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Evaluating the Use of GLP-1 Receptor Agonists in Wolfram syndrome Patients

Publication: medrxiv.org/ | Publication Date: 2 April 2026

Authors: Laura Lee, Abby F. Tang, Anna Asako, Sarah F. Ning, Hayden A. Reed, Eleanor Duncan, Heather M. Lugar, James Hoekel, Bess A. Marshall, Tamara Hershey, Fumihiko Urano

Abstract

Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic β cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve β-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome.

We conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation.

These observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.

Full article

Laura Lee, Abby F. Tang, Anna Asako, Sarah F. Ning, Hayden A. Reed, Eleanor Duncan, Heather M. Lugar, James Hoekel, Bess A. Marshall, Tamara Hershey, Fumihiko Urano. Evaluating the Use of GLP-1 Receptor Agonists in Wolfram syndrome Patients medRxiv April 2, 2026; https://www.medrxiv.org/content/10.64898/2026.03.31.26349885v1.full Retrieved April 29, 2026.

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Pregnancy and Peripartum Multidisciplinary Management in Wolfram Syndrome Type 1: A Case Report

Publication: doi.org | Publication Date: 8 April 2026

Authors: Esteban-Bueno, G.; Serrano Rodríguez, M.L.

Abstract

Background/Objectives:

Wolfram syndrome type 1 (WS1) is a rare, progressive, multisystem neurodegenerative disorder characterized by diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. As survival has improved, an increasing number of affected women are reaching reproductive age. However, evidence on pregnancy and peripartum management in WS1 remains scarce, and practical guidance is limited. This case report describes the multidisciplinary management of pregnancy and delivery in a woman with genetically confirmed WS1 and highlights key considerations for peripartum care.

Case Presentation:

A woman with genetically confirmed WS1 and long-standing multisystem involvement, including diabetes mellitus, diabetes insipidus, neurogenic bladder requiring frequent self-catheterization, progressive neurologic manifestations, and severe sensory impairment, achieved pregnancy through assisted reproduction with oocyte donation and was closely monitored by a multidisciplinary team. Due to persistent breech presentation, a planned external cephalic version was performed at 37 + 5 weeks’ gestation with immediate availability for cesarean delivery. After unsuccessful attempts, cesarean delivery was performed under combined spinal–epidural anesthesia. Peripartum management focused on strict glycemic control, careful monitoring of fluid balance and urine output, neuraxial anesthesia with proactive hemodynamic management, precautions related to the cochlear implant, and tailored communication strategies. Postpartum recovery was favorable, although anemia on postoperative day 1 required transfusion of one unit of packed red blood cells and intravenous iron therapy.

Discussions and Conclusions:

Pregnancy in WS1 represents a high-risk clinical scenario because of the coexistence of endocrine, urologic, and neurologic comorbidities, while published evidence on peripartum management remains limited. This case supports an individualized, multidisciplinary approach to obstetric and anesthetic planning and the use of a practical framework to optimize peripartum management and enhance maternal–fetal safety in this rare condition.

Full article

Esteban-Bueno, G.; Serrano Rodríguez, M.L. Pregnancy and Peripartum Multidisciplinary Management in Wolfram Syndrome Type 1: A Case Report Diagnostics April 8, 2026; https://doi.org/10.3390/diagnostics16081117 Retrieved April 12, 2026.

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Phenotype Correlations of Neurological Manifestations in Wolfram Syndrome: Predictive Modeling in a Spanish Cohort

Publication: doi.org | Publication Date: 16 December 2025

Authors: Esteban-Bueno, G.; Botella, L.-M.; Fernández-Martínez, J.L.

Abstract

Background:

Wolfram syndrome (WS) is an ultrarare neuroendocrine disorder caused by pathogenic variants in WFS1, frequently leading to progressive neurological, autonomic, and cognitive impairment. Anticipating neurological trajectories remains challenging due to marked phenotypic variability and limited genotype–phenotype data.

Methods:

Fortyfive genetically confirmed patients with WS were evaluated between 1998 and 2024 in Spain. All WFS1 variants were systematically classified by exon, zygosity, protein-level functional impact, and predicted wolframin production (Classes 0–3). Machine learning models (Random Forests with engineered gene–gene interaction terms) were applied to predict neurological manifestations and identify the strongest genetic determinants of symptom severity.

