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.

ABCC5, a gene that influences the anterior chamber depth, is associated with primary angle closure glaucoma.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =  -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Attitudes and understanding of premium intraocular lenses in cataract surgery: a public health sector patient survey.

OBJECTIVES: To investigate patient understanding of, and attitudes to, premium (toric, extended depth of focus/multifocal) intraocular lenses (premIOLs) in public health sector patients undergoing cataract surgery (CS) in the UK. METHODS: A 12 question survey with Likert scale questions was designed, to assess patient attitudes to post-operative spectacle dependence, refractive target and desirability of spectacle independence whilst considering possible complications of dysphotopsias and need for premIOL exchange/adjustment. RESULTS: 360 surveys were collected. CS had not been performed in 66.5%. Separate spectacles were worn for reading and distance in 28.8%, 19.2% had varifocals, 11.2% bifocals, 22.9% reading glasses only and 1.6% computer glasses only. Contact lenses were not worn in 95.7%. Only 41.6% were drivers. Most patients (85.8%) did not mind wearing glasses after CS, with 78.9% preferring reading glasses, compared with 29.7% preferring distance glasses. Most patients (75.3%) were not familiar with premIOLs, with 58.9% not willing to consider them in the context of a 2% risk of debilitating dysphotopsia and 54.2% rejecting a 5% risk of second surgery. CONCLUSIONS: There is a lack of awareness of premIOLs in public health sector (NHS) patients in the UK, suggesting limitations in the "fully informed" consent process for CS. Most NHS CS patients are currently willing to wear spectacles after CS, especially reading glasses. There is reluctance in such patients to consider premIOLs on a background of small risks of debilitating dysphotopsias and increased risks of a second operation.

Impact of cessation of regular cataract surgery during the COVID pandemic on the rates of posterior capsular rupture and post-operative cystoid macular oedema.

BACKGROUND/OBJECTIVES: During the COVID-19, elective cataract surgery (CS) was significantly curtailed. We investigated whether consequent reduction of micro-surgical skills practice might lead to higher operative complications. METHODS: Single-centre, electronic note review of consecutive patients undergoing CS during three periods: 1st February 2019 to 13th January 2020 (P1) prior to pandemic; 3rd June 2020 to 11th January 2021 after 1st lockdown (P2); and 25th January to 30th July 2021 (P3) after/during second lockdown. RESULTS: 2276 operations occurred during P1, 999 during P2, 846 during P3. During P1, posterior capsular rupture (PCR) rate was 1.67%, similar to P2 (1.30%, p = 0.54), but lower than P3 (3.55%, p = 0.002). There was no difference in PCR risk percentage scores between routine and PCR cases during P1 (1.90% vs 2.03%, p = 0.83), P2 (2% vs 2.18%, p = 0.18), or P3 (1.87% vs. 2.71%, p = 0.08). During P2 and P3, there was a higher rate of cystoid macular oedema (CMO) compared with P1 (4.9% and 6.86% vs. 1.93%, p = 0.0001), with no differences in proportion of diabetics or cases with CMO in combination with PCR. There was no difference in surgeons grade experiencing PCR. CONCLUSIONS: In P3 following 9 months of curtailed elective CS, PCR rates were increased across all surgeon grades, occurring in cases with similar risk percentage scores. CMO rates were increased during COVID and not related to proportion of diabetics or increased PCR rates. The reduction in elective CS during the pandemic was associated with more complications, perhaps due to attenuation of microsurgical skills.

Clinical Outcomes and Cost Analysis of PreserFlo versus Trabeculectomy for Glaucoma Management in the United Kingdom.

