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Lookup NU author(s): Dr Florence Burte, Dr Holly Duncan, Professor Patrick Chinnery
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The Author(s)OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON). DESIGN: Multicenter cohort study. METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. Main Outcome Measures: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile. RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON.
Author(s): Majander A, Jurkute N, Burte F, Brock K, Joao C, Huang H, Neveu MM, Chan CM, Duncan HJ, Kelly S, Burkitt-Wright E, Khoyratty F, Lai YT, Subash M, Chinnery PF, Bitner-Glindzicz M, Arno G, Webster AR, Moore AT, Michaelides M, Stockman A, Robson AG, Yu-Wai-Man P
Publication type: Article
Publication status: Published
Journal: American Journal of Ophthalmology
Year: 2022
Volume: 241
Pages: 9-27
Print publication date: 01/09/2022
Online publication date: 22/04/2022
Acceptance date: 13/04/2022
Date deposited: 04/07/2023
ISSN (print): 0002-9394
ISSN (electronic): 1879-1891
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.ajo.2022.04.003
DOI: 10.1016/j.ajo.2022.04.003
PubMed id: 35469785
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