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I-Tracking Neurodegeneration in Early Wolfram Syndrome (I-TRACK)

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ClinicalTrials.gov Identifier: NCT03951298
Recruitment Status : Recruiting
First Posted : May 15, 2019
Last Update Posted : May 17, 2019
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
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).

Condition or disease
Wolfram Syndrome

Detailed Description:

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.


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Study Type : Observational
Estimated Enrollment : 115 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: International Tracking Neurodegeneration in Early Wolfram Syndrome
Actual Study Start Date : August 10, 2018
Estimated Primary Completion Date : August 10, 2023
Estimated Study Completion Date : August 10, 2023


Group/Cohort
Wolfram Syndrome Patients
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
Proxy Group
Adult Biological parent(s), biological caregiver or non-biological caregiver of adult and minor participants in the any of the groups.



Primary Outcome Measures :
  1. Change in regional brain volumes over time [ Time Frame: Annually for 5 years. ]
    MRI measures of regional brain volumes over time


Secondary Outcome Measures :
  1. Change in disease severity score [ Time Frame: Annually for 5 years. ]
    WURS physical severity score over time



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Age, gender and handedness-matched participants between the age of 1 day to no upper limit.
Criteria

Wolfram Syndrome Group (WFS):

Inclusion Criteria:

  • 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 an younger than 18 years old

Exclusion Criteria:

  • Participant is unaware of their diagnosis.
  • Inability of patient or guardian to understand informed consent.
  • Advanced disease that makes traveling too problematic and/or uncomfortable for the patient and/or guardian, such as use of ventilator or inability to walk.

Proxy Group: Adult Biological parent(s), biological caregiver or non-biological caregiver of adult and minor participants in the any of the four groups.

Inclusion criteria:

• Biological or non-biological parent/caregiver (proxy) of a participant.

Exclusion Criteria:

• Proxy is unaware of the participant's diagnosis (as it applies).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03951298


Contacts
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Contact: Samantha A Ranck, MSW 314-362-6514 blankens@wustl.edu
Contact: Tasha Doty, MA 314-362-7160 dotyt@npg.wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Samantha Ranck, MSW    314-362-6514    rancks@npg.wustl.edu   
Contact: Tasha Doty, MA    314-362-7160    dotyt@npg.wustl.edu   
Principal Investigator: Tamara G Hershey, PhD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Tamara G Hershey, PhD Washington University Medical School

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03951298     History of Changes
Other Study ID Numbers: 201808060
First Posted: May 15, 2019    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Washington University School of Medicine:
Diabetes Mellitus
Diabetes Insipidus
Optic Atrophy
Deafness

Additional relevant MeSH terms:
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Deafness
Hearing Loss
Syndrome
Nerve Degeneration
Wolfram Syndrome
Disease
Pathologic Processes
Deaf-Blind Disorders
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Optic Atrophies, Hereditary
Optic Atrophy
Optic Nerve Diseases
Cranial Nerve Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Sensation Disorders
Neurologic Manifestations
Blindness
Vision Disorders
Eye Diseases, Hereditary
Eye Diseases
Diabetes Insipidus
Kidney Diseases
Urologic Diseases
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn