Expanding the spectrum of white matter abnormalities in Wolfram syndrome: A retrospective review

Publication: frontiersin.org | Publication Date: 14 October 2025

Authors: Justin Simo, Heather M. Lugar, Elka Miller, Adi Wilf-Yarkoni, Yael Goldberg, Ayça Kocaağa, Shoichi Ito, Sirio Cocozza, Giulio Frontino, Cristina Baldoli, Aziz Benbachir, Catherine Ashton, Guy Rouleau, Tamara Hershey, Yann Nadjar, Roberta La Piana

Background and Objectives

Wolfram syndrome (WFS) is a genetic disorder mainly caused by pathogenic variants in the WFS1 gene. It is characterized clinically by optic atrophy (OA), diabetes mellitus (DM), sensorineural hearing loss (SNHL), diabetes insipidus (DI), and variable neurological/psychiatric symptoms. WFS typically manifests before age 20 and progresses into adulthood. Classical neuroradiological features include cerebellar and/or brainstem atrophy as well as white matter abnormalities ranging from small, ovoid lesions to diffuse, symmetrical changes along the visual pathway. Following the identification of multifocal, progressive white matter abnormalities that prompted the consideration of multiple sclerosis (MS) in two molecularly confirmed WFS subjects, we sought to verify whether MS-like lesions constitute a novel WFS-associated MRI pattern.
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Wolfram Syndrome Global Awareness Day 2025

Wolfram Syndrome Awareness Day is held on October 1st each year. This day was chosen because it is the anniversary of the publication of a 1998 paper on the discovery of the WSf1 gene associated with the syndrome. The day is dedicated to raising awareness of this rare genetic disorder, which affects the body’s metabolism, nervous system, and senses, and to encouraging support for research and treatments.

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FDA Patient Listening Session

On May 21, 2025, The Snow Foundation convened a group of patients (3) and caregivers (4) from across the Wolfram syndrome (WS) community for a virtual patient listening session with over 40 representatives from the Food and Drug Administration (FDA). The small, informal virtual meeting was designed to allow community members to share their lived experiences, perspectives, and unmet needs with FDA.

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Non-syndromic WFS1 mutations are not a rare cause of diabetes in Pakistan

Publication: onlinelibrary.wiley.com | Publication Date: 29 April 2025

Authors: Ibrar Rafique, Asif Mir, Natalija Popovic, Alix Vanpoperinghe, Muhammad Arif Nadeem Saqib, Asher Fawwad, Abdul Basit, Muhammad Naeem, Constantin Polychronakos, Angeliki Makri

Abstract

We examined 68 Pakistani patients with young onset diabetes and found a surprisingly high rate (4/68) of non-syndromic WFS1 diabetes, a recently described recessive condition. This frequency far exceeds the prevalence of the fully expressed syndrome, probing the effect of high consanguinity on the risk of non-syndromic WFS1 diabetes.
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TREATWOLFRAM international clinical trial of sodium valproate in Wolfram syndrome: interim results

First results from the TREATWOLFRAM trial, sponsored by the University of Birmingham, find sodium valproate treatment does not slow vision loss in Wolfram syndrome.

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Long term clinical follow up of four patients with Wolfram syndrome and urodynamic abnormalities

Objectives: Wolfram syndrome is characterised by insulin-dependent diabetes (IDDM), diabetes insipidus (DI), optic atrophy, sensorineural deafness and neurocognitive disorders. The DIDMOAD acronym has been recently modified to DIDMOAUD suggesting the rising awareness of the prevalence of urinary tract dysfunction (UD). End stage renal disease is the commonest cause of mortality in Wolfram syndrome. We present a case series with main objective of long term follow up in four children having Wolfram syndrome with evaluation of their urodynamic profile.
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Investigational oral therapy improves pancreatic function, symptoms in Wolfram syndrome

An oral therapy to treat Wolfram syndrome significantly improved pancreatic functions and induced improvement in symptoms at 24 and 48 weeks for most participants in a phase 2 trial.

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Gonadal function in males with WFS1 spectrum disorder (Wolfram syndrome)—A European cohort perspective

Publication: onlinelibrary.wiley.com | Publication Date: 29 April 2025

Authors: J. Rohayem and O. Cunningham

Abstract

Background

WFS1 spectrum disorder, also known as Wolfram syndrome (WS) is an ultra-rare (<1:500,000; ORPHA: 3463) monogenic (OMIM #222300) progressive neuroendocrine and neurodegenerative disorder, characterised by early-onset insulin-dependent diabetes, optic atrophy, central diabetes insipidus and sensi-neuronal deafness. It is caused predominantly by bi-allelic mutations in the WFS1 gene and exceptionally in the WFS2-gene. There is very limited published data on gonadal function in young people with WS. Expansion of the phenotype has previously included suggestions of abnormalities in puberty in adolescents with (WS) but with little detail.
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Positive Long-Term Results from Phase 2 HELIOS Clinical Trial of AMX0035 in People with Wolfram Syndrome

Amylyx Pharmaceuticals, Inc. today announced positive Week 48 data from the Phase 2 open-label HELIOS clinical trial of AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) in adults living with Wolfram syndrome. These results were presented at the Joint Congress of the European Society for Pediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) in Copenhagen, Denmark and are available on the “Presentations” page of the Amylyx website.

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GABA and GLP-1 receptor agonist combination therapy modifies diabetes and Langerhans islet cytoarchitecture in a rat model of Wolfram syndrome

Publication: biomedcentral.com | Publication Date: 06 March 2025

Authors: Jagomäe, T., Velling, S., Tikva, T.B. et al.

Abstract

Wolfram syndrome (WS) is a rare autosomal disorder caused by WFS1 gene mutations, currently lacking approved treatments. Preclinical and clinical reports suggest that diabetes medications, such as glucagon-like peptide-1 receptor agonist (GLP1-RA), slow WS-related diabetes and neurodegeneration, improving patient outcomes.
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