A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes.

Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and developmental defects. Genome-wide linkage analysis localized the critical interval to chromosome 12p with a maximum two-point LOD score of 4.2 (θ = 0). Next-generation exome sequencing identified a novel homozygous missense variant (c.653 T > C; p.F218S) in peroxisomal biogenesis factor 5 (PEX5), a peroxisome import receptor protein. This missense mutation was confirmed by bidirectional Sanger sequencing. It segregated with the disease phenotype in the family and was absent in ethnically matched control chromosomes. The lens-specific knockout mice of Pex5 recapitulated the cataractous phenotype. In vitro import assays revealed a normal capacity of the mutant PEX5 to enter the peroxisomal Docking/Translocation Module (DTM) in the presence of peroxisome targeting signal 1 (PTS1) cargo protein, be monoubiquitinated and exported back into the cytosol. Importantly, the mutant PEX5 protein was unable to form a stable trimeric complex with peroxisomal biogenesis factor 7 (PEX7) and a peroxisome targeting signal 2 (PTS2) cargo protein and, therefore, failed to promote the import of PTS2 cargo proteins into peroxisomes. In conclusion, we report a novel missense mutation in PEX5 responsible for the defective import of PTS2 cargo proteins into peroxisomes resulting in congenital cataracts and developmental defects.

Mutations in FYCO1 identified in families with congenital cataracts.

Purpose: This study was designed to identify the pathogenic variants in three consanguineous families with congenital cataracts segregating as a recessive trait. Methods: Consanguineous families with multiple individuals manifesting congenital cataracts were ascertained. All participating members underwent an ophthalmic examination. A small aliquot of the blood sample was collected from all participating individuals, and genomic DNAs were extracted. Homozygosity-based linkage analysis was performed using short tandem repeat (STR) markers. The haplotypes were constructed with alleles of the STR markers, and the two-point logarithm of odds (LOD) scores were calculated. The candidate gene was sequenced bidirectionally to identify the disease-causing mutations. Results: Linkage analysis localized the disease interval to chromosome 3p in three families. Subsequently, bidirectional Sanger sequencing identified two novel mutations-a single base deletion resulting in a frameshift (c.3196delC; p.His1066IlefsTer10) mutation and a single base substitution resulting in a nonsense (c.4270C>T; p.Arg1424Ter) mutation-and a known missense (c.4127T>C, p.Leu1376Pro) mutation in FYCO1. All three mutations showed complete segregation with the disease phenotype and were absent in 96 ethnically matched control individuals. Conclusions: We report two novel mutations and a previously reported mutation in FYCO1 in three large consanguineous families. Taken together, mutations in FYCO1 contribute nearly 15% to the total genetic load of autosomal recessive congenital cataracts in this cohort.

Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree.

PURPOSE: To identify the molecular basis of inherited retinal degeneration (IRD) in a familial case of Pakistani origin using whole-exome sequencing. METHODS: A thorough ophthalmic examination was completed, and genomic DNA was extracted using standard protocols. Whole exome(s) were captured with Agilent V5 + UTRs probes and sequenced on Illumina HiSeq genome analyzer. The exomeSuite software was used to filter variants, and the candidate causal variants were prioritized, examining their allele frequency and PolyPhen2, SIFT, and MutationTaster predictions. Sanger dideoxy sequencing was performed to confirm the segregation with disease phenotype and absence in ethnicity-matched control chromosomes. RESULTS: Ophthalmic examination confirmed retinal degeneration in all affected individuals that segregated as an autosomal recessive trait in the family. Whole-exome sequencing identified two homozygous missense variants: c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741) and c.902G > A; p.Gly301Asp in C1QTNF4 (NM_031909). Both variants segregated with the retinal phenotype in the PKRD320 and were absent in ethnically matched control chromosomes. CONCLUSION: Whole-exome sequencing coupled with bioinformatics analysis identified potential novel variants that might be responsible for IRD.

Pathophysiology, diagnosis, and management of glaucoma associated with Sturge-Weber syndrome.

