CDH23-Associated Usher Syndrome: Clinical Features, Retinal Imaging and Natural History

Abstract

Purpose : Biallelic pathogenic variants in CDH23 can cause Usher syndrome type I D (USH1D). There is a lack of longitudinal, robust characterisation of the phenotype in the literature. Herein, we analyse the clinical spectrum and natural history of CDH23-associated USH1D.

Methods : This was a single-center (Moorfields Eye Hospital, London, UK), retrospective observational study in participants with molecularly-confirmed USH1D. Data was extracted from electronic medical records and in-house imaging databases. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) were both obtained with the Spectralis Spectral Domain OCT (Heidelberg Engineering Inc., Heidelberg, Germany). Main outcome measurements were clinical history, best-corrected visual acuity (BCVA), refraction, outer nuclear layer (ONL) thickness and ellipsoid zone width (EZW).

Results : Thirty-one individuals from 29 families were identified with 40 pathogenic variants in CDH23, 10 being novel. The mean (range; ±SD) age of vision-related symptom onset was 10.1 years (1-18; ±4.1). The most common symptoms at presentation were nyctalopia (93.5%) and difficulties with peripheral vision (61.3%). The mean BCVA (range; ±SD) at baseline was 0.25 LogMAR (0 – 0.77; ±0.22) in right and 0.35 LogMAR (-0.1 – 3[AK1] ; ±0.58) in left eyes, which was highly correlated (r= 0.94; p<0.0001; Spearman correlation). The mean annual loss in BCVA was 0.018 LogMAR/year over a mean follow-up of 9.5 years. Three individuals harbouring the c.5237G>A p.(Arg1746Gln) allele had a superior retinal sparing akin to the sectoral retinitis pigmentosa (RP) phenotype (Fig. 1). Refractive errors were mild, the commonest being myopic astigmatism. Hyperautofluorescent rings were typical on FAF imaging and present in 77% of patients, five of whom had double rings. OCT revealed intraretinal cystic spaces in the horizontal transfoveal B-scan of thirteen individuals (43.3%) at some point during follow-up. There was a significantly high interocular correlation of both EZW (r=0.99; p<0.0001) and ONL thickness (r=0.89; p<0.0001) at baseline. The rate of EZW and ONL thickness loss was slow and suggestive of a wide window of preservation up to 50 years (Fig. 2).

Conclusions : Despite the early onset of visual symptoms, USH1D has a slowly progressive retinal phenotype. There is high interocular symmetry across all parameters analysed herein, making it an attractive target for novel therapies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.