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

PURPOSE. The purpose of this study was to analyze the clinical spectrum and natural history of CDH23-associated Usher syndrome type ID (USH1D). METHODS. Molecularly-confirmed individuals had data extracted from medical records. Retinal imaging was extracted from an in-house database. The main outcome measurements were retinal imaging and electroretinography (ERG) and clinical findings, including age of onset, symptoms, best-corrected visual acuity (BCVA), outer nuclear layer (ONL) thickness, ellipsoid zone width (EZW), and hyperautofluorescent ring area. RESULTS. Thirty-one patients were identified, harboring 40 variants in CDH23 (10 being novel). The mean (range, +/- SD) age of symptom onset was 10.1 years (range = 1-18, SD = +/- 4.1). The most common visual symptoms at presentation were nyctalopia (93.5%) and peripheral vision difficulties (61.3%). The mean BCVA at baseline was 0.25 +/- 0.22 in the right eyes and 0.35 +/- 0.58 LogMAR in the left eyes. The mean annual loss rate in BCVA was 0.018 LogMAR/year over a mean follow-up of 9.5 years. Individuals harboring the c.5237G>A > A p.(Arg1746Gln) allele had retinitis pigmentosa (RP) sparing the superior retina. Seventy-seven percent of patients had hyperautofluorescent rings in fundus autofluorescence. Full-field and pattern ERGs indicated moderate-severe rod-cone or photoreceptor dysfunction with relative sparing of macular function in most patients tested. Optical coherence tomography (OCT) revealed intraretinal cysts in the transfoveal B-scan of 13 individuals (43.3%). The rate of EZW and ONL thickness loss was mild and suggestive of a wide window of macular preservation. CONCLUSIONS. Despite the early onset of symptoms, USH1D has a slowly progressive phenotype. There is high interocular symmetry across all parameters, making it an attractive target for novel therapies.