Wolfram syndrome

What is Wolfram syndrome?

Wolfram syndrome is a rare inherited disorder that causes sight loss and problems in other parts of the body. It used to be called DIDMOAD to indicate the main symptoms of Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness.

In 1938, Wolfram and Wagener were the first to report their discovery of juvenile diabetes and optic atrophy in four of eight siblings within a family.1 In 1995, Barrett, Bundey and Macleod provided a comprehensive description of the clinical characteristics of 45 patients with Wolfram syndrome, establishing a set of updated diagnostic criteria for the condition.2

Sight loss in Wolfram syndrome is caused by damage to the optic nerve (the specialised cable that carries visual signals from the eye to the brain). When the optic nerve is damaged, it becomes pale in colour (optic atrophy). The cells within the optic nerve that are affected in Wolfram syndrome are known as retinal ganglion cells. A person’s vision will gradually worsen as more of these cells are lost.

Wolfram syndrome is a rare genetic disorder. Estimates suggest it affects around 1 in 200,000 of the total UK population – that’s about 350 people in the UK.

What causes Wolfram syndrome?

Wolfram syndrome is an inherited condition, which means it is caused by irregular genes that are passed down through families. It can be inherited both as an autosomal recessive or dominant pattern.

In autosomal recessive Wolfram syndrome, two copies of the faulty gene (one inherited from each parent) are required to cause the disease. This means a child whose parents each have one copy of the faulty gene has a 25% chance of inheriting the condition, regardless of sex.

In autosomal dominant Wolfram syndrome, one faulty gene copy from one parent is sufficient to cause disease. There is a 50% chance that a child will inherit the faulty gene copy from the parent who is affected.

So far, faults in two different genes have been identified that cause Wolfram syndrome:

• Wolfram syndrome type 1 (which is much more common) is caused by faults in the gene WFS1.
• Wolfram syndrome type 2 is caused by faults in the gene CISD2. It is extremely rare and has only been reported in a few families worldwide.

The WSF1 gene contains the instructions for making a protein called wolframin, which is thought to play an important role in regulating the amount of calcium in cells and the function of mitochondria – the tiny batteries within our cells that produce energy.

A healthy calcium balance and sufficient energy production are essential for normal cell function and survival. The wolframin protein is found in many different body tissues, including the pancreas, brain, heart, bones, muscles, lungs, liver, and kidneys. Within cells, it is located in the membrane of a cell structure called the ‘endoplasmic reticulum’ – which works as a factory to produce proteins.

WSF1 gene faults lead to a reduction or absence in wolframin function – leading to disrupted calcium regulation and problems with the interaction between the endoplasmic reticulum and mitochondria, ultimately triggering cell death.

The CISD2 gene contains the instructions for making a protein found in the outer membrane of mitochondria. While the exact function of the CISD2 protein is unclear, it is thought to play a key role in the healthy functioning of mitochondria. The CISD2 gene fault that causes Wolfram syndrome type 2 leads to an abnormally small, non-functional CISD2 protein. As a result, the mitochondria do not work effectively and can fragment. Since the mitochondria play a crucial role in energy generation, cells struggle to produce enough energy to survive – and will eventually die.

Some people with Wolfram syndrome do not have an identified fault in the WFS1 or CISD2 gene. The cause of the condition in these patients is unknown – and it is likely there are more genes yet to be identified.

What are the signs and symptoms of Wolfram syndrome?

The key characteristics of Wolfram syndrome are:

• Diabetes insipidus: this is where the body struggles to concentrate the urine due to insufficient production of a hormone called vasopressin by the posterior pituitary gland at the base of the brain. As a result, a person will experience excessive thirst, frequent urination, and very dilute urine.
• Diabetes mellitus: this is where there is a problem with the body’s ability to absorb sugar (glucose) from food. The pancreas normally makes a hormone called insulin, which helps cells absorb glucose from the bloodstream. But if the body doesn’t produce sufficient insulin or the cells don’t respond, a person’s blood sugar can rise too high. Symptoms include frequent urination, increased thirst, blurred vision and unexplained weight loss.
• Optic atrophy: this is where the optic nerve – which transmits messages from the eye to the brain – becomes damaged and stops working. Symptoms include problems with colour perception and gradual loss of vision.
• Deafness: sensorineural hearing loss occurs due to damage to the inner ear. People will usually find it difficult to hear in a crowded room and experience problems hearing high-pitched sounds. This hearing loss will usually worsen over time and can lead to complete deafness.

However, not everyone with Wolfram syndrome will have all these symptoms, and the speed of progression varies from person to person. The two main symptoms are optic atrophy and diabetes mellitus.

Is Wolfram syndrome serious?

People with Wolfram syndrome start to lose their sight in early childhood, and almost all of them will develop severe sight impairment.

Someone affected with Wolfram syndrome will develop difficulties with colour perception and blurring of central vision. These vision problems will progress over time, eventually resulting in significant visual impairment.

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What are the treatments for Wolfram syndrome?

There is no cure for Wolfram syndrome or any treatments to stop or slow down disease progression. Treatment is focused on managing some of the symptoms, such as:

• Diabetes insipidus: can be treated with vasopressin in a nasal spray or tablets.
• Diabetes mellitus: treatment with insulin can help to manage high blood sugar levels.
• Deafness: hearing aids or cochlear implants can help some people with hearing loss.
• Urinary tract problems: these can be treated with medication and if needed, by inserting a catheter (a thin, flexible tube) into the bladder to drain away urine.
• Neurological problems: some of these problems can be treated with medication.

Unfortunately, there are currently no treatments that can stop or slow down sight loss in Wolfram syndrome. Affected individuals who are often also diabetic should have regular eye examinations. Some people may benefit from visual aids to address low vision, such as large print reading materials and high-contrast tablets or computer screens.

What research is there into Wolfram syndrome?

Fight for Sight's Research Strategy has pledged to spend over 20 million on pioneering eye research over the next five years.

If you're personally affected by Wolfram syndrome and are interested in fundraising to help us fund cutting-edge research in this area find out how to set up a family fund.