RESUMEN
Purpose: Pre-Descemet corneal dystrophy (PDCD) with X-linked ichthyosis (XLI) is associated with mutations in or deletions of the steroid sulfatase gene (STS). As only three cases of genetically confirmed PDCD associated with XLI have been reported, we sought to expand our understanding of the genetic basis of PDCD by screening STS in two previously unreported families. Materials and Methods: The affected individuals underwent cutaneous and slit-lamp examinations. Saliva samples collected from each affected individual served as a source of DNA for the amplification of the 10 coding exons of STS and flanking DNA markers. Results: The slit-lamp examination of three affected men (two of whom were brothers) from two families revealed bilateral punctate posterior corneal stromal opacities anterior to the Descemet membrane. Cutaneous examination demonstrated dry, coarse, scaly ichthyotic changes characteristic of XLI in all individuals. Genetic examination of the STS locus on the X chromosome in Case 1 revealed a deletion that spanned across DNA markers DXS1130-DXS237, which includes all the coding exons (exons 1-10) of STS. Genetic screening of Cases 2 and 3 revealed a partial deletion of the STS locus involving exons 1-7 and flanking DNA marker DXS1130 on the X chromosome. Conclusions: PDCD with XLI may be associated with either partial or complete deletion of STS. Despite the identification of point mutations, partial deletion, and complete deletion of STS in different affected families reported to date, there was no apparent difference in the affected phenotype between the families, suggesting that the identified variants likely all resulted in loss of function of steroid sulfatase.
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Distrofias Hereditarias de la Córnea , Ictiosis Ligada al Cromosoma X , Ictiosis , Masculino , Humanos , Esteril-Sulfatasa/genética , Marcadores Genéticos , Ictiosis Ligada al Cromosoma X/complicaciones , Ictiosis Ligada al Cromosoma X/genética , Ictiosis/genética , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/diagnóstico , Eliminación de GenRESUMEN
PURPOSE: To identify the incidence of, risk factors for, and outcomes of posterior segment complications (PSC) after Boston Type 1 keratoprosthesis (KPro) implantation. METHODS: Retrospective, consecutive case series of KPro procedures at the Stein Eye Institute. Data regarding ocular history, intraoperative details, postoperative management, and outcomes were collected. Eyes with at least one PSC (PSC group) were compared with eyes without PSC (No PSC group), and risk factors for PSC were determined. RESULTS: Ninety-five PSC occurred in 69/169 eyes (40.8%), at a mean of 20.1 months after KPro implantation (0.01 complications/eye month). The median follow-up after KPro implantation was 44.0 months (range 3.0-174.4). The most common PSC were epiretinal membrane (16.6%), cystoid macular edema (12.4%), vitritis (11.2%), and retinal detachment (9.5%). Previous retinal detachment repair, concomitant intraocular lens removal, postoperative aphakia, and vitritis were risk factors for retinal detachment. Postoperative infectious keratitis was a risk factor for epiretinal membrane, cystoid macular edema, and vitritis. The posterior segment complication group had a significantly higher rate of eyes failing to maintain visual acuity ≥20/200 (HR = 2.28; 95% CI = 1.35-3.85) and KPro retention failure rate (HR = 1.66; 95% CI = 0.95-2.91). CONCLUSION: Posterior segment complications occur in approximately 40% of eyes after KPro implantation, resulting in reduced visual outcomes and KPro retention.
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Órganos Artificiales , Córnea , Segmento Posterior del Ojo/patología , Complicaciones Posoperatorias , Prótesis e Implantes/efectos adversos , Enfermedades de la Retina/epidemiología , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Implantación de Prótesis , Enfermedades de la Retina/fisiopatología , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Agudeza Visual/fisiologíaRESUMEN
Mutations associated with posterior polymorphous corneal dystrophy (PPCD) have been identified in three genes: ZEB1 (zinc-finger E-box binding homeobox 1) associated with sub-type PPCD3; OVOL2 (ovol-like zinc finger 2) associated with sub-type PPCD1; and GRHL2 (grainyhead like transcription factor 2) associated with sub-type PPCD4. Each of these genes encodes a transcription factor that regulates cell-state transitions. While the discovery of these PPCD-associated genes has greatly expanded our knowledge of the genetic basis of PPCD, the molecular mechanisms via which mutations in these genes lead to indistinguishable disease phenotypes have yet to be elucidated. To characterize the gene expression profiles of the genetic sub-types of PPCD, RNA-seq was performed on corneal endothelium derived from an individual with PPCD1 who harbors a c.-307Tâ¯>â¯C OVOL2 promoter mutation. Transcriptomic analysis of this and previously-reported RNA-seq data from two individuals with PPCD (the first with PPCD3 associated with a ZEB1 truncating mutation (c.1381delinsGACGAT) and the second with genetically unresolved PPCD in which ZEB1 coding region, OVOL2 promoter and GRHL2 promoter, exon 1, and intron 1 mutations were excluded) revealed: OVOL2 expression increased in PPCD1 (259 fold), unchanged in PPCD3 and slightly increased in genetically unresolved PPCD (from 0 TPM to 0.86 TPM, undefined fold change); ZEB1 expression decreased in PPCD1 (-5.9 fold), PPCD3 (-3.95 fold) and genetically unresolved PPCD (-3.96 fold); and GRHL2 expression increased in PPCD1 (333.5 fold), slightly increased (from 0 TPM to 0.67 TPM, undefined fold change) in PPCD3 and increased in genetically unresolved PPCD (1853 fold). Additionally, as the majority of pedigrees affected with PPCD remain genetically unresolved, we screened the promoter, exon 1, and intron 1 regions of GRHL2 in 24 PPCD probands who do not harbor a ZEB1 or OVOL2 mutation. GRHL2 screening did not identify any novel or rare GRHL2 variant in these 24 individuals. As ZEB1 can act as an activator or repressor of downstream target gene expression depending on Wnt signaling pathway activation or deactivation, we also sought to determine whether or not Wnt signaling is active in PPCD by performing immunohistochemistry in corneal tissue sections derived from an individual affected with PPCD3 and from an individual with genetically unresolved PPCD. Immunohistochemistry results demonstrated corneal endothelial nuclear accumulation of S552 phos-ß-catenin and cytosolic localization of S33/37/T42 non-phosphorylated ß-catenin in PPCD, indicating aberrant activation of Wnt signaling, which was not observed in control corneal endothelium. These findings suggest that alterations in the ZEB1-OVOL2-GRHL2 axis (caused by PPCD-associated mutations) lead to changes in corneal endothelial cell state and molecular pathways, including the aberrant activation of the Wnt signaling pathway.
