Tracking Neurodegeneration in Early Wolfram Syndrome

Brief Title

Tracking Neurodegeneration in Early Wolfram Syndrome

Official Title

Tracking Neurodegeneration in Early Wolfram Syndrome

Brief Summary

      The goal of this study is to determine the pattern of early neurodegenerative changes in WFS
      (Wolfram Syndrome). The investigator will perform cross-sectional and longitudinal
      assessments of youth with WFS, targeting sensitive neural systems with quantified
      neuroimaging and behavioral measures. In addition, the investigator will establish the
      utility of a WFS severity rating scale (WFS Unified Rating Scale or WURS). Preliminary data
      support the feasibility of this approach and its potential to generate important new
      information about neurodevelopmental and neurodegenerative patterns in WFS. This work is
      necessary to position the field for future clinical trials to test interventions for WFS
      neurodegeneration. Ultimately, a better understanding of the trajectory of neurodegeneration
      in WFS and the development of effective interventions may be relevant to other more common
      neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases in which ER stress has
      been implicated.
    

Detailed Description

      Specific Aims: Wolfram syndrome (WFS) is a rare (1 in ~770,000) autosomal recessive genetic
      disease characterized by early childhood onset insulin dependent diabetes, optic nerve
      atrophy, vision and hearing loss, diabetes insipidus and neurodegeneration, resulting in
      death in middle adulthood, typically due to brainstem atrophy-induced respiratory failure 3.
      There are no interventions to slow or stop this devastating deterioration. However, much is
      known about the mechanisms underlying these effects. The causative gene (WFS1) was identified
      by the investigators group in 19984, and a number of loss-of-function mutations have been
      described 4-6. Cell 7 and animal models 8 have determined that WFS1 encodes an endoplasmic
      reticulum (ER) membrane-embedded protein called wolframin 9, and that mutant forms of the
      WSF1 protein lead to disturbances of ER calcium homeostasis, driving ER stress-mediated
      apoptosis 10-12. This process kills insulin producing pancreatic β-cells, leading to
      diabetes. WFS1 is also expressed throughout the brain, and cell death via ER stress is
      thought to underlie neurodegeneration in WFS 6,13, as well as being implicated in more common
      neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases 14. Work in animal
      models of WFS is progressing rapidly towards the identification of viable interventions for
      the ER stress related cell death12. Some neurological features of the disease may be feasible
      to target and monitor in clinical trials, due to the fact that diabetes is already present
      when a patient is diagnosed with WFS. Unfortunately, there is limited information on the
      pattern of brain changes associated with WFS. Although clinical retrospective data suggest
      that neurological features occur late (15-30 yrs of age; Fig 10) in the disease process15,16,
      direct measurements (Preliminary Data) suggest that certain neurological abnormalities are
      present at the earliest time point assessed, suggesting altered neurodevelopment, whereas
      others follow a more neurodegenerative pattern. These distinctions are fundamentally new
      insights into this disease and may shape treatment, biomarker selection and the investigators
      understanding of the impact of ER stress on the developing brain. A better understanding of
      the neurodegenerative and neurodevelopmental changes in early WFS is a necessary first step
      towards being ready for future clinical trials. Thus, the primary goal of this proposal is to
      determine the pattern of brain alterations in WFS over time. Only by understanding the
      natural history of brain functional and structural changes in WFS will the investigator be
      prepared to evaluate any benefits of novel treatments. The investigator will perform
      cross-sectional and longitudinal assessments of youth with WFS, targeting sensitive neural
      systems with quantified neuroimaging and relevant behavioral measures. In addition, the
      investigator will validate a new WFS severity rating scale (WFS Unified Rating Scale or
      WURS), which will have utility in future multi-site or treatment studies. Preliminary data
      support the feasibility of this approach and its potential to generate important new
      information about neurologic patterns in WFS. A better understanding of the trajectory of ER
      stress-mediated brain changes in WFS may be relevant to other more common diseases. Specific
      aims follow:

        1. To determine the pattern of neurologic impairment in WFS and its association with
           disease severity in a cross-sectional sample. The investigator hypothesizes that
           specific brain measures will be altered earlier and will associate more closely with
           overall disease severity than others in WFS. The investigator proposes that regional
           white matter microstructural integrity in the cerebellum, optic nerve area, brain stem
           volume, balance and possibly anxiety will distinguish individuals with early WFS from
           controls and will correlate with severity on a standardized rating scale. To test this
           hypothesis, the investigator will perform quantified neuroimaging, cognitive, motor,
           psychiatric, visual and auditory evaluations on individuals with WFS, preferentially
           recruiting those earlier in the disease process, (n=30; age 5 and older, within 10 years
           of diabetes onset) and on matched healthy controls (n=30) and controls with Type 1
           Diabetes Mellitus (T1DM; n=30).

