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Corneal Dystrophies and Degenerations - Genetic and Clinical Update

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Ophthalmology".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 15777

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Special Issue Editors

Dr. Anna Nowinska

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Guest Editor

1. Clinical Department of Ophthalmology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland
2. Ophthalmology Department, Railway Hospital, 40-760 Katowice, Poland
Interests: corneal dystrophy; dry eye disease; cataract; retina; ocular imaging; optical coherence tomography
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Pasquale Aragona

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Guest Editor

Department of Biomedical Sciences, Ophthalmology Clinic, University of Messina, Messina, Italy
Interests: ocular surface; cornea; conjunctiva; refractive surgery; cataract surgery

Prof. Dr. Laszlo Modis

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Guest Editor

Department of Ophthalmology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Interests: infectious corneal diseases; corneal dystrophies and degenerations; dry eye disease; keratoconus; corneal imaging; anterior segment trauma; eye banking; corneal transplantation

Special Issue Information

Dear Colleagues,

Corneal dystrophies (CDs), degenerations and ectasia are rare diseases that cause patients to develop low vision and blindness in the most productive decades of life, with severe impact on quality of life, as more than 90% of the information exchanged is visual.

Current standards for diagnosis are during clinical exploration at advanced stages of the occurring disease, and treatment is focused on corneal laser or manual surgeries based on limited imaging tool information and bears a high cost for the health system with a non-optimal visual outcome.

At present, there are no curative treatments for these conditions, no customized approaches for different genetic disorders, and there is an unmet medical need in the early diagnosis of such disorders.

Moreover, different types of CDs and keratoconus are still yet to establish which gene is responsible for the disease. On the other hand, many well-known CDs with defined genetic bases need to be further studied in the context of corneal morphology features, genotype–phenotype correlations and need to establish new mutations of known genes by population-wide studies.

Additionally, corneal dystrophies with the precisely identified genetic defect fulfils the prerequisites that are required to attempt a clinical gene therapy. Currently, we are faced with new possibilities for the future methods of gene therapy. Such an approach was already employed for Meesman corneal dystrophy; however, it has yet to be employed in a clinical setting.

This Special Issue of the Journal of Clinical Medicine will cover the following important aspects of clinical and genetic data on corneal dystrophies, degenerations and ectatic diseases:

New modalities in diagnostic methods;
Ocular surface and corneal morphology features;
Updates on treatment methods used in clinical setting;
New treatment algorithms;
Genetic update focused on diagnosis and treatment.

Dr. Anna Karolina Nowińska
Prof. Dr. Pasquale Aragona
Prof. Dr. Laszlo Modis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

corneal dystrophy
corneal degeneration
keratoconus
ocular surface
gene therapy
corneal morphology
optical coherence tomography
confocal microscopy
inherited corneal diseases
dry eye disease

Published Papers (9 papers)

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Research

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14 pages, 2135 KiB

Open AccessArticle

Oxidative Stress and Cellular Protein Accumulation Are Present in Keratoconus, Macular Corneal Dystrophy, and Fuchs Endothelial Corneal Dystrophy

by Linda Vottonen, Ali Koskela, Szabolcs Felszeghy, Adam Wylegala, Katarzyna Kryszan, Iswariyaraja Sridevi Gurubaran, Kai Kaarniranta and Edward Wylegala

