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 are the key characteristics 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.
What are the causes of 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 symptoms of Wolfram Syndrome?
The symptoms and speed of progression of Wolfman syndrome can vary considerably between patients. The symptoms of diabetes mellitus, optic atrophy, diabetes insipidus and hearing loss can appear at different ages and progress at different rates.
Typically, the first symptoms to appear are diabetes mellitus and optic atrophy in the first decade of life.
Less common symptoms include:
- Hormone disorders: which can cause growth delays and delay the start of menstruation.
- Neurological symptoms: such as loss of balance, sudden muscle jerks, loss of taste and smell, and breathing problems.
- Psychiatric conditions: such as depression, anxiety, panic attacks, mood swings and aggressive behaviour.
- Urinary tract problems: such as loss of bladder function (which can cause bedwetting, the need to pass urine frequently and loss of bladder control) or urinary tract infections.
- Chronic fatigue: a progressive decline in physical stamina as the condition progresses.
- Gastrointestinal problems: that can result in constipation or diarrhoea.
- People with Wolfram syndrome type 2 may also experience abnormal bleeding and gastrointestinal ulcers, but they do not usually develop diabetes insipidus or psychiatric conditions.
How is vision affected in individuals with Wolfram syndrome?
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.
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 is the latest research into Wolfram syndrome?
A major focus of Wolfram syndrome research is to develop new treatments that can stop or slow down the progression of symptoms, including loss of vision. Researchers are investigating treatment strategies, including:
- Drugs that can prevent cell damage or death.
- Gene therapy to repair or replace the faulty gene.
- Regenerative therapy to heal or replace damaged tissues.
Some of these potential treatments may be available through clinical trials, but others are still in the early stages of development. The TREAT Wolfram trial is currently exploring whether treatment with an oral drug, sodium valproate, can slow down or prevent vision loss and neurological problems in Wolfram syndrome.
Wolfram syndrome clinical trials
You could play an important part in eye research by participating in a clinical research study that may benefit many people. You could even help shape clinical research by becoming more actively involved and having a say. Patients, carer, or anyone with an interest can help.
If you wish to join a trial, discussing this with your doctor or clinical team is always best.
Last Updated November 2023
Approved by Professor Patrick Yu-Wai-Man, BMedSci, MBBS, PhD, FRCPath, FRCOphth, Professor of Ophthalmology and Honorary Consultant Ophthalmologist, University of Cambridge and Moorfields Eye Hospital and Xuehao Cui from University of Cambridge.
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