PURPOSE: Sturge-Weber syndrome (SWS), also known as encephalotrigeminal angiomatosis, is a condition which includes leptomeningeal hemangioma, facial angiomatosis or nevus flammeus, and ocular changes. SWS can lead to severe complications of anterior segment involving conjunctiva and eyelids, whereas posterior segment of the eye may also be affected by diffuse choroidal hemorrhages. This article was written with the objectives to determine the pathophysiology, diagnosis, and treatment of glaucoma associated with this rare and challenging disorder. METHODS: A detailed literature search was conducted on PubMed, EMBASE, Cochrane Library, and Google Scholar using the key words. Forty-five articles matched our inclusion criteria that were included in this systematic review. RESULTS: Glaucoma is the one of the commonest ocular manifestations of SWS. It is caused by anterior chamber malformations, increased pressure in the episcleral veins, and changes in ocular hemodynamics. Glaucoma associated with SWS is usually congenital but can develop adults as well. The treatment of glaucoma associated with SWS is quite challenging because of early-onset, severe visual field impairment at the time of diagnosis, and unresponsiveness to standard medical treatment. Several surgical procedures have been devised but the long-term control of the intraocular pressure and visual function remain unsatisfactory. Modifications in the filtration surgery techniques and use of newer anti-fibrotic agents have produced good control of intraocular pressure. CONCLUSION: Management of glaucoma associated with SWS is multi-dimensional and needs both medical and surgical interventions for better control. The treatment should be devised on case to case basis depending upon the intraocular pressure, stage of the disease, and type of glaucoma.

Comparison of characteristics of femtosecond laser-assisted anterior capsulotomy versus manual continuous curvilinear capsulorrhexis: A meta-analysis of 5-year results.

OBJECTIVE: To perform a meta-analysis on the precision and safety of femtosecond laser-assisted anterior capsulotomy versus conventional manual continuous curvilinear capsulorrhexis. METHODS: This meta-analysis was conducted from February 2010 to November 2014. Literature search on PubMed, Google Scholar, ExcerptaMedica database and Cochrane Library was done to identify randomised controlled trials and case-control studies. SPSS 20 was used for data analysis. RESULTS: Of the 10 articles included, there were 3(30%) randomised controlled trials and 7(70%) non-randomised controlled trials. The meta-analysis was based on a total of 2,882eyes. Of them, 1,498(51.97%) underwent femtosecond laser-assisted capsulotomy and 1,384(48.02%) underwent manual continuous curvilinear capsulorrhexis. The diameter of the capsulotomy and the rates of anterior capsule tear showed no statistical difference between the femtosecond laser group and the manual capsulorrhexis group (p=0.29 and p=0.68). In terms of circularity of capsulotomy, femtosecond laser group had a more significant advantage than the manual capsulorrhexis group (p<0.001). CONCLUSIONS: Femtosecond laser performed capsulotomy with more precision and higher reliability than the manual continuous curvilinear capsulorrhexis.

Femto-lasik: The recent innovation in laser assisted refractive surgery.

Femtosecond laser has been introduced in refractive surgery to create a thin-hinged corneal flap without using any blade. The current review was planned to analyse and compare femtosecond-assisted laser in-situ keratomileusis (LASIK), the latest refractive procedure, with conventional techniques in refractive surgery. The analysis showed that femtosecond-assisted LASIK yielded more predictable corneal flaps, lesser ocular aberrations, better uncorrected visual acuity, lesser variations in intraocular pressure (IOP) and fewer chances of developing dry eyes. Transient light sensitivity, diffuse lamellar keratitis, opaque bubble layer, corneal haze and rainbow glare are some of the demerits of femtosecond-assisted LASIK, but these can be prevented with certain precautions. The early visual rehabilitation and preservation of corneal anatomy are added benefits in the long run. Though it is expensive currently, the competition in market is expected to cut down the cost soon.

A Finite Element Analysis on the Effect of Scanning Pattern and Energy on Residual Stress and Deformation in Wire Arc Additive Manufacturing of EH36 Steel.

Wire arc additive manufacturing (WAAM) is a metal additive manufacturing (AM) technique that has a high throughput and has seen a potential interest for replacing currently available subtractive manufacturing techniques. Contrary to other metal AM machines, WAAM rigs can be built using existing welding plants and using welding wire as feedstock, thus, making it a cheap and viable manufacturing technique for a number of industries, such as the maritime industry. However, the effects of AM parameters, such as the scanning pattern and energy, on the residual stress and deformation, are still not completely understood. In this work, a finite element (FE) study has been conducted to understand the influence of different scanning patterns (alternate, in-out, raster and zigzag) and energies on residual stress and warpage. Analyses show that the in-out scanning pattern leads to the highest residual stress, while the zigzag pattern results in the lowest residual stress for all scanning energies considered in this study. Findings in the present study also show that the scanning pattern affects the residual stress and deformation more than does the scanning energy.

