Zellweger Spectrum Disorder: Ophthalmic Findings from a New Natural History Study Cohort and Scoping Literature Review.

PURPOSE: Individuals with Zellweger spectrum disorder (ZSD) manifest a spectrum of clinical phenotypes but almost all have retinal degeneration leading to blindness. The onset, extent, and progression of retinal findings have not been well described. It is crucial to understand the natural history of vision loss in ZSD to define reliable endpoints for future interventional trials. Herein, we describe ophthalmic findings in the largest number of ZSD patients to date. DESIGN: Retrospective review of longitudinal data from medical charts and review of cross-sectional data from the literature. PARTICIPANTS: Sixty-six patients with ZSD in the retrospective cohort and 119 patients reported in the literature, divided into 4 disease phenotypes based on genotype or clinical severity. METHODS: We reviewed ophthalmology records collected from the retrospective cohort (Clinicaltrials.gov NCT01668186) and performed a scoping review of the literature for ophthalmic findings in patients with ZSD. We extracted available ophthalmic data and analyzed by age and disease severity. MAIN OUTCOME MEASURES: Visual acuity (VA), posterior and anterior segment descriptions, nystagmus, refraction, electroretinography findings, visual evoked potentials, and OCT results and images. RESULTS: Visual acuity was worse at younger ages in those with severe disease compared with older patients with intermediate to mild disease for all 78 participants analyzed, with a median VA of 0.93 logarithm of the minimum angle of resolution (Snellen 20/320). Longitudinal VA data revealed slow loss over time and legal blindness onset at an average age of 7.8 years. Funduscopy showed retinal pigmentation, macular abnormalities, small or pale optic discs, and attenuated vessels with higher prevalence in milder severity groups and did not change with age. Electroretinography waveforms were diminished in 91% of patients, 46% of which were extinguished and did not change with age. OCT in milder patients revealed schitic changes in 18 of 23 individuals (age range 1.8 to 30 years), with evolution or stable macular edema. CONCLUSIONS: In ZSD, VA slowly deteriorates and is associated with disease severity, serial electroretinography is not useful for documenting vision loss progression, and intraretinal schitic changes may be common. Multiple systematic measures are required to assess retinal dystrophy accurately in ZSD, including functional vision measures. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Expression of PRPF31 and TFPT: regulation in health and retinal disease.

PRPF31, a gene located at chromosome 19q13.4, encodes the ubiquitous splicing factor PRPF31. The gene lies in a head-to-head arrangement with TFPT, a poorly characterized gene with a role in cellular apoptosis. Mutations in PRPF31 have been implicated in autosomal dominant retinitis pigmentosa (adRP), a frequent and important cause of blindness worldwide. Disease associated with PRPF31 mutations is unusual, in that there is often non-penetrance of the disease phenotype in affected families, caused by differential expression of PRPF31. This study aimed to characterize the basic promoter elements of PRPF31 and TFPT. Luciferase reporter constructs were made, using genomic DNA from an asymptomatic individual with a heterozygous deletion of the entire putative promoter region. Fragments were tested by the dual-luciferase reporter assay in HeLa and RPE-1 cell lines. A comparison was made between the promoter regions of symptomatic and asymptomatic mutation-carrying individuals. A patient (CAN493) with adRP was identified, harbouring a regulatory region mutation; both alleles were assayed by the dual-luciferase reporter assay. Luciferase assays led to the identification of core promoters for both PRPF31 and TFPT; despite their shared gene architecture, the two genes appear to be controlled by slightly different regulatory regions. One functional polymorphism was identified in the PRPF31 promoter that increased transcriptional activation. The change was not, however, consistent with the observed symptomatic-asymptomatic phenotypes in a family affected by PRPF31-adRP. Analysis of the mutant promoter fragment from CAN493 showed a >50% reduction in promoter activity, suggesting a disease mechanism of functional haploinsufficiency-the first report of this disease mechanism in adRP.

Nonpigmented Adenoma of the Retinal Pigment Epithelium Mimicking a Retinal Vasoproliferative Tumor Managed With Endoresection.

