Amitay Cohen, Ola Karmi, Ulla Najwa Abdulhag, Tehila Klopstock, Yang‐Sung Sohn, Orit Lobel, Abdulsalam Abu Libdeh, Eran Lavi, Michael Wilchansky, Muntaser Abbasi, Maha Abdulhadi-Atwan, Gil Leibowitz, Ariella Weinberg‐Shukron, Paul Renbaum, Ioav Cabantchik, Ephrat Levy‐Lahad, Ron Mittler, Rachel Nechushtai, David Zangen
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.