ウォルフラム症候群

BACKGROUND: Wolfram syndrome is a rare neurodegenerative disorder, most commonly caused by pathogenic variants in WFS1, while cases due to CISD2 are exceedingly rare. The estimated prevalence is 1 in 160,000 to 770,000 individuals worldwide. In these clinical guidelines, disorders caused by WFS1 are referred to as WFS1-Wolfram syndrome, and those caused by CISD2 as CISD2-Wolfram syndrome. Historically, it has been characterized by early-onset, antibody-negative, insulin-dependent diabetes mellitus, progressive optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and brainstem and cerebellar atrophy. More recently, partial and late onset forms have been identified. There are currently no licensed disease-modifying treatments, and international clinical guidelines have not previously been established. METHODS: An international steering committee systematically reviewed 273 peer-reviewed publications and generated draft consensus statements across six clinical domains. These statements were evaluated by international specialists in endocrinology, clinical genetics, neurology, ophthalmology and neuro-ophthalmology, psychiatry, and urology, drawn from North America, Europe, Latin America, Oceania, and Asia, using a modified three-round Delphi process. Additional feedback was incorporated from nurses specializing in multidisciplinary Wolfram syndrome care, from leaders of international patient organizations, and from specialists in the genetic diagnosis of monogenic diabetes. Structured feedback from patients and families was gathered through multiple international patient advocacy organizations. Consensus was defined as ≥80% agreement. RESULTS: All 35 final consensus statements reached the pre-specified consensus threshold of ≥80% agreement, spanning diagnosis and genetic testing, multidisciplinary care organization, neuro-ophthalmology, neurology, endocrinology, urology, gastroenterology, and psychiatry. CONCLUSIONS: These guidelines are the first international clinical consensus for Wolfram syndrome and provide actionable recommendations for clinicians worldwide. Implementation should be accompanied by a prospective audit to expand the evidence base and support future iterations.

We present a middle childhood boy with type 1b diabetes mellitus (defined as insulin-dependent diabetes mellitus without evidence of autoimmunity) diagnosed at the age of 4 years who was on a basal bolus insulin regimen. Identifying the presence of bilateral optic atrophy in him during an ophthalmological evaluation led to a closer clinical assessment for Wolfram syndrome. Although there was no hearing loss on the audiogram and no evidence presently of arginine vasopressin (AVP) deficiency, we proceeded with genetic testing by next-generation sequencing. This confirmed the diagnosis of Wolfram syndrome with significant prognostic implications. Wolfram syndrome, also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a rare autosomal recessive neurodegenerative disorder primarily caused by mutations in the WFS1 and CISD2 genes. It is characterised by early-onset insulin-dependent diabetes mellitus, progressive bilateral optic atrophy, hearing loss and AVP deficiency. Other complications include neurological degeneration, urinary tract dysfunction, psychiatric disturbances and eventually respiratory failure. This case emphasises the importance of early diagnosis, genetic confirmation and a multidisciplinary approach in clinical management.

CONTEXT: Wolfram syndrome type 2 (WS2) is a rare monogenic diabetes syndrome caused by CISD2 mutations. Its cellular pathophysiology remains poorly understood, and no targeted therapies exist. OBJECTIVE: To characterize the clinical phenotype and cellular pathophysiology of the largest WS2 cohort to date, and to evaluate a novel, mechanistically targeted pharmacological intervention. DESIGN: Observational cohort study paired with ex vivo functional cellular assays and a proof-of-concept pilot clinical intervention. SETTING: Multicenter academic and clinical institutions in Israel and the Palestinian territories. PATIENTS: Twenty-two patients from 11 unrelated Palestinian families presenting with atypical juvenile-onset diabetes and gastrointestinal bleeding. Patient-derived fibroblasts (n = 4) were utilized for functional assays. INTERVENTION(S): Fibroblasts and two patients were treated with a combination of the iron chelator deferiprone (DFP) and the antioxidant N-acetylcysteine (NAC). MAIN OUTCOME MEASURE(S): Clinical phenotype, CISD2 genetic analysis, mitochondrial labile iron (mLI) and reactive oxygen species (ROS) levels, organelle morphology, and preliminary clinical response (HbA1c, platelet aggregation). RESULTS: Patients were homozygous for a CISD2 c.109G > C founder mutation (carrier rate 1:40). The clinical phenotype was expanded to include prevalent psychiatric morbidity and congenital heart defects. Patient fibroblasts exhibited profound mitochondrial and endoplasmic reticulum damage, with increased mLI (+25%, p < 0.0001) and mROS (+28%, p < 0.0001). In vitro DFP/NAC treatment fully reversed these cellular anomalies. In a preliminary pilot study, two patients receiving DFP/NAC demonstrated improved reported glycemic control and corrected platelet aggregation. CONCLUSIONS: WS2 is an underdiagnosed monogenic diabetes driven by mitochondrial iron dysregulation and oxidative stress. Repurposing DFP/NAC reverses this toxicity, offering a strong mechanistic rationale for future clinical trials.

AIM: To describe the clinical characteristics of patients with Wolfram syndrome (WFS) and diabetes mellitus (DM) in Aotearoa, New Zealand. Review of response to therapy in those treated with glucagon-like peptide-1 receptor agonists (GLP1RA). METHODS: This retrospective cohort study describes 7 patients with WFS1 genetic variants (1 patient with WFS-like syndrome), and DM from 5 New Zealand families (age range 5-33 years, 4 females, 3 males). All are receiving insulin. In 5 patients receiving GLP1RA therapy, we described their pre- and post-treatment biometric parameters, glycaemic control and visual acuity. RESULTS: Genetic testing identified compound heterozygous variants in the WFS1 gene (inherited from each parent) in five patients. Another two were heterozygous carriers of a single WFS1 missense variant, one of which was associated with uniparental disomy. Among patients receiving GLP1RA therapy, reductions were seen in HbA1c (mean 11.6 mmol/mol) and total daily insulin dose (mean 0.25 units/kg/day). CONCLUSIONS: We report genotypic and phenotypic variability in association with clinical features, including age of onset and severity. GLP1RA therapy was associated with improvements in diabetic control. Longer-term follow-up is required to monitor for sustained benefit and for progression or improvement in other WFS clinical features.

KRASG12D-driven pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge characterized by limited treatment options. While MRTX1133, a potent and selective KRASG12D inhibitor, is currently under clinical evaluation, the emergence of acquired resistance restricts its long-term therapeutic efficacy. In this study, we identified Wolfram syndrome 1 (WFS1) as a potential molecular vulnerability in KRASG12D-driven PDAC. Our findings suggest that WFS1 expression is upregulated following KRASG12D activation and may promote tumorigenesis and metastasis. Moreover, WFS1 expression was further elevated in tumors resistant to MRTX1133, independently of KRAS activation status. Inhibition of WFS1 partially restored sensitivity to MRTX1133 in resistant tumors by inducing excessive and sustained activation of the unfolded protein response (UPR), subsequently triggering apoptosis. Further exploration revealed that, while WFS1 is regulated by the MAPK and PI3K/AKT pathways in MRTX1133-sensitive cells, acquired resistance is associated with downregulation of the E3 ubiquitin ligase Smurf1, leading to increased WFS1 protein stability. Overall, these results highlight WFS1 as an adaptive factor and potential therapeutic target in KRASG12D-driven malignancies, offering a novel approach to enhance the efficacy of KRASG12D inhibitors and overcome acquired resistance.