Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), is a rare genetic disorder, causing diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders. It was first described in four siblings in 1938 by Dr. Don J. Wolfram, M.D. The disease affects the brain (especially the brain stem) and central nervous system.
There are two types of Wolfram syndrome with many overlapping features. The two types are differentiated by their genetic cause. Mutations in the WFS1 gene cause more than 90 percent of Wolfram syndrome type 1 cases whilst mutations in the CISD2 gene are responsible for the type 2 Wolfram syndrome.
It is inherited in an autosomal recessive pattern meaning both copies of the gene in each cell have mutations.
Wolfram syndrome is often fatal by mid-adulthood due to complications from the many features of the condition, such as health problems related to diabetes mellitus or neurological problems.
In the case of Wolfram syndrome type 1, Diabetes mellitus is typically the first symptom, usually diagnosed around age 6. Optic atrophy is often the next symptom to appear, usually around age 11. About 60 percent of people with Wolfram syndrome develop a neurological or psychiatric disorder, most commonly problems with balance and coordination (ataxia), typically beginning in early adulthood. Other neurological problems experienced by people with Wolfram syndrome include irregular breathing caused by the brain's inability to control breathing (central apnea), loss of the sense of smell, loss of the gag reflex, muscle spasms (myoclonus), seizures, reduced sensation in the lower extremities (peripheral neuropathy), and intellectual impairment. Psychiatric disorders associated with Wolfram syndrome include psychosis, episodes of severe depression, and impulsive and aggressive behavior.
In addition to the usual features of Wolfram syndrome, individuals with Wolfram syndrome type 2 have stomach or intestinal ulcers and excessive bleeding after an injury. The tendency to bleed excessively combined with the ulcers typically leads to abnormal bleeding in the gastrointestinal system. People with Wolfram syndrome type 2 do not develop diabetes insipidus.
Mutations in the WFS1 gene cause more than 90 percent of Wolfram syndrome type 1 cases. This gene provides instructions for producing a protein called wolframin that is thought to regulate the amount of calcium in cells. Within cells, wolframin is located in the membrane of a cell structure called the endoplasmic reticulum that is involved in protein production, processing, and transport. WFS1 gene mutations lead to the production of a wolframin protein that has reduced or absent function. As a result, calcium levels within cells are not regulated and the endoplasmic reticulum does not work correctly. When the endoplasmic reticulum does not have enough functional wolframin, the cell triggers its own cell death (apoptosis). The death of cells in the pancreas, specifically cells that make insulin (beta cells), causes diabetes mellitus in people with Wolfram syndrome. The gradual loss of cells along the optic nerve eventually leads to blindness in affected individuals. The death of cells in other body systems likely causes the various signs and symptoms of Wolfram syndrome type 1.
A certain mutation in the CISD2 gene was found to cause Wolfram syndrome type 2. The CISD2 gene provides instructions for making a protein that is located in the outer membrane of cell structures called mitochondria. The CISD2 gene mutation that causes Wolfram syndrome type 2 results in an abnormally small, nonfunctional CISD2 protein. As a result, mitochondria are not properly maintained, and they eventually break down. Since the mitochondria provide energy to cells, the loss of mitochondria results in decreased energy for cells. Cells that do not have enough energy to function will eventually die. Cells with high energy demands such as nerve cells in the brain, eye, or gastrointestinal tract are most susceptible to cell death due to reduced energy. It is unknown why people with CISD2 gene mutations have ulcers and bleeding problems in addition to the usual Wolfram syndrome features.
Diagnosis of WFS and WFS-related disorder is based on clinical findings and molecular genetic testing of WFS1, the only gene in which mutations are known to cause WFS1-related disorders. WFS1-related low-frequency sensorineural hearing loss (LFSNHL) is diagnosed based on audiologic findings and molecular genetic testing.
Life expectancy of people suffering from this syndrome is about 30 years.