Abstract
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. Single-center, prospective case series. 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. 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. 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.
Highlights
A wide range of related retinal dystrophies (RDs), including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and cone(-rod) dystrophies, can be caused by variants in the Crumbs homologue 1 (CRB1) gene.[1,2,3,4] LCA is considered the most severe retinal dystrophy, presenting at birth or early infancy, and is characterized by severe visual impairment, nystagmus, poor pupillary responses, and absent responses on electroretinography.[4]
In this prospective natural history study, we evaluated the functional and structural changes in patients with biallelic CRB1 variants causing a spectrum of retinal dystrophies, as we anticipate the start of gene therapeutic trials for CRB1-associated RDs in the near future
Our two-year analysis of the cohort showed that visual acuity and visual fields did not significantly change during follow-up
Summary
A wide range of related retinal dystrophies (RDs), including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and cone(-rod) dystrophies, can be caused by variants in the CRB1 gene.[1,2,3,4] LCA is considered the most severe retinal dystrophy, presenting at birth or early infancy, and is characterized by severe visual impairment, nystagmus, poor pupillary responses, and absent responses on electroretinography.[4] RP is characterized by primary degeneration of rod photoreceptors, with secondary cone degeneration. Initial symptoms in RP typically include night blindness due to degeneration of the rods, followed by concentric visual field loss, and eventually central vision loss later in life due to cone dysfunction.[5] RP comprises a broad spectrum of phenotypic presentations, and can become symptomatic at different ages, ranging from early childhood (i.e. juvenile RP) to middle age, caused by a broad spectrum of genes.[6]. Other clinical features described in CRB1-associated RDs include hyperopia, optic nerve drusen, preservation of para-arteriolar retinal pigment epithelium, cystoid macular edema, nummular pigmentation and Coats-like exudates.[18]
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