Wendy Dailey

A characteristic phenotypic retinal appearance in Norrie disease.

Purpose: To describe a striking retinal finding that the authors have only seen in Norrie disease eyes and to determine if a particular genotype corresponds to this dramatic presentation. Methods: This is a retrospective, interventional case report of four patients seen in the clinic over a 1-year period. All patients had analysis of the Norrie gene by direct sequencing. Results: All patients presented with a similar retinal appearance of dense stalk tissue, globular dystrophic retina, and peripheral avascular retina with pigmentary changes. Each patient was found to have a mutation in the Norrie gene affecting a cystine residue in the cystine knot domain. The mutations are predicted to disrupt the structure of the protein product, norrin, which is required for activation of the Wnt receptor:&bgr;-catenin pathway. Conclusions: No other vitreoretinopathy that the authors have seen demonstrates this characteristic retinal presentation of severe retinal dysplasia. All four patients were found to have mutations in the Norrie gene which alter the cystine knot motif. Mutations affecting this domain appear to have devastating effects on retinal development and indicate phenotype correlates with mutations affecting the cystine knot domain.

Original articleFrizzled-4 Variations Associated with Retinopathy and Intrauterine Growth Retardation: A Potential Marker for Prematurity and Retinopathy

PURPOSEnTo present the association between mutations affecting the Wnt-signaling receptor protein (FZD4), inherited vitreoretinopathies, and retinopathy of prematurity (ROP).nnnDESIGNnRetrospective analysis of prospective samples at a tertiary referral center.nnnPARTICIPANTSnPatients referred to our practice for management of a variety of pediatric vitreoretinopathies were offered participation in an ophthalmic biobank (421 participants with vitreoretinopathies were included in this study). Full-term healthy infants (n = 98) were recruited to the study as controls.nnnMETHODSnPatients with various vitreoretinopathies were prospectively enrolled in an ophthalmic biobank, approved by the Human Investigation Committee at William Beaumont Hospital. Retrospective genetic analysis of the FZD4 gene was performed (Sanger sequencing). Participants with a diagnosis of familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats disease, bilateral persistent fetal vasculature, and ROP were reviewed for the presence of a FZD4 variant. Data retrieval included status of retinopathy (including staging when possible), gestational age (GA), birth weight (BW) (when available), and family and birth histories.nnnMAIN OUTCOME MEASURESnThe association of FZD4 variants with the presence of vitreoretinopathy.nnnRESULTSnThe sequence variation p.[P33S(;)P168S] is the most prevalent FZD4 variant and is statistically significant for ROP and FEVR (P = 4.6E-04 and P = 2.4E-03, respectively) compared with full-term newborns (P = 1.7E-01). In addition, infants expressing the sequence variation tended to have significantly lower BWs for respective GA (P = 0.04). This suggests that the FZD4 p.[P33S(;)P168S] variant may be a risk factor for retinopathy and restricted intrauterine growth.nnnCONCLUSIONSnTesting for FZD4 gene mutations is useful in patients with suspected FEVR and ROP. The relatively high prevalence of the p.[P33S(;)P168S] variant in ROP and intrauterine growth restriction suggests that it also may be a marker for increased risk of developing ROP and preterm birth.

Intraschisis cavity fluid composition in congenital X-linked retinoschisis.

Purpose: To describe the intraschisis cavity protein composition in congenital X-linked retinoschisis (CXLRS) from two eyes of one child. Methods: The authors present a child with complex, Type 3 CXLRS who underwent bilateral surgical repair with autologous plasmin enzyme-assisted lens-sparing vitrectomy. Undiluted samples of intraschisis fluid and vitreous fluid from two eyes (one child) were obtained and used for protein analysis. Results: The patient underwent successful schisis repair with plasmin-assisted lens-sparing vitrectomy and silicone oil. Two unique protein bands were identified in the intraschisis cavity sample of each eye by gel electrophoresis. The proteins were identified as tenascin-C, an extracellular matrix protein involved in wound healing, and cystatin C, a ubiquitous cysteine protease inhibitor implicated in inflammation. Conclusions: Tenascin-C has previously been described in its complex relationship with decorin and fibronectin in normal wound healing. Tenascin’s upregulation in sites of inflammation and tenascin’s role as an antiadhesive molecule may contribute to the pathogenesis of CXLRS. To the authors’ knowledge, this is the first description of intraschisis cavity fluid.

Effect of intravitreal plasmin on vitreous removal through a 25-gauge cutting system in the rabbit in vivo.

