Aman Chandra

Role of ADAMTSL4 mutations in FBN1 mutation‐negative ectopia lentis patients

Ectopia lentis (EL) is genetically heterogeneous with both autosomal‐dominant and ‐recessive forms. The dominant disorder can be caused by mutations in FBN1, at the milder end of the type‐1 fibrillinopathies spectrum. Recently in a consanguineous Jordanian family, recessive EL was mapped to locus 1q21 containing the ADAMTSL4 gene and a nonsense mutation was found in exon 11 (c.1785T>G, p.Y595X). In this study, 36 consecutive probands with EL who did not fulfill the Ghent criteria for MFS were screened for mutations in FBN1 and ADAMTSL4. Causative FBN1 mutations were identified in 23/36 (64%) of probands while homozygous or compound heterozygous ADAMTSL4 mutations were identified in 6/12 (50%) of the remaining probands. Where available, familial screening of these families confirmed the mutation co‐segregated with the EL phenotype. This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal‐recessive EL in British families. Furthermore; the first compound heterozygous mutation is described resulting in a PTC and a missense mutation in the PLAC (protease and lacunin) domain. The identification of a causative mutation in ADAMTSL4 may allow the exclusion of Marfan syndrome in these families and guide the clinical management, of particular relevance in young children affected by EL.

Warfarin in vitreoretinal surgery: a case controlled series

Introduction Warfarin is a commonly used anticoagulant whose effect in vitreoretinal surgery has not been well studied. Methods A series of 60 patients on warfarin therapy undergoing pars plana vitrectomy were retrospectively case controlled to 60 patients with similar presenting complaints. In addition, an online survey was performed of current practice in the UK. Results 2% of the patients receiving vitrectomy were on warfarin. There were 33 males and 27 females with a median age of 72.5 years; follow-up was for a mean of 0.88 years. The international normalised ratio (INR) ranged between 0.94 and 4.6 (median 2.3). Two cases of suprachoroidal haemorrhages occurred in the control group (one with preoperative choroidal haemorrhage from dislocated lens nucleus), while none occurred in the warfarin group. 12 patients with rhegmatogenous retinal detachment (RRD) in the warfarin group presented with vitreous haemorrhage compared with only four in the control group (p=0.04). From the online survey, 48 respondents (81%) would ask patients to withhold warfarin prior to vitreoretinal surgery based on the INR. Conclusions There was no increase in complications in patients continuing to take warfarin compared with controls. Patients with RRD are more likely to have vitreous haemorrhage at presentation if they are on warfarin.

The revised ghent nosology; reclassifying isolated ectopia lentis

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term ‘IEL’ should be avoided in such cases.

Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.

Posturing after macular hole surgery: a review.

Since the first reports on surgical repair of macular holes, postoperative face-down posturing (FDP) has been part of the management regime. However, prone positioning is unpleasant for patients, and has adverse effects. Over the last decade some vitreoretinal surgeons have reduced the duration of FDP, or even abandoned it altogether. There have been few non-randomised, and even fewer randomised trials addressing this controversy. With high success rates for macular hole surgery and multiple different surgical strategies such as internal limiting membrane peeling, combining macular hole and cataract surgery, and different durations of gas tamponade, analysing the effects of individual factors is difficult. This paper discusses the mechanisms of surgical repair as well as the role of postoperative FDP, and reviews the studies that have attempted to determine its effect on the success of macular hole surgery.

A spontaneous suprachoroidal haemorrhage: a case report

IntroductionWe present a case of spontaneous suprachoroidal haemorrhage in a patient taking Warfarin. This is only the second case reported of a patient whose anticoagulation was within the therapeutic range.Case presentationAn 84 year old white male with a history of end stage atrophic age related macular degeneration presented with angle closure glaucoma. The patient was taking warfarin and had a therapeutic International Normalized Ratio (INR). Ultrasound examination revealed a spontaneous suprachoroidal haemorrhage.ConclusionAnticoagulation is common in those with cardiovascular disease, which increases the risk of haemorrhagic complications. These patients are also more likely to suffer from age related macular degeneration. Suprachoroidal haemorrhage should be considered in such patients presenting with suspicious signs and a low threshold should be had for investigating for this condition in such circumstances. Early detection may reduce the morbidity.

