Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy.

PURPOSE: We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy. DESIGN: Single-center observational case study. PARTICIPANTS: Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included. METHODS: Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing. MAIN OUTCOME MEASURES: Visual acuity, electrophysiology, fluorescein angiography, and OCT findings. RESULTS: Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33-5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography. CONCLUSIONS: Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Pseudoexfoliation and Cataract Syndrome Associated with Genetic and Epidemiological Factors in a Mayan Cohort of Guatemala.

The Mayan population of Guatemala is understudied within eye and vision research. Studying an observational homogenous, geographically isolated population of individuals seeking eye care may identify unique clinical, demographic, environmental and genetic risk factors for blinding eye disease that can inform targeted and effective screening strategies to achieve better and improved health care distribution. This study served to: (a) identify the ocular health needs within this population; and (b) identify any possible modifiable risk factors contributing to disease pathophysiology within this population. We conducted a cross-sectional study with 126 participants. Each participant completed a comprehensive eye examination, provided a blood sample for genetic analysis, and received a structured core baseline interview for a standardized epidemiological questionnaire at the Salama Lions Club Eye Hospital in Salama, Guatemala. Interpreters were available for translation to the patients' native dialect, to assist participants during their visit. We performed a genome-wide association study for ocular disease association on the blood samples using Illumina's HumanOmni2.5-8 chip to examine single nucleotide polymorphism SNPs in this population. After implementing quality control measures, we performed adjusted logistic regression analysis to determine which genetic and epidemiological factors were associated with eye disease. We found that the most prevalent eye conditions were cataracts (54.8%) followed by pseudoexfoliation syndrome (PXF) (24.6%). The population with both conditions was 22.2%. In our epidemiological analysis, we found that eye disease was significantly associated with advanced age. Cataracts were significantly more common among those living in the 10 districts with the least resources. Furthermore, having cataracts was associated with a greater likelihood of PXF after adjusting for both age and sex. In our genetic analysis, the SNP most nominally significantly associated with PXF lay within the gene KSR2 (p < 1 × 10-5). Several SNPs were associated with cataracts at genome-wide significance after adjusting for covariates (p < 5 × 10-8). About seventy five percent of the 33 cataract-associated SNPs lie within 13 genes, with the majority of genes having only one significant SNP (5 × 10-8). Using bioinformatic tools including PhenGenI, the Ensembl genome browser and literature review, these SNPs and genes have not previously been associated with PXF or cataracts, separately or in combination. This study can aid in understanding the prevalence of eye conditions in this population to better help inform public health planning and the delivery of quality, accessible, and relevant health and preventative care within Salama, Guatemala.

Impact and Trends in Global Ophthalmology.

Purpose of Review: Our goal is to provide a review of the impact, global estimates, and projection of vision impairment as well as ongoing systems for eye care delivery. Recent Findings: Many of the blinding diseases in developing countries are preventable or curable, but the lack of ophthalmologists, the lack of education, and the lack of access to any eye care are some of the major obstacles encountered. Summary: As our world becomes more interconnected through globalization, the interactions between different cultures and populations increase. Global ophthalmology is a field dedicated to building sustainable eye care delivery systems to deliver high-quality care in minimal resource settings, with the aim of reducing blindness around the world.

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Local control and results of Leksell Gamma Knife therapy for the treatment of uveal melanoma.

BACKGROUND AND OBJECTIVE: To evaluate the effectiveness of Leksell Gamma Knife stereotactic radio-surgery (Elekta, Stockholm, Sweden) with respect to local tumor control, visual acuity, and radiation side effects for uveal melanoma. PATIENTS AND METHODS: Retrospective, non-comparative case series of 23 patients with uveal melanoma treated with Gamma Knife stereotactic radiosurgery at Tufts Medical Center from 2000 to 2012. Patients received single-fraction stereotactic radiation therapy of 20-25 gray (Gy) (mean: 21.7 Gy), primarily at the 50% isodose line. Follow-up was 4 to 121 months (median: 41.5 months). Main outcome measures included local tumor control, metastasis, visual acuity, and complications of therapy. RESULTS: In 21 of 23 patients (91%), local control was achieved with a single session of Gamma Knife therapy. Both patients who did not have local control, as well as a third patient (three of 23, 13%) developed liver metastases. Visual acuity was 20/200 or better in eight of 23 patients (35%) at last follow-up. Radiation side effects severe enough to cause vision loss were present in 14 of 23 patients (61%). CONCLUSION: Gamma Knife therapy may be an effective alternative to enucleation in patients with uveal melanoma who are deemed less satisfactory candidates for brachytherapy or wish to avoid surgery.

