CRB1-Associated Retinal Dystrophies: Genetics, Clinical Characteristics, and Natural History

Abstract

Purpose: To analyze the clinical characteristics, natural history, and genetics of CRB1-associated retinal dystrophies.

Design: Multicenter international retrospective cohort study.

Methods: Review of clinical notes, ophthalmic images, and genetic testing results of 104 patients (91 probands) with disease-causing CRB1 variants. Macular optical coherence tomography (OCT) parameters, visual function, fundus characteristics, and associations between variables were the main outcome measures.

Results: The mean age of the cohort at the first visit was 19.8 ± 16.1 (median 15) years, with a mean follow-up of 9.6 ± 10 years. Based on history, imaging, and clinical examination, 26 individuals were diagnosed with retinitis pigmentosa (RP; 25%), 54 with early-onset severe retinal dystrophy / Leber congenital amaurosis (EOSRD/LCA; 52%), and 24 with macular dystrophy (MD; 23%). Severe visual impairment was most frequent after 40 years of age for patients with RP and after 20 years of age for EOSRD/LCA. Longitudinal analysis revealed a significant difference between baseline and follow-up best-corrected visual acuity in the 3 subcohorts. Macular thickness decreased in most patients with EOSRD/LCA and MD, whereas the majority of patients with RP had increased perifoveal thickness.

Conclusions: A subset of individuals with CRB1 variants present with mild, adult-onset RP. EOSRD/LCA phenotype was significantly associated with null variants, and 167_169 deletion was exclusively present in the MD cohort. The poor OCT lamination may have a degenerative component, as well as being congenital. Disease symmetry and reasonable window for intervention highlight CRB1 retinal dystrophies as a promising target for trials of novel therapeutics.

Keywords: CRB1; Early Onset Severe Retinal Dystrophy; Fundus autofluorescence; Gene therapy; Genotype; LCA; Macular dystrophy; Optical coherence tomography; Phenotype; RP; Retinal dystrophy.

FIGURE 1

Macular optical coherence tomography findings and qualitative classification. A. Group 1, characterized by normal lamination. To the left the image corresponds to a 16-year-old patient with MD and macular cystic spaces, and to the right to a 33-year-old patient from the RP subgroup. B. Group 2, where the retinal layers are still discernible but appear ill-defined. On the left, the image corresponds to a 50-year-old individual with MD, and on the right an 11-year-old girl with LCA and macular cystic spaces. C. Group 3, defined by a disorganized retina with coalescent layers (particularly within the inner retina) and increased reflectivity of the nuclear layers. The images correspond to 2 patients with EOSRD/LCA, at age 27 years to the left and 29 years to the right. EOSRD = early-onset severe retinal dystrophy, LCA = Leber congenital amaurosis, MD = macular dystrophy.

FIGURE 2

Ultrawide-field color and autofluorescence fundus images from individuals with CRB1 retinopathy. A. Thirty-year-old patient with EOSRD/LCA. His parents and pediatrician noticed he had nystagmus as an infant and he had poor vision his entire life. Deep pigmented nummular lesions, as well as yellow/white dots mainly temporal to the macula, are seen. AF is decreased and an optic disc drusen is visible. B. Sixty-one-year-old patient with LCA. More coalescent pigment deposits and profound macular atrophy are seen. In the AF image, preserved para-arteriolar retinal pigment epithelium (PPRPE) is more readily seen. C. Twenty-eight-year-old with RP and retinal telangiectasia that resulted in exudation and vitreous hemorrhages. D. Eighteen-year-old with RP, with few pigment deposits, macular involvement, and PPRPE. E. Seventy-year-old patient with MD. He reported decreased central vision since age 15 years and normal peripheral field. F. Forty-two-year-old with MD. He had failed a vision screening test at age 24 years old, and his vision had been slowly decreasing since. Of note is the characteristic pattern of hypoautofluorescence that involves the macula and all optic disc borders. AF = autofluorescence, EOSRD = early-onset severe retinal dystrophy, LCA = Leber congenital amaurosis, MD = macular dystrophy, PPRPE = preserved para-arteriolar retinal pigment epithelium, RP = retinitis pigmentosa.

FIGURE 3

Graphic representation of statistical analysis undertaken to analyze various structural optical coherence tomography parameters. A. Bar graphs comparing structural measurements in each group to a control group. Significant differences in all groups are seen (marked with *), with the EOSRD/LCA group showing significantly increased inner ring thickness (IRT), outer ring thickness (ORT), inner ring volume (IRV), and outer ring volume (ORV); the RP group with decreased central macular thickness (CMT) and central macular volume (CMV), and increased ORV; and the patients with MD with thinned CMT, IRT, ORT, CMV, and IRV. B. Linear regression representation of the association between age and structural parameters in the RP subcohort, where we see a significant, positive slope regarding volume (IRV), and a negative one when it comes to thickness (ORT). EOSRD = early-onset severe retinal dystrophy, LCA = Leber congenital amaurosis, MD = macular dystrophy, RP = retinitis pigmentosa.

FIGURE 4

Quantification of the full-field ERG and PERG findings. Full-field ERG findings summarized in 29 subjects tested according to the ISCEV standard methods. A. The amplitudes of the DA 10 ERG a-wave, LA 30 Hz ERG, and LA 3 ERG b-wave are plotted against the primary axis as a percentage of the age-matched lower limit of the (“normal”) reference range, with values arranged in ascending order of DA 10 ERG a-wave amplitude for clarity. The LA 30-Hz peak times are plotted as a difference from the age-matched upper limit of normal timing against the secondary axis. B. PERG P50 amplitudes plotted as a percentage of the lower limit of normal amplitude for the same order of subjects as in panel A; the absence of a column indicates undetectable responses. C. The age of the patients at the time of testing, arranged in same order as in panels A and B. Note the 7 subjects to the right of the vertical broken line in panel A had normal ERGs but abnormal PERG P50 components (B), consistent with a diagnosis of macular dystrophy. The LA 30Hz ERG in subject 29 was subnormal, but in presence of significant eye closure. DA = dark-adapted, ERG = electroretinogram, PERG = pattern electroretinogram.

FIGURE 5

A. Graphic representation of the CRB1 gene and protein, with details on functional domains. Each variant within our cohort is detailed above the protein, with its corresponding location, and with different colors according to the associated phenotype. B. Pie graph representation of the type of variants seen in each phenotypic group. The larger prevalence of null changes can be easily visualized in the MD and EOSRD/LCA groups, compared with the RP group, and also the high prevalence of the p.Ile167_Gly169del in-frame deletion, found exclusively in the MD group. EOSRD = early-onset severe retinal dystrophy, LCA = Leber congenital amaurosis, MD = macular dystrophy, RP = retinitis pigmentosa.