Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study

Background

Common Manifestations and Natural History Wolfram syndrome is an autosomal recessive disorder characterized by juvenile onset diabetes, optic nerve atrophy, and neurodegeneration. The common manifestations of Wolfram syndrome include: diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. Diabetes mellitus is typically the first manifestation, usually diagnosed around age 6. Optic nerve atrophy, marked by loss of color vision and peripheral vision, follows around age 11. Central diabetes insipidus is another common manifestation, affecting approximately 70 percent of Wolfram. Around 65 percent of patients develop sensorineural deafness that can range in severity from deafness beginning at birth to mild hearing loss beginning in adolescence that worsens over time. Urinary tract problems are another major clinical challenge for Wolfram syndrome patients affecting 60 to 90 percent of this population. These problems include obstruction of the ducts between the kidneys and bladder, high-capacity atonal bladder, disrupted urination, bladder sphincter dyssynergia, and difficulty controlling urine flow. About 60 percent of patients with Wolfram syndrome develop neurological manifestations, most commonly presenting as problems with balance and coordination (ataxia) beginning in early adulthood. Brain stem atrophy is also a prominent feature that often results in death secondary to central apnea.

Classification According to the draft International Classification of Diseases (ICD-11), Wolfram Syndrome is categorized as rare specified diabetes mellitus (subcategory 5A16.1, Wolfram Syndrome). There are no classifications or staging systems employed after diagnosis.

Etiology It has now been established that Wolfram syndrome is a prototype of endoplasmic reticulum (ER) disease. The ER is a membrane network within our cells that is involved in protein synthesis, calcium storage, redox regulation, steroid synthesis, cell signaling, and cell death. Given the many vital and complex functions of the ER, there is little wonder that its failure can trigger a range of diseases. Previous studies have shown that pancreatic beta cells and neurons are particularly sensitive to ER dysfunction, likely due to their high rates of protein synthesis. In Wolfram syndrome, pancreatic beta cells and neuronal cells are selectively destroyed as a consequence of mutations in the WFS1 gene. This gene encodes a transmembrane protein localized to the ER and ER dysfunction is a major pathogenic component of Wolfram syndrome. In Wolfram syndrome, WFS1 mutations lead to elevated ER stress levels, pancreatic beta cell dysfunction, and the initiation of ER stress-associated cell death. A small portion of patients has mutations in the WFS2 (CISD2) gene. WFS2 also encodes a transmembrane protein localized to the ER. In patients with WFS2 mutations, diabetes mellitus and hearing impairment are reported. Their clinical phenotype differs from patients carrying WFS1 mutations for the absence of diabetes insipidus and for the presence of upper intestinal ulcers and defective platelet aggregation, suggesting that there are different and overlapping functions of WFS1 and WFS2.

Rationale Wolfram syndrome is a neurodegenerative disorder mediated by ER stress, and characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, and motor, sensory and autonomic nervous system disruption. The progressive loss of neuronal function is due to the neuronal cell death. The prognosis of this syndrome is poor as most patients die prematurely with severe neurological disabilities such as bulbar dysfunction and organic brain syndrome, with the median age at death being 30 years (range, 25-49 years), usually from respiratory failure as a result of brain stem atrophy. Imaging and post mortem studies have shown diffuse neurodegenerative changes in the brain. The only available treatments ameliorate the symptoms of the individual components of the disease, but do not target the underlying cause and are therefore unable to prevent progression of the condition, hence both its debilitating and fatal outcome. There are no effective treatments for Wolfram Syndrome, either in terms of authorized medicinal products in this indication or in terms of commonly used treatments not subject to marketing authorization. The use of careful clinical monitoring and supportive care do not treat the condition itself and act only to lessen the debilitating consequences. Further, although agents are approved for the individual components of Wolfram Syndrome, none of these therapies are able to prevent the continued deterioration in the patient's conditions as they do not address the underlying cause. Thus, there is an urgent need to understand the cause of the disease, identify biomarkers, and develop treatments targeting the underlying cause to stop its progression. To fulfill these unmet medical needs, we will maintain a registry of patients with Wolfram syndrome.