Changwon Kee

Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

Population-based glaucoma prevalence studies in Asians.

Glaucoma-related population-based studies from Japan, Mongolia, India, Singapore, Thailand, China, Bangladesh, Myanmar, Sri Lanka, and South Korea show a higher glaucoma prevalence in Asian patients, including a higher incidence of primary angle-closure glaucoma, than in white patients, although primary open-angle glaucoma (POAG) is still the most commonly reported. Among POAG, normal tension glaucoma predominates over high tension glaucoma, a distinctive finding. Risk factors for glaucoma in population-based studies in both Asian and white patients are similar, except that myopia is a greater risk factor in Asian patients. Diagnostic criteria differ among studies, some using the International Society of Geographic and Epidemiologic Ophthalmology (ISGEO) classification and others not. The devices used to observe the optic disk and test the visual field are also not uniform across studies. Moreover, the ages of patients, and whether rural or urban, were different. To allow reliable comparison of the results of epidemiologic studies, efforts to standardize the diagnostic criteria, devices, and the age range of the study population are required.

Influence of the Extent of Myopia on the Progression of Normal-Tension Glaucoma

PURPOSE To evaluate the influence of the extent of myopia on the progression rate of normal-tension glaucoma (NTG). DESIGN Retrospective, observational case series. METHODS One hundred forty-three eyes of 143 patients with NTG who were treated from 1994 through 2006 and followed up with standard automated perimetry were evaluated in this study. The participants were divided into 4 groups: mild myopia (-0.76 to -2.99 diopters [D]), moderate myopia (-3 to -5.99 D), severe myopia (-6 D or less), and nonmyopia (emmetropia and hyperopia, -0.75 D or more) groups. The change in mean deviation, corrected pattern standard deviation, mean thresholds of 10 zones corresponding to the glaucoma hemifield test, and thresholds of 52 points of the nonmyopia group were compared with those of the other myopia groups. Additionally, we controlled each analysis for age and posttherapeutic intraocular pressure to preclude the possibility of these covariates influencing the analysis of the effect of myopia on the progression of glaucoma. RESULTS There was no statistically significant difference between the nonmyopia group and each of the myopia groups in terms of mean deviation, corrected pattern standard deviation, mean thresholds of 10 zones corresponding to the glaucoma hemifield test, and the thresholds of 52 point changes against refraction. Moreover, with the control of the other covariates (age and posttherapeutic intraocular pressure), no statistically significant differences were noted (multivariate analysis using mixed model, P > .1). CONCLUSIONS Although a high incidence of open-angle glaucoma among myopic patients has been reported previously, myopia did not influence the progression rate of NTG after treatment.

Effect of optic disc size or age on evaluation of optic disc variables.

AIMS/BACKGROUND It has been reported that the number of optic nerve fibres decrease with age, and the cup/disc (C/D) ratio increases as the optic disc size increases. Consequently, the normal value of the optic disc variables measured by an optic disc analyser may change according to the optic disc size or age. The effect of individual variations in optic disc size or age on interpretation of optic disc variables was investigated. METHODS Topographic optic disc variables of 104 normal Asian adults of both sexes aged 40 to 68 were measured using a confocal scanning laser ophthalmoscope (TopSS, Laser Diagnostic Technologies, Inc). Fourteen variables were evaluated according to the optic disc size or age. Statistical analysis was done by regression analysis. RESULTS With an increase in optic disc size, the increase in cup shape, effective area, 1/2 depth area, C/D ratio, neuroretinal rim area, volume above, volume below, and 1/2 depth volume were statistically significant (p<0.05). However, contour variation, mean contour depth, average depth, maximum depth, average slope, and maximum slope were not affected (p>0.1). Age did not have any significant influence on optic disc variables (p>0.1). CONCLUSION Optic disc size, but not age, should be considered in the interpretation of optic disc variables.

Prevention of Early Postoperative Hypotony by Partial Ligation of Silicone Tube in Ahmed Glaucoma Valve Implantation

PurposeTo determine the effectiveness of the partial ligation of a silicone tube of Ahmed glaucoma valve implantation to prevent early postoperative hypotony. Patients and MethodsThirty-two Korean patients were divided into two groups. Ahmed glaucoma valve implantation was performed with or without partial ligation in 16 eyes. The incidence of complications and the success rate in each group were compared. ResultsIn the partial-ligation group, 10 patients (62.5%) had successful intraocular pressure control (> 5 to < 22 mm Hg) without any additional antiglaucoma medications, whereas intraocular pressure in 12 patients (75.0%) was controlled with or without additional antiglaucoma medications. In the nonligation group, nine patients (56.3%) had successful intraocular pressure control without any additional medications, whereas intraocular pressure in 12 patients (75.0%) was controlled with or without additional antiglaucoma medications. Early postoperative hypotony occurred in 1 of 16 (6.3%) patients with partial ligation and 4 of 16 (25%) patients without ligation. ConclusionThe partial ligation of a tube in Ahmed glaucoma valve implantation suggested a lower rate of hypotony and surgical complications. There was no significant difference in final success rate between the partial ligation and nonligation groups.

Amniotic membrane graft for late-onset glaucoma filtering leaks

PURPOSE To evaluate the effectiveness and safety of amniotic membrane graft in the management of late-onset filtering bleb leaks after trabeculectomy with mitomycin C. DESIGN Prospective, noncomparative, interventional case reports. METHODS Two eyes of two patients with late-onset filtering bleb leak received an amniotic membrane graft. RESULTS In both patients, bleb leaks were closed successfully with amniotic membrane graft, and bleb function was maintained during the follow-up period of 34 and 14 months, respectively. CONCLUSION Amniotic membrane graft may be considered an alternative method for treating late-onset filtering bleb leaks while maintaining bleb function. As the number of cases was small, more cases need to be accumulated to verify the usefulness of this technique.

