Background: Wolfram syndrome is a genetic disease, known to cause pediatric diabetes, neurodegeneration with optic atrophy and hearing loss. Recently, a similar phenotype -Wolfram syndrome type 2 (WFS2) - associated with childhood GI ulcers was identified as caused by CISD2 gene mutation. Only 4 families and 2 mutations were so far reported.
Methods and Results: We report patients from 5 different Palestinian families who presented with childhood GI symptoms followed by diabetes that was initially considered as type 1 diabetes and treated by insulin. Following the finding of negative anti GAD antibodies and further investigation into mild (ignored) visual/acoustic symptoms we sequenced the CISD2 gene. In all 5 families the IVS1+6G>C,p.E37Q mutation was identified causing skipping of the 2nd out of 3 exons of the CISD2 gene. Studying 8 microsatellite markers flanking the CISD2 gene indicated a founder effect in all 5 unrelated families. Furthermore, restriction enzyme analysis of 200 healthy control alleles (same ethnic background) showed a surprising high carrier rate of 1/40-2.5%. The presence of c-peptide in the index case serum and the current understanding of CISD2 function in preventing beta cell apoptosis by preventing calcium leak from the Endoplasmatic reticulum (ER) lead us to try oral therapy of Metformin and Sitagliptin. The resultant GLP-1 increase conferres protection against ER stress-mediated cell death . He was successfully weaned from insulin and achieved reasonable glycemic control (HbA1c – 7.2%).
Conclusion: Early manifestation of GI symptoms in anti-GAD negative "type 1 diabetes" should lead to suspect the relatively common diagnosis of WFS2. These patients may be switched to oral therapy. Further mechanistic studies are required to establish effective oral therapy for WFS2.
