Wolfram syndrome (WFS) is a rare (1 in 770,000) autosomal recessive genetic disease with clinical signs apparent in early childhood. It is characterized by insulin-dependent diabetes, followed by optic nerve atrophy, vision loss, hearing loss, diabetes insipidus and neurodegeneration, resulting in death in middle adulthood, typically due to brainstem atrophy-induced respiratory failure. There currently are no treatments that slow or stop this devastating deterioration. However, much is known about the mechanisms underlying these effects. The causative gene (WFS1) was identified by our group in 1998, and a number of loss-of-function mutations have been described. Cell and animal models have determined that WFS1 encodes an endoplasmic reticulum (ER) membrane-embedded protein called wolframin and that mutations lead to disturbances of ER calcium homeostasis, driving ER stress-mediated apoptosis. This process kills insulin producing pancreatic ?-cells, leading to diabetes, and is thought to underlie the striking neurodegeneration in WFS. Work in animal models of WFS is progressing rapidly towards the identification of viable interventions for this process. Neurological features of the disease may be the most feasible to target and monitor in clinical trials, due to the fact that ?-cell loss in the pancreas has already occurred by the time patient is diagnosed with WFS. Unfortunately, there is a dearth of information on the pattern of neurodegeneration associated with WFS, particularly in the early stages of the disease. Thus, the goal of the current proposal is to determine the pattern of early neurodegenerative changes in WFS. We will perform cross-sectional and longitudinal assessments of youth with WFS, targeting sensitive neural systems with quantified neuroimaging and behavioral measures. In addition, we will establish the utility of a WFS severity rating scale (WFS Unified Rating Scale or WURS). Preliminary data support the feasibility of this approach and its potential to generate important new information about neurodevelopmental and neurodegenerative patterns in WFS. This work is necessary to position the field for future clinical trials to test interventions for WS neurodegeneration. Ultimately, a better understanding of the trajectory of neurodegeneration in WFS and the development of effective interventions may be relevant to other more common neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases in which ER stress has been implicated.
Wolfram syndrome is a rare genetic disease that affects young children, causing diabetes, vision and hearing loss and brain degeneration, resulting in death in mid-adulthood. There currently are no treatments that slow or stop this devastating deterioration. However, work in animal models of Wolfram syndrome is progressing rapidly towards the identification of viable interventions for this process. The goal of the current proposal is to determine the pattern of early neurodegenerative changes in Wolfram syndrome. This work is necessary to prepare for future clinical trials to test interventions for Wolfram syndrome neurodegeneration and may be relevant to other, more common disorders that share similar biological mechanisms.
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