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Journal of Human Genetics Jun 2024Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and...
Phenotypic and genotypic heterogeneity in congenital ocular diseases, especially in anterior segment dysgenesis (ASD), have created challenges for proper diagnosis and classification of diseases. Over the last decade, genomic research has indeed boosted our understanding in the molecular basis of ASD and genes associated with both autosomal dominant and recessive patterns of inheritance have been described with a wide range of expressivity. Here we describe the molecular characterization of a cohort of 162 patients displaying isolated or syndromic congenital ocular dysgenesis. Samples were analyzed with diverse techniques, such as direct sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing (WES), over 20 years. Our data reiterate the notion that PAX6 alterations are primarily associated with ASD, mostly aniridia, since the majority of the cohort (66.7%) has a pathogenic or likely pathogenic variant in the PAX6 locus. Unexpectedly, a high fraction of positive samples (20.3%) displayed deletions involving the 11p13 locus, either partially/totally involving PAX6 coding region or abolishing its critical regulatory region, underlying its significance. Most importantly, the use of WES has allowed us to both assess variants in known ASD genes (i.e., CYP1B1, ITPR1, MAB21L1, PXDN, and PITX2) and to identify rarer phenotypes (i.e., MIDAS, oculogastrointestinal-neurodevelopmental syndrome and Jacobsen syndrome). Our data clearly suggest that WES allows expanding the analytical portfolio of ocular dysgenesis, both isolated and syndromic, and that is pivotal for the differential diagnosis of those conditions in which there may be phenotypic overlaps and in general in ASD.
Topics: Humans; Exome Sequencing; PAX6 Transcription Factor; Male; Female; Eye Abnormalities; Phenotype; Anterior Eye Segment; Mutation; Eye Diseases
PubMed: 38459225
DOI: 10.1038/s10038-024-01237-6 -
Cornea Mar 2024Contact lenses are US Food and Drug Administration-regulated medical devices that are a safe and effective method for the correction of refractive error. They are worn...
Contact lenses are US Food and Drug Administration-regulated medical devices that are a safe and effective method for the correction of refractive error. They are worn by an estimated 45 million Americans. Decorative contact lenses (DCLs) can be used for patients with medical conditions such as failed corneas or aniridia. However, DCLs have also gained popularity in the young, contact lens-naïve population. DCL users often buy lenses through unregulated sources without a clinical examination and education on proper use by an eye care professional. These lenses have a significantly higher risk of infection when compared with contact lenses for the correction of refractive error. To reduce the incidence of microbial keratitis, regulators and eye care professionals must make coordinated efforts to generate and disseminate prevention messages to all contact lens users. In addition, physician and patient reporting of contact lens-related complications to regulatory agencies enhances the pathway to risk reduction. This article reviews DCL use and supply, with a specific focus on the increased risk of contact lens-related complications in unsupervised DCL use.
PubMed: 38456820
DOI: 10.1097/ICO.0000000000003522 -
Current Eye Research Jun 2024During life up to 70% of aniridia subjects develop aniridia-associated keratopathy (AAK). AAK is characterized by limbal stem cell insufficiency, impaired corneal...
PURPOSE
During life up to 70% of aniridia subjects develop aniridia-associated keratopathy (AAK). AAK is characterized by limbal stem cell insufficiency, impaired corneal epithelial cell differentiation and abnormal cell adhesion, which leads to centripetal spreading vascularization, conjunctivalization, and thickening of the cornea. Our aim was to examine the subbasal nerve plexus and central corneal stromal microstructure in subjects with congenital aniridia, using confocal laser scanning microscopy CLSM.
METHODS
31 eyes of 18 patients (55.6% males, mean age: 25.22 ± 16.35 years) with congenital aniridia and 46 eyes of 29 healthy subjects (41.4% males, mean age 30 ± 14.82 years) were examined using the Rostock Cornea Module of Heidelberg Retina Tomograph-III. At the subbasal nerve plexus, corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal total branch density (CTBD), and corneal nerve fiber width (CNFW) were analyzed using ACCMetrics software. Keratocyte density in the anterior, middle and posterior stroma was assessed manually.
RESULTS
The CNFD (2.02 ± 4.08 vs 13.99 ± 6.34/mm), CNFL (5.78 ± 2.68 vs 10.56 ± 2.82 mm/mm) and CTBD (15.08 ± 15.62 vs 27.44 ± 15.05/mm) were significantly lower in congenital aniridia subjects than in controls ( < 0.001 for all). CNFW was significantly higher in aniridia subjects than in controls (0.03 ± 0.004 vs 0.02 ± 0.003 mm/mm) ( 0.003). Keratocyte density was significantly lower in all stromal layers of aniridia subjects than in controls ( < 0.001 for all). Stromal alterations included confluent keratocytes, keratocytes with long extensions and hyperreflective dots between keratocytes in aniridia.