PURPOSE: Clinical evaluation and cost analysis of mitomycin-C-augmented PreserFlo MicroShunt versus trabeculectomy. DESIGN: Retrospective cohort study across 3 teaching hospitals. PARTICIPANTS: A total of 134 consecutive eyes of 129 patients (70 undergoing MicroShunt, 64 trabeculectomy). METHODS: Primary and secondary glaucoma cases with uncontrolled intraocular pressure (IOP) were included. Neovascular glaucoma and surgery combined with cataract extraction were excluded. The cost analysis used results from the clinical study to estimate operative costs (equipment and staff costs) and postoperative costs (follow-up visits, nonglaucoma medications, and postoperative procedures) per eye for PreserFlo and trabeculectomy. MAIN OUTCOME MEASURES: The primary clinical outcome measure was surgical failure (defined as IOP > 21 mmHg or < 20% reduction from baseline, IOP ≤ 5 mmHg, reoperation, or loss of light perception) or qualified and complete success (with or without medication) at 18 months. Secondary measures were IOP, glaucoma medications, visual acuity, mean deviation, time to cessation of steroid drops, complications, surgical time, follow-up visits, postoperative interventions, and reoperations. The cost analysis evaluated costs of PreserFlo compared with trabeculectomy. RESULTS: Baseline characteristics were similar, except for more non-White patients in the trabeculectomy group (51% Black and Asian vs. 32% MicroShunt, P = 0.02) and more cases with prior ab externo glaucoma surgery in the MicroShunt group (19% vs. 3% in the trabeculectomy group, P = 0.004). Overall, 59% of eyes had primary open-angle glaucoma. Mean follow-up was 19.9 months for both groups. At 18 months, surgical failure was 25% for MicroShunt compared with 35% for trabeculectomy (P = 0.18). Failure in MicroShunt cases was due to inadequate IOP reduction (84%) or reoperation for glaucoma (16%). Failure in trabeculectomy cases was due to inadequate IOP reduction (58%), persistent hypotony (29%), or reoperation for glaucoma (13%). Combined blebitis and endophthalmitis rate was 1.4% for MicroShunt and 3.1% for trabeculectomy. Cost analysis showed a savings of £245 to £566 per eye in the MicroShunt group, driven mostly by reduced postoperative procedures and follow-up visits. This is in contrast to prior randomized controlled trial data reporting the incremental cost of $2058 of PreserFlo over trabeculectomy. CONCLUSIONS: Our experience of introducing PreserFlo MicroShunt surgery showed it was safer than trabeculectomy and is a cost-saving and effective option that offers potential to free up highly limited National Health Service resources. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Time and Motion Studies to assess surgical productivity in cataract theatre lists within the National Health Service: Immediate Sequential Bilateral Cataract Surgery versus Delayed Sequential Bilateral Cataract Surgery.

BACKGROUND: To compare productivity of National Health Service cataract lists performing unilateral cataract (UC) surgery vs Immediate Sequential Bilateral Cataract Surgery (ISBCS). METHODS: Five 4-hour lists with ISBCS cases and five with UC were observed using time and motion studies (TMS). Individual tasks and timings of each staff member in theatre was recorded by two observers. All operations were performed by consultant surgeons under local anaesthesia (LA). RESULTS: Median number of eyes operated per 4-hour list was 8 (range 6-8) in the ISBCS group and 5 (5-7) in the UC group (p = 0.028). Mean total theatre time (defined as time between the entry of the first patient and the exit of the last patient from theatre) was 177.12 (SD 73.62) minutes in the ISBCS group and 139.16 (SD 47.73) minutes in the UC group (p = 0.36). Mean time to complete two consecutive unilateral cataract surgery operations was 48.71 minutes compared to 42.23 minutes for a single ISBCS case (13.30% time saved). Based on our collected TMS data, a possible 5 consecutive ISBCS cases and 1 UC (total 11 cataract surgeries) could be performed during a four-hour theatre session, with a theatre utilisation quotient of 97.20%, contrasting to nine consecutive UC, with a theatre utilisation quotient of 90.40%. DISCUSSION: Performing consecutive ISBCS cases under LA on routine cataract surgery lists can increase surgical efficiency. TMS are a useful way to investigate surgical productivity and test theoretical models for efficiency improvements.

Functional characterization of a novel c.614-622del rhodopsin mutation in a French pedigree with retinitis pigmentosa.

PURPOSE: To identify and functionally characterize the mutation responsible for autosomal dominant retinitis pigmentosa (adRP) in a large, six-generation French family. METHODS: Twenty individuals from this family participated in the genetic investigation. Six affected and 14 unaffected individuals from three-generations were available for linkage analysis using microsatellite markers flanking the rhodopsin (RHO) gene. A two-point logarithm of odds (LOD) score calculation was undertaken using GENEMARKER and MLINK software. Sanger sequencing of RHO was performed. Cellular localization of the mutant protein was performed by transforming SK-N-SH cells with pEGFP-N1-Rho, pEGFP-N1-Rho(P23H), and pEGFP-N1-Rho(c.614-622del). RESULTS: The proband had nyctalopia, visual field constriction, peripheral bone spicule pigmentation of the fundus, central acuity (6/24 RE; 6/12 LE) at 55 years of age. Linkage analysis of this family suggested RHO as a possible candidate since the flanking marker D3S1292 yielded a LOD score of 2.43 at θ=0. Cloning of an exon 3 PCR product and direct sequencing of single clones identified a novel deletion in the third exon of RHO, c.614-622del (p.Y206-F208del). The deleted mutant protein localized to the endoplasmic reticulum and formed inclusion bodies. CONCLUSIONS: This novel deletion in exon 3 of the RHO gene, c.614-622del results in a classical form of adRP in a multi-generation French family. Protein expression analyses confirmed that the deletion led to protein misfolding and suggest this is a class II mutation, similar to P23H, the most common class II mutation seen in North America.

