Wolfram Syndrome International Registry and Clinical Study

Brief Title

Wolfram Syndrome International Registry and Clinical Study

Official Title

Wolfram Syndrome International Registry and Clinical Study

Brief Summary

      In this study, the investigators hypothesize that studying monogenic variants with strong
      effect associated with severe insulin deficiency of Wolfram syndrome will provide important
      insights into the more complex type 1 and type 2 diabetes mellitus.

      Aim 1. Establish and maintain a registry of patients with Wolfram syndrome. An Internet based
      registry will be employed to enroll participants with the clinical diagnosis of Wolfram
      syndrome (insulin dependent DM and bilateral OA). Clinical information regarding age of
      diagnosis and progression of the disease will be collated and analyzed to better define its
      natural history, along with potential metabolic phenotypes such as glucose intolerance of
      heterozygous parents and unaffected sibs.

      If not already completed, blood for WFS1 sequence analysis will be obtained on the
      participants (parents and sibs also for control purposes) and sent to a CLIA certified lab to
      define the mutation. This information will benefit patient families and referring physicians
      by providing a genetic diagnosis and where indicated. The Wolfram Syndrome Registry will
      foster international collaborations to more efficiently and systematically collect Wolfram
      syndrome patients and their clinical and experimental data.
    

Detailed Description

      Background

      Common Manifestations and Natural History Wolfram syndrome is an autosomal recessive disorder
      characterized by juvenile onset diabetes, optic nerve atrophy, and neurodegeneration. The
      common manifestations of Wolfram syndrome include: diabetes mellitus, optic nerve atrophy,
      central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive
      neurologic difficulties. Diabetes mellitus is typically the first manifestation, usually
      diagnosed around age 6. Optic nerve atrophy, marked by loss of color vision and peripheral
      vision, follows around age 11. Central diabetes insipidus is another common manifestation,
      affecting approximately 70 percent of Wolfram. Around 65 percent of patients develop
      sensorineural deafness that can range in severity from deafness beginning at birth to mild
      hearing loss beginning in adolescence that worsens over time. Urinary tract problems are
      another major clinical challenge for Wolfram syndrome patients affecting 60 to 90 percent of
      this population. These problems include obstruction of the ducts between the kidneys and
      bladder, high-capacity atonal bladder, disrupted urination, bladder sphincter dyssynergia,
      and difficulty controlling urine flow. About 60 percent of patients with Wolfram syndrome
      develop neurological manifestations, most commonly presenting as problems with balance and
      coordination (ataxia) beginning in early adulthood. Brain stem atrophy is also a prominent
      feature that often results in death secondary to central apnea.

      Classification According to the draft International Classification of Diseases (ICD-11),
      Wolfram Syndrome is categorized as rare specified diabetes mellitus (subcategory 5A16.1,
      Wolfram Syndrome). There are no classifications or staging systems employed after diagnosis.

      Etiology It has now been established that Wolfram syndrome is a prototype of endoplasmic
      reticulum (ER) disease. The ER is a membrane network within our cells that is involved in
      protein synthesis, calcium storage, redox regulation, steroid synthesis, cell signaling, and
      cell death. Given the many vital and complex functions of the ER, there is little wonder that
      its failure can trigger a range of diseases. Previous studies have shown that pancreatic beta
      cells and neurons are particularly sensitive to ER dysfunction, likely due to their high
      rates of protein synthesis. In Wolfram syndrome, pancreatic beta cells and neuronal cells are
      selectively destroyed as a consequence of mutations in the WFS1 gene. This gene encodes a
      transmembrane protein localized to the ER and ER dysfunction is a major pathogenic component
      of Wolfram syndrome. In Wolfram syndrome, WFS1 mutations lead to elevated ER stress levels,
      pancreatic beta cell dysfunction, and the initiation of ER stress-associated cell death. A
      small portion of patients has mutations in the WFS2 (CISD2) gene. WFS2 also encodes a
      transmembrane protein localized to the ER. In patients with WFS2 mutations, diabetes mellitus
      and hearing impairment are reported. Their clinical phenotype differs from patients carrying
      WFS1 mutations for the absence of diabetes insipidus and for the presence of upper intestinal
      ulcers and defective platelet aggregation, suggesting that there are different and
      overlapping functions of WFS1 and WFS2.

