Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination.

Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal-recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations.

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.

Efficacy of Topical Nepafenac 0.3% in the Management of Postoperative Cystoid Macular Edema.

PURPOSE: To assess the effect of twice-daily nepafenac ophthalmic suspension 0.3% on postoperative cystoid-macular-edema (CME). PATIENTS AND METHODS: In this prospective, clinic-based, non-randomized case-series, 21 patients (21 eyes) were enrolled with either acute or chronic postoperative CME after cataract extraction. Patients were treated with twice-daily nepafenac 0.3% drops, and followed for at least a 4-month period. Best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT)-derived central retinal thickness (CRT) were measured. RESULTS: From 21 patients, eight presented with acute postoperative CME and 13 with chronic CME. Mean follow-up was 4.82±1.24 months. No adverse events were reported during the study. Baseline BCVA was 0.49±0.36 logMAR and improved to 0.36±0.42 logMAR at the last follow-up visit (P<0.005). CRT decreased from 450.40±90.74 µm at baseline to 354.60±81.49 µm (P<0.05), following treatment. CONCLUSION: Our outcomes strongly suggest that administrating nepafenac 0.3% drops on a twice-daily regimen could be a promising alternative for the management of postoperative CME. Additional studies are necessary to further validate our results.

Optical Biometry Derived Axial Length Measurements Following Intravitreal Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema.

PURPOSE: To evaluate axial length (AL) alterations in patients with macular disease over the course of intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment. METHODS: In this prospective, comparative study, 33 patients with macular edema underwent unilaterally intravitreal anti-VEGF therapy and were followed for two months; the contralateral eyes were considered as controls. Central retinal thickness (CRT) was measured with spectral-domain optical coherence tomography and AL with an IOL-Master optical biometer. RESULTS: CRT of the treated eyes decreased by 35.33 ± 65.59 µm (range, -222.00-67 µm), while AL increased by 0.008 ± 0.062 mm (range, -0.11-0.18 mm). CRT of the control group decreased by 9.82 ± 65.40 µm (range, -203-182 µm), and AL increased by 0.011 ± 0.129 mm (range, -0.20-0.67 mm). No significant correlation was detected between CRT and AL parameters (rhos=0.026, P=0.882). CONCLUSIONS: Anti-VEGF administration has no significant impact on optical biometry-derived AL measurements.

Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol.

PURPOSE: To compare the corneal stromal demarcation line depth using anterior segment optical coherence tomography (AS-OCT) after corneal collagen cross-linking (CXL) using 2 different treatment protocols: the standard Dresden protocol (30 minutes with 3 mW/cm(2)) and a modified-accelerated protocol (14 minutes with 9 mW/cm(2)). DESIGN: Prospective, comparative study. METHODS: Forty-three keratoconic patients (52 eyes) were enrolled. All patients underwent CXL using the same high-intensity ultraviolet-A (UV-A) irradiation device. Twenty-six eyes were treated for 30 minutes with 3 mW/cm(2) according to the standard Dresden protocol (Group 1), while 26 eyes were treated with a novel modified-accelerated CXL protocol for 14 minutes with 9 mW/cm(2) of UV-A irradiation intensity (Group 2). One month postoperatively, corneal stromal demarcation line depth was measured by 2 independent observers using AS-OCT. RESULTS: Corneal stromal demarcation line depth was assessed with no significant difference between observer measurements for both groups (P = .676 for Group 1 and P = .566 for Group 2). Mean corneal stromal demarcation line depth was 337.00 ± 46.46 µm for Group 1 and 322.91 ± 48.28 µm for Group 2. There was no statistically significant difference (P = .243) in the corneal stromal demarcation line depth between the 2 groups. CONCLUSIONS: Corneal stromal demarcation line depth using UV-A with 3 mW/cm(2) for 30 minutes and 9 mW/cm(2) for 14 minutes was similar. A modified-accelerated protocol of 14 minutes of CXL provided the same treatment depth as the classic Dresden protocol.