Autosomal dominant Best disease with an unusual electrooculographic light rise and risk of angle-closure glaucoma: a clinical and molecular genetic study.

PURPOSE: To describe the clinical and molecular characteristics of two families with autosomal dominant Best disease and atypical electrooculography (EOG). METHODS: Four affected individuals from two families were ascertained. Detailed ophthalmic examinations, refraction, and biometry (anterior chamber depth [ACD] and axial length [AL]), gonioscopy, optical coherence tomography of the anterior segment and retina, retinal imaging, and electrophysiological assessment were performed. Arden ratios from EOG testing were calculated by direct measurement of the light peak to dark trough amplitudes. Mutations in bestrophin 1 (BEST1) were identified by bidirectional Sanger sequencing. In family 1, segregation of BEST1 alleles was performed by assaying four microsatellite markers (D11S935, D11S4102, D11S987, and D11S4162) that flank BEST1. RESULTS: The proband from family 1 (three of four siblings affected with Best disease) was 42 years old with bilateral macular vitelliform lesions, advanced angle closure glaucoma (ACG), a normal electroretinogram, and no EOG light rise. Her 44-year-old brother had similar fundus appearances and an EOG light rise of 170%. Their 48-year-old sister had a normal left fundus, whereas the right fundus showed a vitelliform lesion and subretinal thickening. There was no EOG light rise detectable from either eye. Mutation analysis of BEST1 showed all affected siblings to be heterozygous for a missense mutation, c.914T>C, p.Phe305Ser. Their unaffected sister had an EOG light rise of 200%, a normal fundus appearance, and did not harbor the BEST1 mutation. Haplotype analysis of family 1 showed that the affected brother with the 170% EOG light rise had inherited the same nondiseased parental BEST1 allele as his unaffected sister. The other two affected sisters with undetectable EOG light rises shared a different nondiseased parental BEST1 allele. An unrelated 53-year-old female carrying the same c.914T>C, p.Phe305Ser mutation showed typical features of Best disease and an EOG light rise of 180%. All four siblings from family 1 had shorter axial biometry (ACD range 2.06-2.74 mm; AL range 20.46-22.60 mm) than the normal population, contributing to their risk of ACG development. Proband 2 had deeper ACDs (2.83 mm OD and 2.85 mm OS), but similar ALs (21.52 mm OD and 21.42 mm OS) compared to family 1. She had no gonioscopic evidence of angle closure. CONCLUSIONS: A near normal EOG light rise is uncommon in molecularly confirmed Best disease, and in the present report is associated with the same mutation in two families, suggesting a specific role for this amino acid in the retinal pigment epithelium dysfunction associated with this disorder. Haplotype analysis in family 1 was consistent with an effect of the nondisease allele in mediating the presence of an EOG light rise. Clinical assessment of ACG risk is recommended for BEST1 mutation carriers and their first degree relatives.

Pharmacological and environmental factors in primary angle-closure glaucoma.

INTRODUCTION OR BACKGROUND: A large number of drug classes have now been reported to provoke angle closure in high-risk individuals. The mechanism of action can be generalized into three main categories: sympathomimetic, parasympatholytic and idiosyndratic reactions. SOURCES OF DATA: This review of the ophthalmic literature provides a clinical summary of primary angle-closure glaucoma (PACG) and its management. AREAS OF AGREEMENT: External stimuli (pharmacological and environmental) may induce acute, and more often, asymptomatic angle closure, which carries a significant risk of glaucoma. GROWING POINTS: Whenever in doubt, patients at risk of PACG who are starting on drug therapy known to provoke angle closure or aggravate the condition should be referred for detailed gonioscopic examination of the anterior chamber by an ophthalmologist. AREAS FOR DEVELOPING RESEARCH: The use of new imaging methods such as anterior segment optical coherence tomography to assess the presence or risk of angle closure is gaining popularity, and may offer a more rapid method of identifying people who are at risk of sight loss from angle-closure glaucoma precipitated by non-ophthalmological medication.

A synonymous codon variant in two patients with autosomal recessive bestrophinopathy alters in vitro splicing of BEST1.

