8th International Wolfram Symposium Presentation Prof Gil Leibowitz – President of the Israel Endocrine Society (IES), Hadassah Medical center, the Hebrew University, Jerusalem, Israel.
8th International Wolfram Symposium Presentation Prof Gil Leibowitz – President of the Israel Endocrine Society (IES), Hadassah Medical center, the Hebrew University, Jerusalem, Israel.
Pathophysiology and treatment of type 2 Wolfram syndrome.
Abstract: Type 2 Wolfram syndrome results from a missense mutation in the CISD2 gene, encoding NAF-1, which transfers Fe-S clusters from the mitochondria to cytosolic acceptor proteins. The carrier rate of CISD2 missense mutation among the Palestinian population in the Middle East is 1:40, suggesting a founder effect. Type1 and type 2 Wolfram syndrome have common and distinct clinical features, suggesting heterogeneity in disease phenotype and pathophysiology. NAF-1 deficiency leads to increased labile iron accumulation in the mitochondria with subsequent development of mitochondrial dysfunction and oxidative stress, resulting in neurodegeneration and diabetes. Treatment of NAF-1 deficient cells by iron chelation, N-acetylcysteine and GLP-1-RA reduced mitochondrial iron overload and alleviated oxidative stress and mitochondrial dysfunction. I will discuss the therapeutic implications of these findings.
Points noted:
- T2WS is not extremely rare in the Middle east region (compared to WFS1). This is very different from the situation reported elsewhere (e.g. in US – almost all patients have WFS1 mutations rather than CISD2 mutations).
- CISD2 gene mutation (Glutamate – Glutamine, 8 amino acid frameshift with abnormal splicing and stop sequence) generates a protein which is 25% of the size of the native protein that is rapidly degraded. Unrelated families can carry the same mutation.
- Combined GLP-1-RA (e.g. exenatide) and N-acetylcysteine generate increased effects, compared with single treatment (e.g. beta cell protection).
- Better understanding of T2WS has implications for more common forms of Diabetes Mellitus.
- Early intervention is likely to be needed.
- RCTs need broad international collaboration.
- Heterozygous mutations were not studied to date.