# Tracking Neurodegeneration in Early Wolfram Syndrome

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $600,634

## Abstract

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 β 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, rapid...

## Key facts

- **NIH application ID:** 9974547
- **Project number:** 5R01HD070855-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** TAMARA G HERSHEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $600,634
- **Award type:** 5
- **Project period:** 2012-08-17 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974547

## Citation

> US National Institutes of Health, RePORTER application 9974547, Tracking Neurodegeneration in Early Wolfram Syndrome (5R01HD070855-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974547. Licensed CC0.

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