J. Clin. Med. 2023, 12(13), 4332; https://doi.org/10.3390/jcm12134332 - 28 Jun 2023

Cited by 2 | Viewed by 1231

Abstract

The aim of the study was to investigate oxidative stress as well as cellular protein accumulation in corneal diseases including keratoconus (KC), macular corneal dystrophy (MCD), and Fuchs endothelial corneal dystrophy (FECD) at their primary affecting sites. Corneal buttons from KC, MCD, and FECD patients, as well as healthy controls, were analyzed immunohistochemically to evaluate the presence of oxidative stress and the function of the proteostasis network. 4-Fydroxynonenal (4-HNE) was used as a marker of oxidative stress, whereas the levels of catalase and heat-shock protein 70 (HSP70) were analyzed to evaluate the response of the antioxidant defense system and molecular chaperones, respectively. Sequestosome 1 (SQSTM1) levels were determined to assess protein aggregation and the functionality of autophagic degradation. Basal epithelial cells of the KC samples showed increased levels of oxidative stress marker 4-HNE and antioxidant enzyme catalase together with elevated levels of HSP70 and accumulation of SQSTM1. Corneal stromal cells and endothelial cells from MCD and FECD samples, respectively, showed similarly increased levels of these markers. All corneal diseases showed the presence of oxidative stress and activation of the molecular chaperone response to sustain protein homeostasis. However, the accumulation of protein aggregates suggests insufficient function of the protective mechanisms to limit the oxidative damage and removal of protein aggregates via autophagy. These results suggest that oxidative stress has a role in KC, MCD, and FECD at the cellular level as a secondary outcome. Thus, antioxidant- and autophagy-targeted therapies could be included as supporting care when treating KC or corneal dystrophies. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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8 pages, 772 KiB

Open AccessArticle

Comparison of the Predictive Accuracy of Intraocular Lens Power Calculations after Phototherapeutic Keratectomy in Granular Corneal Dystrophy Type 2

by Sook Hyun Yoon, Woo Kyung Jo, Tae-im Kim, Kyoung Yul Seo, Jinseok Choi, Ikhyun Jun and Eung Kweon Kim

J. Clin. Med. 2023, 12(2), 584; https://doi.org/10.3390/jcm12020584 - 11 Jan 2023

Viewed by 1092

Abstract

Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disease affecting vision. Phototherapeutic keratectomy (PTK) is advantageous in removing vision-threatening corneal opacities and postponing keratoplasty; however, it potentially disturbs accurate intraocular lens (IOL) power calculation in cataract surgery. The myopic/hyperopic Haigis-L method with or without the central island has been reported; nevertheless, an optimal method has not yet been established. To compare the predictive accuracy of post-PTK IOL power calculations in GCD2, the retrospective data of 30 eyes from July 2017 to December 2020 were analyzed. All GCD2-affected eyes underwent post-PTK standard cataract surgery using the WaveLight EX500 platform (Alcon Laboratories, Inc., Fort Worth, TX, USA) under a single surgeon. The mean prediction error (MPE) and absolute error (MAE) with the myopic/hyperopic Haigis-L, Barrett Universal II, Barrett True-K, Haigis, and SRK/T by standard keratometry (K) and total keratometry (TK), where possible, were analyzed. Barrett Universal II and SRK/T showed significantly superior MPE, and MAE compared with the myopic/hyperopic Haigis-L method. TK was not significantly superior to K in the same formula. In conclusion, this study suggests that these biometries and formulas, especially Barrett Universal II and SRK/T, are potentially useful in IOL power calculation in GCD2 after PTK. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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7 pages, 864 KiB

Open AccessArticle

Snail Track Lesion with Flat Keratometry in Anterior Segment Dysgenesis Caused by a Novel FOXC1 Variant

by Pavlina Skalicka, Jana Jedlickova, Ales Horinek, Marie Trkova, Alice E. Davidson, Stephen J. Tuft, Lubica Dudakova and Petra Liskova

J. Clin. Med. 2022, 11(17), 5166; https://doi.org/10.3390/jcm11175166 - 31 Aug 2022

Viewed by 1485

Abstract

We report the phenotype of a 15-year-old female patient with anterior segment dysgenesis (ASD) caused by a novel heterozygous loss-of-function FOXC1 variant. The proband underwent an ophthalmic examination as well as a molecular genetic investigation comprising exome sequencing, a single nucleotide polymorphism array to access copy number and Sanger sequencing to exclude non-coding causal variants. There was bilateral mild iris hypoplasia with pupil deformation and iridocorneal adhesions. In addition to these features of ASD, the corneas were flat, with mean keratometry readings of 38.8 diopters in the right eye and 39.5 diopters in the left eye. There was a snail track lesion of the left cornea at the level of the Descemet membrane. The central corneal endothelial cell density was reduced bilaterally at 1964 and 1373 cells/mm² in the right and left eyes, respectively. Molecular genetic analysis revealed that the proband was a carrier of a novel heterozygous frameshifting variant in FOXC1, c.605del p.(Pro202Argfs*113). Neither parent had this change, suggesting a de novo origin which was supported by paternity testing. We found no possibly pathogenic variants in the other genes associated with posterior corneal dystrophies or ASD. Further studies are warranted to verify whether there is a true association between snail track lesions, corneal flattening, and pathogenic variants in FOXC1. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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15 pages, 2708 KiB