CONCLUSIONS
Decrease in CNFD, CNFL, and CTBD, as well as increase in CNFW well refer to the congenital aniridia-associated neuropathy. The decreased keratocyte density and the stromal alterations may be related to an increased cell death in congenital aniridia, nevertheless, stromal changes in different stages of AAK have to be further analyzed in detail.
Topics: Humans; Aniridia; Female; Male; Microscopy, Confocal; Adult; Corneal Stroma; Nerve Fibers; Young Adult; Adolescent; Middle Aged; Ophthalmic Nerve; Child
PubMed: 38444179
DOI: 10.1080/02713683.2024.2320779 -
Clinical Dysmorphology Apr 2024Aniridia is an autosomal dominant condition characterized by the complete or partial absence of the iris, often with additional presentations such as foveal hypoplasia,...
Aniridia is an autosomal dominant condition characterized by the complete or partial absence of the iris, often with additional presentations such as foveal hypoplasia, nystagmus, cataract, glaucoma and other ocular abnormalities. Most cases are caused by heterozygous mutations in the paired box 6 gene (PAX6), which codes for a transcription factor that regulates eye development. Four patients from our hospital who presented with ocular phenotypes were recruited for research sequencing with informed consent. Sanger sequencing of PAX6 coding exons or exome sequencing was performed on genomic DNA from venous blood samples. Variants in PAX6 were identified in the four patients. Two variants are recurrent single-nucleotide substitutions - one is a substitution found in a patient with bilateral aniridia, whereas the other is a splice variant in a patient with nystagmus and neuroblastoma. The other two variants are novel and found in two patients with isolated aniridia. Both are small duplications that are predicted to lead to premature termination. For the recurrent variants, the comparison of phenotypes for patients with identical variants would shed light on the mechanisms of pathogenesis, and the discovery of two novel variants expands the spectrum of PAX6 mutations.
Topics: Humans; Face; Aniridia; Cataract; Exons; Asia, Southeastern; PAX6 Transcription Factor
PubMed: 38441200
DOI: 10.1097/MCD.0000000000000487 -
Journal of Clinical Medicine Feb 2024Boston Keratoprosthesis Type I (BI-KPro I) is a synthetic cornea that can be used to restore vision in patients with corneal blindness. This retrospective study...
Boston Keratoprosthesis Type I (BI-KPro I) is a synthetic cornea that can be used to restore vision in patients with corneal blindness. This retrospective study evaluated the outcomes of BI-KPro implantation in 118 patients. Material: The mean age of the patients was 56.76 ± 14.24 years. Indications for keratoprosthesis implantation were as follows: graft failure, 47 (39.83%); ocular burn, 38 (32.20%); neurotrophic keratopathy, 11 (9.32%), mucous membrane pemphigoid 9 (7.67%); autoimmune, 6 (5.08%); Stevens-Johnson syndrome, 4 (3.39%); and aniridia (2.54%). The surgeries were performed between March 2019 and June 2022 at a single clinical center in two locations. The postoperative visual acuity, complications, and need for additional surgical procedures were analyzed. The Best Corrected Visual Acuity before surgery was 0.01 ± 0.006. After one year (V1), it was 0.30 ± 0.27; at two years (V2), it was 0.27 ± 0.26; and at three years (V3), it was 0.21 ± 0.23. The percentage of patients with visual acuity better than 0.1 on the Snellen chart was 37.29% after 1 year, 49.35% after 2 years, and 46.81% after 3 years of follow up. The most common complications were glaucoma (78 patients; 66.1%), corneal melting (22 patients; 18.6%), and retroprosthetic membranes (20 patients; 17.0%). The BI-KPro can significantly improve visual acuity. The worst long-term results were obtained in the group of patients with autoimmune diseases; therefore, careful consideration should be given to implanting BI-KPro in this group. The high incidence of de novo glaucoma or the progression of pre-existing glaucoma suggests the need for careful monitoring.
PubMed: 38398288
DOI: 10.3390/jcm13040975 -
Eye (London, England) Jun 2024To evaluate the outcomes of trans-scleral sutured posterior chamber black diaphragm intraocular lens (BDIOL) (Morcher) implantations over 11 years.
BACKGROUND/OBJECTIVE
To evaluate the outcomes of trans-scleral sutured posterior chamber black diaphragm intraocular lens (BDIOL) (Morcher) implantations over 11 years.
