PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.

Extraction of image-based biomarkers, such as the presence, visibility, or thickness of a certain layer, from 3-D optical coherence tomography data provides relevant clinical information. We present a method to simultaneously determine the number of visible layers in the outer retina and segment them. The method is based on a model selection approach with special attention given to the balance between the quality of a fit and model complexity. This will ensure that a more complex model is selected only if this is sufficiently supported by the data. The performance of the method was evaluated on healthy and retinitis pigmentosa (RP) affected eyes. In addition, the reproducibility of automatic method and manual annotations was evaluated on healthy eyes. Good agreement between the segmentation performed manually by a medical doctor and results obtained from the automatic segmentation was found. The mean unsigned deviation for all outer retinal layers in healthy and RP affected eyes varied between 2.6 and 4.9 μm. The reproducibility of the automatic method was similar to the reproducibility of the manual segmentation. Overall, the method provides a flexible and accurate solution for determining the visibility and location of outer retinal layers and could be used as an aid for the disease diagnosis and monitoring.