Wolfram syndrome (OMIM #222300) is a rare genetic (autosomal recessive) disease originally described as the combination of insulin dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus and deafness. Neurodegeneration and neurological features were thought to appear at later stages of the disease, ultimately leading to death in middle adulthood (Barrett et al., 1995). There are no interventions to slow or stop this devastating deterioration.
However, much is known about the mechanisms underlying these effects. The causative gene (WFS1) was identified at Washington University in 1998 by Dr. M. Alan Permutt, and cell and animal models have determined that WFS1 encodes an endoplasmic reticulum (ER) membrane-embedded protein called wolframin. Mutant forms of the WSF1 protein lead to disturbances of ER calcium homeostasis, driving ER stress-mediated apoptosis. This process kills insulin producing pancreatic β-cells, leading to diabetes. WFS1 is also expressed throughout the brain, and cell death via ER stress is thought to underlie neurodegeneration in WFS, as well as being implicated in more common neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases.
Work in animal models of WFS is progressing rapidly towards the identification of viable interventions for the ER stress related cell death Unfortunately, there is limited information on the pattern of neurologic changes associated with WFS. A better understanding of the neurodegenerative and neurodevelopmental changes in early WFS is a necessary first step towards being ready for future clinical trials.
Thus, we have established the Washington University Wolfram Syndrome Research Clinic to understand the natural history of neurologic features of Wolfram Syndrome. Data from this ongoing study has revealed important insights into the neuropathological process in Wolfram Syndrome, providing guidance for physicians, parents, patients, and the design of clinical trials. If you are interested in more information on this study, please see the Wolfram Syndrome Research Clinic page.