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WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression

Majander, Anna; Jurkute, Neringa; Burté, Florence; Brock, Kristian; João, Catarina; Huang, Houbin; Neveu, Magella M; ... Yu-Wai-Man, Patrick; + view all (2022) WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression. American Journal of Ophthalmology , 241 pp. 9-27. 10.1016/j.ajo.2022.04.003. Green open access

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Abstract

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 ophthalmological 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 five 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 cleft-like lamination of the OPL is a distinctive OCT feature that strongly points towards dominant WON.

Type: Article
Title: WFS1-Associated Optic Neuropathy: Genotype-Phenotype Correlations and Disease Progression
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajo.2022.04.003
Publisher version: https://doi.org/10.1016/j.ajo.2022.04.003
Language: English
Additional information: © 2022 The Author(s). Published by Elsevier Inc. under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10147920
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