Retina RDH12 Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function Tomas S. Aleman,1,2 Katherine E. Uyhazi,1 Leona W. Serrano,1 Vidyullatha Vasireddy,2 Scott J. Bowman,1 Michael J. Ammar,1 Denise J. Pearson,1 Albert M. Maguire,1,2 and Jean Bennett1,2 1Scheie Eye Institute at the Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania, United States 2Department of Ophthalmology, Center for Advanced Ocular and Retinal Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States Correspondence: Tomas S. Aleman, PURPOSE. To describe the retinal phenotype of pediatric patients with mutations in the retinol Perelman Center for Advanced Med- dehydrogenase 12 (RDH12) gene. icine, University of Pennsylvania, 3400 Civic Center Boulevard, Phila- METHODS. Twenty-one patients from 14 families (ages 2–17 years) with RDH12-associated delphia, PA 19104, USA; inherited retinal degeneration (RDH12-IRD) underwent a complete ophthalmic exam and [email protected]. imaging with spectral domain optical coherence tomography (SD-OCT) and near infrared and TSA and KEU are joint first authors. short-wavelength fundus autofluorescence. Visual field extent was measured with Goldmann kinetic perimetry, visual thresholds with dark-adapted static perimetry or with dark-adapted Submitted: May 29, 2018 chromatic full-field stimulus testing (FST) and transient pupillometry. Accepted: August 29, 2018 RESULTS. Visual acuity ranged from 20/40 to light perception. There was parafoveal Citation: Aleman TS, Uyhazi KE, Ser- rano LW, et al. RDH12 mutations depigmentation or atrophic maculopathies accompanied by midperipheral intraretinal cause a severe retinal degeneration pigment migration. SD-OCT revealed foveal thinning in all patients and detectable but with relatively spared rod function. thinned outer nuclear layer (ONL) at greater eccentricities from the fovea. Photoreceptor Invest Ophthalmol Vis Sci. outer segment (POS) signals were only detectable in small pockets within the central retina. 2018;59:5225–5236. https://doi.org/ Measurable kinetic visual fields were limited to small (<5–108) central islands of vision. 10.1167/iovs.18-24708 Electroretinograms were reported as undetectable or severely reduced in amplitude. FST sensitivities to a 467 nm stimulus were rod-mediated and reduced on average by ~2.5 log units. A thinned central ONL colocalized with severely reduced to nondetectable cone- mediated sensitivities. Pupillometry confirmed the psychophysically measured abnormalities. CONCLUSIONS. RDH12-IRD causes an early-onset, retina-wide disease with particularly severe central retinal abnormalities associated with relatively less severe rod photoreceptor dysfunction, a pattern consistent with an early-onset cone-rod dystrophy. Severely abnormal POS but detectable ONL in the pericentral and peripapillary retina suggest these regions may become targets for gene therapy. Keywords: Leber congenital amaurosis, RDH12, optical coherence tomography, rods, cones, cone-rod dystrophy, photoreceptors eber congenital amaurosis (LCA) and early onset retinal the inner segment against retinaldehyde-induced cytotoxici- L degenerations (EORD) describe a molecularly and clinically ty.10–12 heterogeneous group of inherited retinal degenerations (IRDs) The most frequent retinal phenotype in patients with characterized by severe vision loss recognized during the first RDH12 mutations is an autosomal recessive inherited retinal year of life or early in infancy.1–3 The molecular cause of LCA/ degeneration (IRD) within the spectrum of severity of LCA, EORD has been elucidated in a large proportion of patients and although relatively milder phenotypes have been categorized as there are 25 causative genes identified to date (https://sph.uth. forms of EORD or juvenile-onset retinitis pigmentosa (RP). edu/retnet/disease.htm, available in the public domain).4–7 Rarely, RDH12 can segregate with a milder phenotype in an Mutations in the retinol dehydrogenase 12 gene (RDH12), autosomal dominant fashion.6 Independent of the age at which maps to a locus on chromosome 14 (14q23.3-24.1) presentation of the recessive disease, the phenotypic expres- known as LCA13, accounts for about 4% of all autosomal sion includes a progressive, retina-wide pigmentary retinopathy recessive LCA, a disease that affects about 20% of all children with peripapillary sparing and prominent central changes that that attend schools for the blind.1,4,8,9 The gene encodes a result in early visual acuity (VA) loss.13 protein member of the family of retinol dehydrogenases that RDH12-associated EORDs (RDH12-EORD) or LCA (RDH12- localizes to the photoreceptor inner segment of rods and LCA) do not appear to show the