PurposeIntravitreal plasmin creates a posterior vitreous detachment, but may also liquefy the vitreous. This study measures the rate of vitreous removal from rabbit eyes after plasmin injection in vivo.MethodsIntravitreal injections of 150xa0IU hyaluronidase (nu2009=u20095), 0.5 activity units (AU, nu2009=u20096) or 0.9xa0AU of streptokinase-activated human plasmin (nu2009=u2009four groups of 6) in 0.1xa0ml were performed in rabbits, the fellow eyes received 0.1xa0ml BSS. After 30xa0min (hyaluronidase), 30xa0min, 4xa0h, 12xa0h or 24xa0h (0.9xa0AU plasmin) or 24xa0h (0.5xa0AU plasmin), 1xa0ml of vitreous was removed from each eye without infusion, using a 25-gauge cutter and a standardized protocol. Animals were sacrificed after surgery.ResultsCompared to fellow eyes, the average rate of vitreous removal was increased by hyaluronidase by 68.9u2009±u20096.3% (pu2009<u20090.05) and by 0.5xa0AU plasmin (24xa0h) by 26.8u2009±u20093.3% (pu2009<u20090.05). 0.9xa0AU of plasmin increased removal rates by 0.8u2009±u200910% (n.s.), 15.4u2009±u20096.3% (pu2009<u20090.05), 40.3u2009±u20093.1% (pu2009<u20090.05), and 71.9u2009±u200932.4% (pu2009<u20090.05) after 30xa0min, 4xa0h, 12xa0h and 24xa0h incubation respectively. The ratios of removal rates of treated/control eyes in the 0.9xa0AU groups showed a linear correlation with incubation time (ru2009=u20090.783, pu2009<u20090.0001).ConclusionIntravitreal plasmin increases the rate of vitreous removal in rabbits.

Norrin treatment improves ganglion cell survival in an oxygen-induced retinopathy model of retinal ischemia

ABSTRACT Treatment of a mouse model of oxygen‐induced retinopathy (OIR) with recombinant human Norrin (Norrie Disease Protein, gene: NDP) accelerates regrowth of the microvasculature into central ischemic regions of the neural retina, which are generated after treatment with 75% oxygen. While this reduces the average duration and severity of ischemia overall, we do not know if this accelerated recovery of the microvasculature results in any significant survival of retinal ganglion cells (RGCs). The purpose of this study was to investigate ganglion cell survival with and without the intravitreal injection of Norrin in the murine model of oxygen induced retinopathy (OIR), using two strains of mice: C57BL/6J and Thy1‐YFP mice. Intravitreal injections of Norrin or vehicle were done after five days of exposure to 75% oxygen from ages P7 to P12. The C57BL/J mice were followed by Spectral‐Domain Optical Coherence Tomography (SD‐OCT), and the average nerve fiber layer (NFL) and inner‐plexiform layer (IPL) thicknesses were measured at twenty‐four locations per retina at P42. Additionally, some C57BL/J retinas were flat mounted and immunostained for the RGC marker, Brn3a, to compare the population density of surviving retinal ganglion cells. Using homozygous Thy1‐YFP mice, single intrinsically fluorescent RGCs were imaged in live animals with a Micron‐III imaging system at ages P21, 28 and P42. The relative percentage of YFP‐fluorescent RGCs with dendritic arbors were compared. At age P42, the NFL was thicker in Norrin‐injected OIR eyes, 14.4 &mgr;m, compared to Vehicle‐injected OIR eyes, 13.3 &mgr;m (p = 0.01). In the superior retina, the average thickness of the IPL was greater in Norrin‐injected OIR eyes, 37.7 &mgr;m, compared to Vehicle‐injected OIR eyes, 34.6 &mgr;m (p = 0.04). Retinas from Norrin injected OIR mice had significantly more surviving RGCs (p = 0.03) than vehicle‐injected mice. Based upon NFL thickness and counts of RGCs, we conclude that Norrin treatment, early in the ischemic phase, increased the relative population density of surviving RGCs in the central retinas of OIR mice. HighlightsNorrin treatment accelerates recovery of the mouse OIR model from ischemic insult.SD‐OCT can compare NFL/GCL (nerve fiber layer/ganglion cell layer) thickness in vivo.Norrin treatment counters thinning of the NFL/GCL in the mouse OIR model.Norrin treatment increases the surviving population density of RGCs in OIR retinas.

Ocular coherence tomography image data of the retinal laminar structure in a mouse model of oxygen-induced retinopathy

The data presented in this article are related to the research paper entitled “Norrin treatment improves ganglion cell survival in an oxygen-induced model of retinal ischemia” (Dailey et al., 2017) [1] This article describes treatment with the human Norrin protein, an atypical Wnt-protein, to improve the survival of retinal ganglion cells in a murine model of Oxygen-Induced Retinopathy (OIR). That study utilized Optical coherence tomography (OCT) to visualize retinal layers at high resolution in vivo, and to quantify changes to nerve fiber layer thickness. Organization of the laminar structure of other retinal layers in this model in vivo, were not known because of uncertainties regarding potential artifacts during the processing of tissue for traditional histology. The OCT image data provided here shows researchers the retinal laminar structural features that exist in vivo in this popular mouse OIR model. Traditional H&E stained retinal tissue sections are also provided here for comparison.