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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 9-27 |
| Number of pages | 19 |
| Journal | American Journal of Ophthalmology |
| Volume | 241 |
| Early online date | 22 Apr 2022 |
| DOIs | |
| Publication status | Published - Sept 2022 |
Bibliographical note
Funding Information:Funding/Support: This research was supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC), the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, and the NIHR Moorfields Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Financial Disclosures: Anna Majander receives funding from Suomen Silmätutkimusseura ry:n Apurahasäätiö (Finland). Patrick Yu-Wai-Man is supported by an Advanced Fellowship Award (NIHR301696) from the UK National Institute of Health Research (NIHR) and by a Clinician Scientist Fellowship Award (G1002570) from the Medical Research Council (UK), and also receives funding from Fight for Sight (UK), the Isaac Newton Trust (UK), Moorfields Eye Charity, the Addenbrooke's Charitable Trust, the National Eye Research Centre (UK), the International Foundation for Optic Nerve Disease (IFOND), the UK NIHR as part of the Rare Diseases Translational Research Collaboration, the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), and the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. Neringa Jurkute is supported by Moorfields Eye Charity (GR001203), National Eye Research Centre (SAC051), National Institute of Health Research Biomedical Research Centre (NIHR-BRC) at Moorfields Eye Hospital and UCL Institute of Ophthalmology. Patrick F. Chinnery, Anthony T. Moore, and Patrick Yu-Wai-Man receive funding from the UK NIHR as part of the Rare Diseases Translational Research Collaboration. Patrick F. Chinnery is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society Project Grant (AS-PG-18b-022) and the NIHR-BRC based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. Gavin Arno is supported by a Fight for Sight (UK) Early Career Investigator award (5045/46), Moorfields Eye Charity (Stephen and Elizabeth Archer in memory of Marion Woods), the NIHR-BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology and the NIHR-BRC at Great Ormond Street Hospital Institute of Child Health. Michel Michaelides receives funding from Moorfields Eye Charity, the Foundation Fighting Blindness (USA), Retina, UK, and The Wellcome Trust (099173/Z/12/Z). Andrew Stockman is supported by the Biotechnology and Biological Sciences Research Council grant BB/R019487/1. All authors attest that they meet the current ICMJE criteria for authorship. Author Contributions: Research design: A.M., P.Y.-W.-M.; Data acquisition and/or research execution: A.M., N.J., F.B., K.B., C.J., H.B.H., M.M.N., C.M.C., H.J.D., S.K., E.B.W., F.K., Y.T.L., M.S., P.F.C., M.B.G., G.A., A.R.W., A.T.M., M.M., A.S., A.G.R., P.Y.-W.-M.; Data analysis and/or interpretation: A.M., N.J., F.B., K.B., H.B.H., M.M.N., G.A., M.M., A.S., A.G.R., P.Y.-W.-M.; Manuscript preparation: A.M., N.J., F.B., K.B., M.M.N., G.A., M.M., A.S., A.G.R., P.Y.-W.-M.
Publisher Copyright:
© 2022 The Author(s)
ASJC Scopus subject areas
- Ophthalmology
