Abstract
purpose. To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD).
methods. DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet’s membrane that are characteristic of FCD.
results. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families.
conclusions. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.
Fuchs corneal dystrophy (FCD) is a primary disorder of the endothelium that leads to progressive edema of the corneal stroma (OMIM 136800; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD). Visual disability from this disease is currently the major reason for corneal transplantation.
1 The initial stages of FCD typically begin in the fifth through seventh decades of life and are characterized by localized thickening of Descemet’s membrane and the development of nodular excrescences called guttae. This early phase is followed by long-term decreases in the density and ion transport functions of the overlying corneal endothelial cells, which allows excess water to accumulate in the cornea.
2 3 4 5 6 7 8 Several reports, including the original description by Fuchs, have indicated that two to three times as many females as males are affected by the disease.
2 7 9
As many as 50% of clinical cases of FCD may show familial clustering,
9 and the disease generally follows an autosomal dominant pattern of inheritance.
10 11 12 13 14 15 Nearly all these families show inheritance of late-onset FCD, whereas rare cases
12 14 show disease onset as early as the first decade, with extensive corneal edema by the third or fourth decades. Recently, a multigenerational family exhibiting advanced FCD by their third and fourth decades revealed genetic linkage to a 7 cM region of chromosome 1p34.3-p32.
14 Individuals affected with FCD were found to be heterozygous for a point mutation altering the collagen helix domain of the α2 chain of type VIII collagen (
COL8A2), substituting a lysine for a glutamine (Q455K). Because collagen VIII is a major component of Descemet’s membrane, the mutation provides important evidence that the disease originates as a molecular dysfunction of the extracellular matrix of the endothelium. A second independently ascertained, large family, also described as having early onset, had exactly the same Q455K mutation.
14 This second family showed perfect concordance between the mutation and individuals affected with FCD. In a third independent small family,
14 the Q455K mutation was associated with two patients with posterior polymorphous corneal dystrophy (PPCD), a distinct endothelial cell disorder with some features similar to FCD. To date, no
COL8A2 amino acid sequence variants have been identified that are clearly associated with late-onset FCD.
14 16
We have performed genetic linkage analysis of the large early-onset FCD family originally described by Magovern et al.,
12 and identified a second
COL8A2 mutation, L450W. We report that this mutation is associated with highly distinctive guttae that differ from those of common late-onset FCD and suggest that mutations in
COL8A2 give rise to a rare subtype of FCD. Long-term study of this family has also provided us with the unique opportunity to follow the temporal progression of inherited FCD.
Corneal Slit Lamp Photography and Confocal Specular Microscopy of Fuchs Families with COL8A2 and Non-COL8A2 Mutations
With the L450W-COL8A2 mutation, children as young as 3 years have been found to be affected. All who were in the early stages of the disease at the time of the 1979 study have since progressed to corneal decompensation, and several have undergone penetrating keratoplasty. This natural history fits well with earlier reports of the Q455K-COLA2 mutation, in which FCD was diagnosed in individuals from ages 21 to 48, and those in their 30s and 40s had advanced stages of disease. Because no member of the Q455K family appears to have been screened for very early stages of the disease, it cannot be ruled out that some were affected as early as age 3.
A unique feature of the L450W family is that we have been able to combine data collected in the 1970s with recent examinations of the same individuals, as well as to ascertain new patients. In some cases, disease severity was graded at the time of corneal transplantation. The age-versus-severity distribution of the L450W-COL8A2-carrying patients is much narrower than that of the other 201 patients with late-onset disease. This is not unexpected, because the late-onset group very likely involved great heterogeneity, both in the genes involved and the severity of the specific mutations.