Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma.

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis.

The utility of symptoms in identification of primary angle-closure in a high-risk population.

OBJECTIVE: To examine the frequency of symptoms associated with primary angle closure in an East Asian population with high rates of disease. DESIGN: Population-based survey. PARTICIPANTS: One thousand adults from rural and urban provinces of Mongolia were examined. METHODS: A standard questionnaire was used to determine a history of symptoms of angle closure. All participants underwent applanation tonometry, gonioscopy, and slit-lamp examination by the same observer. The frequency of symptoms was compared between normal subjects and those in 3 high-risk or affected groups: gonioscopically confirmed occludable angles, peripheral anterior synechiae (PAS) detected on gonioscopy, and anterior chamber depth of less than 2.5 mm. MAIN OUTCOME MEASURES: The frequency of symptoms associated with primary angle closure. RESULTS: Symptoms of visual disturbance and ocular pain traditionally linked with angle closure were reported frequently by both normal and potentially affected people. Intermittent blurring of vision at night was the only common symptom of angle closure that was significantly more frequent in people with narrow angles and PAS (P = 0.004, 48.4% vs. 31.0% narrow angles; P = 0.001, 54.3% vs. 30.6% PAS), but not in those with shallow anterior chambers (P = 0.670, 38.3% vs. 30.9%). CONCLUSIONS: Direct questioning about symptoms associated with angle closure identified high rates of positive responses in both affected and unaffected groups. Although the rate of symptoms tended to be higher in affected people, none of these symptoms were specific enough to be considered useful as a diagnostic criterion.

The Nigerian national blindness and visual impairment survey: Rationale, objectives and detailed methodology.

BACKGROUND: Despite having the largest population in Africa, Nigeria has no accurate population based data to plan and evaluate eye care services. A national survey was undertaken to estimate the prevalence and determine the major causes of blindness and low vision. This paper presents the detailed methodology used during the survey. METHODS: A nationally representative sample of persons aged 40 years and above was selected. Children aged 10-15 years and individuals aged <10 or 16-39 years with visual impairment were also included if they lived in households with an eligible adult. All participants had their height, weight, and blood pressure measured followed by assessment of presenting visual acuity, refractokeratomery, A-scan ultrasonography, visual fields and best corrected visual acuity. Anterior and posterior segments of each eye were examined with a torch and direct ophthalmoscope. Participants with visual acuity of < = 6/12 in one or both eyes underwent detailed examination including applanation tonometry, dilated slit lamp biomicroscopy, lens grading and fundus photography. All those who had undergone cataract surgery were refracted and best corrected vision recorded. Causes of visual impairment by eye and for the individual were determined using a clinical algorithm recommended by the World Health Organization. In addition, 1 in 7 adults also underwent a complete work up as described for those with vision < = 6/12 for constructing a normative data base for Nigerians. DISCUSSION: The field work for the study was completed in 30 months over the period 2005-2007 and covered 305 clusters across the entire country. Concurrently persons 40+ years were examined to form a normative data base. Analysis of the data is currently underway. CONCLUSION: The methodology used was robust and adequate to provide estimates on the prevalence and causes of blindness in Nigeria. The survey would also provide information on barriers to accessing services, quality of life of visually impaired individuals and also provide normative data for Nigerian eyes.

Laser peripheral iridotomy in primary angle-closure suspects: biometric and gonioscopic outcomes: the Liwan Eye Study.

PURPOSE: To assess the immediate effect of laser peripheral iridotomy (LPI) and mechanisms of angle closure in a population-based study of primary angle closure (PAC) suspects. DESIGN: Prospective interventional study. PARTICIPANTS: People identified as PAC suspects aged 50 to 79 years from a population-based survey in Guangzhou, China. INTERVENTION: Laser peripheral iridotomy was performed in 1 randomly selected eye. Examinations were carried out before and 2 weeks after the intervention. MAIN OUTCOME MEASURES: Intraocular pressure (IOP), ultrasound biometry, optical pachymetry, and gonioscopy. RESULTS: A total of 72 people with bilateral suspected PAC participated in the study. Mean IOP decreased by 3 mmHg (P<0.001), but axial anterior chamber depth did not change significantly (P = 0.784) after LPI. Median limbal anterior chamber depth increased from 15% to 25% of peripheral corneal thickness (P<0.001, Wilcoxon signed-rank test). Median iridotrabecular angle width increased from 0 degrees to 10 degrees in the superior quadrant and from 10 degrees to 30 degrees in the inferior quadrant (P<0.001). Nevertheless, 14 eyes (19.4%) still had 3 or more quadrants in which the posterior (usually pigmented) trabecular meshwork could not be seen after laser iridotomy. CONCLUSIONS: This study confirms that LPI results in a significant increase in the angle width in Chinese people with narrow angles. However, one fifth of eyes had residual angle closure after LPI. Although this report confirms that iridotomy widens the anterior chamber angle in most PAC suspects, long-term prospective studies with a larger sample size are required to determine if the risks of PAC glaucoma and other related pathologic sequelae are reduced after prophylactic LPI and to investigate the risk-to-benefit ratio before recommending widespread use of prophylactic LPI in this population.

Prevalence and clinical characteristics of glaucoma in adult Chinese: a population-based study in Liwan District, Guangzhou.

