CRB1-associated retinal dystrophies in a Belgian cohort: genetic characteristics and long-term clinical follow-up

Abstract

AimTo investigate the natural history in a Belgian cohort of CRB1-associated retinal dystrophies.MethodsAn in-depth retrospective study focusing on visual function and retinal structure.ResultsForty patients from 35 families were included (ages: 2.5–80.1 years). In patients with a follow-up of >1 year (63%), the mean follow-up time was 12.0 years (range: 2.3–29.2 years). Based on the patient history, symptoms and/or electroretinography, 22 patients (55%) were diagnosed with retinitis pigmentosa (RP), 15 (38%) with Leber congenital amaurosis (LCA) and 3 (8%) with macular dystrophy (MD), the latter being associated with the p.(Ile167_Gly169del) mutation (in compound heterozygosity). MD later developed into a rod-cone dystrophy in one patient. Blindness at initial presentation was seen in the first decade of life in LCA, and in the fifth decade of life in RP. Eventually, 28 patients (70%) reached visual acuity-based blindness (<0.05). Visual field-based blindness (<10°) was documented in 17/25 patients (68%). Five patients (13%) developed Coats-like exudative vasculopathy. Intermediate/posterior uveitis was found in three patients (8%). Cystoid maculopathy was common in RP (9/21; 43%) and MD (3/3; 100%). Macular involvement, varying from retinal pigment epithelium alterations to complete outer retinal atrophy, was observed in all patients.ConclusionBi-allelic CRB1 mutations result in a range of progressive retinal disorders, most of which are generalised, with characteristically early macular involvement. Visual function and retinal structure analysis indicates a window for potential intervention with gene therapy before the fourth decade of life in RP and the first decade in LCA.

The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

“…In patient 48, two pathogenic mutations in CRB1 were identified and refined the clinical diagnosis from STGD to CRD (Table 3). In reality, one of the identified mutations, c.498_506delAATTGATGG; p.(Ile167_Gly169del), was previously reported to cause macular degeneration in compound heterozygosity [15], in agreement with our results. The last two cases (patients 65 and 94) had an initial diagnosis of ACHR but were reclassified to CRD after identifying the causative mutations in POC1B and RPGRIP1, respectively.…”

CRB1-associated retinal dystrophy presenting as self-resolving opsoclonus and posterior uveitis

“… 25 A recent study of 40 Belgian patients with CRB1-associated retinal dystrophies showed that intermediate or posterior uveitis was found in 8% of these patients. 7 In a separate case series about retinal dystrophy presenting as refractory intermediate uveitis, 3 out of the 6 patients (5, 12, and 13 years of age) had mutations in CRB1, with 2 being compound heterozygotes and the other having a homozygous missense mutation. 26 Specific cases have also been described, including an 8-year-old male with intermediate uveitis, retinal capillaritis, and cystoid macular edema who was subsequently found to have compound heterozygous mutations in CRB1 and a 26-year-old male with a homozygous missense mutation in CRB1 who presented with diffuse retinal vascular leakage.…”

“…Genetic testing performed using the retinal dystrophy panel from Blueprint Genetics found the patient had two variants in CRB1, a gene associated with Leber's congenital amaurosis (LCA) type 8 (Mendelian Inheritance in Man (MIM) #613835), autosomal recessive retinitis pigmentosa (RP) type 12 (MIM # 600105 ), and pigmented paravenous chorioretinal atrophy (MIM # 172870 ). 5 , 6 , 7 One of the two variants was a heterozygous missense mutation (c.2300T > C, p.Leu767Pro) known to be pathogenic, and the other was a heterozygous novel deletion involving exon 12 (c.(4005 + 1_4006–1)_(*1_? )del) categorized as likely pathogenic.…”

Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1rd8 Mouse Model

“…Fifth, cyst-like structures within the outer nuclear layer of both models accumulate in the region of the retina where dysplastic lesions occur. These structures may be related to foveolar retinoschisis [82] or macular edema [83], often detected in CRB1 RP patients [25], [84]. The cause of these cyst-like structures is unknown but, based on the observation of vascular leaks upon Müller cell ablation [85], they may ultimately arise from defects in junctions between Müller cells and retinal vascular beds.…”

“…Further, the mouse models described here exhibit new features aligned with human CRB1 pathology, which may aid in developing therapies. The cystlike lesions in both Tvrm266 and Tvrm323 mice may be useful for understanding the origin of and testing treatments for macular and foveal retinoschisis associated with CRB1 variants [25], [82][83][84]. The progressive decline in rod and cone cell ERG responses in Tvrm323 mice is faster than in mice carrying a single homozygous Crb1 mutation, including STOCK Crb1 rd8 mice, and may be useful for understanding and treating functional decline in CRB1 patients.…”