SUBJECTS/METHODS
Retrospective case-series of patients, who underwent BDIOL implantation, identified from electronic patient records system from 2006 to 2016, Moorfields Eye Hospital. Demographics, pre/post-operative, final best-corrected visual acuity (BCVA), diagnosis, symptomatic improvement, intraoperative and postoperative complications immediate or late were collected and analysed to relate outcomes to surgical indication.
RESULTS
Forty eyes of 38 patients (F:M 1:2.8) underwent BDIOL implantation with a mean surgical age of 46.6 years and follow-up of 44.5 months (range of 8-132 months). Indications included 23(57%) ocular trauma, 7(17%) congenital aniridia, 7(17%) iatrogenic lens and/or iris loss, and 3(7%) infectious keratitis. Mean preoperative BCVA was 1.64 logMAR and mean final postoperative BCVA was 0.94 logMAR with an average improvement in BCVA of 0.23 logMAR, equivalent to 1.5 lines of Snellen visual acuity. Visual results varied according to indications. Infectious cause patients had the greatest vision improvement (-0.7 logMAR), followed by trauma (-0.3 logMAR), and 25% of these achieved vision of 0.3 logMAR (6/12 in Snellen acuity) or better. Conversely, the aniridia group had the least improvement (worsened vision of 0.01 logMAR), 17 patients (42%) reported subjective improvement.
CONCLUSION
BDIOLs achieve reasonably good visual outcomes in eyes with complex vision threatening pathology. No significant intra-operative complications are documented and most post-operative complications are related to the pre-existing pathology. Post - trauma and iatrogenic aniridia have better outcomes compared to congenital aniridia.
Topics: Humans; Middle Aged; Female; Retrospective Studies; Male; Visual Acuity; Lens Implantation, Intraocular; Sclera; Aged; Aniridia; Adult; Lenses, Intraocular; Suture Techniques; Adolescent; Young Adult; Postoperative Complications; Follow-Up Studies; Child; Eye Injuries; Aged, 80 and over; Treatment Outcome; Intraoperative Complications; Prosthesis Design
PubMed: 38388833
DOI: 10.1038/s41433-024-02982-w -
Acta Paediatrica (Oslo, Norway : 1992) Jun 2024This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome).
AIM
This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome).
METHODS
Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing.
RESULTS
Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software.
CONCLUSION
WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.
Topics: Humans; Female; Twins, Monozygotic; WAGR Syndrome; Aniridia; Wilms Tumor; Infant; Corneal Opacity; Anterior Eye Segment; Eye Abnormalities; Diseases in Twins; Kidney Neoplasms
PubMed: 38363039
DOI: 10.1111/apa.17160 -
PloS One 2024To describe a novel corneal surgical technique combining Deep Anterior Lamellar Keratoplasty (DALK) with grafting of allogeneic limbus (Limbo-DALK) for the treatment of...
PURPOSE
To describe a novel corneal surgical technique combining Deep Anterior Lamellar Keratoplasty (DALK) with grafting of allogeneic limbus (Limbo-DALK) for the treatment of eyes with corneal stromal pathology and limbal stem cell deficiency (LSCD).
METHODS
Clinical records of six Limbo-DALKs performed in five patients diagnosed with LSCD and corneal stromal pathology requiring keratoplasty were retrospectively reviewed. All patients were diagnosed with LSCD due to various pathologies including thermal and chemical burns, congenital aniridia or chronic inflammatory ocular surface disease. Parameters analysed included demographics, diagnoses, clinical history, thickness measurements using anterior segment OCT, visual acuity, and epithelial status. Regular follow-up visits were scheduled at 6 weeks as well as 3, 6, 9, and 12 and 18 months postoperatively. Main outcome measures were time to graft epithelialisation and the occurrence of corneal endothelial decompensation.
RESULTS
Two grafts showed complete epithelial closure at 2 days, two at 14 days. In one eye, complete epithelial closure was not achieved after the first Limbo-DALK, but was achieved one month after the second Limbo-DALK. No endothelial decompensation occurred except in one patient with silicone oil associated keratopathy. Endothelial graft rejection was not observed in any of the grafts.
CONCLUSION
Based on the data from this pilot series, limbo-DALK appears to be a viable surgical approach for eyes with severe LSCD and corneal stromal pathology, suitable for emergency situations (e.g. corneal ulceration with impending corneal perforation), while minimising the risk of corneal endothelial decompensation.
Topics: Humans; Limbal Stem Cell Deficiency; Retrospective Studies; Corneal Diseases; Corneal Transplantation; Hematopoietic Stem Cell Transplantation; Keratoplasty, Penetrating; Treatment Outcome; Follow-Up Studies
PubMed: 38346049
DOI: 10.1371/journal.pone.0298241 -
Journal of the College of Physicians... Feb 2024To evaluate the correlation of cerebrospinal fluid total protein and serum neutrophil-to-lymphocyte ratio with the clinical outcomes and the various clinical and...