Craniosynostosis with Ectopia Lentis and a Homozygous 20-base Deletion in ADAMTSL4

Craniosynostosis with ectopia lentis has been described five times since 1950 with unknown inheritance and variable phenotype. The patient was diagnosed with right coronal synostosis at age 10 weeks requiring surgery, and bilateral ectopia lentis with high myopia at 10 months. No other family member was affected. There is no known consanguinity within the family. Genetic screening ruled out FBN1, TGFBR2, and the known craniosynostosis hotspots (FGFR2 exon 8 and exon 10 and FGFR3 exon 6) as the cause. A homozygous deletion in exon 6 of ADAMTSL4 (c.767_786del 20) that has been shown to cause isolated ectopia lentis was found. The mutation results in a premature termination codon (p.Gln256ProfsX38). The proband’s mother, father and one sibling are heterozygous carriers of the mutation. This is the first detailed report of a possible genetic determinant of craniosynostosis with ectopia lentis. Although this mutation causes isolated ectopia lentis, this may be evidence of pleiotropic effects of ADAMTSL4 and may represent an overlapping syndrome with a causative mutation in ADAMTSL4. These findings need to be confirmed in further cases with craniosynostosis and ectopia lentis.

Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina

Background Mutations in ADAMTSL4 have recently been shown to be the major cause of autosomal recessive isolated ectopia lentis (IEL). However, the function and ocular localisation of the protein is yet to be fully established. We therefore aimed to confirm the expression of this gene and protein in normal ocular tissue. Methods Donor ocular tissue was obtained within 48 h post-mortem and iris, choroid and retina were isolated for analysis. Expression of mRNA coding for ADAMTSL4 was examined in four eyes using reverse transcription PCR. Protein coding for this molecule was also investigated in two eyes by western blot analysis. Furthermore, the in situ localisation of ADAMTSL4 was investigated in cryostat sections of whole eyes following immunostaining for this protein and confocal analysis of the stained tissue. Results mRNA and protein coding for ADAMTSL4 were both demonstrated to be expressed in iris and choroidal tissue but were absent from the neural retina. Confocal studies revealed ADAMTS-Like 4 to be present in the ciliary body and ciliary processes and also in the retinal pigment epithelium. Conclusions We have confirmed the gene and protein expression of ADAMTSL4 in human ocular tissue. The pattern of expression may suggest further functions of this gene beyond those suggested by its causative role in IEL.

Prospective randomized controlled trial to compare the effect on the macula of AquaLase liquefaction and ultrasound phacoemulsification cataract surgery.

PURPOSE: To compare the effect of ultrasound (US) phacoemulsification and AquaLase liquefaction (Alcon Laboratories) cataract surgery on the macula using optical coherence tomography (OCT). SETTING: Department of Ophthalmology, Queen Marys Hospital, London, United Kingdom. METHODS: Sixty‐three patients having cataract surgery were randomized to receive US phacoemulsification or AquaLase liquefaction cataract surgery. Macular thickness and volume were evaluated by OCT preoperatively and 2 and 6 weeks postoperatively. The primary outcomes were OCT central macular thickness and best corrected visual acuity at 6 weeks. Secondary outcomes were OCT macular volume and perioperative and postoperative complications. RESULTS: Over the 6‐week study, the median increase in foveal thickness in the study eye compared with that in the fellow eye was 11 μm (interquartile range [IQR] −21 to 23 μm) in the AquaLase group and 17 μm (IQR −11 to 33 μm) in the phacoemulsification group (P = .229). A subgroup analysis of diabetic patients found a median increase in foveal thickness in the study eye versus the fellow eye of 2 μm (IQR −14 to 23 μm) in the AquaLase group and 29 μm (IQR 11 to 41 μm) in the phacoemulsification group (P = .07). CONCLUSIONS: The results in this study suggest that AquaLase liquefaction cataract extraction is as safe as standard US phacoemulsification cataract extraction and may carry less risk for the development of postoperative cystoid macular edema. This may be most evident in diabetic patients.

Ethnic variation in rhegmatogenous retinal detachments

PurposeWe aimed to investigate the clinical variation of rhegmatogenous retinal detachments (RD) in patients of different ethnicities.MethodsPatients presenting with a primary RD from two ethnic groups were recruited from our tertiary referral hospital between August 2010 and December 2012. Patients who self-reported their ethnic origin either as European Caucasian (EC) or South Asian (SA) were included. Exclusion criteria included trauma, previous vitreoretinal procedures, age under 18 years, complicated cataract surgery and the presence of syndromes known to be associated with a high prevalence of RD. Detailed phenotypic data were collected. Descriptive and comparative statistical analyses were undertaken.Results1269 Patients were recruited. 1173 (92.4%) were EC. Mean age of onset was 58.3 years (EC) and 54.5 years (SA) (P=0.006). 75.3% EC and 58.4% SA were phakic (P<0.001). 12.8% of EC and 19.4% of SA patients had a lattice retinal degeneration in the affected eye (P=0.003). Refractive myopia was greater in SA patients (mean: −6.1DS) than EC (−4.2DS) (P=0.032). Additionally, SA patients had a greater mean axial length (25.65 mm) than EC (25.06 mm) (P=0.014). No differences were demonstrated in laterality, family history, type of retinal break or macular status.ConclusionsSA patients present with RD at an earlier age and have a more severe phenotype than ECs. Future management strategies for RD may need to reflect these differences.