        2. To determine the longitudinal pattern of neurologic deterioration in WFS. The
           investigator hypothesize that measures specified in Aim 1 will show detectable change,
           and that the most sensitive measures will show change in the early Wolfram patients
           compared to control groups. To test this hypothesis, WFS, T1DM and control participants
           will be re-assessed annually for 3 years. Variables of interest identified in
           cross-sectional analyses will be targeted and compared between groups and correlated
           with change in disease severity as measured with the investigators standardized rating
           scale.

        3. To explore brain structure-function relationships within WFS. To determine if
           neuroimaging measures identified in Aims 1 and 2 have functional correlates, the
           investigator will explore how differences (cross-sectional data) or change (longitudinal
           data) in neuroimaging variables correlate with differences or change in selected
           functional measures. Such data would help build hypotheses about the neural
           underpinnings of functional changes in WFS. For example, the investigator speculates
           that the integrity of the brainstem and cerebellum will be related to gait and balance
           and that optic nerve area will be related to visual acuity.
    


Study Type

Observational


Primary Outcome

Change in regional brain volume

Secondary Outcome

 Change in disease severity score

Condition

Type 1 Diabetes


Study Arms / Comparison Groups

 Wolfram Syndrome Group
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

101

Start Date

April 2012

Completion Date

July 12, 2017

Primary Completion Date

July 12, 2017

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 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.

        T1DM Group:

        Inclusion criteria:

          -  Age within the 0-28 yrs age range of WS participant

          -  Dx of T1 diabetes mellitus

        Exclusion criteria:

          -  Participant is unaware of their diagnosis.

          -  Inability of patient or guardian to understand informed consent.

          -  Diagnosis of any major neurological or medical condition.

          -  Chronic disease other than T1DM, well-controlled asthma, or Hashimoto's thyroiditis.

          -  Other current serious medical illness

          -  Co-morbid psychiatric illness: such as mania, mental retardation, or psychoactive drug
             dependence.

          -  Co-morbid neurological illness: stroke, seizure, major loss of consciousness, other
             brain trauma/surgery, or head injuries (i.e. near drowning), encephalitis, or
             hydrocephalus, blindness, deafness.

          -  Pre-maturity at birth >4 wks early (<36 wk term) w/ sequelae (e.g. on respirator at
             NICU)

          -  Contraindication to MRI scan (e.g. claustrophobia, metal implants, foreign bodies)

          -  Orthodontic braces. Full and top braces will exclude.

        Healthy Control (HC) Group:

        Inclusion criteria:

        • Age within the 0-28 yrs age range of WFFS participants

        Exclusion criteria:

          -  Inability of patient or guardian to understand informed consent.

          -  Dx of T1 diabetes mellitus

          -  Diagnosis of any major neurological or medical condition.

          -  Chronic disease other than well-controlled asthma, or Hashimoto's thyroiditis.

          -  Other current serious medical illness

          -  Co-morbid psychiatric illness: such as mania, mental retardation, or psychoactive drug
             dependence.

          -  Co-morbid neurological illness: stroke, seizure, major loss of consciousness, other
             brain trauma/surgery, or head injuries (i.e. near drowning), encephalitis, or
             hydrocephalus, blindness, deafness

          -  Pre-maturity at birth >4 wks early (<36 wk term) w/ sequelae (e.g. on respirator at
             NICU)

          -  Contraindication to MRI scan (e.g. claustrophobia, metal implants, foreign bodies)

          -  Orthodontic braces. Full and top braces will exclude. Bottom braces are ok (but the
             scan might not work out). Retainers are ok.

        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

Accepts Healthy Volunteers

Contacts

Tamara Hershey, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02455414

Organization ID

201301004

Secondary IDs

R01HD070855-02

Responsible Party

Sponsor

Study Sponsor

Washington University School of Medicine

Collaborators

 National Institutes of Health (NIH)

Study Sponsor

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


Verification Date

July 2018