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Distrofias Hereditarias de la Córnea/genética , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/fisiología , Mutación , Factores de Transcripción/genética , Vía de Señalización Wnt/fisiología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Anciano , Distrofias Hereditarias de la Córnea/metabolismo , Distrofias Hereditarias de la Córnea/patología , Exones/genética , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Intrones/genética , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN , Transcripción GenéticaRESUMEN
PURPOSE: To associate donor, recipient, and operative factors with graft success 3 years after Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study (CPTS). DESIGN: Cohort study within a multicenter, double-masked, randomized clinical trial. PARTICIPANTS: One thousand ninety individuals (1330 study eyes) with a median age of 70 years undergoing DSAEK for Fuchs endothelial corneal dystrophy (94% of eyes) or pseudophakic or aphakic corneal edema (PACE; 6% of eyes). METHODS: Eyes undergoing DSAEK were randomized to receive a donor cornea with preservation time (PT) of 0 to 7 days (n = 675) or 8 to 14 days (n = 655). Donor, recipient, and operative parameters were recorded prospectively. Graft failure was defined as regraft for any reason, a graft that failed to clear by 8 weeks after surgery, or an initially clear graft that became and remained cloudy for 90 days. Failure in the first 8 weeks was classified further as primary donor failure or early failure, in the absence or presence of operative complications, respectively. Proportional hazards and logistic regression models were used to estimate risk ratios (RR) and 99% confidence intervals (CIs) for graft failure. MAIN OUTCOME MEASURES: Graft success at 3 years. RESULTS: One thousand two hundred fifty-one of 1330 grafts (94%) remained clear at 3 years and were considered successful. After adjusting for PT, tissue from donors with diabetes (RR, 2.35; 99% CI, 1.03-5.33) and operative complications (RR, 4.21; 99% CI, 1.42-12.47) were associated with increased risk for primary or early failure. Preoperative diagnosis of PACE (RR, 3.59; 99% CI, 1.05-12.24) was associated with increased risk for late failure by 3 years after surgery compared with Fuchs dystrophy. Graft success showed little variation among other factors evaluated, including donor age (RR, 1.19 per decade; 99% CI, 0.91-1.56 per decade), preoperative donor endothelial cell density (RR, 1.10 per 500 cells; 99% CI, 0.74-1.63 per 500 cells), graft diameter (RR, 1.22 per 1 mm; 99% CI, 0.39-3.76 per 1 mm), and injector use for graft insertion (RR, 0.92; 99% CI, 0.40-2.10). CONCLUSIONS: Descemet stripping automated endothelial keratoplasty success in the early and entire postoperative period is more likely when the donor did not have diabetes and was without operative complications and in the long-term postoperative period in recipients with Fuchs dystrophy compared with those with PACE. Mechanisms whereby diabetic donors and PACE recipients reduce the rate of graft success after DSAEK warrant further study.