structural functional cones. RDH12 and RDH8 provide most of the reductase dissociation observed in other forms of LCA, particularly LCA activity in the inner and outer segment and reduce all-trans- associated with mutations in RPE65 (RPE65-LCA), a disease retinal released after photoactivation, a step needed for caused by loss-of-function of another visual cycle protein photopigment regeneration.10 More importantly, there is (RPE65) that has successfully been treated with gene therapy.14 evidence that by reducing free all-trans-retinal, RDH12 protects Despite potential differences in disease mechanisms and Copyright 2018 The Authors iovs.arvojournals.org j ISSN: 1552-5783 5225 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 09/27/2021 Retinal Structure and Function in RDH12-LCA IOVS j October 2018 j Vol. 59 j No. 12 j 5226 expression, there is reasonable hope that other genetic forms near infrared reflectance (NIR-REF) and autofluorescence (NIR- of IRD within the spectrum of EORD may be similarly treatable FAF) images were obtained during the acquisition of the OCTs with gene augmentation. To increase our understanding of the with overlapping 308 and/or 558 fields. In a subset of patients retinal structural changes and associated visual dysfunction (n ¼ 5) short-wavelength autofluorescence (SW-FAF) imaging resulting from RDH12 mutations, we studied a relatively large was performed in a similar manner. group of pediatric patients with RDH12-LCA/EORD using psychophysics, measures of the transient pupillary light reflex Pupillometry (TPLR), and multimodal retinal imaging. The ultimate goal was to determine the treatment potential and targets as well as The direct transient pupillary light reflex (TPLR) was elicited eligibility of patients for future gene augmentation clinical trials by full-field, short duration (100 msec), chromatic stimuli, for this condition. delivered using the stimulator of the system used for full field stimulus testing (FST; Espion 3; Diagnosys, Lowell, MA, USA).21 The pupil was illuminated and imaged with a head-mounted METHODS near infrared LED and infrared-sensitive video camera, respec- tively, and the images of the pupil were recorded and Patients processed by an eye-tracker (EyeFrame; Arrington Research, Scottsdale, AZ, USA). A separate program (VoltagePoint; Twenty-one patients, ages 2–17 years, representing 14 families Arrington Research) synchronized both instruments through diagnosed with RDH12-LCA and RDH12-EORD were included a signal input delivered by the software of the stimulator in this prospective, cross-sectional study. Genotyping was system.22 TPLR luminance response functions were recorded undertaken using saliva samples when not already determined. with increasing intensities of scotopically matched blue (peak Informed consent and assent were obtained after explanation 467 nm; from À4.25 to þ4.25 log scot-cd.s.mÀ2) and red (peak of the nature of the study; procedures complied with the 637 nm; À4.25 to þ3.25 log scot-cd.s.mÀ2) lights presented at Declaration of Helsinki and were approved by the institutional 0.5 log unit increments in the dark-adapted (>45 minutes) review board (IRB #808828, 815348). All patients underwent a state.22 The recording window was 4 seconds long. Interstim- comprehensive eye examination. Fixation pattern and tracking ulus intervals were long enough to allow the pupil to return to was documented in the youngest patient (Patient 1, P1); the its baseline diameter and varied from ~15 seconds at lower rest of the patients had VAs measured with Snellen visual acuity intensities to ~30 seconds at the higher end. In patients, the charts. Testing was done for each eye independently; for starting intensity was arbitrarily selected at ~2 log units above clarity, imaging results illustrated in figures correspond to the normal dark-adapted TPLR thresholds.22 TPLR amplitudes were eye with better acuity or favored by the patient. measured as the difference in horizontal pupil diameter between baseline and a fixed 0.6-second time after stimulus Retinal Imaging presentation; TPLR thresholds were defined as pupil contrac- tion amplitudes reaching a 0.3 mm criterion response as Imaging was performed with spectral domain optical coher- defined previously.22 A video clip was recorded by the ence tomography (SD-OCT; Spectralis; Heidelberg Engineering, pupillometer, which was used to perform manual measures Carlsbad, CA, USA) with 9 mm-long horizontal sections in patients with wandering eye movements or large-amplitude crossing the anatomical fovea, extending when possible into nystagmus in which the automated software was unable to the midperipheral retina (n ¼ 14 patients).