Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization
Issued Date
2025-12-01
Resource Type
ISSN
00029394
eISSN
18791891
Scopus ID
2-s2.0-105015173169
Pubmed ID
40803642
Journal Title
American Journal of Ophthalmology
Volume
280
Start Page
154
End Page
168
Rights Holder(s)
SCOPUS
Bibliographic Citation
American Journal of Ophthalmology Vol.280 (2025) , 154-168
Suggested Citation
Zhang W., Duong H., Jongkhajornpong P., Hang D.T.T., Pham H., Nguyen M., Choo C., Williams D., Nguyen X., Nguyen T.D., Aguirre B., Khan S., Wadehra M., Tomatsu S., Aldave A.J. Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization. American Journal of Ophthalmology Vol.280 (2025) , 154-168. 168. doi:10.1016/j.ajo.2025.08.006 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/112064
Title
Peripheral Macular Endothelial Dystrophy: Clinical, Histopathologic, Genetic and Functional Characterization
Corresponding Author(s)
Other Contributor(s)
Abstract
Objective: To report a CHST6-associated corneal endothelial dystrophy. Design: Prospective observational case series. Participants: Thirty-five individuals from seven families, including 13 affected individuals exhibiting corneal epithelial and stromal edema, peripheral posterior corneal macular opacities, and endothelial guttae, as well as 22 unaffected family members. Methods: Whole-exome sequencing was performed in 3 families and Sanger sequencing of CHST6 was performed in all individuals. Histological examination of Descemet membrane (DM) excised at the time of endothelial keratoplasty was performed for three probands. Serum keratan sulfate (KS) levels were measured in members of six families. Functional analysis of identified mutations was performed using CHST6 promoter containing CHST6 expression vector in human keratocytes (HK) and corneal endothelial cells (HCEnC). Main Outcome Measures: Clinical phenotype; genetic analysis; functional analysis of identified CHST6 mutations; serum KS levels; histologic examinations of DM. Results: All affected individuals demonstrated peripheral macular opacities at the level of DM. Visually significant corneal edema in affected individuals was successfully managed by endothelial keratoplasty. Genetic analysis demonstrated a rare CHST6 promoter mutation (c.-690G>C) in the homozygous state in affected individuals from three families and in the compound heterozygous state with a CHST6 coding mutation (p.R211Q, p.Y268C or p.P280L) in affected individuals from the other four families. In silico analysis predicted c.-690G>C to be a regulatory variant, located at the RNA polymerase II binding site. Functional analysis in vitro demonstrated that c.-690G>C leads to increased KS sulfation in the corneal endothelium and DM, with no change of KS sulfation in keratocytes. Histologic examination of DM from affected individuals revealed elevated levels of sulfated and non-sulfated KS in DM and endothelium, consistent with the functional analysis. Minimum changes in serum sulfated KS levels were observed in affected individuals. Conclusions: We suggest the name Peripheral macular endothelial dystrophy (PMED) to describe this dystrophy that is characterized by peripheral posterior corneal macular opacities and endothelial dysfunction without stromal haze or opacities. Given that both PMED and macular corneal dystrophy are associated with promoter and coding region mutations in CHST6, we propose that they be categorized as CHST6-associated corneal dystrophies.