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Edema Corneal/cirugía , Queratoplastia Endotelial de la Lámina Limitante Posterior/métodos , Distrofia Endotelial de Fuchs/cirugía , Supervivencia de Injerto/fisiología , Preservación de Órganos , Donantes de Tejidos , Receptores de Trasplantes , Adulto , Anciano , Recuento de Células , Estudios de Cohortes , Edema Corneal/fisiopatología , Método Doble Ciego , Endotelio Corneal/citología , Bancos de Ojos , Femenino , Distrofia Endotelial de Fuchs/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Factores de Tiempo , Estudios de Tiempo y Movimiento , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To investigate the functional role that the zinc e-box binding homeobox 1 (ZEB1) gene, which underlies the genetic basis of posterior polymorphous corneal dystrophy 3 (PPCD3), plays in corneal endothelial cell proliferation, apoptosis, migration, and barrier function. METHODS: A human corneal endothelial cell line (HCEnC-21T) was transfected with siRNA targeting ZEB1 mRNA. Cell proliferation, apoptosis, migration, and barrier assays were performed: Cell proliferation was assessed with cell counting using a hemocytometer; cell apoptosis, induced by either ultraviolet C (UVC) radiation or doxorubicin treatment, was quantified by measuring cleaved caspase 3 (cCASP3) protein levels; and cell migration and barrier function were monitored with electric cell-substrate impedance sensing (ECIS). RESULTS: ZEB1 knockdown in HCEnC-21T cells transfected with siRNA targeting ZEB1 did not result in a significant difference in cell proliferation when compared with control. Although knockdown of ZEB1 in HCEnC-21T cells sensitized the cells to UV-induced apoptosis, ZEB1 knockdown did not alter the cells' susceptibility to doxorubicin-induced apoptosis, as measured with cCASP3 protein levels, compared with controls. Similarly, no difference was observed in cell migration following ZEB1 knockdown. However, cell barrier function increased significantly following ZEB1 knockdown. CONCLUSIONS: The corneal endothelium in PPCD3 is characterized by morphologic, anatomic, and molecular features that are more consistent with an epithelial-like rather than an endothelial-like phenotype. Although these characteristics have been well documented, we demonstrate for the first time that susceptibility to UV-induced apoptosis and cell barrier function are significantly altered in the setting of reduced ZEB1. The significance of an altered cellular response to apoptotic stimuli and increased cell barrier function in the pathobiology of PPCD remains to be fully elucidated.
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Distrofias Hereditarias de la Córnea/fisiopatología , Endotelio Corneal/fisiología , Regulación de la Expresión Génica/fisiología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Antibióticos Antineoplásicos/toxicidad , Apoptosis/fisiología , Western Blotting , Caspasa 3/metabolismo , Línea Celular , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Doxorrubicina/toxicidad , Impedancia Eléctrica , Endotelio Corneal/efectos de la radiación , Técnicas de Silenciamiento del Gen , Humanos , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Transfección , Rayos Ultravioleta/efectos adversosRESUMEN
PURPOSE: To evaluate the safety of concurrent Boston type I keratoprosthesis (KPro) and glaucoma drainage device (GDD) implantation. DESIGN: Retrospective comparative study of a consecutive cohort of patients. SUBJECTS: Patients who underwent KPro implantation by a single surgeon (A.J.A.) with or without 1 concurrent Ahmed GDD (New World Medical, Inc., Rancho Cucamonga, CA) implantation between January 1, 2005, and January 31, 2015, were included. Patients with fewer than 3 months of follow-up or a history of previous KPro implantation were excluded. METHODS: Preoperative, operative, and postoperative data were collected for each procedure. All comparisons were made between KPro procedures performed with or without concurrent GDD implantation. The Fisher exact test (2-tailed) was used to compare proportions, Student t test and Wilcoxon rank-sum test were used to compare means, and the log-rank test was used to compare time-to-outcome events. MAIN OUTCOME MEASURES: The primary outcome was frequency of the composite variable, that is, any serious vision-threatening postoperative complication, which included sterile vitreitis, endophthalmitis, hypotony maculopathy, suprachoroidal hemorrhage, retinal detachment, stromal necrosis, and infectious keratitis. Secondary outcomes included intraocular pressure control, worsening of visual acuity, cystoid macular edema, retroprosthetic membrane formation, persistent epithelial defect formation, GDD exposure, and KPro removal. RESULTS: One hundred thirty-seven KPro procedures were performed in 129 patients: 91 (66.4%) KPro alone and 46 (33.6%) KPro plus GDD. There were no statistically significant differences between the 2 groups in terms of the incidence of vision-threatening postoperative complications. None of the 46 GDDs placed at the same time as the KPro became exposed during an average follow-up of 44 months. CONCLUSIONS: Compared with KPro alone, GDD placement combined with KPro was not associated with increased postoperative complications.
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Órganos Artificiales , Enfermedades de la Córnea/cirugía , Implantes de Drenaje de Glaucoma , Glaucoma/cirugía , Prótesis e Implantes , Implantación de Prótesis/métodos , Adulto , Anciano , Femenino , Implantes de Drenaje de Glaucoma/efectos adversos , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Prótesis e Implantes/efectos adversos , Implantación de Prótesis/efectos adversos , Estudios RetrospectivosRESUMEN
Congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (CHED with progressive sensorineural deafness), and potentially a subset of individuals with late-onset Fuchs' endothelial corneal dystrophy are caused by mutations in the SLC4A11 gene that results in corneal endothelial cell abnormalities. Originally classified as a borate transporter, the function of SLC4A11 as a transport protein remains poorly understood. Elucidating the transport function(s) of SLC4A11 is needed to better understand how its loss results in the aforementioned posterior corneal dystrophic disease processes. Quantitative PCR experiments demonstrated that, of the three known human NH2-terminal variants, SLC4A11-C is the major transcript expressed in human corneal endothelium. We studied the expression pattern of the three variants in mammalian HEK-293 cells and demonstrated that the SLC4A11-B and SLC4A11-C variants are plasma membrane proteins, whereas SLC4A11-A is localized intracellularly. SLC4A11-B and SLC4A11-C were shown to be multifunctional ion transporters capable of transporting H+ equivalents in both a Na+-independent and Na+-coupled mode. In both transport modes, SLC4A11-C H+ flux was significantly greater than SLC4A11-B. In the presence of ammonia, SLC4A11-B and SLC4A11-C generated inward currents that were comparable in magnitude. Chimera SLC4A11-C-NH2-terminus-SLC4A11-B experiments demonstrated that the SLC4A11-C NH2-terminus functions as an autoactivating domain, enhancing Na+-independent and Na+-coupled H+ flux without significantly affecting the electrogenic NH3-H(n)+ cotransport mode. All three modes of transport were significantly impaired in the presence of the CHED causing p.R109H (SLC4A11-C numbering) mutation. These complex ion transport properties need to be addressed in the context of corneal endothelial disease processes caused by mutations in SLC4A11.
