[Show abstract][Hide abstract] ABSTRACT: Congenital cataracts are a significant cause of lifelong visual loss. They may be isolated or associated with microcornea, microphthalmia, anterior segment dysgenesis (ASD) and glaucoma, and there can be syndromic associations. Genetic diagnosis is challenging due to marked genetic heterogeneity. In this study, next-generation sequencing (NGS) of 32 cataract-associated genes was undertaken in 46 apparently non-syndromic congenital cataract probands, around half sporadic and half familial cases. We identified pathogenic variants in 70% of cases, and over 68% of these were novel. In almost two-thirds (20/33) of these cases, this resulted in new information about the diagnosis and/or inheritance pattern. This included identification of: new syndromic diagnoses due to NHS or BCOR mutations; complex ocular phenotypes due to PAX6 mutations; de novo autosomal dominant or X-linked mutations in sporadic cases; and mutations in two separate cataract genes in one family. Variants were found in the crystallin and gap junction genes, including the first report of severe microphthalmia and sclerocornea associated with a novel GJA8 mutation. Mutations were also found in rarely reported genes including MAF, VIM, MIP, and BFSP1. Targeted NGS in presumed non-syndromic congenital cataract patients provided significant diagnostic information in both familial and sporadic cases. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: To determine the ability of blue-on-yellow multifocal visual evoked potentials (BonY mfVEP) to identify functional loss in preperimetric glaucoma.
Prospective case series.
Thirty patients with glaucomatous optic discs and normal standard visual fields.
All patients underwent BonY mfVEP, dilated optic disc stereophotography, and optical coherence tomography (Fast RNFL protocol). Optic disc photographs were assessed by 2 independent examiners in a masked fashion.
The mfVEP amplitude asymmetry and latency values were analyzed and compared topographically with findings of disc assessment. Average retinal nerve fiber layer (RNFL) thickness, RNFL asymmetry, and sectors with RNFL thinning were compared between patients with and without mfVEP defects.
Fourteen (46.7%) patients demonstrated significant abnormality on amplitude asymmetry deviation plots of BonY mfVEP. In all 14 cases, the defect was monocular and corresponded to the eye with the worse disc. In 13 of 14 patients, the defect also corresponded to the location of the worst affected rim. Average RNFL thickness of eyes with mfVEP defects was 81.2+/-9.9 microm, significantly lower than that of patients without defects (90+/-10.5 microm; P = 0.035). Mean asymmetry of RNFL (better minus worse eye) also was significantly higher for patients with mfVEP defects compared with those without such defects (9.0+/-6.4 microm vs. 3.0+/-7 microm; P = 0.03). Average latency of both eyes of glaucomatous patients was delayed compared with that of controls, with no difference in latency between worse and better eyes of glaucoma patients. There was no association of latency delay with either the location of disc changes or mfVEP amplitude defects.
Amplitude asymmetry of the BonY mfVEP seems to be a promising tool to identify functional loss in preperimetric glaucoma.
Proprietary or commercial disclosure may be found after the references.
[Show abstract][Hide abstract] ABSTRACT: Disorders of eye development such as microphthalmia and anophthalmia (small and absent eyes respectively), anterior segment dysgenesis where there may be pupillary and iris anomalies, and associated cataract and glaucoma, often lead to visual impairment or blindness. Currently treatment options are limited, as much is unknown about the molecular pathways that control normal eye development and induce the aberrant processes that lead to ocular defects. Mutation detection rates in most of the known genes are generally low, emphasizing the genetic heterogeneity of developmental ocular defects. Identification of the disease genes in these conditions improves the clinical information available for affected individuals and families, and provides new insights into the underlying biological processes for facilitation of better treatment options. Investigation of chromosomal rearrangements associated with an ocular phenotype has been especially powerful for disease gene identification. Molecular characterization of such rearrangements, which pinpoints the region by physically disrupting the causative gene or its regulatory sequences, allows for rapid elucidation of underlying genetic factors that contribute to the phenotype. Genes including PAX6, PITX2, FOXC1, MAF, TMEM114, SOX2, OTX2 and BMP4 have been identified in this way to be associated with developmental eye disorders. More recently, new methods in chromosomal analysis such as comparative genomic hybridization (CGH) microarray, have also enhanced our ability in disease gene identification.
