ウォルフラム症候群

Type 1 Wolfram syndrome is a rare, neurodegenerative pathology characterized by the association of insulin-dependent diabetes and optic atrophy. Other symptoms include diabetes insipidus, hearing loss and neurological damage. Fecal incontinence was recently recognized as a new symptom. Its pathophysiological mechanism remains unknown. We plan to collect data on the severity of the syndrome at the onset of fecal incontinence, the frequency of signs suggestive of pons volume reduction, and the frequency of urinary disturbances. Based on this information, we will investigate the possible location of the neurological involvement causing this symptom.

Wolfram syndrome (WS) is a neurodegenerative disorder caused by mutations in the endoplasmic reticulum (ER) transmembrane protein WFS1. Mutations in WFS1 lead to ER stress and dysregulated calcium signaling, resulting in progressive neurological dysfunction. Myelination is a core pathological process in various central nervous system (CNS) diseases. However, the role of WFS1 in oligodendrocyte development and myelination remains unknown. Here, using CRISPR-Cas9-generated wfs1a/wfs1b double-knockout (wfs1-/-) zebrafish, we demonstrated that wfs1 deficiency significantly delayed the dorsal distribution of oligodendrocyte precursor cells (OPCs) along Mauthner axons. Furthermore, wfs1 mutation was associated with early hypomyelination of axons at 5 dpf, with partial recovery observed by 8 dpf. Mechanistically, combined transcriptomic and pharmacological analysis revealed that wfs1 mutation led to the suppression of the steroid biosynthesis pathway through downregulation of hmgcs1, which encodes the upstream condensation enzyme of the mevalonate pathway and supplies substrate for the downstream rate-limiting enzyme HMGCR, thereby potentially reducing isoprenoid precursor availability. Pharmacological supplementation with geranylgeraniol (GGOH) specifically rescued dorsal distribution defects, supporting involvement of the isoprenylation pathway, although direct regulation of hmgcs1 by wfs1 and complete rescue of myelin structure require further mechanistic validation. Taken together, our study supports a novel wfs1-hmgcs1 axis, which may regulate dorsal distribution and myelination through the isoprenylation pathway; notably, classical ER stress markers were also concurrently upregulated in wfs1-/- larvae, although whether the isoprenylation deficiency and ER stress act independently or synergistically remains to be determined. These findings provide new insights into WS-associated early hypomyelination and suggest hmgcs1 as a potential therapeutic target for myelin defects caused by WS.

Wolfram syndrome (WS) is a rare, progressive monogenic neurodegenerative disorder in which childhood-onset, insulin-deficient diabetes mellitus usually precedes optic atrophy and other multisystemic manifestations such as hearing loss, diabetes insipidus, urological and neuro-psychiatric abnormalities. This review summarises the underlying genetic basis and pathophysiology of Wolfram syndrome type 1 (WS1) and Wolfram syndrome type 2 (WS2), their neuro-ophthalmologic manifestations and phenotypic spectrum, as well as the multimodal biomarkers that are being used to objectively measure disease severity. Although classically known as a recessive condition with complex, severe, multiorgan involvement, WS1 caused by dominant WFS1 variants and a more limited form of the disease are increasingly being recognized. Biomarkers based on optical coherence tomography (OCT) parameters show promise for early diagnosis and disease monitoring. Lastly, emerging therapeutic options and future directions for treatment trials are discussed.

INTRODUCTION: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene and characterized by early-onset, insulin-dependent diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration driven by chronic endoplasmic reticulum (ER) stress; no proven disease-modifying therapy currently exists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) augment glucose-dependent insulin secretion and, in preclinical models, preserve β-cell mass, attenuate ER stress, and confer neuroprotection - properties of particular therapeutic relevance to Wolfram syndrome. METHODS: 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, with additional longitudinal data for participants co-enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study. We characterized the prevalence of GLP-1 RA use and the documented rationale for initiation, and evaluated within-participant pre-post changes in glycemic (HbA1c, body mass index) and visual (LogMAR best-corrected visual acuity, retinal nerve fiber layer thickness) parameters, along with adverse effects and reasons for discontinuation. RESULTS: Thirty of the 84 participants (35.7%) had received a GLP-1 RA in addition to insulin. No statistically significant changes in HbA1c or body mass index were observed at one or two years. Best-corrected visual acuity (LogMAR) declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common (56.7% of users) and were the leading cause of discontinuation. DISCUSSION: In this largest reported evaluation of GLP-1 RA use in Wolfram syndrome, these agents were already integrated into clinical care and were generally tolerated, but showed no glycemic or visual benefit over one to two years. Given the retrospective, uncontrolled design, the small number of participants with paired pre-post measurements, and the absence of a longitudinally followed comparator group, these findings are preliminary and hypothesis-generating rather than definitive, and provide a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.

Background/Objectives: Wolfram syndrome is an ultra-rare, progressive multisystem disorder in which endocrine and sensory manifestations coexist with neurological involvement. Quantitative magnetic resonance imaging (MRI) may help characterize central nervous system involvement in this condition; however, evidence derived from small imaging cohorts requires cautious interpretation. This study aimed to examine the relationships between different MRI-derived attributes and neurological symptoms in Wolfram syndrome, with the goal of identifying exploratory imaging patterns that may suggest the involvement of specific neural systems. Methods: We analyzed a Spanish cohort of 45 genetically confirmed patients with Wolfram syndrome. A homogeneous subset of 15 patients with standardized 3-Tesla multimodal MRI and adequate image quality was included in the quantitative imaging analysis. T1-weighted MRI, T2-weighted/fluid-attenuated inversion recovery (FLAIR) imaging, and diffusion tensor imaging (DTI) were processed using a standardized workflow for brain extraction, anatomical segmentation, cortical reconstruction, and quantitative feature extraction. A total of 172 MRI-derived features were examined in relation to neurological phenotypes, including dysphagia, ataxia, gait instability, and cognitive impairment. Analyses included principal component analysis, exploratory factor analysis, correlation analyses, and symptom-specific group comparisons. Given the small MRI sample size and the high feature-to-subject ratio, all analyses were considered exploratory and hypothesis-generating, and the findings should be interpreted cautiously pending validation in larger, independent cohorts. Results: Multimodal MRI-derived features showed distributed associations with neurological manifestations. The most recurrent exploratory imaging correlates involved the thalamus, lateral geniculate nucleus, cerebellum, brainstem, ventricular system, corpus callosum, posterior cortical regions, and white-matter pathways. FLAIR-derived signal heterogeneity in the thalamus and lateral geniculate nucleus appeared repeatedly across several clinical manifestations. Dysphagia was associated with a distributed pattern involving cortical thinning, thalamic and brainstem volume reduction, reduced cerebellar white-matter integrity, increased FLAIR heterogeneity, and ventricular enlargement. Ataxia and gait instability showed overlapping but partially distinct imaging profiles, whereas cognitive impairment was associated with broader cortical, subcortical, callosal, cerebellar, and ventricular alterations. Conclusions: In this exploratory pilot study, multimodal MRI-derived features showed clinically plausible associations with neurological manifestations in Wolfram syndrome. The findings support a distributed model of neurological involvement affecting cerebello-thalamo-cortical circuits, visual relay structures, brainstem pathways, and long-range white-matter connections. These results should be interpreted as exploratory MRI-derived attributes rather than as validated biomarkers, prognostic indicators, or clinically applicable imaging signatures. Confirmation in future longitudinal, multicenter studies with harmonized imaging protocols and external validation will be required.