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Proteínas de Transporte de Anión/genética , Antiportadores/genética , Variación Genética/genética , Transporte Iónico/genética , Línea Celular , Membrana Celular/genética , Distrofias Hereditarias de la Córnea/genética , Endotelio Corneal/metabolismo , Células HEK293 , Pérdida Auditiva Sensorineural/genética , Humanos , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación/genéticaRESUMEN
PURPOSE: To investigate a possible effect of intraocular inflammation on corneal endothelium by describing corneal endothelial cell density (ECD) and morphologic variables in eyes with anterior uveitis, and to investigate factors that may influence these findings. DESIGN: Cross-sectional, observational study. Observers were not masked. PARTICIPANTS: Volunteers with histories of unilateral or bilateral anterior segment inflammation (anterior, intermediate, or panuveitis); included were 52 patients (84 eyes with uveitis). METHODS: Endothelial cell density and morphologic variables of both eyes of all study participants were determined by specular microscopy; central corneal thickness was determined by ultrasound pachymetry. MAIN OUTCOME MEASURES: Central corneal ECD, coefficient of variability, percentage hexagonality, and central corneal thickness. RESULTS: Central ECD was lower among eyes that had undergone cataract or glaucoma surgery or both (n = 28; P = 0.0004). After exclusion of eyes with surgery, variables for eyes with uveitis (n = 56) were compared with 2 historical populations of normal, age-matched controls and with contralateral eyes in individuals with unilateral uveitis. Central ECD was lower in eyes with uveitis than in control eyes for all age groups (P ≤ 0.01 for four of six 10-year age intervals compared with the primary control group). Among patients with unilateral uveitis who had not undergone surgery in either eye (n = 12), central ECD was lower in eyes with uveitis (2324 cells/mm(2) [range, 1543-3289 cells/mm(2)]) than in contralateral eyes (2812.5 cells/mm(2) [range, 1887-3546 cells/mm(2)]; P = 0.0005), and percentage hexagonality was lower in eyes with uveitis (54% [range, 33%-66%]) than in contralateral eyes (58.5% [range, 52%-82%]; P = 0.004). There was no significant difference in central corneal thickness between eyes with and without uveitis (P = 0.27). No eyes had clinically apparent central corneal edema. Relationships remained unchanged after exclusion of eyes with herpetic anterior uveitis. Host and disease-related characteristics were evaluated as risk factors for variations in outcome measures. Central ECD was correlated to the duration of active uveitis (r = -0.41; P < 0.0001), maximum intraocular pressure during the course of disease (r = -0.40; P = 0.0002), and maximum laser flare photometry value (r = -0.26; P = 0.020). CONCLUSIONS: Observed relationships suggest that anterior segment inflammation adversely affects the corneal endothelium. Longitudinal studies are warranted to determine whether long-standing anterior uveitis increases risk of endothelial dysfunction, especially in the setting of intraocular surgery.
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Pérdida de Celulas Endoteliales de la Córnea/etiología , Endotelio Corneal/patología , Uveítis Anterior/complicaciones , Adolescente , Adulto , Anciano , Extracción de Catarata , Recuento de Células , Niño , Pérdida de Celulas Endoteliales de la Córnea/diagnóstico , Paquimetría Corneal , Estudios Transversales , Femenino , Cirugía Filtrante , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Factores de Riesgo , Uveítis Anterior/diagnósticoRESUMEN
PURPOSE: To compare repeat penetrating keratoplasty (PK) with Boston type I keratoprosthesis (KPro) implantation for full-thickness donor corneal graft failure. DESIGN: Previous donor graft failure is a common indication for both PK and KPro implantation. Selection of the surgical procedure is entirely dependent on the surgeon because there are no studies available for guidance. Therefore, a systematic review was undertaken to examine vision, device retention, graft clarity, and postoperative glaucoma and infection outcomes after repeat PK versus KPro implantation. METHODS: Articles with data regarding repeat PK published between 1990 and 2014 were identified in PubMed, EMBASE, the Latin American and Caribbean Health Sciences Literature Database, and the Cochrane Central Register of Controlled Trials and were reviewed. Results were compared with a retrospective review of consecutive, nonrandomized, longitudinal case series of KPro implantations performed at 5 tertiary care centers in the United States. Visual acuity at 2 years was the primary outcome measure. The proportion of clear grafts in the repeat PK group, device retention in the KPro group, and the development of postoperative glaucoma and infection were secondary outcome measures. RESULTS: The search strategy identified 17 128 articles in the PK analysis. After screening, 26 studies (21 case series and 5 cohort studies) were included in the review. Pooled analysis of the 26 unique studies demonstrated a 42% (95% confidence interval [CI], 30%-56%) likelihood of maintaining 20/200 or better at 2 years after repeat PK, compared with an 80% (95% CI, 68%-88%) probability with KPro implantation. The probability of maintaining a clear graft at 5 years was 47% (95% CI, 40%-54%) after repeat PK, whereas the probability of retention of the KPro at 5 years was 75% (95% CI, 64%-84%). The rate of progression of glaucoma at 3 years was 25% (95% CI, 10%-44%) after repeat PK and 30% in the KPro cohort. CONCLUSIONS: These results demonstrate favorable outcomes of KPro surgery for donor corneal graft failure with a greater likelihood of maintaining visual improvement without higher risk of postoperative glaucoma compared with repeat donor PK.