Open AccessArticle

Corneal Densitometry and In Vivo Confocal Microscopy in Patients with Monoclonal Gammopathy—Analysis of 130 Eyes of 65 Subjects

by Kitti Kormányos, Klaudia Kovács, Orsolya Németh, Gábor Tóth, Gábor László Sándor, Anita Csorba, Cecília Nóra Czakó, László Módis, Jr., Achim Langenbucher, Zoltán Zsolt Nagy, Gergely Varga, László Gopcsa, Gábor Mikala and Nóra Szentmáry

J. Clin. Med. 2022, 11(7), 1848; https://doi.org/10.3390/jcm11071848 - 26 Mar 2022

Cited by 4 | Viewed by 1691

Abstract

Background: Corneal imaging may support an early diagnosis of monoclonal gammopathy. The goal of our study was to analyze corneal stromal properties using Pentacam and in vivo confocal cornea microscopy (IVCM) in subjects with monoclonal gammopathy. Patients and methods: In our cross-sectional study, patients with monoclonal gammopathy (130 eyes of 65 patients (40.0% males; age 67.65 ± 9.74 years)) and randomly selected individuals of the same age group, without hematological disease (100 eyes of 50 control subjects (40.0% males; age 60.67 ± 15.06 years)) were included. Using Pentacam (Pentacam HR; Oculus GmbH, Wetzlar, Germany), corneal stromal light scattering values were obtained (1) centrally 0–2 mm zone; (2) 2–6 mm zone; (3) 6–10 mm zone; (4) 10–12 mm zone. Using IVCM with Heidelberg Retina Tomograph with Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany), the density of hyperreflective keratocytes and the number of hyperreflective spikes per image were manually analyzed, in the stroma. Results: In the first, second and third annular zone, light scattering was significantly higher in subjects with monoclonal gammopathy, than in controls (p ≤ 0.04). The number of hyperreflective keratocytes and hyperreflective spikes per image was significantly higher in stroma of subjects with monoclonal gammopathy (p ≤ 0.012). Conclusions: Our study confirms that increased corneal light scattering in the central 10 mm annular zone and increased keratocyte hyperreflectivity may give rise to suspicion of monoclonal gammopathy. As corneal light scattering is not increased at the limbal 10–12 mm annular zone in monoclonal gammopathy subjects, our spatial analysis provides evidence against the limbal origin of corneal paraprotein deposition. Using IVCM, stromal hyperreflective spikes may represent specific signs of monoclonal gammopathy. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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9 pages, 2752 KiB

Open AccessArticle

The Role of Hi-Tech Devices in Assessment of Corneal Healing in Patients with Neurotrophic Keratopathy

by Leandro Inferrera, Emanuela Aragona, Adam Wylęgała, Antonio Valastro, Gianluigi Latino, Elisa I. Postorino, Romana Gargano, Bogusława Orzechowska-Wylęgała, Edward Wylęgała and Anna M. Roszkowska

J. Clin. Med. 2022, 11(6), 1602; https://doi.org/10.3390/jcm11061602 - 14 Mar 2022

Cited by 3 | Viewed by 1924

Abstract

To prove the role of high-tech investigation in monitoring corneal morphological changes in patients with neurotrophic keratopathy (NK) using Keratograph 5M (K5M) and anterior segment OCT (AS-OCT), corneal healing was monitored with Keratograph 5M (Oculus, Wetzlar, Germany) and AS-OCT (DRI, Triton, Topcon, Tokyo, Japan) in 13 patients (8F and 5M), aged from 24 to 93 years (67.8 ± 19) with severe NK, who were treated with Cenegermin 0.002% (20 μg/mL) (Oxervate^®, Dompè, Farmaceutici Spa, Milan, Italy). The surface defects were evaluated on Keratograph 5M with ImageJ software and the corneal thickness variations were measured using DRI-Triton OCT software. Instrumental procedures were performed at baseline, and after 4 and 8 weeks of the treatment, respectively. The main outcome measures were reduction of the ulcers’ area and corneal thickness recovery. The mean area of the corneal ulcers was reduced between baseline and 4 weeks examination in all patients, and at 8 weeks all ulcers were completely healed. An increase of the corneal thickness was evidenced between the baseline visit and after the 4- and 8-week follow-up, respectively. Additionally, only in collaborating subjects the In Vivo Confocal Microscopy (IVCM) was performed with HRT Rostock Cornea Module (Heidelberg Eng GmbH) to study the corneal nerves fibres. High-tech diagnostics with K5M, AS-OCT and IVCM proved useful in the assessment of corneal morphology and the healing process in patients with NK and could be extended to assess other corneal pathologies. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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11 pages, 1215 KiB