Purpose: To present a case with signs suggestive of a retinal vasoproliferative tumor. Methods: A case report was evaluated and a surgical video presented. Results: A 61-year-old White man presented with an amelanotic retinal tumor associated with exudation, retinal edema, and overlying telangiectatic vessels, suggestive of a retinal vasoproliferative tumor. Standardized echography showed an irregular mass with medium-to-high internal reflectivity and internal calcification, which suggested chronicity. He was initially treated for an exudative retinal detachment (RD) in the context of a presumed vasoproliferative tumor but later developed combined exudative and rhegmatogenous RD, prompting surgical repair with tumor endoresection. Pathology showed nonpigmented adenoma of the retinal pigment epithelium (RPE). Conclusions: Nonpigmented adenoma of the RPE is a rare tumor, and its clinical similarity to a vasoproliferative tumor should be noted. Endoresection may be considered in cases resulting in RD.

Comparative long-term outcomes of vitrectomy combined with anterior chamber intraocular lens to intra-scleral haptic fixation of posterior chamber intraocular lens.

PURPOSE: To evaluate the long-term clinical outcomes in patients with combined pars plana vitrectomy (PPV) with anterior chamber intraocular lens (ACIOL) to intrascleral haptic fixation (ISHF) using the Agarwal technique with fibrin glue to secure the scleral flap of a posterior chamber intraocular lens. METHODS: Retrospective, consecutive, single-center, comparative case series. 83 eyes were studied. Patients with < 8 months of follow-up were excluded. Detailed pre-, intra-, and post-operative complications were analyzed using mixed model univariate analysis and t-test. Pre- and post-operative best corrected visual acuity (BCVA) was analyzed. RESULTS: Twenty-five subjects met entry criteria. Mean age at time of surgery was 70.4 ± 17.7 years in the ACIOL group (n = 12) and 54.6 ± 21.1 years in the ISHF group (n = 13; p = 0.03). Mean follow-up was 38.2 months. Incidence of corneal decompensation was similar in the ACIOL and ISHF lens group (p = 0.93). There was no difference in the BCVA mean change or cystoid macular edema (CME) at the final visit between the groups (p = 0.47; p = 0.08), but there was a trend toward increased CME in the ACIOL group. CONCLUSIONS: PPV with concomitant placement of either ACIOL or ISHF lens result in improvement in BCVA. Both procedures are well tolerated and result in favorable outcomes with long-term follow-up though varying patient populations do not allow precise comparison between the two groups.

Predominance of hyperopia in autosomal dominant Best vitelliform macular dystrophy.

BACKGROUND/AIMS: Patients with BEST1-associated autosomal dominant Best vitelliform macular dystrophy (AD-BVMD) have been reported to be hyperopic, but the prevalence of refractive error has not been described. This study aimed to characterise the type and degree of refractive error in a large cohort of patients with AD-BVMD compared with an age-similar group with ABCA4-associated Stargardt disease. METHODS: This was a retrospective chart review of consecutive patients with molecularly confirmed AD-BVMD and Stargardt macular dystrophy seen at a single academic centre. Demographic information, including age, gender and genotype were extracted from the chart. The best corrected visual acuity (BCVA), as well as type and degree of refractive error on manifest refraction for each eye on each visit, were recorded and compared. RESULTS: A total of 178 eyes from 89 patients with AD-BVMD (35 women, 54 men; mean age 36.6 years) and 306 eyes from 153 patients (94 women, 59 men, mean age 30.2 years) with Stargardt disease were included in the study. Mean BCVA was excellent for both AD-BVMD and Stargardt eyes (logMAR 0.23 vs logMAR 0.31, respectively; p=0.55). At initial refraction, 73.0% of AD-BVMD eyes (130/178) were hyperopic, with mean spherical equivalent (SE) +1.38 dioptres (median +0.88) whereas 80.7% of Stargardt eyes (247/306) were myopic, with mean SE of -1.76 dioptres (median -1.19) (p<0.001). CONCLUSION: Patients with AD-BVMD are predominantly hyperopic, whereas those with Stargardt disease are predominantly myopic. The findings provide further evidence of a role for BEST1 in ocular growth and development.

