J Clin Endocrinol Metab. 2026 Jun 24:dgag250. doi: 10.1210/clinem/dgag250. Online ahead of print.
ABSTRACT
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.
PMID:42339507 | DOI:10.1210/clinem/dgag250