An inherited disorder with splenomegaly, cytopenias, and vision loss.

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered.

Comparison of Hanna and Hessburg-Barron trephine and punch systems using histological, anterior segment optical coherence tomography, and elliptical curve fitting models.

BACKGROUND: This study analyzes the characteristics of donor and recipient tissue preparation between the Hessburg-Barron and Hanna punch and trephine systems by using elliptical curve fitting models, light microscopy, and anterior segment optical coherence tomography (AS-OCT). METHODS: Eight millimeter Hessburg-Barron and Hanna vacuum trephines and punches were used on six cadaver globes and six corneal-scleral rims, respectively. Eccentricity data were generated using measurements from photographs of the corneal buttons and were used to generate an elliptical curve fit to calculate properties of the corneal button. The trephination angle and punch angle were measured by digital protractor software from light microscopy and AS-OCT images to evaluate the consistency with which each device cuts the cornea. RESULTS: The Hanna trephine showed a trend towards producing a more circular recipient button than the Barron trephine (ratio of major axis to minor axis), ie, 1.059 ± 0.041 versus 1.110 ± 0.027 (P = 0.147) and the Hanna punch showed a trend towards producing a more circular donor cut than the Barron punch, ie, 1.021 ± 0.022 versus 1.046 ± 0.039 (P = 0.445). The Hanna trephine was demonstrated to have a more consistent trephination angle than the Barron trephine when assessing light microscopy images, ie, ±14.39° (95% confidence interval [CI] 111.9-157.7) versus ±19.38° (95% CI 101.9-150.2, P = 0.492) and OCT images, ie, ±8.08° (95% CI 106.2-123.3) versus ±11.16° (95% CI 109.3-132.6, P = 0.306). The angle created by the Hanna punch had less variability than the Barron punch from both the light microscopy, ie, ±4.81° (95% CI 101.6-113.9) versus ±11.28° (95% CI 84.5-120.6, P = 0.295) and AS-OCT imaging, ie, ±9.96° (95% CI 95.7-116.4) versus ±14.02° (95% CI 91.8-123.7, P = 0.825). Statistical significance was not achieved. CONCLUSION: The Hanna trephine and punch may be more accurate and consistent in cutting corneal buttons than the Hessburg-Barron trephine and punch when evaluated using elliptical curve fitting models, light microscopy, and AS-OCT.

Dose de-escalation with gamma knife radiosurgery in the treatment of choroidal melanoma.

PURPOSE: Single-fraction targeted radiation therapy delivered by the Leksell Gamma Knife system is a minimally invasive treatment option for choroidal melanoma that has been used as an alternative to enucleation, proton beam therapy, or brachytherapy. Previously reported Gamma Knife series involved the treatment of choroidal melanomas with a dose of 40 to 50 Gy at the tumor margin. We report our institutional experience using a significantly lower dose. METHODS AND MATERIALS: Fourteen patients with choroidal melanoma were treated with the Leksell Gamma Knife at our institution over a 7-year period. The treatment and clinical data were analyzed in a retrospective fashion after a mean follow-up of 32.2 months. RESULTS: The mean dose to the tumor margin was 22.2 +/- 2.4 Gy (range, 20- 25 Gy). Mean treated tumor volume was 1.1 +/- 1.2 cc. Local control was achieved in 13 cases (93%). In 1 patient both intraocular spread and distant metastatic disease developed after treatment. Visual function of the affected eye was preserved in 5 patients (36%) at latest follow-up, in 9 patients (64%) visual loss ensued. Mild to moderate radiation toxicity developed in 8 patients. CONCLUSIONS: Choroidal melanoma can be safely and effectively treated using Leksell Gamma Knife stereotactic radiosurgery with a marginal dose of less than 25 Gy.

Correlation of visual outcome and patient satisfaction with preoperative keratometry after hyperopic laser in situ keratomileusis.

