{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T12:52:22Z","timestamp":1765889542517,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Andalusian Regional Ministry of Health (Consejer\u00eda de Salud de Andaluc\u00eda)","award":["AP-0009-2020-C1-F2","2\/2021"],"award-info":[{"award-number":["AP-0009-2020-C1-F2","2\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Wolfram syndrome is a rare neurodegenerative disorder primarily known for its multisystemic manifestations. Although classically associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, emerging evidence suggests a consistent pattern of executive dysfunction in many affected individuals. Methods: Based on findings from a scoping review and results obtained through the Dysexecutive Questionnaire in a Spanish patient cohort, we propose that WFS1 gene mutations\u2014via chronic endoplasmic reticulum stress\u2014disrupt serotonergic and cholinergic neurotransmission, leading to impairments in planning, inhibition, and emotional regulation. Results: Importantly, recent studies have highlighted the interplay between WFS1-related molecular dysfunction and circadian regulation. Given the role of the endoplasmic reticulum and mitochondrial signaling in circadian homeostasis, and the frequent sleep disturbances observed in patients with Wolfram syndrome, we hypothesize that circadian dysregulation may contribute to the neurobehavioral phenotype. Conclusions: This essay explores neuropsychological foundations of executive dysfunction in WS, and frames the current evidence as hypothesis-generating rather than causal; executive difficulties may be a salient clinical feature and merit consideration in routine care. Furthermore, the potential involvement of circadian mechanisms opens new avenues for future research and therapeutic approaches. Because circadian disruption is linked to psychiatric symptoms and fatigue, emphasizing diurnal patterns, sleep\u2013wake timing, and chronotype may guide circadian-informed assessment.<\/jats:p>","DOI":"10.3390\/diagnostics15182338","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T16:27:33Z","timestamp":1757953653000},"page":"2338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Circadian Rhythm and Psychiatric Features in Wolfram Syndrome: Toward Chrono Diagnosis and Chronotherapy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7554-9434","authenticated-orcid":false,"given":"Gema","family":"Esteban-Bueno","sequence":"first","affiliation":[{"name":"UGC La Ca\u00f1ada (Primary Care Management Unit), Almer\u00eda Periphery\u2013Almer\u00eda Health District, Andalusian Health Service (SAS), 04009 Almer\u00eda, Spain"},{"name":"Spanish Association for Research and Support to Wolfram Syndrome, 04120 Almer\u00eda, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annabel","family":"Jim\u00e9nez-Soto","sequence":"additional","affiliation":[{"name":"Learning and Cognition Research Group (HUM646), Department of Social Psychology, Faculty of Psychology, University of Seville, 41018 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4758-2832","authenticated-orcid":false,"given":"Juan Luis","family":"Fern\u00e1ndez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Group of Inverse Problems, Optimization and Machine Learning, Department of Mathematics, University of Oviedo, 33007 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3107-6337","authenticated-orcid":false,"given":"Enrique","family":"Fern\u00e1ndez-Vilas","sequence":"additional","affiliation":[{"name":"Social Research Unit on Health and Rare Diseases, Department of Sociology and Social Work, University of Valladolid, 42004 Soria, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1140-7351","authenticated-orcid":false,"given":"Juan R.","family":"Coca","sequence":"additional","affiliation":[{"name":"Social Research Unit on Health and Rare Diseases, Department of Sociology and Social Work, University of Valladolid, 42004 Soria, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Esteban Bueno, G., and Fern\u00e1ndez Mart\u00ednez, J.L. 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