Open AccessArticle

Swept Source Optical Coherence Tomography Analysis of a Selected Eye’s Anterior Segment Parameters in Patients with Pseudoexfoliation Syndrome

by Michał Dembski, Anna Nowińska, Klaudia Ulfik-Dembska and Edward Wylęgała

J. Clin. Med. 2022, 11(1), 268; https://doi.org/10.3390/jcm11010268 - 05 Jan 2022

Cited by 3 | Viewed by 1381

Abstract

Background: Pseudoexfoliation syndrome (PEX) is a systemic, age-related disorder characterized by the production and accumulation of pseudoexfoliation material. To date, detailed characteristics have not been published regarding the iridocorneal angle and cornea in patients with pseudoexfoliation syndrome determined through swept source optical coherence tomography (SS-OCT). Methods: A total of 150 eyes of patients with pseudoexfoliation syndrome (ages 69–86 years) and 166 eyes in a control group (ages 54–79 years) were analyzed. Results: The central corneal thickness in the PEX group was 549.56 μm and was slightly (insignificantly) higher than that of the control group (540.56 µm). The anterior chamber of the eye was visibly shallower in patients with PEX syndrome than in those of the control group (2.49 mm vs. 3.07 mm; p < 0.001). The Fourier analysis parameters of the cornea showed multiple differences between the PEX and control groups. With respect to iris area, the parameters showed statistically significant differences between the PEX and control groups in all four quadrants of the eye. No statistical significance was found in the PEX group for the iridocorneal angle parameters, or corneal and lens parameters depending on gender and age. Conclusions: PEX syndrome is characterized by a significant impact on the anterior eye segment, including higher anterior and posterior keratometric values, lower anterior chamber depth, higher iris thickness, and narrower angle parameters. The characteristic anterior eye segment features of PEX syndrome can be detected using SS-OCT, which could potentially assist clinicians in properly managing the disease. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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10 pages, 258 KiB

Open AccessArticle

Common ALDH3A1 Gene Variant Associated with Keratoconus Risk in the Polish Population

by Mariusz Berdyński, Piotr Krawczyk, Krzysztof Safranow, Beata Borzemska, Jacek P. Szaflik, Karolina Nowakowska-Żawrocka, Cezary Żekanowski and Joanna Giebułtowicz

J. Clin. Med. 2022, 11(1), 8; https://doi.org/10.3390/jcm11010008 - 21 Dec 2021

Cited by 2 | Viewed by 2037

Abstract

Background: ALDH3A1 protein is important in maintaining corneal physiology and protecting the eye from UV damage. However, none of the genome-wide association studies has indicated that the ALDH3A1 locus is associated with keratoconus. In this study, we examined the potential role of ALDH3A1 variants as risk factors for keratoconus incidence and severity in a large group of Polish keratoconus patients. Methods: In the first stage we analyzed the coding region sequence of the ALDH3A1 in a subgroup of keratoconus. Then, we genotyped three selected ALDH3A1 variants in a larger KC group of patients (n = 261) and healthy controls (n = 317). Results: We found that the rs1042183 minor allele A is a risk factor for keratoconus in the dominant model (OR = 2.06, 95%CI = 1.42–2.98, p = 0.00013). The rs2228100 variant genotypes appear to be associated with an earlier age of KC diagnosis in the Polish population (p = 0.055 for comparison of three genotypes and p = 0.022 for the dominant inheritance model). Conclusions: The rs1042183 variant in ALDH3A1 is associated with keratoconus risk in the Polish population. The differences in the allele frequency between both populations could be partially responsible for the difference in the disease prevalence. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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8 pages, 1299 KiB