PURPOSE: To prospectively study the dependence of visual outcomes and patient satisfaction on corneal keratometry (K) in hyperopic laser in situ keratomileusis (LASIK). SETTING: John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, USA. METHODS: Twenty-six patients (49 eyes) who had hyperopic LASIK from January to October 2005 were prospectively studied. Twelve patients (24 eyes) with a preoperative K value less than 43.0 diopters (D) (Group 1) were compared with 14 patients (25 eyes) with a preoperative K value greater than 44.0 D (Group 2). RESULTS: The mean preoperative hyperopia was +3.44 D (range +1.57 to +5.25 D). Ten patients in Group 2 and 1 patient in Group 1 lost 2 or more lines of best spectacle-corrected visual acuity (BSCVA). There was a statistically significant difference in subjective patient satisfaction (scale 1 to 4; 4=most satisfied) between Group 1 and Group 2 (mean 2.75+/-0.61 and 1.52+/-0.66, respectively) (P<.0001). Group 2 had a statistically significantly higher dryness score (scale 0 to 3; 3=severe) (mean 1.84+/-0.70 versus 0.17+/-0.38) (P<.0001). There was no between-group difference in the degree of preoperative hyperopia or keratometric change. CONCLUSIONS: An increased incidence of loss of BSCVA and decreased patient satisfaction was associated with a preoperative K value greater than 44.0 D in hyperopic LASIK, indicating caution is required when performing LASIK in eyes with moderate to high hyperopia and steep preoperative corneal keratometry.

Solid-state, dye-labeled DNA detects volatile compounds in the vapor phase.

This paper demonstrates a previously unreported property of deoxyribonucleic acid-the ability of dye-labeled, solid-state DNA dried onto a surface to detect odors delivered in the vapor phase by changes in fluorescence. This property is useful for engineering systems to detect volatiles and provides a way for artificial sensors to emulate the way cross-reactive olfactory receptors respond to and encode single odorous compounds and mixtures. Recent studies show that the vertebrate olfactory receptor repertoire arises from an unusually large gene family and that the receptor types that have been tested so far show variable breadths of response. In designing biomimetic artificial noses, the challenge has been to generate a similarly large sensor repertoire that can be manufactured with exact chemical precision and reproducibility and that has the requisite combinatorial complexity to detect odors in the real world. Here we describe an approach for generating and screening large, diverse libraries of defined sensors using single-stranded, fluorescent dye-labeled DNA that has been dried onto a substrate and pulsed with brief exposures to different odors. These new solid-state DNA-based sensors are sensitive and show differential, sequence-dependent responses. Furthermore, we show that large DNA-based sensor libraries can be rapidly screened for odor response diversity using standard high-throughput microarray methods. These observations describe new properties of DNA and provide a generalized approach for producing explicitly tailored sensor arrays that can be rationally chosen for the detection of target volatiles with different chemical structures that include biologically derived odors, toxic chemicals, and explosives.

Hexosamines regulate leptin production in 3T3-L1 adipocytes through transcriptional mechanisms.

This study was undertaken to examine the regulation of leptin gene (LEP) transcription and leptin release by hexosamines in 3T3-L1 adipocytes. Glucosamine (1 mM), an intermediate in hexosamine biosynthesis, increased leptin release to 117.0 +/- 7.3% (P = 0.0430; n = 9) and 134.6 +/- 6.5% of the control value (P = 0.0367; n = 4) by 48 and 96 h, respectively. With 0.01 mM glucosamine, leptin release was increased to 120.0 +/- 3.0% of the control value (P = 0.0069; n = 4) by 96 h of treatment. Glucose at 5 and 20 mM stimulated leptin release to 759 +/- 227% and 1104 +/- 316% of the control value over the 96-h culture period. Inhibition of hexosamine biosynthesis with 6-diazo-5-oxonorleucine (20 microM) reduced glucose-stimulated leptin release 13 +/- 2.3% and 29.9 +/- 6.6% at 24 and 96 h, respectively (n = 4; P < 0.05). A 24-h incubation in 5 mM glucose significantly increased (163.0 +/- 19.3%; n = 7) the activity of a human LEP promoter electroporated into differentiated 3T3-L1 cells. Glucosamine (1 mM; 48 h) also increased LEP promoter activity 170.0 +/- 13.0% (n = 5). Mutation of the three Sp1 binding sites in the LEP construct significantly reduced promoter activity. However, glucose (5 mM; 24 h) and glucosamine (1 mM; 48 h) increased the activity of the mutated promoter to 165 +/- 40% (n = 8) and 143 +/- 13% of the control value (n = 8). Glucosamine significantly increased O-glycosylation of Sp1 by 16.1 +/- 4.5% (P = 0.0305; n = 3). These data demonstrate that glucose and hexosamines regulate leptin production through transcriptional mechanisms localized to the proximal portion of the LEP promoter. Hexosamine-mediated regulation of LEP gene expression does not depend on Sp1 binding to traditional sites on the promoter.