Tracking Neurodegeneration in Early Wolfram Syndrome

Specific Aims: Wolfram syndrome (WFS) is a rare (1 in ~770,000) autosomal recessive genetic disease characterized by early childhood onset insulin dependent diabetes, optic nerve atrophy, vision and hearing loss, diabetes insipidus and neurodegeneration, resulting in death in middle adulthood, typically due to brainstem atrophy-induced respiratory failure 3. 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 by the investigators group in 19984, and a number of loss-of-function mutations have been described 4-6. Cell 7 and animal models 8 have determined that WFS1 encodes an endoplasmic reticulum (ER) membrane-embedded protein called wolframin 9, and that mutant forms of the WSF1 protein lead to disturbances of ER calcium homeostasis, driving ER stress-mediated apoptosis 10-12. 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 6,13, as well as being implicated in more common neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases 14. Work in animal models of WFS is progressing rapidly towards the identification of viable interventions for the ER stress related cell death12. Some neurological features of the disease may be feasible to target and monitor in clinical trials, due to the fact that diabetes is already present when a patient is diagnosed with WFS. Unfortunately, there is limited information on the pattern of brain changes associated with WFS. Although clinical retrospective data suggest that neurological features occur late (15-30 yrs of age; Fig 10) in the disease process15,16, direct measurements (Preliminary Data) suggest that certain neurological abnormalities are present at the earliest time point assessed, suggesting altered neurodevelopment, whereas others follow a more neurodegenerative pattern. These distinctions are fundamentally new insights into this disease and may shape treatment, biomarker selection and the investigators understanding of the impact of ER stress on the developing brain. 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, the primary goal of this proposal is to determine the pattern of brain alterations in WFS over time. Only by understanding the natural history of brain functional and structural changes in WFS will the investigator be prepared to evaluate any benefits of novel treatments. The investigator will perform cross-sectional and longitudinal assessments of youth with WFS, targeting sensitive neural systems with quantified neuroimaging and relevant behavioral measures. In addition, the investigator will validate a new WFS severity rating scale (WFS Unified Rating Scale or WURS), which will have utility in future multi-site or treatment studies. Preliminary data support the feasibility of this approach and its potential to generate important new information about neurologic patterns in WFS. A better understanding of the trajectory of ER stress-mediated brain changes in WFS may be relevant to other more common diseases. Specific aims follow:

1. To determine the pattern of neurologic impairment in WFS and its association with disease severity in a cross-sectional sample. The investigator hypothesizes that specific brain measures will be altered earlier and will associate more closely with overall disease severity than others in WFS. The investigator proposes that regional white matter microstructural integrity in the cerebellum, optic nerve area, brain stem volume, balance and possibly anxiety will distinguish individuals with early WFS from controls and will correlate with severity on a standardized rating scale. To test this hypothesis, the investigator will perform quantified neuroimaging, cognitive, motor, psychiatric, visual and auditory evaluations on individuals with WFS, preferentially recruiting those earlier in the disease process, (n=30; age 5 and older, within 10 years of diabetes onset) and on matched healthy controls (n=30) and controls with Type 1 Diabetes Mellitus (T1DM; n=30).
2. To determine the longitudinal pattern of neurologic deterioration in WFS. The investigator hypothesize that measures specified in Aim 1 will show detectable change, and that the most sensitive measures will show change in the early Wolfram patients compared to control groups. To test this hypothesis, WFS, T1DM and control participants will be re-assessed annually for 3 years. Variables of interest identified in cross-sectional analyses will be targeted and compared between groups and correlated with change in disease severity as measured with the investigators standardized rating scale.
3. To explore brain structure-function relationships within WFS. To determine if neuroimaging measures identified in Aims 1 and 2 have functional correlates, the investigator will explore how differences (cross-sectional data) or change (longitudinal data) in neuroimaging variables correlate with differences or change in selected functional measures. Such data would help build hypotheses about the neural underpinnings of functional changes in WFS. For example, the investigator speculates that the integrity of the brainstem and cerebellum will be related to gait and balance and that optic nerve area will be related to visual acuity.