Multiple developmental defects derived from impaired recruitment of ASC-2 to nuclear receptors in mice: implication for posterior lenticonus with cataract.

ABSTRACT ASC-2, a recently isolated transcriptional coactivator molecule, stimulates transactivation by multiple transcription factors, including nuclear receptors. We generated a potent dominant negative fragment of ASC-2, encompassing the N-terminal LXXLL motif that binds a broad range of nuclear receptors. This fragment, termed DN1, specifically inhibited endogenous ASC-2 from binding these receptors in vivo, whereas DN1/m, in which the LXXLL motif was mutated to LXXAA to abolish the receptor interactions, was inert. Interestingly, DN1 transgenic mice but not DN1/m transgenic mice exhibited severe microphthalmia and posterior lenticonus with cataract as well as a variety of pathophysiological phenotypes in many other organs. Our results provide a novel insight into the molecular and histopathological mechanism of posterior lenticonus with cataract and attest to the importance of ASC-2 as a pivotal transcriptional coactivator of nuclear receptors in vivo.

The Distribution of Intraocular Pressure in Urban and in Rural Populations: The Namil Study in South Korea

PURPOSE To evaluate the intraocular pressure (IOP) distribution and its regional association in the South Korean population. DESIGN Cross-sectional, epidemiologic study. METHODS All participants underwent interview and the following ocular examinations: visual acuity measurement, autorefraction, pachymetry, anterior segment evaluation, slit-lamp examination, Goldmann applanation tonometry, binocular optic disc evaluation, fundus photography, and visual field test. Patients with ocular diseases other than mild senile cataract or with history of ocular surgery were excluded. RESULTS A total of 3191 subjects residing in urban and rural areas were recruited. Mean IOP of patients from the urban area was significantly higher than that of those from the rural area (14.45 ± 2.67 mm Hg vs 13.53 ± 2.76 mm Hg, P < .05). There was regional difference of mean IOP, even after controlling for different demographic factors in the 2 areas (P < .05). Average IOP in the right eye of the investigated sample of South Korean population was 14.10 ± 2.74 mm Hg. Multiple regression analysis showed positive correlation between mean IOP and central corneal thickness, vertical cup-to-disc ratio, history of hypertension, smoking, and female sex, whereas IOP tended to decrease by approximately 0.2 mm Hg when age increased by 10 years. CONCLUSIONS This is the first population-based epidemiologic study measuring IOP in the South Korean population. Mean IOP of the urban area was found to be significantly higher than the corresponding value of the rural area. Therefore, the regional difference, as well as other various factors, has to be considered in epidemiologic study of the distribution of IOP.

Comparison of visual field progression between relatively low and high intraocular pressure groups in normal tension glaucoma patients.

Purpose:To determine the risk factors of visual field (VF) progression in relatively low and high intraocular pressure (IOP) groups in normal tension glaucoma (NTG) patients and to compare progression rate of VF defects between the 2 groups. Methods:Forty-nine eyes of 49 NTG patients with untreated IOP of ⩽15 mm Hg (group A) and 49 eyes of 49 NTG patients matched by age and baseline VF mean deviation (MD) who had untreated IOP of >15 mm Hg (group B) were included in this retrospective chart review study. All patients were followed >5 years. Risk factors for VF progression were evaluated using Cox proportional hazards models in each group, separately. Changes in VF indexes were compared between the 2 groups. Results:Mean IOP and IOP fluctuation were significantly greater in group B than in group A (P<0.001 and P=0.016), whereas other factors did not differ between the groups. In multivariable analysis, VF progression was significantly associated with disc hemorrhage in group A (HR, 6.19; P=0.017) and mean IOP in group B (HR, 1.77; P=0.029). There was no significant difference between the groups in incidence of progression and in changes of MD, pattern SD, and VF index (P=0.942, 0.874, and 0.887, respectively). Conclusions:Although progression rate was similar, the risk factors for VF progression were different in the 2 groups. These findings may suggest that IOP-dependent and IOP-independent factors affect VF progression differently in the 2 groups.

Effect of ginkgo biloba Extract on Visual Field Progression in Normal Tension Glaucoma

Purpose:To evaluate the long-term effect of Ginkgo biloba extract (GBE) on progression of visual field (VF) defects in patients with normal tension glaucoma (NTG). Methods:Forty-two eyes of 42 patients with treated NTG who received 80 mg GBE 2 times daily and who had at least 5 VF tests using the Humphrey Visual Field Analyzer for more than a 4-year period before and after GBE treatment were evaluated in this retrospective study. We evaluated the change of progression rate using mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI) after GBE treatment. The time course of mean total deviation in 10 zones corresponding to the glaucoma hemifield test was analyzed using a linear mixed effects model with unequal random effect variances. Results:The mean follow-up period was 12.3 years. The posttherapeutic intraocular pressures before and after GBE treatment were not significantly different (P=0.509 paired t test). Before GBE treatment, the regression coefficients (RCs) of MD, PSD, and VFI change were −0.619 dB/y, 0.626 dB/y, and −2.153%/y, respectively. After GBE treatment, the RCs of MD, PSD, and VFI change improved significantly to −0.379 dB/y, 0.342 dB/y, and −1.212%/y (P <0.001), respectively. In zone 1, the RC of mean total deviation change was significantly increased after GBE administration (P <0.005). Conclusions:GBE administration slowed the progression of VF damage in patients with NTG, especially in zone 1 corresponding to the superior central field.