PURPOSE: Autosomal recessive bestrophinopathy (ARB) is a newly defined retinal dystrophy caused by biallelic mutations in bestrophin-1 (BEST1) and is hypothesized to represent the null bestrophin-1 phenotype in humans. The aim was to determine whether a synonymous BEST1 variant, c.102C>T, identified in two unrelated ARB patients, alters pre-mRNA splicing of the gene. Additionally a detailed phenotypic characterization of this distinctive condition is presented for both patients. METHODS: BEST1 was analyzed by direct sequencing. Patients underwent standard ophthalmic assessment. In silico and in vitro analysis using a minigene system was performed to assess whether a synonymous variant identified, c.102C>T p.Gly34Gly, alters pre-mRNA splicing of BEST1. RESULTS: Both ARB patients harbored either proven (patient 1; c.102C>T p.Gly34Gly and c.572T>C p.Leu191Pro) or presumed (patient 2; c.102C>T p.Gly34Gly and c.1470_1471delCA, p.His490GlnfsX24) biallelic mutations in BEST1 and were found to have phenotypes consistent with ARB. In vitro analysis of the synonymous variant, c.102C>T p.Gly34Gly, demonstrated it to introduce a cryptic splice donor site 52 nucleotides upstream of the actual splice donor site. CONCLUSIONS: The novel BEST1 variant identified, c.102C>T p.Gly34Gly, alters pre-mRNA splicing in vitro and is potentially pathogenic. In vivo this splicing variant is predicted to lead to the production of an mRNA transcript with a premature termination codon (p.Glu35TrpfsX11) that is predicted to be degraded by NMD.

From Conventional Angle Surgery to 360-Degree Trabeculotomy in Pediatric Glaucoma.

PURPOSE: To describe the transition from conventional angle surgery (CAS), trabeculotomy with rigid probe or goniotomy, to 360-degree trabeculotomy assisted with microcatheter (MCT). DESIGN: Retrospective comparative interventional case series. METHODS: Review of consecutive children with glaucoma undergoing angle surgery, including cases with previous surgery, from January 2012 until March 2018 at Moorfields Eye Hospital. Main outcome measure was success rate, defined as intraocular pressure (IOP) ≤21 mm Hg with a minimum of 20% of IOP reduction and no further glaucoma surgery (complete success: without the need of glaucoma drops; qualified success: drops were needed to keep the IOP under control). RESULTS: Among the 106 eyes (77 patients) included were 54 MCT and 52 CAS eyes. At last visit, after a single surgery, qualified success was 85% (46 eyes) in MCT and 37% (19 eyes) in CAS. Complete success was 69% (37 cases) in MCT and 23% (12 cases) in CAS. The mean (95% confidence interval) change in axial length after surgery was -0.03 mm (-0.34 to 0.40) for MCT and +1.35 mm (-0.64 to 1.62) for CAS (P < .001). The percentage of IOP reduction was 52.1% in MCT and 45.5% in CAS (P = .1616). Further glaucoma surgery was required in 5.5% (3) in MCT and 63.4% (33) in CAS. At 1 year, 94.3% of MCT cases achieved qualified success compared to 34.6% of CAS (P < .0001). No significant complications were found on either group. CONCLUSION: MCT achieved better results with significantly lower reoperation rates. The transition from CAS to MCT can be easily achieved, even in difficult cases or those previously operated.

Acceptability of immediate sequential bilateral cataract surgery (ISBCS) in a public health care setting before and after COVID-19: a prospective patient questionnaire survey.

OBJECTIVE: To ascertain patient acceptance of immediate sequential bilateral cataract surgery (ISBCS) in the National Health Service (NHS). METHODS: A survey was devised using a 5-point Likert scale for questions related to ISBCS, which patients undertook during their cataract outpatient appointment pre-COVID-19 lockdown and by telephone during the lockdown. RESULTS: Questionnaires were completed for 267 patients. Most respondents were aged over 71 (51%) and were female individuals (60%). Forty-five per cent agreed/strongly agreed with opting for ISBCS. A positive correlation was identified between opting for ISBCS and convenience to the patient (r=0.76, p<0.01) and family/carer/partner (r=0.71, p<0.01) and wanting to limit numbers of hospital visits (r=0.57, p<0.01). Fifty per cent agreed/strongly agreed that they were worried about the risk of simultaneous bilateral ocular complications, with this correlating with being less likely to opt for ISBCS (r=-0.49, p<0.01) and being scared of ISBCS (r=0.67, p<0.01). During COVID-19 lockdown, patients were less likely to want to minimise the time taken off work (p<0.05) and less intolerant of a prolonged hospital visit (p<0.05). Only 23% of respondents agreed/strongly agreed that they had familiarity with ISBCS. CONCLUSIONS: ISBCS was acceptable to 45% of our sampled population, suggesting limited routine implementation in the NHS is possible. Convenience and reduction in hospital visits appeared to contribute to this acceptance. Half of the patients expressed concern regarding bilateral complications and such concerns need addressing. Some attitudes did appear to change during the COVID-19 lockdown period. The familiarity of the concept of ISBCS is low suggesting the need for patient education.