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Órganos Artificiales , Enfermedades de la Córnea/cirugía , Rechazo de Injerto/cirugía , Supervivencia de Injerto , Queratoplastia Penetrante/métodos , Prótesis e Implantes , Humanos , Reoperación , Agudeza VisualRESUMEN
PURPOSE: To report potentially pathogenic mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes in two individuals with clinically diagnosed Meesmann corneal dystrophy (MECD). METHODS: Slit-lamp examination was performed on the probands and available family members to identify characteristic features of MECD. After informed consent was obtained, saliva samples were obtained as a source of genomic DNA, and screening of KRT3 and KRT12 was performed. Potentially pathogenic variants were screened for in 200 control chromosomes. PolyPhen-2, SIFT, and PANTHER were used to predict the functional impact of identified variants. Short tandem repeat genotyping was performed to confirm paternity. RESULTS: Slit-lamp examination of the first proband demonstrated bilateral, diffusely distributed, clear epithelial microcysts, consistent with MECD. Screening of KRT3 revealed a heterozygous missense variant in exon 1, c.250C>T (p.(Arg84Trp)), which has a minor allele frequency of 0.0076 and was not identified in 200 control chromosomes. In silico analysis with PolyPhen-2 and PANTHER predicted the variant to be damaging to protein function; however, SIFT analysis predicted tolerance of the variant. The second proband demonstrated bilateral, diffusely distributed epithelial opacities that appeared gray-white on direct illumination and translucent on retroillumination. Neither parent demonstrated corneal opacities. Screening of KRT12 revealed a novel heterozygous insertion/deletion variant in exon 6, c.1288_1293delinsAGCCCT (p.(Arg430_Arg431delinsSerPro)). This variant was not present in either of the proband's parents or in 200 control chromosomes and was predicted to be damaging by PolyPhen-2, PANTHER, and SIFT. Haplotype analysis confirmed paternity of the second proband, indicating that the variant arose de novo. CONCLUSIONS: We present a novel KRT12 mutation, representing the first de novo mutation and the first indel in KRT12 associated with MECD. In addition, we report a variant of uncertain significance in KRT3 in an individual with MECD. Although the potential pathogenicity of this variant is unknown, it is the first variant affecting the head domain of K3 to be reported in an individual with MECD and suggests that disease-causing variants associated with MECD may not be restricted to primary sequence alterations of either the helix-initiation or helix-termination motifs of K3 and K12.
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Distrofia Corneal Epitelial Juvenil de Meesmann/genética , Queratina-12/genética , Queratina-3/genética , Mutación , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Secuencia de Bases , Niño , Distrofia Corneal Epitelial Juvenil de Meesmann/patología , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Mutación INDEL , Queratina-12/química , Queratina-3/química , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
PURPOSE: To report the identification of a novel frameshift mutation and copy number variation (CNV) in PIKFYVE in two probands with fleck corneal dystrophy (FCD). METHODS: Slit-lamp examination was performed to identify characteristic features of FCD. After genomic DNA was collected, PCR amplification and automated sequencing of all 41 exons of PIKFYVE was performed. Using genomic DNA, quantitative PCR (qPCR) was performed to detect CNVs within PIKFYVE. RESULTS: In the first FCD proband, numerous panstromal punctate opacities were observed in each of the proband's corneas, consistent with the diagnosis of FCD. Screening of PIKFYVE demonstrated a novel heterozygous frameshift mutation in exon 19, c.3151dupA, which is predicted to encode for a truncated PIKFYVE protein, p.(Asp1052Argfs*18). This variant was identified in an affected sister but not in the proband's unaffected mother or brother or 200 control chromosomes. The second FCD proband presented with bilateral, discrete, punctate, grayish-white stromal opacities. Exonic screening of PIKFYVE revealed no causative variant. However, CNV analysis demonstrated the hemizygous deletion of exons 15 and 16. CONCLUSIONS: We report a novel heterozygous frameshift mutation (c.3151dupA) and a CNV in PIKFYVE, representing the first CNV and the fifth frameshift mutation associated with FCD.