Effect of Phase Transformations on Scanning Strategy in WAAM Fabrication.

Due to its high production rates and low cost as compared to other metal additive manufacturing processes, wire arc additive manufacturing (WAAM) has become an emerging technology in the manufacturing industry. However, the residual stress generation and part distortion hinder its widespread adoption because of the complex thermal build-histories of WAAM parts. One of the ways to alleviate this problem is to consider the effects of scan strategies as it directly influences the thermal history of the built part. Since WAAM itself is an evolved welding process and even though it is evident from welding studies that phase transformations directly affect the residual stresses in welded parts, it remains unclear how the consideration of phase transformations for different scan strategies will affect the residual stresses and distortions in the WAAMed parts. A FEM study has been performed to elucidate the effects of phase transformations on residual stresses and the distortion for different deposition patterns. The current findings highlight that for the fabrication of low-carbon martensitic steels: The consideration of phase transformations for line-type discontinuous patterns (alternate and raster) do not significantly affect the residual stresses. Consideration of phase transformations significantly affects residual stresses for continuous patterns (zigzag, in-out and out-in). To accurately simulate complex patterns, phase transformations should be considered because the patterns directly influence the temperature history of the built part and will thus affect the phase transformations, the residual stresses and the warpage. During the fabrication of WAAM parts, whenever possible, discontinuous line scanning patterns should be considered as they provide the part with uniform residual stress and distortion. The alternate line pattern has been found to be the most consistent overall pattern.

Features and Diagnostic Accuracy of Optical Coherence Tomography Angiography in Neovascular Age-related Macular Degeneration.

Introduction Age-related macular degeneration (AMD) is one of the important causes of visual impairment in aging population. Fundus fluorescein angiography (FFA) is gold standard for the diagnosis of neovascular AMD (nAMD) while optical coherence tomography (OCT) aids in the diagnosis of nAMD and is very useful for follow-up. OCT angiography (OCTA) is an evolving imaging technology that can be used as a valid diagnostic tool to study morphology of choroidal neovascularization (CNV) that is seen in nAMD. This study was conducted with the objective to determine diagnostic accuracy and OCTA features of occult and classic CNV in patients with nAMD. Methods In this prospective observational study, 90 eyes of 58 patients with nAMD were studied with OCT, OCTA and FFA. OCTA scans were analyzed to qualitatively describe the morphological appearance of CNV in terms of location, pattern and configuration. The OCTA sensitivity and specificity for CNV detection were calculated by comparing it with FFA. Results FFA detected CNV in 70 of the 90 eyes (77.77%) whereas OCTA identified CNV in 69 eyes (76.7%). Among 69 eyes with CNV, it was well-defined in 51 (73.9%) eyes and poorly defined in 18 (26.1%) eyes. There were four false positive and five false negative cases. The sensitivity, specificity, positive predictive value and negative predictive value of OCTA in detection of nAMD were found to be 92.85%, 80.0%, 94.2 and 76.2, respectively. Conclusion OCTA is a useful, noninvasive, reproducible imaging tool for diagnosing, classifying and localizing CNV. The technique has high sensitivity and specificity and can be used reliably in cases where FFA is contraindicated or inconclusive.

Ophthalmic Manifestations of Acute Leukemia.

Introduction Ocular involvement in leukemia may occur because of direct leukemic infiltration or because of secondary ophthalmic involvement as a result of abnormalities related to blood like anemia, thrombocytopenia, and leukocytosis. In some patients with leukemia, ophthalmic signs can precede the systemic features and can help in early diagnosis of systemic leukemia. Due to the scarcity of data on this topic from Pakistan, we conducted this study to determine the pattern of ocular involvement in patients with leukemia presenting in our settings. Methods This cross-sectional study was conducted in a tertiary care hospital of Pakistan over a period of one year. The study comprised of both newly diagnosed and follow-up patients of acute leukemia of age more than 15 years. Patients underwent detailed ophthalmic anterior and dilated posterior segment examination. Patient's demographic profile, type of leukemia, chemotherapy status, and hematologic findings were also documented. Results There were 97 leukemic patients in the study with 55 (56.7%) males and 42 (43.3%) females. Various ophthalmic manifestations were observed in 47 (48.45%) patients. Forty-two (43.3%) were diagnosed cases with acute lymphocytic leukemia (ALL) and 55 (56.7%) suffered from acute myelogenous leukemia (AML). Ophthalmic manifestations were present in 29 patients of AML (52.7%) and 18 patients of ALL (42.85%). Ocular involvement was significantly more common in newly diagnosed (n=32) as compared with follow-up patients (n=15) (p-value = 0.032). Posterior segment (n=48) was the most common site of ocular involvement (n=48, 49.5%) with retinal hemorrhages seen in 40 patients (41.2%) and papilloedema in seven cases (7.2%). Thirty-three (70.2%) out of 47 patients with ophthalmic manifestations were asymptomatic while 14 (29.8%) had ocular symptoms at the time of initial presentation. Conclusion Ophthalmic manifestations were present in about half of the patients with leukemia. Ocular involvement was more prevalent in newly diagnosed cases and in patients with AML.