PURPOSE: To assess the prevalence and mechanism of glaucoma in adults living in an urban area of southern China. METHODS: Random clustering sampling was used to identify adults aged 50 years and over in Liwan District, Guangzhou. Glaucoma was diagnosed with the ISGEO (International Society of Geographical and Epidemiological Ophthalmology) classification scheme. All subjects underwent gonioscopy. RESULTS: In the study, 1504 subjects (75.3% participation rate) were examined, with a crude prevalence of all glaucoma of 3.8% (95% confidence interval [CI], 2.8%-4.8%). Primary open-angle glaucoma (POAG) was found in 2.1% (95% CI, 1.4%-2.8%) and primary angle-closure glaucoma (PACG) in 1.5% (95% CI, 0.8%-2.1%). The prevalence of all glaucoma was significantly higher in older people and men. CONCLUSIONS: POAG was more common than PACG in this southern Chinese population, with rates similar to those reported in Chinese Singaporeans. The age-adjusted rate of POAG was similar to that found in European-derived populations, but PACG was more common among Chinese, indicating that there is a large burden of glaucoma in the Chinese people.

Ocular biometry and refraction in Mongolian adults.

OBJECTIVE: To describe the variation in ocular biometry and its association with refraction in adult Mongolians. METHODS: The study included 1800 subjects, aged 40 years or more, who were selected in two Mongolian provinces-Hövsgöl and Omnögobi-to participate in this population survey. Axial length (AL) and its components, as well as noncycloplegic autorefraction and corneal power (CP), were measured. RESULTS: Of those selected, 1617 subjects (90.0%) were examined. Mean +/- SD of AL was 23.13 +/- 1.15 mm. There was a very small but significant increase in mean AL with age (0.05 mm per decade, P = 0.03). Autorefraction was performed on 620 of 675 subjects of those examined in Omnögobi. The age and gender standardized prevalences of myopia (< -0.5 D), emmetropia, hyperopia (> +0.5 D), astigmatism (< -0.5 D of cylinder) and anisometropia (>1.0 D difference between eyes) were 17.2%, 49.9%, 32.9%, 40.9%, and 10.7%, respectively. Prevalence of myopia showed no clear trend with increasing age, whereas hyperopia, astigmatism, and anisometropia all increased monotonically. Multiple regression models revealed that AL (P < 0.001) and VCD (P < 0.001) were the strongest determinants of refractive error. CONCLUSIONS: In this cross-sectional study of adult Mongolians, a much lower prevalence of myopia was found than in other East Asian populations studied to date. The mean AL differed little between age groups, in marked contrast to data on Chinese people.

Associations between narrow angle and adult anthropometry: the Liwan Eye Study.

PURPOSE: To assess the associations between narrow angle and adult anthropometry. METHODS: Chinese adults aged 50 years and older were recruited from a population-based survey in the Liwan District of Guangzhou, China. Narrow angle was defined as the posterior trabecular meshwork not visible under static gonioscopy in at least three quadrants (i.e. a circumference of at least 270°). Logistic regression models were used to examine the associations between narrow angle and anthropomorphic measures (height, weight and body mass index, BMI). RESULTS: Among the 912 participants, lower weight, shorter height, and lower BMI were significantly associated with narrower angle width (tests for trend: mean angle width in degrees vs weight p < 0.001; vs height p < 0.001; vs BMI p = 0.012). In univariate analyses, shorter height, lower weight and lower BMI were all significantly associated with greater odds of narrow angle. The crude association between height and narrow angle was largely attributable to a stronger association with age and sex. Lower BMI and weight remained significantly associated with narrow angle after adjustment for height, age, sex, axial ocular biometric measures and education. In analyses stratified by sex, the association between BMI and narrow angle was only observed in women. CONCLUSION: Lower BMI and weight were associated with significantly greater odds of narrow angle after adjusting for age, education, axial ocular biometric measures and height. The odds of narrow angle increased 7% per 1 unit decrease in BMI. This association was most evident in women.

Physical activity and ocular perfusion pressure: the EPIC-Norfolk eye study.

PURPOSE: To examine the relationship between physical activity and ocular perfusion pressure (OPP), a consistent risk factor for glaucoma. METHODS: The relationship between previous physical activity and current OPP in 5650 participants aged 48 to 90 who attended the first (1993-1997) and third (2006-2010) health check as part of the European Prospective Investigation into Cancer (EPIC)-Norfolk study was examined. Usual combined physical activity at work and leisure was assessed using a validated instrument. Individuals were categorized as inactive, moderately inactive, moderately active, or active. Three IOP measurements were obtained (Ocular Response Analyzer [ORA]; Reichert, Inc., Depew, NY). Mean Goldmann correlated IOP (IOPg) from one eye was used in the analysis. Systolic and diastolic blood pressure (BP) were recorded as the mean of two measurements taken with a sphygmomanometer. Associations between physical activity and low (≤40 mm Hg) mean OPP (2/3 mean arterial pressure - IOP) and low (≤50 mm Hg) diastolic OPP (diastolic BP - IOP) were tested using logistic regression, adjusting for age, sex, body mass index, social class, IOP, and BP. RESULTS: Active people had a lower risk of mean OPP ≤ 40 mm Hg and diastolic OPP ≤ 50 mm Hg after adjusting for age, sex, social class, and body mass index (odds ratio, 0.75; 95% confidence interval [CI], 0.60-0.93; P < 0.01) and (odds ratio, 0.73, 95% CI, 0.58-0.93; P = 0.01), respectively. The association between physical activity and perfusion pressure was independent of IOP, but largely mediated through diastolic BP. CONCLUSIONS: Lower levels of physical activity were associated with lower OPP. Further research is needed to investigate the potential benefit of increased physical activity as a safe and simple method of modifying glaucoma risk.