{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:45:17Z","timestamp":1787237117756,"version":"build-2736575974"},"reference-count":79,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G&gt;A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G&gt;C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients.<\/jats:p>","DOI":"10.3390\/medicina60071064","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T03:42:30Z","timestamp":1719546150000},"page":"1064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Wolfram Syndrome Type I Case Report and Review\u2014Focus on Early Diagnosis and Genetic Variants"],"prefix":"10.3390","volume":"60","author":[{"given":"Alexandru Daniel","family":"Jurca","sequence":"first","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa Bianca","family":"Galea-Holhos","sequence":"additional","affiliation":[{"name":"Department of Morphological Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora Alexandra","family":"Jurca","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diter","family":"Atasie","sequence":"additional","affiliation":[{"name":"Departament II Medical Clinic, Faculty of Medicine, University \u201cLucian Blaga of Sibiu\u201d, Lucian Blaga Street 2A, 550169 Sibiu, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8442-6791","authenticated-orcid":false,"given":"Codruta Diana","family":"Petchesi","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania"},{"name":"Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-615X","authenticated-orcid":false,"given":"Emilia","family":"Severin","sequence":"additional","affiliation":[{"name":"Genetics Department, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020027 Bucharest, District 2, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Maria","family":"Jurca","sequence":"additional","affiliation":[{"name":"Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania"},{"name":"Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"ref_1","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. Diabetes Rep."},{"key":"ref_2","unstructured":"(2024, May 25). Orphanet Report Series\u2014Prevalence of Rare Diseases: Bibliographic Data\u2014November 2023. Available online: http:\/\/www.orpha.net\/orphacom\/cahiers\/docs\/GB\/Prevalence_of_rare_diseases_by_alphabetical_list.pdf."},{"key":"ref_3","first-page":"715","article-title":"Diabetes Mellitus and Simple Optic Atro Phy among Siblings: Report of Four Cases","volume":"13","author":"Wolfram","year":"1938","journal-title":"Mayo Clin. Proc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/humu.23233","article-title":"Monogenic Diabetes Syndromes: Locus-Specific Databases for Alstr\u00f6m, Wolfram, and Thiamine-Responsive Megaloblastic Anemia","volume":"38","author":"Astuti","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1055\/s-0033-1357160","article-title":"Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications","volume":"122","author":"Zmyslowska","year":"2014","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39","DOI":"10.18544\/PEDM-22.01.0049","article-title":"Wolfram Syndrome. Case Report","volume":"22","author":"Drachal","year":"2016","journal-title":"Pediatr. Endocrinol. Diabetes Metab."},{"key":"ref_7","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":"Nunes","year":"2013","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Iafusco, D., Zanfardino, A., Piscopo, A., Curto, S., Troncone, A., Chianese, A., Rollato, A.S., Testa, V., Iafusco, F., and Maione, G. (2022). Metabolic Treatment of Wolfram Syndrome. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19052755"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/S0140-6736(95)92473-6","article-title":"Neurodegeneration and Diabetes: UK Nationwide Study of Wolfram (DIDMOAD) Syndrome","volume":"346","author":"Barrett","year":"1995","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/sj.mp.4000787","article-title":"Mutation Screening of the Wolfram Syndrome Gene in Psychiatric Patients","volume":"6","author":"Torres","year":"2001","journal-title":"Mol. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"K\u00f5ks, S. (2023). Genomics of Wolfram Syndrome 1 (WFS1). Biomolecules, 13.","DOI":"10.3390\/biom13091346"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1016\/j.ophtha.2016.05.036","article-title":"WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity","volume":"123","author":"Grenier","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_13","unstructured":"K\u00f5ks, S., Luuk, H., Plaas, M., and Vasar, E. (2008). Wfs1 protein in the neuropsychiatric disorders\u2013possible involvement of ER stress. Wfs1 Protein (Wolframin): Emerging Link between the Emotional Brain and Endocrine Pancreas, Research Signpost."