Reversible mitochondrial iron toxicity in Wolfram syndrome type 2 monogenic diabetes
Authors' conclusion
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.
Study context
- Population
- Patients with WS2 (atypical juvenile-onset diabetes and gastrointestinal bleeding) from 11 unrelated Palestinian families; academic and clinical institutions in Israel and the Palestinian territories11 families
- Participants
- 22 patients
- Exposure
- Patient fibroblasts vs controls; Deferiprone (DFP)/N-acetylcysteine (NAC) treatment
- WS2n = Twenty-two
- DFP/NACn = two
- Outcome
- Clinical phenotype, CISD2 genetic analysis, mitochondrial labile iron (mLI) and reactive oxygen species (ROS) levels, organelle morphology, and preliminary clinical response (HbA1c, platelet aggregation)
Methodological detailsmulticenter
- Multicenter
Main finding
As reported in the abstract
Genetics, phenotype and fibroblast mitochondrial iron/ROS
Homozygous CISD2 c.109G > C founder mutation; carrier rate
1:40
Patient fibroblasts: increased mitochondrial labile iron (mLI)
+25%
p < 0.0001
Patient fibroblasts: increased mROS
+28%
p < 0.0001
Observational data: associations, not effects.
Further findings
In vitro DFP/NAC treatment
- DFP/NAC fully reversed the cellular anomalies
Pilot clinical response to DFP/NAC
- Two patients on DFP/NAC: improved reported glycemic control and corrected platelet aggregation
- Preliminary pilot study
Original publication
Reversible mitochondrial iron toxicity in Wolfram syndrome type 2 monogenic diabetes. J Clin Endocrinol Metab. Published 24 June 2026. doi:10.
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