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.
SourceAvailable from: Ricardo Frausto[Show abstract] [Hide abstract]
ABSTRACT: PURPOSE: To provide an evidenced-based review of the genetic basis of the corneal endothelial dystrophies. METHODS: A review of the English-language peer-reviewed literature describing the molecular genetic basis of posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), Fuchs endothelial corneal dystrophy (FECD) and X-linked endothelial corneal dystrophy (XECD) was performed. RESULTS: Mutations in several genes have been implicated as playing a pathogenic role in the corneal endothelial dystrophies: VSX1 mutations in PPCD1; COL8A2 mutations in PPCD2 and FECD; ZEB1 mutations in PPCD3 and FECD; and SLC4A11 mutations in CHED2 and FECD. However, linkage, association and familial segregation analyses support a role of only one gene in each corneal endothelial dystrophy: ZEB1 in PPCD3, SLC4A11 in CHED2 and COL8A2 in FECD (early onset). In addition, insufficient evidence exists to consider the autosomal dominant form of CHED (CHED1) as distinct from PPCD. CONCLUSIONS: An accurate classification of the corneal endothelial dystrophies requires a critical review of the evidence to support the role of each suggested chromosomal locus, gene and genetic mutation associated with a corneal endothelial dystrophy. Only after the separation of evidence from opinion is performed can a critical examination of the molecular pathways that lead to endothelial dysfunction in each of these disorders be accurately performed.Clinical Genetics 05/2013; DOI:10.1111/cge.12191 · 3.65 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 dystrophies represent a highly heterogeneous group of hereditary disorders, consisting of more than 30 distinct entities, of which only 16 have their molecular basis partially or completely elucidated. The genetic characterization of corneal dystrophies revealed both genetic heterogeneity, i.e. different genes (KRT3 and KRT12) causing one single dystrophic phenotype, as well as phenotypic heterogeneity with one single gene (TGFBI) causing different dystrophic phenotypes (see below 5.5 keratoepithelinopathies).