Results:

Neurological involvement was present in 93% of patients. The most prevalent manifestations were absence of gag reflex (67%), gait instability (64%), dysphagia (60%), and sialorrhea (60%), followed by dysmetria (56%), impaired tandem gait (53%), anosmia (44%), dysarthria (44%), and adiadochokinesia (42%). Most symptoms emerged in early adulthood (23–26 years), whereas cognitive decline occurred later (29.9 ± 12.2 years). Homozygosity for truncating variants—particularly c.409_424dup16 (Val142fsX110)—and complete loss of wolframin production (Class 0; 67–83% across symptoms) were the strongest predictors of early and severe neurological involvement. Machine learning models achieved high discrimination for ataxia, gait instability, and absent gag reflex (AUC 0.63–0.86; calibrated AUC up to 0.97), identifying Mut1_Protein_Class and Mut2_Protein_Class as dominant predictors across all phenotypes, followed by coherent secondary effects from zygosity × exon interaction terms (Prod_mgm).

Conclusions:

Integrating detailed genetic classification with machine learning methods enables accurate prediction of neurological outcomes in WS. Protein-level dysfunction and allele interaction structure are the principal drivers of neurological vulnerability. This framework enhances precision diagnosis and offers a foundation for individualized surveillance, clinical risk stratification, and future therapeutic trial design in WFS1-related disorders.

Full article

Esteban-Bueno, G.; Botella, L.-M.; Fernández-Martínez, J.L. Phenotype Correlations of Neurological Manifestations in Wolfram Syndrome: Predictive Modeling in a Spanish Cohort. Diagnostics December 16, 2025; https://doi.org/10.3390/diagnostics15243213 Retrieved April 12, 2026.

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Gonadal Dysfunction in Wolfram Syndrome: A Prospective Study

Publication: doi.org | Publication Date: 24 June 2025

Authors: Esteban-Bueno, G.; Fernández-Martínez, J.L.

Abstract

Background:

Wolfram syndrome (WFS), also known as DIDMOAD, is a rare monogenic neurodegenerative disorder characterized by four key components: non-autoimmune insulin-dependent diabetes mellitus (DM), optic atrophy, sensorineural hearing loss, and diabetes insipidus. Although it significantly affects quality of life, gonadal dysfunction, particularly hypogonadism, remains underrecognized.

Methods:

In total, 45 patients (25 men, 20 women) with genetically confirmed WFS from a single tertiary-care center were prospectively followed to assess gonadal function. Men underwent hormonal evaluations, semen analysis, imaging tests, and testicular biopsies. In women, data on age at menarche, menstrual irregularities, and age at menopause were recorded. Hormonal analyses, including anti-Müllerian hormone (AMH) levels, and imaging tests were also conducted.

Results:

Hypogonadism was identified in 19 men (76.0%), of whom 17 (68.0%) had hypergonadotropic hypogonadism and 2 (8.0%) had hypogonadotropic hypogonadism. Testicular biopsies showed seminiferous tubule damage, Sertoli cell predominance, and reduced Leydig cells. Azoospermia was observed in 12 patients, whereas others presented with oligozoospermia, teratozoospermia, or asthenozoospermia. Most patients exhibited low testosterone levels along with elevated LH and FSH, suggesting primary testicular failure, except for two cases of hypogonadotropic hypogonadism. Correlations between biomarkers, onset age and severity have been analyzed and provide important insights regarding medical treatment. In women, menstrual irregularities were universal, with 20% experiencing premature menopause. Four patients had low AMH levels, with ovarian atrophy in three and a postmenopausal uterus in two, indicating early hypogonadism risk.

Conclusions:

Gonadal dysfunction is a significant yet overlooked feature of WFS, requiring systematic evaluation during puberty and beyond. Proper management is essential to mitigate metabolic disturbances and psychological impacts, including infertility distress, relationship challenges, and quality of life concerns. Addressing sexual health is crucial as WFS patients live longer and aspire to establish relationships or start families.

Full article

Esteban-Bueno, G.; Fernández-Martínez, J.L. Gonadal Dysfunction in Wolfram Syndrome: A Prospective Study. Diagnostics June 24, 2025; https://doi.org/10.3390/diagnostics15131594 Retrieved April 12, 2026.

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Circadian Rhythm and Psychiatric Features in Wolfram Syndrome: Toward Chrono Diagnosis and Chronotherapy

Publication: doi.org | Publication Date: 15 September 2025

Authors: Esteban-Bueno, G.; Jiménez-Soto, A.; Fernández-Martínez, J.L.; Fernández-Vilas, E.; Coca, J.R.

Abstract

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—via chronic endoplasmic reticulum stress—disrupt 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–wake timing, and chronotype may guide circadian-informed assessment.

Full article

Esteban-Bueno, G.; Jiménez-Soto, A.; Fernández-Martínez, J.L.; Fernández-Vilas, E.; Coca, J.R. Circadian Rhythm and Psychiatric
Features in Wolfram Syndrome: Toward Chrono Diagnosis and Chronotherapy. Diagnostics September 15, 2025; https://doi.org/10.3390/diagnostics15182338 Retrieved April 12, 2026.

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