Full-text · Article · Aug 2008 · Twin Research and Human Genetics
[Show abstract][Hide abstract] ABSTRACT: Uveal melanoma is extremely rare in the paediatric population and can be associated with various pre-existing conditions. We report the case of a 9-year-old girl with no predisposing factor who presented with choroidal melanoma. A review of the literature is presented and various clinical, histopathological and prognostic features of paediatric uveal melanoma are discussed.
No preview · Article · Jun 2008 · Clinical and Experimental Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: Nance-Horan syndrome is typically characterized by severe bilateral congenital cataracts and dental abnormalities. Truncating mutations in the Nance-Horan syndrome (NHS) gene cause this X-linked genetic disorder. NHS encodes two isoforms, NHS-A and NHS-1A. The ocular lens expresses NHS-A, the epithelial and neuronal cell specific isoform. The NHS-A protein localizes in the lens epithelium at the cellular periphery. The data to date suggest a role for this isoform at cell-cell junctions in epithelial cells. This study aimed to identify the causative mutations in new patients diagnosed with Nance-Horan syndrome and to investigate the effect of mutations on subcellular localization of the NHS-A protein.
All coding exons of NHS were screened for mutations by polymerase chain reaction (PCR) and sequencing. PCR-based mutagenesis was performed to introduce three independent mutations in the NHS-A cDNA. Expression and localization of the mutant proteins was determined in mammalian epithelial cells.
Truncating mutations were found in 6 out of 10 unrelated patients from four countries. Each of four patients carried a novel mutation (R248X, P264fs, K1198fs, and I1302fs), and each of the two other patients carried two previously reported mutations (R373X and R879X). No mutation was found in the gene in four patients. Two disease-causing mutations (R134fs and R901X) and an artificial mutation (T1357fs) resulted in premature truncation of the NHS-A protein. All three mutant proteins failed to localize to the cellular periphery in epithelial cells and instead were found in the cytoplasm.
This study brings the total number of mutations identified in NHS to 18. The mislocalization of the mutant NHS-A protein, revealed by mutation analysis, is expected to adversely affect cell-cell junctions in epithelial cells such as the lens epithelium, which may explain cataractogenesis in Nance-Horan syndrome patients. Mutation analysis also shed light on the significance of NHS-A regions for its localization and, hence, its function at epithelial cell junctions.
[Show abstract][Hide abstract] ABSTRACT: To examine the natural history of multifocal visual evoked potentials (mfVEPs) within 12 months of the first episode of optic neuritis (ON) in patients with possible multiple sclerosis (MS).
Twenty-seven patients with a first episode of ON, no previous demyelinating events, and MRI lesions consistent with demyelination were examined with mfVEP. Changes in amplitude and latency of mfVEP were analyzed at 1, 3, 6, and 12 months after an acute attack.
Five of 27 patients had persistent loss of amplitude after 12 months of follow-up. This loss was most marked centrally. Amplitude recovered in the remaining 22 patients at 1 month, but delayed latency, which was also most marked centrally, persisted. Of these, two distinct subgroups were identified: six patients with no improvement in latency and 16 patients with significant latency recovery over the 12 months of follow-up, suggesting remyelination. Conversion to MS was highest in the group with severe amplitude loss, followed by the group with no latency recovery. The conversion rate was lowest in the group of patients with latency improvement.
Distinct patterns of disease evolution were identified using mfVEP in patients with first episode of optic neuritis and at high risk for MS, supporting the concept of heterogeneity of early lesions in MS.
[Show abstract][Hide abstract] ABSTRACT: To determine whether simultaneous binocular (dichoptic) stimulation for multifocal visual evoked potentials (mfVEP) detects glaucomatous defects and decreases intereye variability.
Twenty-eight patients with glaucoma and 30 healthy subjects underwent mfVEP on monocular and dichoptic stimulation. Dichoptic stimulation was presented with the use of virtual reality goggles (recording time, 7 minutes). Monocular mfVEPs were recorded sequentially for each eye (recording time, 10 minutes).
