Multimodal Imaging And Asymmetry Of Disease Progression In Rhodopsin-Associated Autosomal Dominant Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited retinal degenerative diseases with no known cure to date. The recent gene therapy treatment for Leber’s congenital amaurosis and RP caused by mutations in RPE65 have resulted in dramatic improvements in vision, leading to excitement for other potential gene therapies on the horizon. Upcoming clinical trials will be targeting patients with specific mutations, and measurements of disease progression will be needed for each genetic subtype of RP in order to determine whether treatments are successful. In this retrospective cohort study, we examined 27 RP patients with confirmed autosomal dominant mutations in the rhodopsin gene by monitoring rates of progression as measured structurally with ellipsoid zone (EZ) line width on spectral domain optical coherence tomography (SD-OCT), horizontal and vertical hyperautofluorescent ring diameters on short wavelength fundus autofluorescence (SW-FAF), and as measured functionally with 30 Hz flicker amplitudes on electroretinography (ERG). Each structural parameter was measured twice by the author four weeks apart. The mean rates of progression were -158.5 μm per year (-8.4%) for EZ line widths, -122.7 μm per year (-3.5%) for horizontal diameters, and -108.3 μm per year (-3.9%) for vertical diameters. High test-retest reliability was observed for the parameters (EZ line intraclass coefficient [ICC] = 0.9989, horizontal diameter ICC = 0.9889, vertical diameter ICC = 0.9771). The three parameters were also correlated with each other (r = 0.9325 for EZ line and horizontal diameter; r = 0.9081 for EZ line and vertical diameter; r = 0.9630 for horizontal and vertical diameters). No significant changes in ERG amplitude were seen. The subjects were classified by rhodopsin mutation class (I, IIa, IIb, III) and morphology of the hyperautofluorescent ring (typical vs. atypical). No significant differences in rates of structural progression were observed by rhodopsin mutation class or by ring morphology. Finally, higher rates of asymmetry of progression between the left and right eyes were detected for EZ line width (23% of subjects), horizontal diameter (17%), and vertical diameter (25%), as compared to studies on other forms of RP. Acknowledgments I would like to thank my mentors and thesis advisors Dr. Stephen Tsang and Dr. Ron Adelman for their mentorship and guidance with this project and my path through medicine and ophthalmology. I would also like to thank members of the Tsang lab for their invaluable assistance, including Dr. Ronaldo Carvalho for his help with planning the experimental design and Jimmy Duong for his much-needed statistical wizardry and patience with my incompetence. Furthermore, I also thank Dr. Ching-Hwa Sung from Weill Cornell Medicine for her expertise in biochemical characterization of rhodopsin mutations. I would like to express my gratitude to Dr. Ninani Kombo for her efforts in helping me with the revision process. I also want to show my deepest appreciation to the Yale Department of Ophthalmology and Visual Science, especially to Deana Ralston for her incredible guidance with finalizing the thesis. I thank my wonderful friends, classmates, mentors, and family for their unending support for as long as I can remember. Finally, I want to thank my fiancée and life partner Yue Meng for her unconditional love and guidance at every step of my life these past seven years.