The classic form of Wolfram syndrome and the Ashkenazi Jewish subtype are both caused by mutations in the WFS1 gene on chromosome 4. However, the Ashkenazi subtype is caused by a specific mutation, c.1672C>T (p.Arg558Cys or p.R558C). Despite this shared genetic basis, they present differently, with distinct patterns of symptom severity, prognosis and management.
In the Ashkenazi Jewish population, the majority of affected individuals are homozygous for the p.R558C variant — meaning they inherited the Ashkenazi variant from both parents. Overall, these patients tend to have a milder clinical course than those with classic Wolfram syndrome.
Wolfram syndrome results from dysfunction in the endoplasmic reticulum (ER), a part of the cell that helps proteins mature and manage cell stress. Recent clinical and genetic findings indicate that Wolfram syndrome is best understood as a spectrum disorder.
Find an extensive list of the symptoms of Jewish Wolfram syndrome here, as well as therapies currently in development here.
Comparing Classic Wolfram and Jewish Wolfram syndrome
