{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T10:12:28Z","timestamp":1760609548642,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T00:00:00Z","timestamp":1688515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Wolfram syndrome is a neurodegenerative disorder caused by pathogenic variants in the genes WFS1 or CISD2. Clinically, the classic phenotype is composed of optic atrophy, diabetes mellitus type 1, diabetes insipidus, and deafness. Wolfram syndrome, however, is phenotypically heterogenous with variable clinical manifestations and age of onset. We describe four cases of genetically confirmed Wolfram syndrome with variable presentations, including acute-on-chronic vision loss, dyschromatopsia, and tonic pupils. All patients had optic atrophy, only three had diabetes, and none exhibited the classic Wolfram phenotype. MRI revealed a varying degree of the classical features associated with the syndrome, including optic nerve, cerebellar, and brainstem atrophy. The cohort\u2019s genotype and presentation supported the reported phenotype\u2013genotype correlations for Wolfram, where missense variants lead to milder, later-onset presentation of the Wolfram syndrome spectrum. When early onset optic atrophy and\/or diabetes mellitus are present in a patient, a diagnosis of Wolfram syndrome should be considered, as early diagnosis is crucial for the appropriate referrals and management of the associated conditions. Nevertheless, the condition should also be considered in otherwise unexplained, later-onset optic atrophy, given the phenotypic spectrum.<\/jats:p>","DOI":"10.3390\/brainsci13071030","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:34:30Z","timestamp":1688603670000},"page":"1030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Neuro-Ophthalmologic Variability in Presentation of Genetically Confirmed Wolfram Syndrome: A Case Series and Review"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2367-7298","authenticated-orcid":false,"given":"Ruben","family":"Jauregui","sequence":"first","affiliation":[{"name":"Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8288-6268","authenticated-orcid":false,"given":"Nicolas J.","family":"Abreu","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shani","family":"Golan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph F.","family":"Panarelli","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meenakshi","family":"Sigireddi","sequence":"additional","affiliation":[{"name":"Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Pediatrics, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1144-653X","authenticated-orcid":false,"given":"Gopi K.","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Radiology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doria M.","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet C.","family":"Rucker","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven L.","family":"Galetta","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7033-5226","authenticated-orcid":false,"given":"Scott N.","family":"Grossman","sequence":"additional","affiliation":[{"name":"Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/2441","article-title":"A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)","volume":"20","author":"Inoue","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rigoli, L., Caruso, V., Salzano, G., and Lombardo, F. (2022). Wolfram Syndrome 1: From Genetics to Therapy. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19063225"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/gim.2012.180","article-title":"Genotypic classification of patients with Wolfram syndrome: Insights into the natural history of the disease and correlation with phenotype","volume":"15","author":"Cleries","year":"2013","journal-title":"Genet. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1093\/hmg\/ddg214","article-title":"Wolfram syndrome: Structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product","volume":"12","author":"Hofmann","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/ana.22160","article-title":"Neurologic features and genotype-phenotype correlation in Wolfram syndrome","volume":"69","author":"Chaussenot","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.2337\/dc10-1937","article-title":"Diabetes and neurodegeneration in Wolfram syndrome: A multicenter study of phenotype and genotype","volume":"34","author":"Rohayem","year":"2011","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11892-015-0702-6","article-title":"Wolfram Syndrome: Diagnosis, Management, and Treatment","volume":"16","author":"Urano","year":"2016","journal-title":"Curr. Diab. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.jaapos.2014.07.162","article-title":"Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome","volume":"18","author":"Hoekel","year":"2014","journal-title":"J. AAPOS"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1038\/sj.eye.6701591","article-title":"Hereditary optic neuropathies","volume":"18","author":"Newman","year":"2004","journal-title":"Eye"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ajo.2021.09.030","article-title":"Reduced Corneal Sensitivity With Neuronal Degeneration is a Novel Clinical Feature in Wolfram Syndrome","volume":"236","author":"Waszczykowska","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1177\/112067210201200202","article-title":"Ophthalmologic findings in fifteen patients with Wolfram syndrome","volume":"12","author":"Jarrah","year":"2002","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120267","DOI":"10.1016\/j.jns.2022.120267","article-title":"Neuro-ophthalmological manifestations of Wolfram syndrome: Case series and review of the literature","volume":"437","author":"Kabanovski","year":"2022","journal-title":"J. Neurol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1001\/archneur.1977.00500240047008","article-title":"Juvenile diabetes mellitus and optic atrophy","volume":"34","author":"Lessell","year":"1977","journal-title":"Arch. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/pedi.13291","article-title":"Longitudinal progression of diabetes mellitus in Wolfram syndrome: The Washington University Wolfram Research Clinic experience","volume":"23","author":"Ray","year":"2022","journal-title":"Pediatr. Diabetes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.3174\/ajnr.A6831","article-title":"Longitudinal Assessment of Neuroradiologic Features in Wolfram Syndrome","volume":"41","author":"Samara","year":"2020","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e213","DOI":"10.1212\/WNL.0000000000001082","article-title":"Teaching NeuroImages: MRI of brain findings of Wolfram (DIDMOAD) syndrome","volume":"83","author":"Gocmen","year":"2014","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1002\/ana.410390312","article-title":"Wolfram syndrome: Hereditary diabetes mellitus with brainstem and optic atrophy","volume":"39","author":"Scolding","year":"1996","journal-title":"Ann. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.disamonth.2014.03.008","article-title":"A review of optic neuropathies","volume":"60","author":"Dworak","year":"2014","journal-title":"Dis. Mon."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1056\/NEJMra1413352","article-title":"Ischemic Optic Neuropathies","volume":"372","author":"Biousse","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_20","first-page":"1236","article-title":"Optic Neuritis","volume":"25","author":"Bennett","year":"2019","journal-title":"Continuum"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.4103\/0301-4738.77035","article-title":"Toxic optic neuropathy","volume":"59","author":"Sharma","year":"2011","journal-title":"Indian J. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.ajo.2005.03.017","article-title":"Hereditary optic neuropathies: From the mitochondria to the optic nerve","volume":"140","author":"Newman","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/brain\/awac395","article-title":"The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands","volume":"146","author":"Rocatcher","year":"2023","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/ajmg.a.31809","article-title":"Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome","volume":"143A","author":"Cano","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/cge.12437","article-title":"Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders","volume":"87","author":"Chaussenot","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Matsunaga, K., Tanabe, K., Inoue, H., Okuya, S., Ohta, Y., Akiyama, M., Taguchi, A., Kora, Y., Okayama, N., and Yamada, Y. (2014). Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106906"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1136\/jmedgenet-2020-107257","article-title":"WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome","volume":"59","author":"Hu","year":"2022","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e578","DOI":"10.1212\/NXG.0000000000000578","article-title":"Mild Phenotype of Wolfram Syndrome Associated with a Common Pathogenic Variant Is Predicted by a Structural Model of Wolframin","volume":"7","author":"Shor","year":"2021","journal-title":"Neurol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1007\/s00125-018-4690-3","article-title":"Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals","volume":"61","author":"Bansal","year":"2018","journal-title":"Diabetologia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/humu.23233","article-title":"Monogenic diabetes syndromes: Locus-specific databases for Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia","volume":"38","author":"Astuti","year":"2017","journal-title":"Hum. Mutat."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/7\/1030\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:06:35Z","timestamp":1760126795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/7\/1030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,5]]},"references-count":30,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["brainsci13071030"],"URL":"https:\/\/doi.org\/10.3390\/brainsci13071030","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2023,7,5]]}}}