Analysis of phenotype changes of deposits in granular corneal dystrophy type 2 and possible explanation for diffuse haze

Abstract

Background:

Granular corneal dystrophy type 2 (GCD2) is a hereditary disease, which is caused by an autosomal dominant Arg124His mutation in the transforming growth factor-β induced gene (TGFBI). In GCD2, corneal deposits appear as granular lesion, linear (lattice-like) lesion and diffuse haze. GCD2 has known to show profound differences in the severity of phenotype. TGFBIp is understood to be the main substance forming various types of deposits. But there are no studies that explain the development of TGFBIp into 3 types of deposits. TGFBIp is thought to be generated in epithelial cell and move gradually to deep stroma forming deposits in various levels. Linear lesion is considered to be formed with the degraded TGFBIp fragments. Diffuse haze is formed with the undegraded TGFBIp. Late onset developing of diffuse haze demonstrates the possibility that an increase of age is associated with decrease of the ability of degrading TGFBIp.

Methods:

We retrospectively reviewed the records and slit-lamp photographs of 533 patients with GCD2. All patients were diagnosed as being GCD2 heterozygous by DNA analysis from peripheral blood. Deposits were classified into granular lesion, linear lesion and diffuse haze. We evaluated the area of each type of deposit using inForm® software (Perkin Elmer, Inc, Waltham, MA, USA), and the tendency of the area of each type was investigated according to age. The correlation among the area of 3 types was analyzed. To study the relationship between diffuse haze and linear lesion especially, we evaluated the difference of the amount of the diffuse haze in proportion of the linear lesion (paired eye test). The relationship between visual acuity and the area of each type was also evaluated.

Results:

For all types of deposits, the area had an increasing tendency with age (all for p<0.001). In detail, the area of diffuse haze increased in earnest since 40’s. Linear lesion showed a tendency of increase until 40’s, but this tendency of increase stopped from 40’s. The area of diffuse haze and linear lesion significantly showed negative correlation (Pearson correlation coefficient; -0.10, p=0.04). Diffuse haze also had negative correlation with linear lesion between granular and linear lesion (Pearson correlation coefficient; -0.15, p<0.01). In paired eye study, there was statistically significant negative tendency showing that cornea with more linear lesion had less area of diffuse haze than apposite eye (p<0.001). In logistic analysis, the group with larger linear lesion between granular and linear lesion significantly had less diffuse haze comparing to the group with smaller linear lesion (adjusted OR=0.50, p=0.02). In 3 types of deposits, diffuse haze had the worst effect on visual acuity.

Conclusion:

In GCD2, diffuse haze is the main cause of visual impairment and formed mostly after 40’s. This late onset formation is associated with the stop of the linear lesion formation, and this association would suggest that decline of the degradability of TGFBIp in corneal cells with age might be related with the formation of diffuse haze.