Abstract: Wolfram syndrome (WS) is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (often referred to as DIDMOAD), and overall severe neurodegenerative fallback. The global prevalence of this disease is estimated at 1 in 770,000 (Lee et al., 2023). It is most commonly caused by biallelic (point)mutations in the Wolframin endoplasmic reticulum (ER) transmembrane glycoprotein (WFS1) gene (in case of WS type 1), but mutations in the CDGSH Iron Sulfur Domain 2 (CISD2) are also linked to WS (type 2). The latter, however, often present with less severe pathological manifestations (Lee et al., 2023). WFS1 is located on chromosome 4p16.1 and spans over 33 kilobases. Many mutation variants have been identified in WFS1, encompassing missense, nonsense, and frameshift mutations. These mutations are spread across the coding region of WFS1, but certain regions, such as exon 8, the largest exon, appear particularly mutationprone and associated with the classical WS type 1 phenotype (Lee et al., 2023). Wolframin, the protein encoded by WFS1, is essential for ER calcium homeostasis, regulation of the unfolded protein response, and ensuring proper ERmitochondrial communication. Mutations in WFS1 that result in a loss-of-function, consequently lead to chronic ER stress and activation of apoptotic pathways, particularly in metabolically demanding cells such as pancreatic β-cells and neurons. As such, a spectrum of clinical manifestations arises in WS patients (Lee et al., 2023). The disease typically manifests during early childhood, beginning with diabetes and followed by progressive optic nerve atrophy, hearing loss, and various neurological and urological complications. Other symptoms may include psychiatric manifestations, sleep disturbances, ataxia, and cognitive decline. Life expectancy is significantly reduced, often due to brainstem atrophy and respiratory failure in the third to fourth decade of life (Lee et al., 2023).