Wolfram syndrome

Wolfram syndrome
Classification and external resources
Photographic image of the patient right eye showing optic atrophy without diabetic retinopathy; from Manaviat et al., 2009[1]
OMIM	222300
DiseasesDB	3787
MeSH	D014929

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.^[2][3] The disease affects the brain (especially the brainstem) and central nervous system.

Causes

It is thought to be caused by both a malfunction of the mitochondria and of myelination, the latter in effect similar to multiple sclerosis. It may have autosomal recessive or dominant or mitochondrial inheritance depending on the genes involved.

Three genetic forms have been described: Wolfram Syndrome 1 (WFS1),^[4] Wolfram Syndrome 2 (WFS2)^[5] and a possible mitochondrial syndrome.^[6]

WFS1

The WFS1 or wolframin gene^[7] provides instructions for making the wolframin protein. The WFS1 gene is active in cells throughout the body, with strong activity in the heart, brain, lungs, inner ear, and pancreas. The pancreas provides enzymes that help digest food, and it also produces the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy.

Within cells, wolframin is located in a structure called the endoplasmic reticulum. Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape to function properly. The endoplasmic reticulum also helps transport proteins, fats, and other materials to specific sites within the cell or to the cell surface. The function of wolframin is unknown. Based on its location in the endoplasmic reticulum, however, it may play a role in protein folding or cellular transport. In the pancreas, wolframin may help fold a protein precursor of insulin (called proinsulin) into the mature hormone that controls blood glucose levels. Research findings also suggest that wolframin may help maintain the correct cellular level of charged calcium atoms (calcium ions) by controlling how much is stored in the endoplasmic reticulum. In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing.

More than 30 WFS1 mutations have been identified in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA6. Individuals with DFNA6 deafness cannot hear low tones (low-frequency sounds), such as a tuba or the "m" in moon. DFNA6 hearing loss is unlike most forms of nonsyndromic deafness that affect high tones (high-frequency sounds), such as birds chirping, or all frequencies of sound. Most WFS1 mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. One mutation deletes an amino acid from wolframin. WFS1 mutations probably alter the 3-dimensional shape of wolframin, which could affect its function. Because the function of wolframin is unknown, however, it is unclear how WFS1 mutations cause hearing loss. Some researchers suggest that altered wolframin disturbs the balance of charged particles in the inner ear, which interferes with the hearing process.

Other disorders - caused by mutations in the WFS1 gene

Mutations in the WFS1 gene cause Wolfram syndrome, which is also known by the acronym DIDMOAD. This syndrome is characterised by childhood-onset diabetes mellitus (DM), which results from the improper control of glucose due to the lack of insulin; a gradual loss of vision caused by optic atrophy (OA), in which the nerve that connects the eye to the brain wastes away; and deafness (D). This syndrome can sometimes cause diabetes insipidus (DI), a condition in which the kidneys cannot conserve water. Other complications that affect the bladder and nervous system may also occur.

Researchers have identified more than 100 WFS1 mutations that cause Wolfram syndrome. Some mutations delete or insert DNA from the WFS1 gene. As a result, little or no wolframin is present in cells. Other mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. These mutations appear to reduce wolframin activity dramatically. Researchers suggest that the loss of wolframin disrupts the production of insulin, which leads to poor glucose control and diabetes mellitus. It is unclear how WFS1 mutations lead to other features of Wolfram syndrome.

WFS2

The dysfunction of the CISD2 gene can cause WFS2.^[8]

Treatment

There is no known direct treatment. Current treatment efforts focus on managing the complications of Wolfram syndrome, such as diabetes.

Prognosis

The first symptom is typically diabetes mellitus, which is usually diagnosed around the age of 6. The next symptom to appear is often optic atrophy, the wasting of optic nerves, around the age of 11. The first signs of this are loss of colour vision and peripheral vision. The condition worsens over time, and people with optic atrophy are usually blind within 8 years of the first symptoms.^[9] Life expectancy of people suffering from this syndrome is about 30 years.

Research

Research is ongoing via the Washington University Wolfram Study Group, supported by The Snow Foundation for Wolfram research.

See also

• WFS1
• Chromosome 4 disorders
• Nonsyndromic deafness
• List of rare diseases

References

External links

• Ellie White Foundation for Rare Genetic Disorders
• Snow Foundation
• Washington University in St. Louis Wolfram Study Group

Wikimedia Commons has media related to Wolfram syndrome.

• OMIM DIDMOAD search
• Genetics Home Reference WFS1