OBJECTIVE
To evaluate the correlation of cerebrospinal fluid total protein and serum neutrophil-to-lymphocyte ratio with the clinical outcomes and the various clinical and electrophysiological variants of Guillain-Barre syndrome.
STUDY DESIGN
Cross-sectional study. Place and Duration of the Study: Department of Neurology, Mayo Hospital and King Edward Medical University, Lahore, Pakistan, from November 2022 to April 2023.
METHODOLOGY
Fourty-six Guillain-Barre syndrome patients, aged 12-70 years, were included in the study diagnosed by using the Brighton's criteria. Functional disability and respiratory insufficiency were assessed by using the modified Hughes disability score and the Erasmus Guillain-Barre syndrome respiratory insufficiency score, respectively. Serum neutrophil-to-lymphocyte ratio and cerebrospinal fluid total protein were calculated for each patient at the time of admission.
RESULTS
Axonal variants had a higher mean neutrophil-to-lymphocyte ratio (5.29 ± 4.38) than demyelinating variants (4.71 ± 3.4) and Miller-Fischer syndrome (3 ± 2.828). This ratio was positively correlated with the modified Hughes's disability score (r = 0.790, p = 0.001) and the Erasmus Guillain-Barre syndrome respiratory insufficiency score (r = 0.936, p = 0.002). Mean cerebrospinal fluid total protein was higher for demyelinating (218 ± 136 mg/dl) than axonal variants (86 ± 56 mg/dl) and Miller-Fischer syndrome (34 ± 21 mg/dl). However, higher modified Hughes disability score (4-6) (r = 0.020, p = 0.117) and a high Erasmus Guillain-Barre syndrome respiratory insufficiency score (5-7) (r = 0.115, p = 0.302) did not significantly affect mean cerebrospinal fluid total proteins.
CONCLUSION
Serum neutrophil-to-lymphocyte ratio can be regarded as a reliable biomarker to assess disease severity and clinical outcome in Guillain-Barre syndrome. Cerebrospinal fluid total protein is a poor predictor of the prognosis and severity of Guillain-Barre syndrome.
KEY WORDS
Guillain-Barre syndrome (GBS), Clinical outcome, Cerebrospinal fluid total protein (CSF-TP), Neutrophil-to-lymphocytic ratio (NLR), Prognostic biomarker.
Topics: Humans; Guillain-Barre Syndrome; Neutrophils; Cross-Sectional Studies; Biomarkers; Lymphocytes; Respiratory Insufficiency; Chromosome Deletion; WAGR Syndrome; Abnormalities, Multiple; Limb Deformities, Congenital; Mandibulofacial Dysostosis; Micrognathism; Chromosomes, Human, Pair 11
PubMed: 38342870
DOI: 10.29271/jcpsp.2024.02.187 -
PloS One 2024The purpose of this study was to investigate the repeatability of biometric measures and also to assess the interactions between the uncertainties in these measures for...
PURPOSE
The purpose of this study was to investigate the repeatability of biometric measures and also to assess the interactions between the uncertainties in these measures for use in an error propagation model, using data from a large patient cohort.
METHODS
In this cross-sectional non-randomised study we evaluated a dataset containing 3379 IOLMaster 700 biometric measurements taken prior to cataract surgery. Only complete scans with at least 3 successful measurements for each eye performed on the same day were considered. The mean (Mean) and standard deviations (SD) for each sequence of measurements were derived and analysed. Correlations between the uncertainties were assessed using Spearman rank correlations.
RESULTS
In the dataset with 677 eyes matching the inclusion criteria, the within subject standard deviation and repeatability for all parameters match previously published data. The SD of the axial length (AL) increased with the Mean AL, but there was no noticeable dependency of the SD of any of the other parameters on their corresponding Mean value. The SDs of the parameters are not independent of one another, and in particular we observe correlations between those for AL, anterior chamber depth, aqueous depth, lens thickness and corneal thickness.
CONCLUSIONS
The SD change over Mean for AL measurement and the correlations between the uncertainties of several biometric parameters mean that a simple Gaussian error propagation model cannot be used to derive the effect of biometric uncertainties on the predicted intraocular lens power and refraction after cataract surgery.
Topics: Humans; Lenses, Intraocular; Cross-Sectional Studies; Axial Length, Eye; Prospective Studies; Biometry; Cataract; Anterior Chamber
PubMed: 38330090
DOI: 10.1371/journal.pone.0297869