A new, X-linked endothelial corneal dystrophy
ABSTRACT To describe the clinical spectrum, the histopathologic findings obtained from one corneal button, and the genetic mapping of an X-linked endothelial corneal dystrophy (XECD).
Observational case series and experimental study.
We examined a total of 60 members of a family with this dystrophy at the slit-lamp. Light and electron microscopic findings of the corneal button were recorded following one male patient's penetrating keratoplasty. A panel of 25 microsatellite markers covering the X chromosome was typed in genomic DNA from 50 family members. The data were analyzed using the ALLEGRO program to obtain two-point and multipoint likelihood of the odds (LOD) scores and to generate haplotypes.
A total of 35 trait carriers were identified in four generations of the family. Nine male patients demonstrated severe corneal opacifications: two congenital corneal cloudings in form of ground glass, milky appearance and seven subepithelial band keratopathies combined with endothelial changes resembling moon craters. Twenty-two female and four male patients disclosed only endothelial alterations resembling moon craters. No instance of male-to-male transmission of the disease was encountered in the family. Light and electron microscopy disclosed focal discontinuities and degeneration of the endothelial cell layer and marked thickening of Descemet's membrane. Multipoint analysis showed linkage with a maximum LOD score of 10.90 between markers DXS8057 and DXS1047.
To the best of our knowledge, this represents the first fully documented report of X-linked inheritance of an endothelial corneal dystrophy. Late subepithelial band keratopathy is a landmark of XECD. A locus for this corneal dystrophy maps to Xq25.
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ABSTRACT: Purpose: To comprehensively characterize human corneal endothelial cell (HCEnC) gene expression, age-dependent differential gene expression and to identify expressed genes mapped to chromosomal loci associated with the corneal endothelial dystrophies PPCD1, FECD4 and XECD. Methods: Total RNA was isolated from ex vivo corneal endothelium obtained from six pediatric and five adult donor corneas. Complimentary DNA was hybridized to the Affymetrix GeneChip 1.1ST array. Data analysis was performed using Partek Genomics Suite software and differentially expressed genes were validated by digital molecular barcoding technology. Results: Transcripts corresponding to 12,596 genes were identified in HCEnC. Nine genes displayed the most significant differential expression between pediatric and adult HCEnC: CAPN6, HIST1H3A, HIST1H4E and HSPA2 were expressed at higher levels in pediatric HCEnC, while ITGBL1, NALCN, PREX2, TAC1 and TMOD1 were expressed at higher levels in adult HCEnC. Analysis of the PPCD1, FECD4 and XECD loci demonstrated transcription of 53/95 protein-coding genes in the PPCD1 locus, 27/40 in the FECD4 locus, and 35/68 in the XECD locus. Conclusions: An analysis of the HCEnC transcriptome reveals the expression of almost 13,000 genes, with less than 1% mapped to chromosomal loci associated with PPCD1, FECD4 and XECD. At least nine genes demonstrated significant differential expression between pediatric and adult HCEnC, defining specific functional properties distinct to each age group. This data will serve as a resource for vision scientists investigating HCEnC gene expression and can be used to focus the search for the genetic basis of the corneal endothelial dystrophies for which the genetic basis remains unknown.Investigative Ophthalmology & Visual Science 11/2014; 55(12). DOI:10.1167/iovs.14-15021 · 3.66 Impact Factor
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ABSTRACT: Homozygous mutations in SLC4A11 cause 2 rare recessive conditions: congenital hereditary endothelial dystrophy (CHED), affecting the cornea alone, and Harboyan syndrome consisting of corneal dystrophy and sensorineural hearing loss. In addition, adult-onset Fuchs endothelial corneal dystrophy (FECD) is associated with dominant mutations in SLC4A11. In this report, we investigate whether patients with CHED go on to develop hearing loss and whether their parents, who are carriers of an SLC4A11 mutation, show signs of having FECD. Patients with CHED were screened for mutations in the SLC4A11 gene and underwent audiometric testing. The patients and their parents underwent a clinical examination and specular microscopy. Molecular analyses confirmed SLC4A11 mutations in 4 affected individuals from 3 families. All the patients were found to have varying degrees of sensorineural hearing loss at a higher frequency range. Guttate lesions were seen in 2 of the 4 parents who were available for examination. Our observations suggest that CHED caused by homozygous SLC4A11 mutations progresses to Harboyan syndrome, but the severity of this may vary considerably. Patients with CHED should therefore be monitored for progressive hearing loss. We could not determine conclusively whether the parents of the patients with CHED were at increased risk of developing late-onset FECD.Cornea 12/2013; 33(3). DOI:10.1097/ICO.0000000000000041 · 2.36 Impact Factor
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ABSTRACT: Corneal endothelium is formed of 1 layer of mitochondria-rich cubic cells whose main role is to maintain corneal transparency. Corneal endothelial disorders represent group of both inherited and noninherited and may affect proper vision.A 36-year-old male patient with suspicion of corneal endothelial dystrophy underwent visual acuity, intraocular pressure, the basic slit-lamp examination, anterior segment optical coherence tomography (AS-OCT) (Visante, Carl Zeiss Meditec, Dublin, CA), and corneal confocal microscopy in vivo (Rostock Cornea Module, Heidelberg Engineering Retina Tomograph III, Heidelberg, Germany). During the 3-year observation the patient reported symptoms mainly in the right eye. Slit-lamp examination revealed endothelial changes, much more pronounced in the right eye. Examination by the AS-OCT Visante showed hyperreflective dots within the right corneal endothelium. In order to assess endothelial cell morphology, analysis using corneal confocal microscopy in vivo was performed. Scans revealed presence of single endothelial deposits and severe cell changes of different morphology in both eyes. In the right eye, less pronounced changes of the polymorphic structure-polygonal guttas in different stages, linear and branched loss with "nuclear-like" formations and accompanying sediments. In the left eye, severe homomorphous polygonal "guttas-like" changes with "nuclear-like" formations were observed. Endothelial cysts' features were dynamically changing during follow-up time with different effects on the patient's clinical state.Corneal confocal microscopy allows accurate imaging of the endothelial cells and their detailed characteristics. Structural changes within the endothelial cells are not always proportional to visual acuity and slit-lamp image. The presented case is an example of an unusual corneal endothelial syndrome with probably nondystrophic background due to observed dynamic state with regressive tendency.Medicine 03/2015; 94(9):e564. DOI:10.1097/MD.0000000000000564 · 4.87 Impact Factor