CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

Xuan Thanh An Nguyen, Mays Talib, Mary J. van Schooneveld, Jan Wijnholds, Maria M. van Genderen, Nicoline E. Schalij-Delfos, Caroline C.W. Klaver, Herman E. Talsma, Marta Fiocco, Ralph J. Florijn, Jacoline B. ten Brink, Frans P.M. Cremers, Magda A. Meester-Smoor, L. Ingeborgh van den Born, Carel B. Hoyng, Alberta A.H.J. Thiadens, Arthur A. Bergen, Camiel J.F. Boon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.

Original languageEnglish
Pages (from-to)37-48
Number of pages12
JournalAmerican Journal of Ophthalmology
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding/Support: This research was supported by Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Landelijke Stichting voor Blinden en Slechtzienden (LSBS), and the Oogfonds, which contributed through UitZicht (Delft, the Netherlands), as well as the Curing Retinal Blindness Foundation, Stichting Blindenhulp, Bontius Stichting, and Retina Fonds. These funding organizations had no role in the design or conduct of this research. Financial Disclosures: Leiden University Medical Center is the holder of patent application PCT/NL2014/050549, which describes the potential clinical use of CRB2. Jan Wijnholds is listed as inventor on this patent and is an employee of Leiden University Medical Center. The other authors indicate no financial support or conflicts of interest. All authors attest that they meet the current ICMJE criteria for authorship. Acknowledgments:: L. Ingeborgh van den Born, Carel B. Hoyng, and Camiel J.F. Boon are members of the European Reference Network for Rare Eye diseases (ERN-EYE).

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