I-Tracking Neurodegeneration in Early Wolfram Syndrome

Brief Title

I-Tracking Neurodegeneration in Early Wolfram Syndrome

Official Title

International Tracking Neurodegeneration in Early Wolfram Syndrome

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).
    

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.
    


Study Type

Observational


Primary Outcome

Change in regional brain volumes over time

Secondary Outcome

 Change in disease severity score

Condition

Wolfram Syndrome


Study Arms / Comparison Groups

 Wolfram Syndrome Patients
Description:  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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

115

Start Date

August 10, 2018

Completion Date

August 10, 2023

Primary Completion Date

August 10, 2023

Eligibility 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).
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Tamara G Hershey, PhD, 314-362-6514, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03951298

Organization ID

201808060


Responsible Party

Sponsor

Study Sponsor

Washington University School of Medicine


Study Sponsor

Tamara G Hershey, PhD, Principal Investigator, Washington University Medical School


Verification Date

June 2021