Comparison of mean relative asymmetry coefficient (RAC; calculated as difference in amplitudes between eyes/sum of amplitudes of both eyes at each segment) on monocular and dichoptic mfVEP revealed significantly lower RAC on dichoptic (0.003 +/- 0.03) compared with monocular testing (-0.02 +/- 0.04; P = 0.002). In all 28 patients, dichoptic mfVEP identified defects with excellent topographic correspondence. Of 56 hemifields (28 eyes), 33 had Humphrey visual field (HFA) scotomas, all of which were detected by dichoptic mfVEP. Among 23 hemifields with normal HFA, two were abnormal on monocular and dichoptic mfVEP. Five hemifields (five patients) normal on HFA and monocular mfVEP were abnormal on dichoptic mfVEP. In all five patients, corresponding rim changes were observed on disc photographs. Mean RAC of glaucomatous eyes was significantly higher on dichoptic (0.283 +/- 0.18) compared with monocular (0.199 +/- 0.12) tests (P = 0.0006).
Dichoptic mfVEP not only detects HFA losses, it may identify early defects in areas unaffected on HFA and monocular mfVEP while reducing testing time by 30%. Asymmetry was tighter among healthy subjects but wider in patients with glaucoma on simultaneous binocular stimulation, which is potentially a new tool in the early detection of glaucoma.
[Show abstract][Hide abstract] ABSTRACT: We have employed proteomics to establish a proteome map of the normal rat retina. This baseline map was then used for comparison with the early diabetic rat retinal proteome. Diabetic rat retinae were obtained from Dark Agouti rats after 10 wk of streptozotocin-induced hyperglycaemia. Extracted proteins from normal and diabetic rat retinae were separated and compared using 2-DE. A total of 145 protein spots were identified in the normal rat retina using MALDI-MS and database matching. LC-coupled ESI-MS increased the repertoire of identified proteins by 23 from 145 to 168. Comparison with early diabetic rat retinae revealed 24 proteins unique to the diabetic gels, and 37 proteins absent from diabetic gels. Uniquely expressed proteins identified included the HSPs 70.1A and 8, and platelet activating factor. There were eight spots with increased expression and 27 with decreased expression on diabetic gels. Beta catenin, phosducin and aldehyde reductase were increased in expression in diabetes whilst succinyl coA ligase and dihydropyrimidase-related protein were decreased. Identification of such changes in protein expression has given new insights and a more comprehensive understanding of the pathogenesis of diabetic retinopathy, widening the scope of potential avenues for new therapies for this common cause of blindness.
[Show abstract][Hide abstract] ABSTRACT: While the number of individuals able to benefit from transplantation increases with technological developments, donation rates remain insufficient to cater for demand. A universal response to the insufficient number of donor organs has been public education to increase knowledge about donation and transplantation, and to encourage individuals to register their wishes about donation. Although education appears to have increased knowledge and encouraged individuals to register their wishes, it has not increased the number of organs available for transplantation. In fact, there is some evidence that encouraging people to register their wishes may be detrimental to increasing net donation rates. The failure of education programs to increase organ donation rates may be due in part to a failure to recognise that attitudes to donation are influenced by complex socio-cultural and personal beliefs, and not simply by knowledge. Research aiming to increase the rate at which organs are procured for donation must recognise that some individuals do not support transplantation and have their own personal reasons for maintaining this position. Educational interventions should not assume that increasing knowledge or simply encouraging individuals to declare a decision about donation will increase consent to donation.
No preview · Article · Mar 2007 · Journal of law and medicine
[Show abstract][Hide abstract] ABSTRACT: Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high-resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22-23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22-23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22-23 deletion patients.
Full-text · Article · Aug 2006 · American Journal of Medical Genetics Part A
[Show abstract][Hide abstract] ABSTRACT: Maternal infection with rubella in the first trimester is an important cause of congenital cataract. Any injury affecting the foetus following maternal rubella infection in the phase of organogenesis results in congenital defects collectively termed as congenital rubella syndrome (CRS). Although rubella embryopathy is a less common cause for congenital cataract than in the past, it is still seen. The number of cases reduced to one in 1997 after which there were no new cases till 2002. However, there have been two new cases of CRS in 2003. Herein another one in early 2004 is reported. Outbreaks of CRS will continue until the percentage of susceptible individuals is reduced to a minimum through immunization. The majority of rubella cases in Australia are confined to young female immigrants, many coming for marriage. We must continue to immunize children, identify and immunize vaccine failures and susceptible women before they become pregnant, and to screen pregnant women so they can be vaccinated after delivery.
No preview · Article · Jan 2006 · Clinical and Experimental Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: This study investigated the effects of cognitive influence on the multifocal visual evoked potential (mVEP) at different levels of eccentricity. Three different foveal fixation conditions were utilized involving varying levels of task complexity. A more complex visual fixation task has been known to suppress peripheral signals in subjective testing.
Twenty normal subjects had monocular mVEPs recorded using the AccuMap objective perimeter. This allowed simultaneous stimulation of 58 segments of the visual field to an eccentricity of 24 degrees. The mVEP was recorded using three different fixation conditions in random order. During task 1 the subject passively viewed the central fixation area. For task 2 alternating numbers were displayed within the fixation area; the subject on viewing the number '3' in the central fixation area indicated recognition by pressing a button. Throughout task 3, numbers were displayed as in task 2. The subject had the cognitive task of summating all the numbers.
Analysis revealed that the increased attention and concentration demanded by tasks 2 and 3 in comparison with task 1 resulted in significantly enhanced central amplitudes of 9.41% (Mann-Whitney P = 0.0002) and 13.45% (P = 0.0002), respectively. These amplitudes became reduced in the periphery and approached those of task 1, resulting in no significant difference between the three tasks. Latencies demonstrated no significant difference between each task nor at any eccentricity (P > 0.05). As the complexity of each task increased the amount of alpha rhythm was significantly reduced.
Our findings indicate that task 1 required a minimal demand of cognition and was associated with the greatest amount of alpha rhythm. It was also the most difficult to perform because of loss of interest. The other two tasks required a greater demand of higher order cognitive skills resulting in significantly enhanced amplitudes centrally and the attenuation of alpha rhythm. Therefore, amplitudes are increased around the area of attention.
No preview · Article · Oct 2005 · Clinical and Experimental Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: This report describes different modes of management in 3 sisters with anterior megalophthalmos. We report our management of the anterior megalophthalmos and a new technique of anterior chamber intraocular lens implantation, which was used in 1 case.
No preview · Article · Aug 2005 · Journal of Cataract and Refractive Surgery
[Show abstract][Hide abstract] ABSTRACT: This study sought to examine the in vitro interaction of human RPE cells with indocyanine green (ICG). The interaction between ICG and the RPE may have clinical relevance in the interpretation of clinical ICG angiography.
Cultured primary human RPE cells were incubated with ICG. Infrared fluorescence microscopy was used to detect RPE cell ICG fluorescence. The proportions of cells exhibiting ICG infrared fluorescence were quantified. Separate RPE cell populations were incubated with ouabain for 24 and 72 hours, respectively, before addition of the ICG to examine its effect on the uptake of ICG. The effect of ouabain on cell viability was assessed with trypan blue exclusion.
Normal human RPE cells incubated with ICG exhibited strong infrared fluorescence. Exposure to ouabain for 24 hours before incubation with ICG had little effect on cell viability but significantly reduced cellular ICG fluorescence. In contrast, exposure to ouabain for 72 hours reduced cell viability and increased cellular ICG fluorescence.
Cultured human RPE cells take up ICG dye. ICG uptake by RPE cells may involve active transport, as cells incubated with ouabain for 24 hours showed no reduction in cell viability but exhibited reduced infrared fluorescence. The paradoxical increased uptake of ICG into the cells after more prolonged exposure to ouabain may be due to ICG's movement through the damaged cell membrane. Fluorescence due to ICG uptake by RPE has clinical relevance in that it contributes to the fluorescence patterns observed in ICG angiography.
[Show abstract][Hide abstract] ABSTRACT: To determine the effect of different stimulus frame rates and check sizes on blue-yellow multifocal visual evoked potentials (mVEP).
Subjects were examined at the Save Sight Institute at the University Sydney. Experiment 1 involved five adult subjects who underwent binocular stimulation by the Accumap multifocal objective perimeter. The eyes were stimulated with a cortically scaled dartboard pattern consisting of isoluminant blue and yellow checks. These were arranged in three concentric rings extending to an eccentricity of 26 degrees in the visual field. The stimulus pattern was driven by binary sequences resulting in pseudorandom binary exchange of two opposite checkerboard patterns at each of the 32 sites in the visual field. The mVEP were recorded at two different rates of display of the pattern stimulus. In experiment 2, mVEP were tested on 10 normal subjects. Each of the 36 stimulation sites contained a checkerboard pattern of 20, 30, 42 or 56 checks/site, the stimulation pattern was displayed at the optimum rate found in experiment 1. The size of the checks was inversely proportional to the number of checks per site.
In experiment 1, the slow frame rate significantly increased the average amplitude throughout the field tested by 50 +/- 10.1% (P = 0.001). Latency was significantly shortened by 6.3% (P < 0.01). In experiment 2, the average amplitude peaked at 30 checks per segment; however, this was only calculated to be significantly different from the smallest check size (F(crit range 4,27) = 0.09 P < 0.05, anova, Tukey's T method). A similar difference was found in ring 1 (F(crit range 4,27) = 0.09, P < 0.05, anova, Tukey's T method). In ring 2, however, there was also a significant difference between 56 checks and 20, 30 and 42 (F(crit range 4,27) = 0.09, anova, P < 0.05). Altering the check sizes did not significantly affect the amplitudes in ring 3. The latencies were not significantly modified by altering check size at any eccentricity.
These findings suggest that slowing the stimulation rate and displaying 30 checks per stimulation segment optimizes the blue-yellow mVEP stimulus.
No preview · Article · Jun 2004 · Clinical and Experimental Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: To determine the safety of a single intravitreal injection of triamcinolone acetonide (4 mg) in patients with subfoveal choroidal neovascularization caused by age-related macular degeneration.
A double-masked, placebo-controlled, randomized clinical trial was conducted at a public tertiary referral eye hospital. Patients participating had age-related macular degeneration with evidence of choroidal neovascularization, any part of which was classic; age older than 59 years; and best-corrected visual acuity of 20/200 or better. Eyes were assigned to active study treatment or to placebo. Intraocular pressure and cataract grading were performed every 6 months for 3 years. Adverse events, from mild to vision-threatening or life-threatening, were recorded as procedure-related or corticosteroid-related.
Seventy-five eyes were assigned to study treatment and 76 eyes to placebo. There were no moderate or severe adverse events related to the surgical procedure in either group. Triamcinolone-treated eyes had a significantly increased risk of developing mild or moderate elevation of the intraocular pressure. Topical glaucoma medication reduced intraocular pressure to acceptable levels in all patients. There was significant progression of cataract in the triamcinolone-treated eyes.
Despite a significant adverse event profile, intravitreal triamcinolone is generally well tolerated by the human eye as long as patients are carefully followed up by their surgeon and treated appropriately, when necessary.
Full-text · Article · Apr 2004 · Archives of Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: To describe the natural history of optic pathway gliomas (OPGs) in patients with neurofibromatosis type 1 (NF1), and to evaluate the current recommended guidelines for monitoring and follow-up of OPGs in this population.
Retrospective case series.
Patients with OPGs and NF1 seen in the neurofibromatosis clinic at the Children's Hospital at Westmead in Sydney, Australia.
Patients with definite NF1 and confirmed OPGs were identified and their medical records searched to obtain data on demographics, details of the OPG diagnosis, and serial ophthalmic examination findings. Patients were stratified into groups according to age and mode of presentation.
Visual acuity was recorded for each eye and grouped into mild (Snellen equivalent > or = 6/12), moderate (Snellen equivalent = 6/15-6/60), and severe (Snellen equivalent < 6/60) visual impairment at time of diagnosis, during follow-up, and at the most recent examination.
Data were collected on 54 patients, the majority of whom (78%) were seen from 1990 to 2002, with an average follow-up of 8.6 years. The mean age at the time of OPG diagnosis was 5.2 years, with 32 patients having symptoms or signs at the time of diagnosis. Seventeen patients were diagnosed after the age of 6 years (range, 7-15). Twenty-two patients had tumor progression within 1 year of diagnosis, and a further 6 patients showed progression after 1 year. Most patients' conditions were managed conservatively (68.5%). At follow-up, 17 patients (31.5%) had severe visual impairment (<6/60 Snellen equivalent) in their worse eye, and 16.7% had bilateral moderate/severe visual impairment.
Contrary to some previous reports, our results show that OPGs in patients with NF1 often present in older children and may progress some time after diagnosis. Given the potential for serious visual consequences, these findings indicate a need for regular ophthalmological monitoring of this population for a long duration.