What is Wolfram Syndrome?
Wolfram syndrome (WS) encompasses several distinctly identifiable disorders including WS1, WS2, and WFS1-related disorder.
Wolfram Syndrome Type 1
Wolfram syndrome is a rare, autosomal recessive genetic disorder (the mother and the father must each pass one affected copy of the gene to the child), caused by mutations in the WFS1 gene. Historically WS has been considered an ultra-rare disease afflicting 1 in 200,000 to 500,000 people. Medical experts have estimated between 15,000 and 30,000 patients worldwide have Wolfram syndrome, including 1,000-2,000 in the United States. Recent data now suggests that WS may be up to 10 times more common than previously determined, and in people with milder symptoms the disease may go unrecognized for decades.
There are currently no approved drug therapies or cures for WS. Treatment focuses on symptom management. More than 60% of Wolfram patients die before age 40.
Autosomal Recessive Genetic Diseases
The primary manifestations of WS are insulin-dependent diabetes mellitus and optic nerve atrophy. Other common manifestations are neurodegenerative in nature and may include diabetes insipidus, sensorineural hearing loss, trigeminal neuralgia-like headaches, dysphagia (difficulty swallowing), bladder dysfunction, loss of sense of smell and taste, problems with balance and coordination, muscle spasms and seizures, gastrointestinal problems, and irregular breathing. Anxiety and Depression are also common manifestations of WS related to both neurodegenerative processes, and the experience of coping with a chronic disease.
Diabetes mellitus is typically the first manifestation of WS and is usually diagnosed between the ages of 6 and 8, with optic nerve atrophy typically diagnosed between the ages of 10 and 12. Other manifestations tend to vary in onset.
Clinically, Wolfram syndrome is best characterized as a spectrum of disease, ranging in severity from mild to severe symptoms. WS patients carrying two missense mutations tend to have milder manifestations than those who have frameshift or non-sense variants. The WFS1 p.R558C missense variant, for example, is associated with milder manifestations, and has a relatively common carrier frequency (around 3%) in the Ashkenazi Jewish population. In addition, some polymorphisms (common genetic variations) of the WFS1 gene have been linked to Type 2 diabetes.
Wolfram Syndrome Type 2
Mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene have been found in a small fraction of patients with WS. Wolfram Syndrome patients carrying two recessive mutations in the CISD2 gene develop the primary features of WS, including diabetes mellitus and optic nerve atrophy, but they tend to develop other symptoms that are not typically seen in patients carrying pathogenic WFS1 variants, such as upper gastrointestinal ulceration and bleeding. Individuals with WS2 typically do not develop diabetes insipidus, and are less frequently affected by psychiatric and mood disorders than people with WS1.
WFS1-Related Disorders (Wolfram-like)
Individuals with dominant, pathogenic WFS1 mutations have WFS1-related disorder. These single mutations of the WFS1 gene are present in a distinct subset of patients who develop only one or a few of the symptoms typically seen in WS. Some dominant pathogenic variants of the WFS1 gene cause isolated deafness or diabetes. Other dominant WFS1 variants are associated with deafness combined with mild optic nerve atrophy. It has been reported that autosomal dominant congenital cataracts are also associated with dominant variants of WFS1.
Dr. Urano at Washington University In St. Louis and Dr. Hattersley at the University of Exeter have identified several dominant de novo WFS1 variants associated with a distinct genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts. These patients also have WFS1-Related disorder(Figure 1).
For more information on WFS1-Related Disorders, please contact Dr. Urano at urano@wustl.edu
There are currently no drug therapies or cures that exist for Wolfram Syndrome. As a result, more than 60% of Wolfram patients die before age 40.
Wolfram syndrome and WFS1-related disorders
| Less Severe | Varying Severity | More Severe |
|---|---|---|
| WFS1-related disorder | Wolfram Syndrome | WFS1-related disorder |
| 1+ pathogenic WFS1 mutation | 2 pathogenic WFS1 or CISD2 mutations | 1+ pathogenic WFS1 mutation |
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Affected individuals have one or more of the following symptoms:
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Varying severity and symptomatology depending on mutations:
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Neonatal presentation, Hattersley & Urano, 2017
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Why Research Wolfram Syndrome?
Researchers believe that finding treatments and a cure for Wolfram Syndrome may open doors for treating more common forms of diabetes and neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases.
It is crucial that we gain a complete understanding of the complexities of Wolfram Syndrome by performing rigorous research. This research will serve as the platform to discover and clinically test successful treatment options for Wolfram syndrome, with the potential to treat many more common diseases.