      Rationale Wolfram syndrome is a neurodegenerative disorder mediated by ER stress, and
      characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, and motor, sensory
      and autonomic nervous system disruption. The progressive loss of neuronal function is due to
      the neuronal cell death. The prognosis of this syndrome is poor as most patients die
      prematurely with severe neurological disabilities such as bulbar dysfunction and organic
      brain syndrome, with the median age at death being 30 years (range, 25-49 years), usually
      from respiratory failure as a result of brain stem atrophy. Imaging and post mortem studies
      have shown diffuse neurodegenerative changes in the brain. The only available treatments
      ameliorate the symptoms of the individual components of the disease, but do not target the
      underlying cause and are therefore unable to prevent progression of the condition, hence both
      its debilitating and fatal outcome. There are no effective treatments for Wolfram Syndrome,
      either in terms of authorized medicinal products in this indication or in terms of commonly
      used treatments not subject to marketing authorization. The use of careful clinical
      monitoring and supportive care do not treat the condition itself and act only to lessen the
      debilitating consequences. Further, although agents are approved for the individual
      components of Wolfram Syndrome, none of these therapies are able to prevent the continued
      deterioration in the patient's conditions as they do not address the underlying cause. Thus,
      there is an urgent need to understand the cause of the disease, identify biomarkers, and
      develop treatments targeting the underlying cause to stop its progression. To fulfill these
      unmet medical needs, we will maintain a registry of patients with Wolfram syndrome.

      Study Design

      Aim 1. Maintain a registry of patients with Wolfram syndrome. An Internet-based registry will
      be employed to enroll patients with Wolfram syndrome based on the following diagnostic
      criteria.

      Major Criteria

        -  Diabetes mellitus <16 yrs

        -  Optic atrophy <16 yrs

      Minor Criteria

        -  Diabetes insipidus

        -  Diabetes mellitus >16yrs

        -  Optic atrophy >16 yrs

        -  Sensorineural deafness

        -  Neurological signs (ataxia, epilepsy, cognitive impairment)

        -  Renal tract abnormalities (structural or functional)

        -  1 loss of function mutation in WFS1/CISD2 AND/OR family history of Wolfram syndrome

      Minimum Required

        -  2 major OR

        -  1 major plus 2 minor criteria OR

        -  2 pathological WFS1 or CISD2 mutations are identified

      Other variable suggestive evidence

        -  Hypogonadism (males)

        -  Absence of type 1 diabetes auto-antibodies

        -  Bilateral cataracts

        -  Psychiatric disorder

        -  Gastrointestinal

      Clinical information regarding age of diagnosis and progression of the disease will be
      collated and analyzed to better define its natural history, along with potential metabolic
      phenotypes such as glucose intolerance of heterozygous parents and unaffected sibs.

      If not already completed, blood for WFS1 sequence analysis will be obtained on the patient
      (parents and sibs also for control purposes) and sent to a CLIA certified lab to define the
      mutation. This information will benefit patient families and referring physicians by
      providing a genetic diagnosis and where indicated. The Wolfram Syndrome Registry will foster
      international collaborations to more efficiently and systematically collect Wolfram syndrome
      patients and their clinical and experimental data. We will continue to enroll patients and
      analyze their data.

      Registry participants may also be eligible to enroll in the Wolfram Syndrome Research Clinic
      study at Washington University and other studies (TRACK IRB# 201104010). If they are
      eligible, a study coordinator for the research clinic will contact them to explain the study
      and to see if they are interested. Their contact information will not be released to the
      research clinic Principal Investigator unless you have given permission. Their parents and
      unaffected sibs may also be invited to participate.

      Registry participants may also be eligible to enroll in the Wolfram Dantrolene Safety Trial
      (IRB #201607006) and other upcoming clinical trials. If they are possibly eligible, the PI or
      a clinical coordinator for that study will contact them to explain the study to see if they
      are interested. Their participation in this safety trial and other future clinical trials
      will have no effect on your Registry participation.

      Potential Contribution: How will this project contribute to the literature and/or the field?
      We believe in the strong power of rare diseases, especially Wolfram syndrome, to understand
      the pathogenesis and develop novel therapeutic modalities for more prevalent diseases,
      including type 1 diabetes and neurodegeneration. Our study on Wolfram may lead to a
      breakthrough for treatments of common diseases, such as type 1 diabetes, type 2 diabetes, and
      neurodegeneration, in which endoplasmic reticulum dysfunction is involved.

      Aim 2. Collect blood and urine samples from registrants to monitor levels of biomarkers,
      identify disease-modifying genes, and understand the mechanisms of the disease.

      We will collect blood samples up to three times a year and urine samples up to three times a
      year from Wolfram syndrome patients participating in the registry study. The blood sample is
      for sequencing of the Wolfram syndrome causative genes if not already done, monitoring levels
      of biomarkers, including calcium, C-peptide, circulating beta cell DNA, and mesencephalic
      astrocyte-derived neurotrophic factor, calpain-2 activation and endoplasmic reticulum stress
      marker levels, and next-generation sequencing for identifying disease-modifying genes.
      Similarly, the urine will be used for monitoring levels of biomarkers, including calcium,
      C-peptide, mesencephalic astrocyte-derived neurotrophic factor, calpain-2 activation and
      endoplasmic reticulum stress marker levels.