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Secuencia de Bases , Distrofias Hereditarias de la Córnea/genética , Variaciones en el Número de Copia de ADN , Mutación del Sistema de Lectura , Fosfatidilinositol 3-Quinasas/genética , Eliminación de Secuencia , Adulto , Córnea/metabolismo , Córnea/patología , Distrofias Hereditarias de la Córnea/diagnóstico , Distrofias Hereditarias de la Córnea/patología , Análisis Mutacional de ADN , Exones , Femenino , Expresión Génica , Heterocigoto , Humanos , Datos de Secuencia MolecularAsunto(s)
Distrofias Hereditarias de la Córnea/diagnóstico , Distrofias Hereditarias de la Córnea/genética , Trasplante de Córnea , Proteínas de la Matriz Extracelular/genética , Mutación Missense , Factor de Crecimiento Transformador beta/genética , Distrofias Hereditarias de la Córnea/cirugía , Sustancia Propia/diagnóstico por imagen , Sustancia Propia/patología , Exones/genética , Femenino , Humanos , Persona de Mediana Edad , Recurrencia , Microscopía con Lámpara de Hendidura , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: To describe 7 patients with paraproteinemic keratopathy and to highlight the clinical and pathologic diversity of this rare entity and the importance of timely, systemic evaluation. DESIGN: Retrospective, multicenter collaborative case series. PARTICIPANTS: Seven patients with paraproteinemic keratopathy. METHODS: Clinical and pathologic records were reviewed to identify patients with well-documented corneal immunoglobulin deposits. Detailed ophthalmologic and medical histories were assembled. In 6 patients, corneal tissue was evaluated histochemically and immunohistochemically; in selected cases, corneal tissue was evaluated by in situ hybridization and ultrastructurally. MAIN OUTCOME MEASURES: Visual acuity and anterior segment examination at presentation and follow-up; local therapy; systemic diagnosis and management; and histopathologic, immunohistochemical, in situ hybridization, and ultrastructural findings. RESULTS: Seven patients were identified with corneal immunoglobulin deposition. In addition to previously reported crystalline, nummular, patch-like, and lattice-like corneal opacities, prominent corneal vascularization was present in 2 patients mimicking interstitial keratitis and limbal stem cell deficiency. All patients had evidence of paraproteinemia in a setting of monoclonal gammopathy of undetermined significance, smoldering plasma cell myeloma, or Waldenström macroglobulinemia. Corneal findings were the first manifestation of systemic disease in 4 patients, and the diagnosis was not suspected in 3 of these patients. Pathologic evaluation of biopsied corneal and conjunctival tissues demonstrated immunoglobulin deposits. Previously unreported ultrastructural patterns in the cornea were noted: large scroll-like immunotactoid deposits, immune complex-like deposits, and randomly arranged fibrils morphologically intermediate between amyloid and immunotactoid deposits. Surgical intervention to improve vision was performed in 4 patients, with recurrence of deposits in 3 patients. Three patients underwent systemic therapy with diminution of the deposits and improvement in vision in 1 patient. CONCLUSIONS: The clinical and pathologic expressions of corneal immunoglobulin deposits are protean and present a diagnostic challenge. Early recognition of this rare entity is important to address the potentially serious associated systemic disease.
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Enfermedades de la Córnea/diagnóstico , Paraproteinemias/diagnóstico , Anciano , Anciano de 80 o más Años , Córnea/patología , Enfermedades de la Córnea/inmunología , Enfermedades de la Córnea/cirugía , Femenino , Humanos , Técnicas para Inmunoenzimas , Inmunoglobulina G/sangre , Cadenas Pesadas de Inmunoglobulina/inmunología , Queratoplastia Penetrante , Masculino , Persona de Mediana Edad , Paraproteinemias/inmunología , Paraproteinemias/cirugía , Estudios Retrospectivos , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To understand the efficacy of various approaches for ocular surface reconstruction in eyes with implanted Boston Type I keratoprosthesis. METHODS: All eyes implanted with a Boston Type I keratoprosthesis over a 9-year period by a single surgeon were reviewed. Any case in which mucosal rehabilitation was performed was included in the study sample. The type, number, approach, and outcome for all eyelid and ocular surface procedures were assessed. RESULTS: A total of 22 mucosal surface surgeries were performed before, concurrent with, and after implantation of 11 keratoprostheses and 1 penetrating keratoplasty (after keratoprosthesis removal) in 9 eyes of 9 patients. Most of the ocular surface reconstructive surgeries (81.8%; 18/22) were performed at the time of or following keratoprosthesis implantation, with the most common indication being corneal stromal necrosis (44.4%; 8/18). Free grafting and simple advancement resulted in graft retraction for each case, and pedicle or bucket handle flaps resulted in a stable vascularized graft for half of the cases. Graft retraction occurred in 6 of the 9 eyes in this study, including in all 5 eyes of patients with Stevens Johnsons syndrome (SJS). CONCLUSIONS: Free grafting and simple advancement flaps do not appear to be effective for rehabilitation in these eyes. However, even vascularized pedicle and bucket handle flaps retracted 50% of the time. Individuals with SJS were more likely to both require conjunctival rehabilitation after keratoprosthesis surgery and develop graft retraction in the course of management.