Correlation of features on OCT with visual acuity and Gass lesion type in Best vitelliform macular dystrophy.

OBJECTIVE: To correlate structural features seen on optical coherence tomography (OCT) with best-corrected visual acuity (BCVA) and Gass lesion type in patients with Best vitelliform macular dystrophy (BVMD). METHODS AND ANALYSIS: This is a retrospective case series of consecutive patients with molecularly confirmed BEST1-associated BVMD. OCT scans were reviewed for lesion status and presence of subretinal pillar, focal choroidal excavation (FCE), intraretinal fluid or atrophy. Available OCT angiography images were used to evaluate for the presence of choroidal neovascularisation (CNV). These features were then correlated with BCVA and Gass lesion type. RESULTS: 95 eyes from 48 patients (mean age 38.9 years, range 4-87) were included. The presence of a pillar (24.2%), FCE (20.0%) and atrophy (7.4%) were associated with poor BCVA (p<0.05). Gass lesion type 1 eyes were correlated with good BCVA (LogMAR <0.4) whereas type 5 eyes had poor BCVA (LogMAR >0.4). Among 65 eyes with longitudinal data (mean follow-up 5.1 years), 7 eyes (10.8%) reverted from higher to lower Gass lesion type; of these, 4 eyes (57.1%) had CNV responsive to intravitreal anti-vascular endothelial growth factor treatment. CONCLUSION: OCT-based structural features are readily identifiable in patients with BVMD and have prognostic importance due to their correlation with BCVA.

Cell-Matrix Interactions in the Eye: From Cornea to Choroid.

The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch's membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon's layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-ß, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed.

Retrobulbar anaesthesia for adjustable strabismus surgery in adults: a prospective observational study.

OBJECTIVE: To characterize the ocular response to retrobulbar anaesthesia and to evaluate the efficacy of retrobulbar anaesthesia for adjustable strabismus surgery in adults. DESIGN: Prospective observational study. PARTICIPANTS: Adult patients undergoing adjustable strabismus surgery under retrobulbar anaesthesia. METHODS: Surgical success was defined by ocular alignment within 10 prism diopters (PD) of orthotropia for horizontal rectus surgery and within 5 PD for vertical rectus surgery. After retrobulbar injection of Xylocaine with epinephrine, the onset time and the degree of visual impairment, ocular akinesia, and analgesia were evaluated. Postoperative parameters included the restoration of vision, onset of pain, resolution of ptosis, normalization of pupil, resolution of extraocular motility deficits, and the timing of postoperative adjustment. Perioperative complications were also documented. RESULTS: A total of 33 patients were initially included in this study. Two patients experienced complications (perioperative retrobulbar hemorrhage, postoperative suprachoroidal hemorrhage) and were excluded from data analysis. Of the remaining 31 patients (mean age, 50.2 ± 14.8 years), surgical outcome was satisfactory in 30/31 (96.8%) patients at the first postoperative visit and in 15/19 (78.9%) cases at last follow-up (mean, 6.1 ± 1.6 months). Excellent intraoperative ocular akinesia and analgesia was achieved with retrobulbar anaesthesia. After retrobulbar injection, visual impairment was the first to resolve to preoperative levels within (mean ± SD) 3.7 ± 1.9 hours postinjection, followed by onset of pain at 4.1 ± 1.0 hours, resolution of ptosis at 4.3 ± 1.9 hours, and normalization of pupil reactivity at 6.1 ± 1.0 hours. The resolution of anaesthesia upon extraocular motility occurred within 5.7 ± 1.0 hours postinjection (range, 4.5-8.0 hours), allowing for subsequent same-day postoperative adjustment. CONCLUSIONS: Retrobulbar anaesthesia in the context of adult, adjustable strabismus surgery is a relatively safe and effective technique. It provides excellent intraoperative analgesia and akinesia. Retrobulbar anaesthesia enables for same-day suture adjustments to be reliably performed.