gene can present different phenotypes and a careful clinical evaluation is indispensable for the selection/prioritisation of patients that can benefit from available therapeutic options