PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History

Shaima Awadh Hashem; Michalis Georgiou; Genevieve Wright; Yu Fujinami-Yokokawa; Yannik Laich; Malena Daich Varela; Thales A C de Guimaraes; Omar A Mahroo; Andrew R Webster; Kaoru Fujinami; Michel Michaelides

doi:10.1016/j.oret.2024.08.018

PDE6A-Associated Retinitis Pigmentosa, Clinical Characteristics, Genetics, and Natural History

Ophthalmol Retina. 2024 Aug 31:S2468-6530(24)00405-6. doi: 10.1016/j.oret.2024.08.018. Online ahead of print.

Affiliations

¹ Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
² Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
³ UCL Institute of Ophthalmology, University College London, London, United Kingdom; Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan; Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan.
⁴ Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Eye Center, Faculty of Medicine, University Freiburg, Freiburg im Breisgau, Germany.
⁵ Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Section of Ophthalmology, King's College London, London, United Kingdom; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; Eye Department, St Thomas' Hospital, London, United Kingdom; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
⁶ Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan.
⁷ Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom. Electronic address: michel.michaelides@ucl.ac.uk.

PMID: 39218074
DOI: 10.1016/j.oret.2024.08.018

Abstract

Purpose: To analyze the genetics, clinical characteristics, and natural history of PDE6A-associated retinitis pigmentosa.

Design: Retrospective, longitudinal, observational cohort study.

Participants: Patients with molecularly confirmed PDE6A-associated retinal dystrophy in a single tertiary referral center.

Methods: Review of medical records and retinal imaging, including fundus autofluorescence (FAF) imaging and spectral-domain OCT. Genetic results were reviewed, and the detected variants were assessed.

Main outcome measures: Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis.

Results: Sixteen patients (32 eyes) were identified and evaluated longitudinally. Genetic analysis identified 14 variants in the PDE6A gene, including 8 novel variants. The mean age (± standard deviation, range) was 34.8 years (± 17.4, 12-76) at baseline, with a mean follow-up time of 4.8 years. Best-corrected visual acuity was 0.45 ± 0.45 logarithm of the minimum angle of resolution (logMAR) (range 0.0-1.6) at baseline and 0.65 ± 0.7 logMAR (range 0.0-2.3) at the last visit. Best-corrected visual acuity was similar among eyes in 88% of patients. A hyperautofluorescent ring was observed on FAF in 50% and 43.8% of the eyes at baseline and follow-up visit, respectively, with a mean area of 9.7 ± 4.5 mm² at baseline and mean of 8.6 ± 4.8 mm² at the follow-up visit. Mean horizontal ellipsoid zone width (EZW) at baseline was 1765 ± 1093 μm, which decreased to 1580 ± 1077 μm at follow-up. Eighteen eyes exhibited cystoid macular edema at baseline (56%), and 17 eyes (53%) at follow-up. There were statistically significant changes during the follow-up period in terms of BCVA, hyperautofluorescent ring area, and the EZW.

Conclusions: This study highlights the natural history of PDE6A-retinopathy. Most patients in this cohort had mild BCVA loss, and slowly progressive disease, based on FAF and OCT measurements.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Gene therapy; Natural history; PDE6A; Retinal dystrophy; Retinitis pigmentosa.