Frequency of Depression in Patients with Type 2 Diabetes Mellitus and its Relationship with Glycemic Control and Diabetic Microvascular Complications.

Introduction Various clinical studies have reported that clinical depression is a common co-morbidity in patients with type 2 diabetes mellitus. Depression can badly affect the lifestyle of diabetic patients and impair the proper management of diabetes mellitus. Therefore, there exists a need to identify risk factors of depression in diabetic patients especially in relation to various clinical parameters, glycemic control and diabetic microvascular complications. Materials and methods It was a cross-sectional study conducted in a tertiary care hospital in Pakistan from August 2018 to April 2019. We recruited type 2 diabetic patients and measured their various clinical and hematological parameters. We evaluated depression using Patient Health Questionnaire (PHQ-9) and evaluated its relationship with glycemic control, duration of diabetes, fasting lipid profile and presence of various diabetic microvascular complications. Results There were 100 subjects in the study having a mean age 58.3 ± 12.4 (range: 36 - 71) years with a male to female ratio of 1:1.2. The mean duration of type 2 diabetes mellitus was 11.2 ± 9.2 years. The mean PHQ-9 score of the study population was 10.2 ± 8.1. The frequency of depression was found to be 40.0%. Depression was most frequently found in women and in patients between 40 to 60 years of age (60.0%). Depression was more common in patients with dyslipidemia (p-value = 0.0015). Patients with diabetic retinopathy, diabetic nephropathy and diabetic neuropathy were 3.8 times, 4.2 times and 2.1 times more likely to have clinical depression than the patients without these complications. Patients with glycated hemoglobin (HbA1c) worse than 7.5% had a significantly higher rate of depression than those whose HbA1c ranged from 6.5 - 7.5 % (p-value = 0.0028). Duration of diabetes mellitus did not significantly affect the frequency of depression in diabetic patients. Conclusion Depression is common in a large number of diabetic patients. Female gender, dyslipidemia, diabetic microvascular complications and impaired glycemic control are significantly associated with depression in diabetic patients.

Pathologic Study of Supernumerary Orbital Band in Type I Duane Syndrome.

BACKGROUND/AIMS: Accessory orbital bands are relatively rare and very few reports detail histopathology. Cases in the literature describe the composition of the bands as muscular and/or fibrous. The composition of the supernumerary band lying deep in the medial rectus muscle in a patient with type I Duane syndrome was investigated. METHODS: Histochemical stains were used in conjunction with polarized light for differentiating compressed collagen from muscle. Immunohistochemistry was used for verification of the presence of muscle. RESULTS: Compressed collagen appeared red using Masson trichrome staining. Collagen was positively identified by illumination with polarized light on several stains including the underutilized Sirius red dye. CONCLUSIONS: The findings of dense collagen fibers in the fibrotic band with focal striated muscle correlated with the restrictive strabismus. In concert with other cases in the literature, it is proposed that the fibrous bands are generally associated with restrictive strabismus. Bands that are muscular may or may not be associated with strabismus. Special techniques are needed to positively identify compressed collagen.

Decompensated Esophoria as a Benign Cause of Acquired Esotropia.

