I-Tracking Neurodegeneration in Early Wolfram Syndrome

NCT03951298 | Completed DMC

• 1 other identifier: 201808060
• Study Type: observational
• Target: 127
• Locations: 1 country
• Sites: 1

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).

Conditions

Wolfram Syndrome

Keywords

Diabetes Mellitus; Diabetes Insipidus; Optic Atrophy; Deafness

Outcome Measures

Primary Outcomes (1)

• Change in regional brain volumes over time

  MRI measures of regional brain volumes over time

  Annually for 5 years.

Secondary Outcomes (1)

• Change in disease severity score

  Annually for 5 years.

Study Arms (2)

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.

Eligibility Criteria

• Age: 1 Day+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Age, gender and handedness-matched participants between the age of 1 day to no upper limit.

You may qualify if:

• Patient has confirmation of a WFS1 mutation OR
• Both of the following conditions:
• diabetes mellitus requiring insulin and
• optic nerve atrophy diagnosed by a physician.

You may not qualify if:

• Patient 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 the use of a ventilator or inability to walk.
• 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.
• Inability of participant or guardian to understand informed consent.
• Proxy Group: Adult Biological parent(s), biological caregiver, or non-biological caregiver of adult and minor participants in any of the four groups.
• Biological or non-biological parent/caregiver (proxy) of a participant.
• Proxy is unaware of the participant's diagnosis (as it applies).

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

MeSH Terms

Conditions

Wolfram Syndrome; Diabetes Mellitus; Diabetes Insipidus; Optic Atrophy; Deafness

Condition Hierarchy (Ancestors)

Deaf-Blind Disorders; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Optic Atrophies, Hereditary; 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; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pituitary Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Tamara G Hershey, PhD

  Washington University Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2019
• First Posted: May 15, 2019
• Study Start: August 10, 2018
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: August 6, 2024

Record last verified: 2024-08

Locations

US (1)