<span style="color: black; mso-color-alt: windowtext; background: white;">Executive Dysfunction in Wolfram Syndrome: A Neuropsychological Hypothesis Linked to WFS1-Related and Circadian Mechanisms

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. 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—via chronic endoplasmic reticulum stress—disrupt serotonergic and cholinergic neurotransmission, leading to impairments in planning, inhibition, and emotional regulation. 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. This essay explores both the molecular and neuropsychological foundations of executive dysfunction in WS, suggesting it may be a primary feature and advocating for its inclusion in routine clinical care. Furthermore, the potential involvement of circadian mechanisms opens new avenues for future research and therapeutic approaches.