      We will collect blood sample from parents for sequencing of the Wolfram syndrome causative
      genes if not already done, monitoring levels of biomarkers, including calcium, C-peptide,
      circulating beta cell DNA, mesencephalic astrocyte-derived neurotrophic factor, calpain-2
      activation and endoplasmic reticulum stress marker levels, and next-generation sequencing for
      identifying disease-modifying genes. Similarly, the urine will be used for monitoring levels
      of biomarkers, including calcium, C-peptide, mesencephalic astrocyte-derived neurotrophic
      factor, calpain-2 activation and endoplasmic reticulum stress marker levels.

      We will collect blood samples from unaffected siblings. of a patient with Wolfram syndrome
      for sequencing of the Wolfram syndrome causative genes if not already done, monitoring levels
      of biomarkers, including calcium, C-peptide, circulating beta cell DNA, mesencephalic
      astrocyte-derived neurotrophic factor, calpain-2 activation and endoplasmic reticulum stress
      marker levels, and next-generation sequencing for identifying disease-modifying genes.
      Similarly, the urine will be used for monitoring levels of biomarkers, including calcium,
      C-peptide, mesencephalic astrocyte-derived neurotrophic factor, calpain-2 activation and
      endoplasmic reticulum stress marker levels.

      Aim 3. Administer an electronic activity assessment questionnaire one-time to all
      registrants.

      We will electronically administer a questionnaire to all individuals on the registry
      (self-report or parent proxy). The revised questionnaire will be sent to all Registry
      participants to have a large sample size as well as more representation from individuals who
      are older or have more severe symptoms compared to those at the clinic. The data will be
      collected in REDCap and analyzed in Excel and SPSS.

      This ultimately aims to increase participation in life activities and quality of life for
      those with Wolfram syndrome. The questionnaire will serve as a needs assessment. The
      identified needs will guide the development of a list of comprehensive resources for families
      with Wolfram syndrome and guidelines for OT clinicians, working with Wolfram syndrome, which
      can be accessed online. A long term goal is to offer OT services through Washington
      University for local individuals with Wolfram syndrome.

      Aim 4. Generation of induced pluripotent stem cells (optional):

      We may isolate and culture cells from their skin biopsies, blood or urine samples, bank them
      and reprogram them into induced pluripotent stem cells (iPSCs) at a later date. Additionally,
      we may genetically engineer the reprogrammed iPSCs to introduce or repair mutations. The
      reprogrammed and/or genetically engineered iPSCs may be differentiated into various tissue
      types for future studies. The banked cells from their samples as well as their derivatives
      may also be shared with researchers at Washington University, at other research centers and
      institutions, or industry sponsors of research.
    


Study Type

Observational [Patient Registry]


Primary Outcome

Changes in C-peptide levels in participants

Secondary Outcome

 Changes in best-corrected visual acuity in participants measured by Snellen optotype

Condition

Wolfram Syndrome



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

200

Start Date

July 2011

Completion Date

December 2025

Primary Completion Date

December 2025

Eligibility Criteria

        Any patient worldwide with a diagnosis of Wolfram syndrome and with access to the Internet
        can be enrolled in the Registry. Since the disease usually manifests in the first decade of
        life and tends to have an inevitably progressive course, participation of minors is
        important for establishing the natural course of the disease.

        Inclusion Criteria:

        Major Criteria

          -  Diabetes mellitus <16 yrs

          -  Optic atrophy <16 yrs

        Minor Criteria

          -  Diabetes insipidus

          -  Diabetes mellitus >16yrs

          -  Optic atrophy >16 yrs

          -  Sensorineural deafness

          -  Neurological signs (ataxia, epilepsy, cognitive impairment)

          -  Renal tract abnormalities (structural or functional)

          -  1 loss of function mutation in WFS1/CISD2 AND/OR family history of Wolfram syndrome

        Minimum Required

          -  2 major OR

          -  1 major plus 2 minor criteria OR

          -  2 pathological WFS1 or CISD2 mutations are identified

        Other variable suggestive evidence

          -  Hypogonadism (males)

          -  An absence of type 1 diabetes auto-antibodies

          -  Bilateral cataracts

          -  Psychiatric disorder

          -  Gastrointestinal

        Exclusion Criteria:

        Inability of a patient and/or a guardian to obtain help with translation and thus,
        inability to understand questionnaire.

        Parent, Sibs, and Spouses:

        - Parents, sibs, and spouses that are unaffected will be recruited as controls. Inclusion
        criterion is having the unaffected status and exclusion criterion is if the person cannot
        understand the Informed Consent Document.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, +1-314-362-8683, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02841553

Organization ID

201107067

Secondary IDs

UL1TR000448

Responsible Party

Sponsor

Study Sponsor

Washington University School of Medicine

Collaborators

 American Diabetes Association

Study Sponsor

, , 


Verification Date

April 2021