Iron Chelators Are an Effective Treatment for a Relatively Common Cause of Anti-GAD Negative "Type 1Diabetes" - a Founder CISD2 Mutation

Presentation Number: OR12-5
Date of Presentation: April 4th, 2017

David Zangen*1, Ulla Najwa Abdulhag1, Ariella Weinberg-Shukron2, Abdulsalam Abulibdeh1, Maha Abdulhadi-Atwan3, Gil Leibowitz4, Ephrat Levy-Lahad2, Ola Karmi5, Yang-Sung Sohn5 and Rachel Nechushtai5
1Hadassah Hebrew University Medical Center, Jerusalem, Israel, 2Shaare Zedek Medical Center, Jerusalem, Israel, 3Al-Yamama Hospital Bethlehem, Bethlehem, Israel, 4Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 5Hebrew University of Jerusalem, Jerusalem, Israel


Background: CISD2/NAF-1 gene mutations were recently reported to cause Wolfram syndrome type 2 (WFS2) – characterized by childhood GI ulcers, diabetes, and neurodegeneration with optic atrophy and hearing loss. . NAF-1 suppression in cells results in intra-mitochondrial iron accumulation, increased ROS generation and a consequent increased cellular apoptosis. So far only 2 mutations in 4 families were reported.

Objective: Elucidate the genetic etiology, the clinical characteristics and novel therapeutic approachs in patients from 9 unrelated Palestinian consanguineous families with anti gad negative "type 1 diabetes"

Patients and Methods: 17 children/adolescents from 9 different families were treated by insulin for "juvenile onset diabetes". Negative serum anti-GAD antibodies associated with uncovering a history of personal/familial pediatric upper GI bleeding/ulcer and mild (ignored) visual /acoustic symptoms lead to sequencing of the CISD2 gene. Based on patients' biopsied and cultured fibroblasts response in vitro, a therapeutic trial with iron chelators combined with DPP-4 inhibitor was offered.

Results: The homozygous splice-site (IVS1+6G>C), CISD2 gene mutation resulting in skipping of the 2nd out of 3 exons was identified in all 19 patients. Studying 8 microsatellite markers flanking the CISD2 gene indicated a founder effect in at least 7 unrelated families. Restriction enzyme analysis of 200 healthy control alleles (same ethnic background) showed a surprising high carrier rate of 1/40-2.5%. Given the role of NAF-1 in preventing mitochondrial toxic iron accumulation and following the patients' fibroblasts positive response to iron chelator therapy in vitro a therapeutic pilot study with dipheriprone 20mg/Kg/day was initiated. Two months treatment resulted in complete resolution of the WFS2 platelet aggregation defect, increasing the response to collagen from 40 to 85%, and in improving the glycemic control represented by a 0.8% decrease in HbA1c levels and by significantly increasing the c-peptide/glucose ratio in our first 2 patients.

Conclusion: Infantile GI ulcers associated with anti-GAD negative "type 1 diabetes" highly indicates the possibility of WFS2 caused by the founder p. E37Q CISD2 mutation. Iron chelators reverse the toxic iron accumulation in patient's fibroblasts in vitro and in vivo restore platelet dysfunction and improve glycemic control. . Further mechanistic studies with direct therapeutic consequences are underway to enable a definitive ad effective therapy for the degenerative pathophysiology in WFS2.


Nothing to Disclose: DZ, UNA, AW, AA, MA, GL, EL, OK, YSS, RN