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4000","DOI":"10.1016\/j.febslet.2006.06.036","article-title":"Wolfram Syndrome-associated Mutations Lead to Instability and Proteasomal Degradation of Wolframin","volume":"580","author":"Hofmann","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6996","DOI":"10.1038\/s41467-021-27344-y","article-title":"WFS1 Functions in ER Export of Vesicular Cargo Proteins in Pancreatic \u03b2-Cells","volume":"12","author":"Wang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1093\/hmg\/10.5.477","article-title":"WFS1 (Wolfram Syndrome 1) Gene Product: Predominant Subcellular Localization to Endoplasmic Reticulum in Cultured Cells and Neuronal Expression in Rat Brain","volume":"10","author":"Takeda","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1016\/j.febslet.2006.09.007","article-title":"WFS1 protein modulates the free Ca2+concentration in the endoplasmic reticulum","volume":"580","author":"Takei","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1093\/hmg\/ddm296","article-title":"Sodium-Potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress","volume":"17","author":"Zatyka","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"263300402110395","DOI":"10.1177\/26330040211039518","article-title":"Wolfram Syndrome: New Pathophysiological Insights and Therapeutic Strategies","volume":"2","author":"Mishra","year":"2021","journal-title":"Ther. Adv. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/s41390-019-0487-4","article-title":"Wolfram Syndrome 1 in the Italian Population: Genotype-Phenotype Correlations","volume":"87","author":"Rigoli","year":"2020","journal-title":"Pediatr. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39609","DOI":"10.1074\/jbc.M507426200","article-title":"WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells","volume":"280","author":"Fonseca","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1093\/hmg\/ddh125","article-title":"Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion","volume":"13","author":"Ishihara","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1093\/hmg\/ddl081","article-title":"WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells","volume":"15","author":"Yamada","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1086\/302609","article-title":"Clinical and Molecular Genetic Analysis of 19 Wolfram Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations in WFS1","volume":"65","author":"Hardy","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1034\/j.1399-0004.2001.590214.x","article-title":"Homozygosity for a 4-Bp Deletion in a Patient with Wolfram Syndrome Suggesting Possible Phenotype and Genotype Correlation: Mutation Detection in Wolfram Syndrome","volume":"59","author":"Sam","year":"2001","journal-title":"Clin. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1186\/s13023-023-02938-5","article-title":"Wolfram Syndrome Type 1: A Case Series","volume":"18","author":"Du","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/s41419-018-0406-3","article-title":"Wolfram Syndrome: MAMs\u2019 Connection?","volume":"9","author":"Delprat","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/0140-6736(90)92157-D","article-title":"Psychiatric Findings in Wolfram Syndrome Homozygotes","volume":"336","author":"Swift","year":"1990","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/sj.mp.4000344","article-title":"Predisposition of Wolfram Syndrome Heterozygotes to Psychiatric Illness","volume":"3","author":"Swift","year":"1998","journal-title":"Mol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/sj.mp.4001681","article-title":"Wolframin Mutations and Hospitalization for Psychiatric Illness","volume":"10","author":"Swift","year":"2005","journal-title":"Mol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1017\/S1461145704004791","article-title":"Polymorphisms in Wolframin (WFS1) Gene Are Possibly Related to Increased Risk for Mood Disorders","volume":"8","author":"Koido","year":"2005","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12017-008-8056-8","article-title":"Common Variations in 4p Locus Are Related to Male Completed Suicide","volume":"11","author":"Must","year":"2009","journal-title":"Neuromol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Frontino, G., Raouf, T., Canarutto, D., Tirelli, E., Di Tonno, R., Rigamonti, A., Cascavilla, M.L., Baldoli, C., Scotti, R., and Leocani, L. (2021). Case Report: Off-Label Liraglutide Use in Children with Wolfram Syndrome Type 1: Extensive Characterization of Four Patients. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.755365"},{"key":"ref_37","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_38","first-page":"461","article-title":"Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome","volume":"18","author":"Hoekel","year":"2014","journal-title":"J. AAPOS Off. Publ. Am. Assoc. Pediatr. Ophthalmol. Strabismus"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1399-0004.2010.01522.x","article-title":"Wolfram syndrome and WFS1 gene","volume":"79","author":"Rigoli","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"344","DOI":"10.4239\/wjd.v12.i4.344","article-title":"Diagnosis, Treatment and Prevention of Type 2 Diabetes Mellitus in Children and Adolescents","volume":"12","author":"Serbis","year":"2021","journal-title":"World