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

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Majander , A , Jurkute , N , Burte , F , Brock , K , Joao , C , Huang , H , Neveu , M M , Chan , C M , Duncan , H J , Kelly , S , Burkitt-Wright , E , Khoyratty , F , Lai , Y T , Subash , M , Chinnery , P F , Bitner-Glindzicz , M , Arno , G , Webster , A R , Moore , A T , Michaelides , M , Stockman , A , Robson , A G & Yu-Wai-Man , P 2022 , ' WFS1-Associated Optic Neuropathy : Genotype-Phenotype Correlations and Disease Progression ' , American Journal of Ophthalmology , vol. 241 , pp. 9-27 . https://doi.org/10.1016/j.ajo.2022.04.003

Title: WFS1-Associated Optic Neuropathy : Genotype-Phenotype Correlations and Disease Progression
Author: Majander, Anna; Jurkute, Neringa; Burte, Florence; Brock, Kristain; Joao, Catarina; Huang, Houbin; Neveu, Magella m.; Chan, Choi mun; Duncan, Holly j.; Kelly, Simon; Burkitt-Wright, Emma; Khoyratty, Fadil; Lai, Yoon tse; Subash, Mala; Chinnery, Patrick f.; Bitner-Glindzicz, Maria; Arno, Gavin; Webster, Andrew r.; Moore, Anthony t.; Michaelides, Michel; Stockman, Andrew; Robson, Anthony g.; Yu-Wai-Man, Patrick
Contributor organization: HUS Head and Neck Center
Department of Ophthalmology and Otorhinolaryngology
Clinicum
University of Helsinki
Date: 2022-09
Language: eng
Number of pages: 19
Belongs to series: American Journal of Ophthalmology
ISSN: 0002-9394
DOI: https://doi.org/10.1016/j.ajo.2022.04.003
URI: http://hdl.handle.net/10138/346328
Abstract: center dot OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON).center dot DESIGN: Multicenter cohort study. center dot 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.center dot 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. center dot 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. (Am J Ophthalmol 2022;241: 927. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))
Subject: VISUAL-EVOKED POTENTIALS
WOLFRAM-SYNDROME
WFS1 GENE
MISSENSE MUTATION
ISCEV STANDARD
ATROPHY
PATTERN
NEURODEGENERATION
IDENTIFICATION
EXPRESSION
3125 Otorhinolaryngology, ophthalmology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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