Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by juvenile-onset diabetes, optic nerve atrophy, and neurodegeneration.
Common Manifestations And Natural History
Diabetes mellitus is typically the first manifestation, usually diagnosed around age 6. Optic nerve atrophy is often the next manifestation, usually diagnosed around age 11. The first signs of optic nerve atrophy are loss of color vision and peripheral vision. Diabetes insipidus is one of the common symptoms, and approximately 70 percent of patients with Wolfram syndrome have central diabetes insipidus. 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. One of the major clinical challenges for Wolfram syndrome patients is a urinary tract problem. 60 to 90 percent of patients have urinary tract problems, including obstruction of the ducts between the kidneys and bladder, high-capacity atonal bladder, disrupted urination, bladder sphincter dyssynergia, and difficulty controlling the flow of urine. About 60 percent of patients with Wolfram syndrome develop neurological manifestations, most commonly problems with balance and coordination (ataxia), typically beginning in early adulthood. Brain stem atrophy is a prominent feature.
Wolfram syndrome was initially categorized as a mitochondrial disease due to the symptoms and several reports reporting the mitochondrial mutations. However, it has been now established that Wolfram syndrome is a prototype of endoplasmic reticulum (ER) disease. Endoplasmic reticulum 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 suggest that pancreatic b cells and neurons are particularly sensitive to ER dysfunction. In Wolfram syndrome, pancreatic b 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, suggesting that ER dysfunction is a major pathogenic component of Wolfram syndrome. In Wolfram syndrome, WFS1 mutations lead to elevated ER stress levels, pancreatic cell dysfunction, and initiation of ER stress-associated cell death. A small portion of patients have 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.