Open AccessCase Report

De Novo L509P Mutation of the TGFBI Gene Associated with Slit-Lamp Findings of Lattice Corneal Dystrophy Type IIIA

by Yong Woo Ji, Hyunmin Ahn, Kyoung-Jin Shin, Tae-im Kim, Kyoung Yul Seo, R. Doyle Stulting and Eung Kweon Kim

J. Clin. Med. 2022, 11(11), 3055; https://doi.org/10.3390/jcm11113055 - 28 May 2022

Viewed by 1637

Abstract

Background: Mutations of the transforming growth factor-β-induced (TGFBI) gene produce various types of corneal dystrophy. Here, we report a novel de novo L509P mutation not located in a known hot spot of the transforming growth factor-β-induced (TGFBI) gene and its clinical phenotype, which resembles that of lattice corneal dystrophy type IIIA (LCD IIIA). Case presentation: A 36-year-old man (proband) visited our clinic due to decreased visual acuity with intermittent ocular irritation in conjunction with painful recurrent erosions in both eyes for 10 years. Molecular genetic analyses revealed a TGFBI L509P mutation (c.1526T>C) in the proband and one of his sons. Interestingly, neither TGFBI mutations nor corneal abnormalities were detected in either of the proband’s biological parents, indicating the occurrence of a de novo L509P mutation. Clinical examinations, including slit-lamp retro-illumination and Fourier-domain anterior segment optical coherence tomography (FD-OCT), revealed gray deposits in the anterior stroma and deeper refractile lines extending from limbus to limbus in both corneas of the proband, consistent with a diagnosis of LCD IIIA. Superficial diffuse haze and surface irregularity were observed in conjunction with corneal erosions and visual impairment, necessitating phototherapeutic keratectomy (PTK). A 60 μm PTK of the Bowman layer and anterior stroma of the proband’s left eye was performed following the removal of the epithelium in order to remove superficial corneal opacities. His BCVA improved from 20/400 to 20/50 at postoperative week 8 and was maintained for 45 months. Pinhole-corrected VA was 20/20 at the last visit, and corneal opacities had not recurred. Conclusions: An inheritable de novo mutation of L509P in the TGFBI gene can produce severe LCD IIIA, which can be successfully treated with OCT-guided PRK. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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11 pages, 4389 KiB

Open AccessCase Report

Raman Spectroscopic Study of Amyloid Deposits in Gelatinous Drop-like Corneal Dystrophy

by Giuseppe Acri, Antonio Micali, Rosalia D’Angelo, Domenico Puzzolo, Pasquale Aragona, Barbara Testagrossa, Emanuela Aragona, Edward Wylegala and Anna Nowinska

J. Clin. Med. 2022, 11(5), 1403; https://doi.org/10.3390/jcm11051403 - 04 Mar 2022

Cited by 6 | Viewed by 1912

Abstract

The genetic and histopathological features of the cornea of a Polish patient with Gelatinous Drop-like Corneal Dystrophy (GDCD) and the molecular composition with Raman spectroscopy of corneal deposits were examined. A 62 year-old Polish woman was diagnosed with GDCD and underwent penetrating corneal transplant. A blood sample was collected, and genetic analysis was performed. The cornea was processed for light microscopy and Raman analysis. The genetic exam revealed a previously undescribed homozygous 1-base pair deletion in exon 1 of TACSTD2 gene (c.185delT), resulting in a frame shift causing a premature stop codon. When compared with a control cornea, in GDCD cornea stained with PAS evident deposits were present over the anterior stroma, with apple green birefringence under polarized light. Raman spectroscopy showed peculiar differences between normal and GDCD cornea, consisting in peaks either of different height or undetectable in the normal cornea and related to amyloid. The possible causative role of the novel mutation was discussed and Raman spectroscopy as a further morphological tool in the evaluation of corneal dystrophies, characterized by the deposition of abnormal materials, was suggested. Full article

(This article belongs to the Special Issue Corneal Dystrophies and Degenerations - Genetic and Clinical Update)

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