An observational study in Wolfram Syndrome, sponsored by Washington University School of Medicine. Completed at 1 site in United States. Open to participants aged 1 Day and older. Per ClinicalTrials.gov, last updated 2026-09-23.
Sponsored by Washington University School of Medicine · Observational
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 researchers 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, the research team has built a successful annual research clinic for WFS, that has met or exceeded 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).
In this new grant, researchers 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. The research team proposea 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 the ability to draw conclusions about axonal and myelin integrity over time. Researchers will assess WFS patients annually at our WU Wolfram Research Clinic using these methods.
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. 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.
8,290 studies on the registry are indexed under Diabetes Mellitus; 1,077 are open to participants now.
This study's enrollment of 128 is below the median of 246 across 1,936 observational studies indexed under Diabetes Mellitus.
Browse Diabetes Mellitus studies →Washington University School of Medicine is the lead sponsor of 1,803 studies on the registry; 271 are open to participants now.
Of its 329 completed or terminated interventional studies of FDA-regulated products, 216 (66%) have results posted.
Counted across the registry records on this site, refreshed daily.
Age, gender and handedness-matched participants between the age of 1 day to no upper limit.
Wolfram Syndrome Group (WFS):
Inclusion Criteria:
Both of the following conditions:
Exclusion Criteria:
Sibling Group: Biological, half and step-siblings who do not have any symptoms of WFS and/or have had genetic testing to show that they do not have WFS may participate.
Exclusion Criteria:
Proxy Group: Adult Biological parent(s), biological caregiver, or non-biological caregiver of adult and minor participants in any of the four groups.
Inclusion criteria:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participant has confirmation of a WFS1 mutation OR Both of the following conditions: diabetes mellitus requiring insulin and optic nerve atrophy diagnosed by a physician. Both conditions diabetes mellitus and optic nerve atrophy had to be diagnosed at age younger than 18 years old
Adult Biological parent(s), biological caregiver or non-biological caregiver of adult and minor participants in the Wolfram group. These individuals report on symptoms of their family member with Wolfram.
Sibling Group: Biological, half and step-siblings who do not have any symptoms of WFS and/or have had genetic testing to show that they do not have WFS may participate. Exclusion Criteria: • Inability of participant or guardian to understand informed consent.
Regional Pons Volume
MRI measure of pons brain volume for Wolfram and sibling groups
Time frame: last assessment in this longitudinal study, each participant was followed between 1 and 5 years.
Disease Severity Score
WURS physical severity score; rated by physician; range is 0 (no impairment) to 132 (most severe impairment)
Time frame: last assessment in this longitudinal study, each participant was followed between 1 and 5 years.
| Milestone | Wolfram Syndrome Patients | Proxy Group | Siblings |
|---|---|---|---|
| Started | 53 | 55 | 20 |
| Completed | 53 | 55 | 20 |
| Not completed | 0 | 0 | 0 |
MRI measure of pons brain volume for Wolfram and sibling groups
| cubic millimeters | Wolfram Syndrome Patients | Siblings |
|---|---|---|
| Regional Pons Volume | 6855 ± 223 | 10529 ± 295 |
WURS physical severity score; rated by physician; range is 0 (no impairment) to 132 (most severe impairment)
| points on rating scale | Wolfram Syndrome Patients |
|---|---|
| Disease Severity Score | 16.6 ± 1.9 |
Collected over from each individual's enrollment to their last visit; a period of no more than 5 years.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Wolfram Syndrome Patients | 0/53 (0%) | 0/53 (0%) | 0/53 (0%) |
| Siblings | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) |
| Proxy Group | 0/55 (0%) | 0/55 (0%) | 0/55 (0%) |
| Age, Continuous(years) | Wolfram Syndrome Patients | Proxy Group | Sibling | Total |
|---|---|---|---|---|
| Mean | 14.7 ± 7.3 | 45.8 ± 7.8 | 7.8 ± 7.9 | 28.5 ± 16.9 |
| Sex: Female, Male(Participants) | Wolfram Syndrome Patients | Proxy Group | Sibling | Total |
|---|---|---|---|---|
| Female | 30 | 34 | 7 | 71 |
| Male | 23 | 21 | 13 | 57 |
| Race (NIH/OMB)(Participants) | Wolfram Syndrome Patients | Proxy Group | Sibling | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 36 | 0 | 13 | 49 |
| More than one race | 0 | 44 | 0 | 44 |
| Unknown or Not Reported | 17 | 11 | 7 | 35 |
| Ethnicity (NIH/OMB)(Participants) | Wolfram Syndrome Patients | Proxy Group | Sibling | Total |
|---|---|---|---|---|
| Hispanic or Latino | 18 | 15 | 6 | 39 |
| Not Hispanic or Latino | 35 | 40 | 14 | 89 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
PDFs hosted by the registry, ClinicalTrials.gov.
This study is completed, as verified in Sep 2026. You cannot join it, but the record below documents what was studied.
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