Wolfram syndrome (WFS; OMIM #222300) is a rare autosomal recessive disease clinically defined in 1938 as the combination of childhood-onset insulin dependent diabetes, optic nerve atrophy, diabetes insipidus and deafness. Based on early descriptions, neurological features were thought to appear later in the disease with death occurring in middle adulthood. Importantly, the major causative gene (WFS1) was identified in 1998. This discovery allowed researchers to determine that the WFS1 gene encodes the protein wolframin, which helps protect cells from endoplasmic reticulum (ER) stress-mediated apoptosis, potentially via intracellular calcium homeostasis. Pathogenic mutations in WFS1 can result in death or dysfunction of cells that are under high ER stress, such as insulin-producing pancreatic ? cells, causing insulin dependent diabetes. In addition, knowing the causative gene has allowed us to identify patients by their WFS1 mutation rather than the classic set of symptoms, leading to the increasing realization that the WFS1-related phenotype (including neurologic symptoms) is much more variable than previously understood. The first iteration of this grant (HD070855 ?Tracking Neurodegeneration in Early Wolfram Syndrome?) contributed to this shift in understanding. In this time, we have built a successful annual research clinic for WFS, met or exceeded our recruitment goals for patients and controls, validated a clinical severity rating scale for WFS, described an unexpectedly early neurophenotype of reduced balance, smell identification and ventral pons volume, identified alterations in traditional diffusion tensor imaging (DTI) metrics that suggest hypomyelination as a pervasive neuropathological feature of WFS and provided justification for the selection of two primary outcomes (visual acuity and ventral pons volume) in a newly funded clinical efficacy study in WFS (Barrett, PI). Our findings suggest two lines of investigation going forward. First, we hypothesize that ER stress- related dysfunction could inhibit production of myelin during neurodevelopment in WFS, as active and developing oligodendrocytes (cells that produce myelin in the brain) are more vulnerable to ER stress than mature ones. However, standard DTI methods conflate inflammatory processes (which can also be associated with ER stress) in the extra-axonal space with metrics of axonal and myelin integrity, leading to potentially confounded measurements. We propose to collect novel, validated diffusion sequences on a new state of the art MRI scanner (Siemens Prisma) and apply cutting-edge analysis approaches to measure white matter integrity throughout the brain and in the optic nerve, improving our ability to draw conclusions about axonal and myelin integrity over time. Second, larger and more diverse samples are needed to determine the predictors of WFS degeneration. We will pool key variables from WU with baseline and placebo conditions from a new clinical trial in the UK, rapidly increasing our sample and allowing for more complex analyses. Findings from this work may indicate future targets for brain-specific intervention, identify outcome measures or high-risk subgroups for clinical trials targeting neurological symptoms and will lay the groundwork for additional international collaborations. These data will also greatly expand our understanding of the cross-sectional and longitudinal phenotype of WFS1-mutation related disorders, rather than classically defined Wolfram Syndrome. Such knowledge will have a significant impact on patients and families by allowing physicians to provide more accurate prognoses. Finally, forms of ER stress-mediated apoptosis have been implicated in more common neurodegenerative, endocrine and neurodevelopmental diseases, which may benefit from the insights gained here.

Public Health Relevance

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. The goal of the current proposal is to determine the pattern of early neurodegenerative changes in Wolfram syndrome and predictors of these changes. 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD070855-07
Application #
9762126
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
King, Tracy
Project Start
2012-08-17
Project End
2023-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bumpus, Emily; Hershey, Tamara; Doty, Tasha et al. (2018) Understanding activity participation among individuals with Wolfram Syndrome. Br J Occup Ther 81:348-357
Hoekel, James; Narayanan, Anagha; Rutlin, Jerrel et al. (2018) Visual pathway function and structure in Wolfram syndrome: patient age, variation and progression. BMJ Open Ophthalmol 3:e000081
Doty, Tasha; Foster, Erin R; Marshall, Bess et al. (2017) The effects of disease-related symptoms on daily function in Wolfram Syndrome. Transl Sci Rare Dis 2:89-100
Lugar, Heather M; Koller, Jonathan M; Rutlin, Jerrel et al. (2016) Neuroimaging evidence of deficient axon myelination in Wolfram syndrome. Sci Rep 6:21167
Bischoff, Allison N; Reiersen, Angela M; Buttlaire, Anna et al. (2015) Selective cognitive and psychiatric manifestations in Wolfram Syndrome. Orphanet J Rare Dis 10:66
Hoekel, James; Chisholm, Smith Ann; Al-Lozi, Amal et al. (2014) Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome. J AAPOS 18:461-465.e1
Lu, Simin; Kanekura, Kohsuke; Hara, Takashi et al. (2014) A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci U S A 111:E5292-301
Karzon, Roanne K; Hullar, Timothy E (2013) Audiologic and vestibular findings in Wolfram syndrome. Ear Hear 34:809-12
Earhart, Gammon M (2013) Dynamic control of posture across locomotor tasks. Mov Disord 28:1501-8
Marshall, Bess A; Permutt, M Alan; Paciorkowski, Alexander R et al. (2013) Phenotypic characteristics of early Wolfram syndrome. Orphanet J Rare Dis 8:64

Showing the most recent 10 out of 14 publications