Wolfram Syndrome Symptoms

How do the Symptoms of Wolfram Syndrome Develop?

The symptoms of WS are caused by dysfunctional wolframin protein. In WS the endoplasmic reticulum (ER), a protein maker and powerhouse for the cell, is not able to do its job well because it lacks functional wolframin protein. Wolframin helps fold other proteins properly and maintain proper calcium levels in the ER. Without properly functioning wolframin, misfolded proteins accumulate, calcium leaks into the body of the cell, and ultimately the cell dies. The cells most affected in WS are insulin producing beta cells and neurons.

Of great interest in WS is the realization that there appear to be 3 levels at which cells are affected. At level 1 cells are still functional. At level 2 cells are dormant and thus still alive, though not functioning properly. At level 3 cells have gone through apoptosis and have died. The cells existing at level 2 have the potential to be revived and thus function restored and protected in patients with Wolfram syndrome.

In normal cells, pathways that involve wolframin protein are activated to rescue the cell when ER stress occurs. In Wolfram syndrome wolframin is unable to help rescue the cell, and apoptosis (cell death) ultimately occurs.