{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:03:39Z","timestamp":1788455019294,"version":"build-2803163510"},"reference-count":92,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease\u2019s progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient\u2019s relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1\u2019s neurophysiopathology is critical for achieving the goal of improving patients\u2019 quality of life and life expectancy.<\/jats:p>","DOI":"10.3390\/genes15080984","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T13:10:28Z","timestamp":1721913028000},"page":"984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Wolfram Syndrome 1: A Neuropsychiatric Perspective on a Rare Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1955-8074","authenticated-orcid":false,"given":"Valerio","family":"Caruso","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Psychiatric Section, Azienda Ospedaliera Universitaria Pisana (A.U.O.P.), 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9423-346X","authenticated-orcid":false,"given":"Accursio","family":"Raia","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychiatric Section, Azienda Ospedaliera Universitaria Pisana (A.U.O.P.), 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Rigoli","sequence":"additional","affiliation":[{"name":"Department of Human Pathology of Adulthood and Childhood G. Barresi, University of Messina, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,25]]},"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","first-page":"2021","DOI":"10.1093\/hmg\/7.13.2021","article-title":"Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein","volume":"7","author":"Strom","year":"1998","journal-title":"Hum. Mol. 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