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Órganos Artificiales , Enfermedades de la Conjuntiva/cirugía , Enfermedades de la Córnea/cirugía , Enfermedades de los Párpados/cirugía , Implantación de Prótesis , Síndrome de Stevens-Johnson/cirugía , Trastornos de la Visión/rehabilitación , Anciano , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Oftalmológicos , Colgajos QuirúrgicosRESUMEN
PURPOSE: To study the long-term outcomes of Boston type 1 keratoprosthesis (KPro) surgery. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: A total of 158 eyes of 150 patients underwent KPro implantation at 5 participating tertiary centers in the United States between January 2003 and December 2006. Of those, 139 eyes of 133 patients were included in the analyses. METHODS: The medical records of consecutive adult patients who received KPro surgery were reviewed. All patients with at least 1 postoperative visit were retained in the outcomes analyses. In eyes in which a repeat KPro procedure was performed, only the outcomes of the initial surgery were analyzed. MAIN OUTCOME MEASURES: Visual acuity (VA) outcomes, postoperative complications, and device retention. RESULTS: The mean follow-up was 46.7 ± 26 months with all but 4 eyes having at least 6 months of follow-up. Preoperatively, only 10.8% of the eyes had VA of ≥ 20/200. Postoperatively, the VA in 70% of eyes improved to ≥ 20/200. The probability of maintaining VA of ≥ 20/200 at 7 years was 50%. The device retention rate was estimated at 67% at 7 years. The 7-year cumulative incidence of complications was 49.7% for retroprosthetic membrane formation, 21.6% for glaucoma surgery, 18.6% for retinal detachment, and 15.5% for endophthalmitis. CONCLUSIONS: Although the risk for complications with longer follow-up seemed to increase, this large multicenter cohort demonstrates favorable outcomes with KPro, with a large number of patients achieving and retaining useful vision over a 7-year period.
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Órganos Bioartificiales , Córnea , Enfermedades de la Córnea/cirugía , Supervivencia de Injerto/fisiología , Complicaciones Posoperatorias , Prótesis e Implantes , Agudeza Visual/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades de la Córnea/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: The aim of this study was to report a novel heterozygous variant c.1712G>T (p.Gly571Val) in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3 gene ( NLRP3 ) in a previously unreported non-Finnish individual with keratitis fugax hereditaria (KFH). METHODS: Ophthalmologic examination of the proband was performed with slit-lamp biomicroscopy and anterior segment optical coherence tomography. Saliva was collected as a source of DNA, after which targeted exome sequencing of candidate genes was performed using a commercially available panel. Identified presumed pathogenic variants were confirmed by Sanger sequencing. RESULTS: Slit-lamp examination of the 52-year-old female proband revealed peripheral arcus-like degeneration and bilateral central corneal opacification, observed on anterior segment optical coherence tomography to involve the anterior half of the corneal stroma. Examination of the proband's parents revealed clear corneas in each eye. Genetic testing of the proband identified the presence of a novel heterozygous NLRP3 missense mutation (c.1712G>T, p.Gly571Val), which was confirmed by Sanger sequencing. This mutation was absent in the proband's parents. CONCLUSIONS: Although KFH has been reported only in individuals of Finnish descent and only in association with a missense mutation in exon 1 of NLRP3 , we report an individual of non-Finnish descent with KFH associated with a novel heterozygous variant in exon 2 of NLRP3 . Thus, ophthalmologists should be aware of the ethnic and genetic heterogeneity associated with KFH.
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Queratitis , Proteína con Dominio Pirina 3 de la Familia NLR , Femenino , Humanos , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Mutación , Queratitis/diagnóstico , Queratitis/genética , Mutación Missense , LinajeRESUMEN
PURPOSE: To assess outcomes of Descemet stripping endothelial keratoplasty (DSEK) in eyes with custom artificial iris (CAI) implantation. METHODS: This is a retrospective, interventional, consecutive, surgical case series of patients who underwent DSEK after CAI implantation between 2010 and 2021 at 2 referral centers. Primary safety measures were loss of corrected distance visual acuity (CDVA), increase in intraocular pressure (IOP), development or progression of glaucoma, and intraoperative and postoperative complications. Efficacy measures were graft survival at year 1 and improvement in cosmesis at postoperative month 3. In general, measures were compared between baseline and postoperative year 1 while any complication was reported for the full follow-up period. RESULTS: Thirty-nine eyes of 39 patients were identified. 64.1% of eyes had acquired aniridia from trauma. The mean follow-up interval was 27.7 months (range 12.2-117.4). Median CDVA improved from logMAR 1.0 to 0.7 at year 1 (P = 0.0047). At the final follow-up, permanent loss of CDVA occurred in 25.6% of eyes, of which 90% was due to glaucoma. The most common postoperative complication was IOP elevation (66.7% of eyes). Graft survival at postoperative year 1 was 82.0% (95% confidence interval, 66.3-91.4). Secondary graft failure occurred in 28.2% of eyes at a mean duration of 39.7 months (SD 27.9 months) after DSEK. Cosmesis improved among 87.2% of eyes at postoperative month 3. CONCLUSIONS: DSEK is an effective procedure for addressing corneal edema in eyes with a CAI, but a majority develop elevated IOP and graft survival is shorter than in eyes without a CAI.