J. Diabetes"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0168-8227(94)90052-3","article-title":"Analysis of the Contribution of the HLA System to the Inheritance in the Wolfram Syndrome","volume":"22","author":"Vendrell","year":"1994","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zmyslowska, A., Malkowski, B., Fendler, W., Borowiec, M., Antosik, K., Gnys, P., Baranska, D., and Mlynarski, W. (2014). Central Nervous System PET-CT Imaging Reveals Regional Impairments in Pediatric Patients with Wolfram Syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115605"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.coph.2009.07.003","article-title":"Endoplasmic reticulum stress in beta-cells and development of diabetes","volume":"9","author":"Fonseca","year":"2009","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.2337\/dc14-1898","article-title":"Retinal Thinning as a Marker of Disease Progression in Patients with Wolfram Syndrome","volume":"38","author":"Zmyslowska","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_45","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_46","doi-asserted-by":"crossref","unstructured":"Morikawa, S., Blacher, L., Onwumere, C., and Urano, F. (2022). Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.849204"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/dom.13379","article-title":"Effects of proinsulin misfolding on \u03b2-cell dynamics, differentiation and function in diabetes","volume":"20","author":"Riahi","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cmet.2006.07.007","article-title":"Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1","volume":"4","author":"Lipson","year":"2006","journal-title":"Cell Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/ajmg.a.31809","article-title":"Identification of Novel Mutations in WFS1 and Genotype\u2013Phenotype Correlation in Wolfram Syndrome","volume":"143A","author":"Cano","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/ejhg.2012.154","article-title":"Identification of Homozygous WFS1 Mutations (p.Asp211Asn, p.Gln486*) Causing Severe Wolfram Syndrome and First Report of Male Fertility","volume":"21","author":"Haghighi","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/dmcn.14040","article-title":"Optical coherence tomography and magnetic resonance imaging visual pathway evaluation in Wolfram syndrome","volume":"61","author":"Zmyslowska","year":"2019","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1007\/s00592-017-1042-6","article-title":"Retinal thickness as a marker of disease progression in longitudinal observation of patients with Wolfram syndrome","volume":"54","author":"Zmyslowska","year":"2017","journal-title":"Acta Diabetol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1399-5448.2009.00518.x","article-title":"Wolfram Syndrome: Important Implications for Pediatricians and Pediatric Endocrinologists","volume":"11","author":"Kumar","year":"2010","journal-title":"Pediatr. Diabetes"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000074187","article-title":"Sex-related hearing impairment in Wolfram syndrome patients identified by inactivating WFS1 mutations","volume":"9","author":"Pennings","year":"2004","journal-title":"Audiol. Neurootol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1515\/JPEM.2005.18.12.1391","article-title":"Clinical picture, evolution and peculiar molecular findings in a very large pedigree with Wolfram syndrome","volume":"18","author":"Lombardo","year":"2005","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s40618-013-0039-4","article-title":"Phenotypical and genotypical expression of Wolfram syndrome in 12 patients from a Sicilian district where this syndrome might not be so infrequent as generally expected","volume":"37","author":"Lombardo","year":"2014","journal-title":"J. Endocrinol. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/pr.2018.17","article-title":"Genetic and Clinical Aspects of Wolfram Syndrome 1, a Severe Neurodegenerative Disease","volume":"83","author":"Rigoli","year":"2018","journal-title":"Pediatr. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"bcr2018225839","DOI":"10.1136\/bcr-2018-225839","article-title":"A Case of Young Diabetes and Parasuicide","volume":"2018","author":"Lodha","year":"2018","journal-title":"BMJ Case Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/S0006-3223(00)00244-4","article-title":"Psychiatric Disorders and Mutations at the Wolfram Syndrome Locus","volume":"47","author":"Swift","year":"2000","journal-title":"Biol. Psychiatry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1167\/iovs.63.10.9","article-title":"Comprehensive Genetic Analysis Unraveled the Missing Heritability in a Chinese Cohort with Wolfram Syndrome 1: Clinical and Genetic Findings","volume":"63","author":"Zhang","year":"2022","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Delvecchio, M., Iacoviello, M., Pantaleo, A., and Resta, N. (2021). Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype\u2013Phenotype Correlations. