WFS1-Wolfram syndrome (WFS1-WS) is a rare genetic disease that occurs in approximately 1/200,000 to 1/500,000 people. The classic presentation of WFS1-Wolfram syndrome is insulin dependent diabetes by age 5 to 6, optic nerve atrophy with profound vision impairment or blindness by age 15 to 20, and other medical issues including, but not limited to, diabetes insipidus, deafness, and neurodegeneration. Death may occur by age 30 in approximately 50% of people with classic Wolfram syndrome. However, some variants of WFS1 cause a milder form of this disease. Each variant may manifest as a different presentation of the disease with a different level of severity.
Most WFS1 variants cause WFS1-Wolfram syndrome in the recessive form, in which an individual carries a variant in both WFS1 genes. Some WFS1 variants may cause symptoms when only one WFS1 gene is affected, the dominant form. This is known as WFS1-related-disorder, which is a milder condition than Wolfram syndrome in general. It is now well documented that Wolfram syndrome and WFS1-related disorder present as a spectrum of symptoms and severity.
While some WFS1 variants are more common than others, there is no single variant that, if corrected, would treat the disease for all WS1 patients. The ultimate goal for treating WFS1-WS will be to correct individual variants within the WFS1 gene. In the meantime we search for strategies to correct the disease process that occurs in the cell as a result of WFS1 variants.
The symptoms of WFS1-WS are caused by dysfunctional wolframin, the endoplasmic reticulum (ER) transmembrane protein encoded by the WFS1 gene. Wolframin appears to help fold other proteins properly and maintain proper calcium levels in the ER. Without fully functional wolframin the Unfolded Protein Response (UPR) is triggered, 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.
It is important to note that an additional rarer form of Wolfram syndrome, CISD2-Wolfram syndrome, is caused by variants in the CISD2 gene. This form of Wolfram syndrome shares many characteristics of WFS1-WS, but lacks diabetes insipidus, and may present with gastric ulcers or platelet dysfunction. Wolfram syndrome is thus viewed as a spectrum of disease with 3 distinct forms, WFS1-WS, WFS1-related disorder, and CISD2-WS under its umbrella.
The Power of Wolfram syndrome Although Wolfram syndrome is an ultra-rare genetic disorder, its constituent medical components (e.g. diabetes mellitus, deafness, and retinal degeneration) and underlying ER pathophysiology are individually present in many more common diseases. Consequently, novel treatments designed for WS may have broader implications for more common medical conditions related to ER stress and dysfunction. Thus, by leveraging the tools and therapeutic efforts targeting Wolfram syndrome, researchers may very well identify novel treatment modalities for more prevalent disorders such as diabetes mellitus and neurodegenerative diseases.
