Clinical Trial: Wolfram Syndrome International Registry and Clinical Study

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational [Patient Registry]

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 Summary:

Background

Wolfram syndrome (OMIM #222300) is an autosomal recessive disorder characterized by insulin dependent diabetes mellitus (DM) in the first decade of life, followed by optic atrophy (OA), blindness, and deafness. Death from widespread neurodegeneration occurs in the third or fourth decades. Postmortem studies revealed a non-autoimmune loss of pancreatic beta-cells responsible for the diabetes.The investigators discovered that mutations in the WFS1 gene cause Wolfram syndrome, a rare Mendelian disease of strong effect in which the signaling pathway may have relevance for the more complex type 1 and type 2 diabetes mellitus.

Protein synthesis in mammalian cells occurs primarily in the endoplasmic reticulum (ER). There are a number of metabolic conditions that disrupt this process, including increased protein synthesis, synthesis of mutated proteins, and others. When these conditions occur, they trigger an adaptive response by ER stress sensors that serve to slow protein synthesis, and in extreme conditions lead to apoptosis. The investigators discovered that beta-cells exhibit high levels of ER stress in animal models of Wfs1 deficiency. High levels of ER stress promoting beta-cell death may be related to the etiology of Wolfram syndrome in patients, but this is unknown at present.

Rationale

Immunocytochemistry and subcellular fractionation studies have indicated that Wolfram protein is localized in the endoplasmic reticulum (ER) membrane with nine transmembrane segments. Fibroblasts from a patient with a non-sense mutation in the gene revealed that protein absence was caused by rapid decay of the transcript, and a patient with compound missense mutations exhibited markedly reduced protein stability. Thus, in patients
Sponsor: Washington University School of Medicine

Current Primary Outcome: Changes in C-peptide levels in participants [ Time Frame: 10 years ]

Original Primary Outcome: Same as current

Current Secondary Outcome: Changes in best-corrected visual acuity in participants measured by Snellen optotype [ Time Frame: 10 years ]

Original Secondary Outcome: Same as current

Information By: Washington University School of Medicine

Dates:
Date Received: July 6, 2016
Date Started: July 2011
Date Completion: December 2020
Last Updated: October 5, 2016
Last Verified: July 2016