A new paradigm for delivering personalised care: integrating genetics with surgical interventions in BEST1 mutations.

BACKGROUND: The availability and reduced cost of genotyping has improved gene susceptibility testing and our scientific understanding of disease pathophysiology. Whilst several personalised translational models exist within medical frameworks, genetic-based surgical therapy is a translational application not widely used in surgical specialties. METHOD: We present a clinical series of five patients with genetically confirmed bestrophinopathy and malignant glaucoma (MG). Patients were followed up for 12 months or more after receiving surgical intervention to manage refractory intraocular pressure (IOP) resistant to medical treatment. FINDINGS: Patients with BEST1 gene mutations are at higher risk of MG after filtration surgery. A multi-disciplinary approach after four patients experienced poor outcomes concluded that traditional first-line glaucoma surgery was not sufficient to prevent visual loss. A fifth patient presenting with the identified at-risk phenotype underwent primary pars plana vitrectomy, with pars plana Baerveldt tube insertion, successfully preventing MG and had no glaucoma progression after 5 years. INTERPRETATION: We provide proof-of-principle that genetic analysis can be used to inform the selection of surgical therapy to improve outcomes. In this case, a refinement of current surgical methods to avoid MG. Although challenges remain, personalised surgery has the potential to improve clinical outcomes beyond the scope of current surgical practice.

The treatment of refractory angle-closure glaucoma in a patient with X-linked juvenile retinoschisis.

X-Linked Retinoschisis (XLRS) is a common genetically determined form of macular degeneration affecting young males. XLRS is due to mutations in the RS1 gene located on chromosome Xp22 which codes for retinoschisin and is estimated to affect between 1:5000 to 1:20000 individuals worldwide. We report a case of refractory angle-closure glaucoma in a thirty-nine-year-old Caucasian man with atypical XLRS. The patient presented with a two-day history of left eye pain, acutely reduced vision and a nine-month history of hemicranial pain. Examination identified left intraocular pressure (IOP) of 52mmHg. Gonioscopy confirmed complete angle closure. Following failure of medical management and persistently raised left IOP (43-46mmHg), the patient underwent left phacoemulsification and intraocular lens insertion without complication. After surgery, his IOP reduced to 10-14mmHg on all follow up examinations without the need for glaucoma drops. His iridocorneal angle remained open and vision improved to 20/100. Our case demonstrates the additional role of lens surgery in the treatment of secondary angle-closure glaucoma in the presence of an inherited retinal dystrophy. All patients with inherited retinopathy presenting with a headache or eye pain should undergo gonioscopic examination to exclude angle-closure glaucoma.

Five-year experience of the 2-incision push-pull technique for anterior and posterior capsulorrhexis in pediatric cataract surgery.

PURPOSE: To describe the authors' 5-year experience of the 2-incision push-pull (TIPP) technique for pediatric anterior and posterior capsulorrhexis formation. DESIGN: Retrospective descriptive study over a 5-year period. PARTICIPANTS: A total of 84 eyes of 63 patients who had undergone cataract surgery in 1 center. METHODS: Retrospective review of all consecutive patients who underwent pediatric cataract extraction with planned intraocular lens implantation and TIPP rhexis between January, 1999, and August, 2004. Any lost capsulorrhexis, or capsular tears at any stage of the operation, and the relation of optic size to anterior capsulorrhexis size were noted. MAIN OUTCOME MEASURES: Complications during TIPP rhexis formation and any late complications at last visit. RESULTS: The mean age at operation was 70.21 months (range, 4 weeks-18 years). All eyes had anterior TIPP rhexis; 41 eyes also had posterior TIPP rhexis, and there were no anterior or posterior capsulorrhexis loss or tears while performing the technique. In no patient in whom TIPP rhexis was performed for the posterior capsule was there an inadvertent vitreous loss during rhexis formation. All eyes had anterior rhexis diameters that were smaller than the optic diameter (5.5-6.0 mm), approximately 4 to 4.5 mm in diameter. Four capsular tears were reported; 1 tear occurred during irrigation and aspiration and the others during rigid lens insertion. No late complications were noted. CONCLUSIONS: Our 5-year experience with the TIPP rhexis in pediatric cataract surgery has shown this to be a reliable method for producing a consistent-size capsulorrhexis opening in both anterior and posterior capsulorrhexis.