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Purpose: We sought to introduce the materials, design, and biocompatibility of a flexible and suturable artificial corneal device. Methods: Single-piece, fully synthetic, optic-skirt design devices were made from compact perfluoroalkoxy alkane. The skirt and the optic wall surfaces were lined with a porous tissue ingrowth material using expanded polytetrafluoroethylene. Full-thickness macroapertures around the skirt perimeter were placed to facilitate nutrition of the recipient cornea. Material properties including the skirt's modulus of elasticity and bending stiffness, optic light transmission, wetting behavior, topical drug penetrance, and degradation profile were evaluated. Results: The final prototype suitable for human use has a transparent optic with a diameter of 4.60 mm anteriorly, 4.28 mm posteriorly, and a skirt outer diameter of 6.8 mm. The biomechanical and optical properties of the device closely align with the native human cornea with an average normalized device skirt-bending stiffness of 4.7 kPa·mm4 and light transmission in the visible spectrum ranging between 92% and 96%. No optical damage was seen in the 36 devices tested in fouling experiments. No significant difference was observed in topical drug penetrance into the anterior chamber of the device implanted eye compared with the naïve rabbit eye. Conclusions: The flexibility and biocompatibility of our artificial cornea device may offer enhanced tissue integration and decreased inflammation, leading to improved retention compared with rigid keratoprosthesis designs. Translational Relevance: We have developed a fully synthetic, flexible, suturable, optic-skirt design prototype artificial cornea that is ready to be tested in early human feasibility studies.
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Materiales Biocompatibles , Córnea , Ensayo de Materiales , Diseño de Prótesis , Animales , Conejos , Materiales Biocompatibles/química , Ensayo de Materiales/métodos , HumanosRESUMEN
Mutations in the solute linked carrier family 4 member 11 (SLC4A11) gene are associated with congenital hereditary endothelial dystrophy (CHED) and Fuchs corneal endothelial dystrophy type 4 (FECD4), both characterized by corneal endothelial cell (CEnC) dysfunction and/or cell loss leading to corneal edema and visual impairment. In this study, we characterize the impact of CHED-/FECD4-associated SLC4A11 mutations on CEnC function and SLC4A11 protein localization by generating and comparing human CEnC (hCEnC) lines expressing wild type SLC4A11 (SLC4A11WT) or mutant SLC4A11 harboring CHED-/FECD4-associated SLC4A11 mutations (SLC4A11MU). SLC4A11WT and SLC4A11MU hCEnC lines were generated to express either SLC4A11 variant 2 (V2WT and V2MU) or variant 3 (V3WT and V3MU), the two major variants expressed in ex vivo hCEnC. Functional assays were performed to assess cell barrier, proliferation, viability, migration, and NH3-induced membrane conductance. We demonstrate SLC4A11-/- and SLC4A11MU hCEnC lines exhibited increased migration rates, altered proliferation and decreased cell viability compared to SLC4A11WT hCEnC. Additionally, SLC4A11-/- hCEnC demonstrated decreased cell-substrate adhesion and membrane capacitances compared to SLC4A11WT hCEnC. Induction with 10mM NH4Cl led SLC4A11WT hCEnC to depolarize; conversely, SLC4A11-/- hCEnC hyperpolarized and the majority of SLC4A11MU hCEnC either hyperpolarized or had minimal membrane potential changes following NH4Cl induction. Immunostaining of primary hCEnC and SLC4A11WT hCEnC lines for SLC4A11 demonstrated predominately plasma membrane staining with poor or partial colocalization with mitochondrial marker COX4 within a subset of punctate subcellular structures. Overall, our findings suggest CHED-associated SLC4A11 mutations likely lead to hCEnC dysfunction, and ultimately CHED, by interfering with cell migration, proliferation, viability, membrane conductance, barrier function, and/or cell surface localization of the SLC4A11 protein in hCEnC. Additionally, based on their similar subcellular localization and exhibiting similar cell functional profiles, protein isoforms encoded by SLC4A11 variant 2 and variant 3 likely have highly overlapping functional roles in hCEnC.
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Proteínas de Transporte de Anión , Antiportadores , Distrofias Hereditarias de la Córnea , Distrofia Endotelial de Fuchs , Humanos , Proteínas de Transporte de Anión/genética , Antiportadores/genética , Trastornos de los Cromosomas , Distrofias Hereditarias de la Córnea/genética , Células Endoteliales , Distrofia Endotelial de Fuchs/genética , Mutación , Proteínas SLC4ARESUMEN
PURPOSE: To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). DESIGN: Multicenter cohort study. METHODS: A discovery cohort of 27 individuals with LECD from 17 families, including 7 affected members from the original LECD family, 6 patients from 2 new families and 14 simplex cases, was recruited. A cohort of 6 individuals carrying a pathogenic MCOLN1 (mucolipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequencing were used in all patients to identify pathogenic or likely pathogenic variants and penetrance of variants. RESULTS: Nine rare heterozygous MCOLN1 variants were identified in 23 of 27 affected individuals from 13 families. The truncating nature of 7 variants and functional testing of 1 missense variant indicated that they result in MCOLN1 haploinsufficiency. Importantly, in the homozygous and compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysosomal storage disorder mucolipidosis IV (MLIV). Autosomal recessive MLIV is a systemic disease and comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. However, the 6 parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype, suggesting MCOLN1 haploinsufficiency may be associated with reduced penetrance and variable expressivity. CONCLUSIONS: MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlapping clinical features of corneal epithelial cells with autofluorescent inclusions reported in both LECD and MLIV, it is concluded that some carriers of MCOLN1 haploinsufficiency-causing variants present with LECD.