Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies

Publication: Hindawi.com | Publication Date: 2018

Authors: N. B. Toppings, J. M. McMillan, P. Y. B. Au, O. Suchowersky and L. E. Donovan

Abstract

Background. Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in WFS1, a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care. Case. We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations in WFS1 were identified, supporting a diagnosis of classical WS. Conclusions. The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserve β-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies for β-cell preservation for individuals with type 1 and 2 diabetes.

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Dr. Urano’s August 2018 Update

Fumihiko “Fumi” Urano, MDAugust 9, 2018

Dear Friends,

I’d like to begin by thanking all of you for your continued support, trust, and faith in me. I always feel your support and energy. It is always my pleasure to update you about our progress. 

To achieve a cure for Wolfram syndrome, we need breakthrough treatments. We currently have three new candidate drugs that can potentially delay or halt the progression of Wolfram syndrome. In parallel, we are developing regenerative gene therapy to protect and regrow remaining eye and brain cells. We usually test the efficacy of candidate drugs and gene therapies in cell models of Wolfram syndrome first. Wolfram cell models are cells derived from our patients or cells lacking normal Wolfram syndrome 1 gene. These cells are sensitive to cell stress and susceptible to cell death. So we are looking for candidate drugs and gene therapies that can reduce cell stress and cell death in Wolfram cell models. The advantage of using cell models is that we can test multiple drug candidates at the same time within a few months. As a next step, we use a mouse model of Wolfram syndrome to test the efficacy of new treatments on visual acuity, brain function, and diabetes. These are genetically engineered mice that do not have Wolfram syndrome 1 gene and develop diabetes, visual impairment, and brain dysfunction. Although these mice are quite useful, it is challenging to test the efficacy of a type of gene therapy called gene editing because they don’t carry abnormal Wolfram syndrome 1 gene variants that our patients carry. In addition, because mice are so small, it is challenging for us to test the efficacy of new treatments in their eyes. Their eyes are so small. To overcome these challenges, I have designed mice and rats carrying Wolfram syndrome 1 gene variants that our patients carry. We call them humanized Wolfram mice and rats. If successful, we can test our new gene therapy and assess the efficacy of new treatments on visual acuity in these humanized Wolfram mice and rats. This will accelerate the pace of our therapeutic development. 

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. I cannot thank you enough.

With passion, hope, and gratitude,

Fumi Urano

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2018 EAT DRINK GIVE – Gianna’s Vision of Hope

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