PURPOSE: To determine informative clinical and magnetic resonance imaging (MRI) characteristics of patients with symptomatic adult acquired, comitant esotropia due to decompensated esophoria. DESIGN: Retrospective, interventional case series. METHODS: Setting: Institutional. STUDY POPULATION: Patients with decompensated esophoria who developed acute acquired comitant esotropia. OBSERVATION PROCEDURES: Ophthalmic examination, stereopsis, and strabismus measurements at distance and near using prism cover tests in diagnostic gaze positions were performed. Patients underwent high-resolution surface coil MRI of extraocular muscles with target fixation, and MRI of the brain. Strabismus surgery was performed under topical anesthesia with adjustable sutures wherever possible. Paired t testing was used to evaluate postoperative changes with 0.05 considered significant. MAIN OUTCOME MEASURE: Clinical and MRI characteristics, and surgical outcome of patients with decompensated esophoria. RESULTS: Eight cases were identified involving subjects of mean age 29 ± 9.4 (range: 20-48) years having gradually progressive intermittent horizontal, binocular diplopia for 10 months to 3 years. Mean preoperative esotropia was 31 ± 12 Δ at distance and 29 ± 12 Δ at near, although this was intermittent in 5 patients who exhibited enhanced fusional divergence. Neurologic evaluation and MRI of brain, orbits, and extraocular muscles were unremarkable in all cases. Orthotropia was successfully restored in all by standard or enhanced doses of bimedial rectus muscle recession surgery, improving mean stereoacuity from 535 to 68 arc seconds, although 5 patients exhibited 2-14 Δ asymptomatic residual esophoria. CONCLUSION: Decompensated esophoria is a benign clinical entity causing acute, acquired, comitant esotropia treatable with enhanced medial rectus recession.

Moebius Syndrome with Hypoglossal Palsy, Syndactyly, Brachydactyly, and Anisometropic Amblyopia.

Moebius syndrome is a rare cause of congenital facial and abducens palsy. It is sometimes associated with musculoskeletal abnormalities and other cranial nerve palsies. Genetics and ischemic insults to the fetus are considered to be the cause of this syndrome. We report here a 12-year-old female patient who was presented to us with poor cosmesis of her face, with associated decreased vision and lagophthalmos in her left eye. She didn't have any signs of exposure keratopathy in the affected eye. Her best-corrected vision was 20/20 and 20/60 in right and left eyes respectively. The cause of decreased vision in her left eye was found to be anisometropic amblyopia, due to asymmetric hyperopic astigmatism in her eyes. She did not report diplopia in any gaze position. Examination of her cranial nerve revealed left facial, abducens, and hypoglossal nerve palsy, leading us to the diagnosis of Moebius syndrome. Apart from that, she had syndactyly in one of her hands, and brachydactyly in both. Since the eyes were straight in their primary position, no surgical intervention was carried out for her lagophthalmos, which was measured to be only 2 mm. This was to prevent any post-operative iatrogenic ptosis. The condition requires a multidisciplinary approach involving the opinions of a neuro-ophthalmologist, strabismologist, and oculoplastics for the management of the complications associated with the disease.

Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening.

Purpose: To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. Methods: Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. Results: Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. Conclusions: The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population.

Challenges in the management of glaucoma in developing countries.

Glaucoma is the most common optic neuropathy characterized by normal to raised intraocular pressure (IOP), visual field defects, loss of retinal nerve fiber layer, thinning of the neuroretinal rim, and cupping of the optic disc. IOP reduction by medical, laser, or surgical therapies remains the only clinically proven treatment of glaucoma. The challenges in glaucoma management are diverse. They include early detection and diagnosis, setting of appropriate target IOP, choice of treatment, monitoring of quality of life and sight, and compliance with the treatment. Early diagnosis can be made by assessing optic nerve structure using imaging devices and optic nerve function through perimetry. Reducing IOP and controlling its fluctuations are considered to be the most important factors in limiting progression of glaucoma. Selection of the best suitable therapy out of medical, surgical, or laser treatment options is yet another management challenge. Patients suffering from glaucoma experience poor quality of life owing to the diagnosis itself, functional visual loss, inconvenience and cost of treatment, and side effects of treatment. All these factors lead to poor compliance, adherence, and persistence to treatment, and further progression of the disease. It is, therefore, important that ophthalmologists keep all the aforementioned factors in mind when managing patients with glaucoma.

Femtosecond laser assisted cataract surgery, beginning of a new era in cataract surgery.

The purpose of this article is to analyze and understand the mechanism of action, effectiveness, cost and time benefits, advantages and disadvantages of the femtosecond laser (FSL) assisted cataract surgery. A PubMed search was done using the topic and the keywords. Research shows considerable improvements in corneal incisions, anterior capsulotomy, and phacofragmentation using FSL. We will also discuss and compare FSL with conventional cataract extraction techniques in terms of both short-term and long-term advantages and disadvantages. Limitations of the studies reviewed include small sample size and short-term follow-up. The major dilemma is still considered to be its heavy financial feasibility to date.