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18094796"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Lee, E.M., Verma, M., Palaniappan, N., Pope, E.M., Lee, S., Blacher, L., Neerumalla, P., An, W., Campbell, T., and Brown, C. (2023). Genotype and Clinical Characteristics of Patients with Wolfram Syndrome and WFS1-Related Disorders. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1198171"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"E5292","DOI":"10.1073\/pnas.1421055111","article-title":"A Calcium-Dependent Protease as a Potential Therapeutic Target for Wolfram Syndrome","volume":"111","author":"Lu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7841","DOI":"10.1038\/ncomms8841","article-title":"RTN1 Mediates Progression of Kidney Disease by Inducing ER Stress","volume":"6","author":"Fan","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/hmg\/dds400","article-title":"Vacuolar-Type H+-ATPase V1A Subunit Is a Molecular Partner of Wolfram Syndrome 1 (WFS1) Protein, Which Regulates Its Expression and Stability","volume":"22","author":"Gharanei","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_66","unstructured":"(2024, May 23). Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients with Wolfram Syndrome, Available online: https:\/\/clinicaltrials.gov\/study\/NCT03717909."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Jagomae, T., Seppa, K., Reimets, R., Pastak, M., Plaas, M., Hickey, M.A., Kukker, K.G., Moons, L., Groef, L.D., and Vasar, E. (2021). Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype. Cells, 10.","DOI":"10.21203\/rs.3.rs-903256\/v1"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Morikawa, S., and Urano, F. (2022). The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010230"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1038\/s41598-021-81768-6","article-title":"Liraglutide, 7,8-DHF and their co-treatment prevents loss of vision and cognitive decline in a Wolfram syndrome rat model","volume":"11","author":"Seppa","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1159\/000510852","article-title":"Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report","volume":"93","author":"Scully","year":"2020","journal-title":"Horm. Res. Paediatr."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"15742","DOI":"10.1038\/s41598-019-52295-2","article-title":"GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome","volume":"9","author":"Seppa","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.cmet.2006.10.001","article-title":"GLP-1 receptor activation improves \u03b2 cell function and survival following induction of endoplasmic reticulum stress","volume":"4","author":"Yusta","year":"2006","journal-title":"Cell Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1007\/s00125-018-4679-y","article-title":"Activation of GLP-1 Receptor Signalling Alleviates Cellular Stresses and Improves Beta Cell Function in a Mouse Model of Wolfram Syndrome","volume":"61","author":"Kondo","year":"2018","journal-title":"Diabetologia"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ito, F., Sono, Y., and Ito, T. (2019). Measurement and Clinical Significance of Lipid Peroxidation as a Biomarker of Oxidative Stress: Oxidative Stress in Diabetes, Atherosclerosis, and Chronic Inflammation. Antioxidants, 8.","DOI":"10.3390\/antiox8030072"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s12967-019-1993-1","article-title":"Wolfram Syndrome, a Rare Neurodegenerative Disease: From Pathogenesis to Future Treatment Perspectives","volume":"17","author":"Pallotta","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1136\/bjophthalmol-2015-308329","article-title":"Genetic Manipulation for Inherited Neurodegenerative Diseases: Myth or Reality?","volume":"100","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Gerhardt, M.J., Priglinger, C.S., Rudolph, G., Hufendiek, K., Framme, C., J\u00e4gle, H., Salchow, D.J., Ansch\u00fctz, A., Michalakis, S., and Priglinger, S.G. (2022). Gene Therapy with Voretigene Neparvovec Improves Vision and Partially Restores Electrophysiological Function in Pre-School Children with Leber Congenital Amaurosis. Biomedicines, 11.","DOI":"10.3390\/biomedicines11010103"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.tips.2019.07.011","article-title":"Current Landscape of Treatments for Wolfram Syndrome","volume":"40","author":"Abreu","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.celrep.2014.03.023","article-title":"MANF Is Indispensable for the Proliferation and Survival of Pancreatic \u03b2 Cells","volume":"7","author":"Lindahl","year":"2014","journal-title":"Cell Rep."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/7\/1064\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:06:43Z","timestamp":1760108803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/7\/1064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,28]]},"references-count":79,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["medicina60071064"],"URL":"https:\/\/doi.org\/10.3390\/medicina60071064","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,28]]}}}