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Pediatric and Adolescent Endocrinology

ORF10-01 - Alleviating Mitochondrial Stress Improves Symptoms in Wolfram Syndrome Type 2

Saturday, June 13, 2026
1:45 PM - 1:50 PM CT
Location: Room W183BC
Disclosure(s):
Amitay Cohen: No financial relationships to disclose



Objective: Wolfram syndrome type 2 (WS2) is a rare neurodegenerative disorder caused by mutations in the CISD2 gene, clinically distinguished from classic Wolfram syndrome by juvenile onset gastrointestinal bleeding and ulcers, and the absence of diabetes insipidus. This study aimed to characterize the largest WS2 cohort so far, elucidate its pathophysiology, and test a novel therapeutic approach.

Research Design and

Methods: We identified 22 patients from 11 unrelated Palestinian families with the CISD2 G109C mutation. Genetic screening established carrier prevalence. Clinical characterization was performed, and expression studies on patient fibroblasts assessed endoplasmic reticulum (ER) and mitochondrial morphology, and mitochondrial labile iron and ROS levels. A combination therapy of the iron chelator Deferiprone and the antioxidant (glutathione precursor) N-acetyl-Cysteine was tested in vitro and in a two-patient pilot study.

Results: A founder effect was confirmed, with a carrier prevalence of 1:40 in Southern West Bank Palestinians. The clinical phenotype included interestingly also a high prevalence of psychiatric disturbances and congenital heart defects. Patient fibroblasts showed a 25% increase in mitochondrial labile iron (17-31%, P< 0.001) and a 28% increase in mitochondrial reactive oxygen species (26-29%, P< 0.001), a 14.5% reduction in mitochondrial membrane potential (0-22%, P< 0.001) and abnormal mitochondrial and ER morphology. The Deferiprone/N-acetyl-Cysteine combination reversed these cellular defects and, in the pilot study on2 patients, improved platelet aggregation, glycemic control, and well-being.

Conclusions: The high carrier prevalence suggests WS2 is probably underdiagnosed. Our findings elucidate key pathophysiological mechanisms involving mitochondrial iron metabolism dysregulation and oxidative stress, and propose a novel combination therapy. Screening for CISD2 mutations should be considered in diabetic patients with associated gastrointestinal or psychiatric symptoms.