Wolfram Syndrome

What is Wolfram syndrome?

Wolfram syndrome is a rare genetic disease. It’s a progressive, neurodegenerative disorder that damages your brain and other tissues in your body. A series of symptoms usually appear during childhood and into adulthood. Diabetes and vision changes before age 15 are usually the first symptoms. Eventually, impaired brain function can lead to early death.

What are the types of Wolfram syndrome?

Healthcare providers have identified two genes involved in Wolfram syndrome. Genes are sequences of DNA that carry genetic information.

People with Wolfram syndrome have changes (mutations) in their genes. Healthcare providers classify Wolfram syndrome based on the affected genes:

• Wolfram syndrome type 1 is the result of a mutation of the WFS1 gene.
• Wolfram syndrome type 2 is the result of a mutation of the WFS2 (CISD2) gene.

How is Wolfram syndrome inherited?

To pass on Wolfram syndrome, usually both biological parents must carry the same gene mutation. But in some cases, a person can inherit Wolfram syndrome type 1 when only one parent has the mutation.

How common is Wolfram syndrome?

Because Wolfram syndrome is so rare, healthcare providers don’t know exactly how often it occurs. One study estimated that Wolfram syndrome affects 1 in 770,000 people in the United Kingdom. Studies from other countries suggest it may be more common in areas where people who are close relatives marry and have children.

Wolfram syndrome type 2 is extremely rare. Healthcare providers have reported cases in only a few families worldwide.

What are the four most common features of Wolfram syndrome type 1?

Symptoms of Wolfram syndrome type 1 may vary from person to person. But often, they appear in a predictable order during childhood and adolescence. This is the typical sequence and average age that symptoms appear:

1. Diabetes mellitus (age 6): Diabetes mellitus is a problem with your body’s ability to absorb sugar (glucose) from the food you eat. Normally, your pancreas makes insulin, which helps your cells absorb sugars (glucose) from your bloodstream. If you don’t make enough insulin or if your cells don’t respond to insulin, your blood sugar can rise too high. Wolfram syndrome-related diabetes is similar to Type 1 diabetes, but it’s not an autoimmune disease. Diabetes symptoms include frequent urination, increased thirst, blurred vision and unexplained weight loss.
2. Optic atrophy (age 11): Optic atrophy is the degeneration of your optic nerve, which carries signals from your eyes to your brain. Symptoms include blurred, dulled or reduced peripheral (side) vision.
3. Sensorineural hearing loss (age 13): Sensorineural hearing loss occurs due to damage in your inner ear. This type of hearing loss usually gets worse as you get older and can lead to deafness.
4. Diabetes insipidus (age 14): Diabetes insipidus isn’t related to diabetes mellitus. It’s an issue with the production of an antidiuretic hormone that controls the amount of water in your urine (pee). People with diabetes insipidus have large amounts of watery urine. This excess urination can cause dehydration, electrolyte disturbance, weakness, dry mouth and constipation.

An outdated name for Wolfram syndrome is DIDMOAD. This acronym incorporates the primary symptoms:

• Diabetes insipidus (DI).
• Diabetes mellitus (DM).
• Optic atrophy (OA).
• Deafness (D).

What are the other symptoms of Wolfram syndrome type 1?

Less common symptoms include:

• Hormone disorders: Hypopituitarism, low sex drive (hypogonadism), growth delays and delayed start of menstrual periods.
• Neurological symptoms: Problems with movement and coordination (ataxia), dementia, headaches, central sleep apnea, epilepsy and decreased sense of taste and smell.
• Psychiatric conditions: Depression, anxiety, panic attacks, mood swings and aggressive behavior.
• Urinary tract abnormalities: Urinary tract infections, urinary incontinence and incomplete emptying of your bladder.

What are the symptoms of Wolfram syndrome type 2?

Symptoms of Wolfram syndrome type 2 are similar to type 1, but may also include:

• Abnormal bleeding.
• Gastrointestinal ulcers.

People with Wolfram syndrome type 2 usually don’t have diabetes insipidus or psychiatric conditions.

What causes Wolfram syndrome?

Wolfram syndrome occurs when biological parents pass on changes (mutations) in the WFS1 or WFS2 (CISD2) genes to their children.

How is Wolfram syndrome diagnosed?

Diagnosing Wolfram syndrome can be challenging. Healthcare providers may diagnose individual conditions but not make the connection between them. Often, diagnosis occurs after multiple symptoms develop.

If your provider suspects Wolfram syndrome, they’ll recommend genetic testing. This test detects mutations in the WFS1 and WFS2 (CISD2) genes and can confirm your diagnosis.

How is Wolfram syndrome treated?

Currently, there aren’t any standard treatments to stop or slow the progression of Wolfram syndrome. Treatment focuses on managing related symptoms. For example, healthcare providers treat diabetes mellitus with insulin to help manage blood sugar levels. Hearing aids can help people with hearing loss.

Are other treatments under investigation?

Researchers are studying therapies that may improve the outlook for people with Wolfram syndrome. Leading treatment strategies include:

• Drugs to reduce cell damage caused by disruption of proteins.
• Gene therapy to repair or replace mutated WFS1 and WFS2 (CISD2) genes.
• Regenerative therapy to heal or replace damaged tissues.

Some treatments are now available through clinical trials. Others are still in development. Talk to your healthcare provider about emerging treatments and whether they might be an option for you or your child.

Can I prevent Wolfram syndrome?

You can’t prevent genetic conditions such as Wolfram syndrome.

Is Wolfram syndrome fatal?

People with Wolfram syndrome have a poor prognosis. In one study of 45 patients, life expectancy ranged from 25 to 49 years with an average of 30. The most common cause of death was due to deterioration of the brainstem that controls vital functions like breathing and heart rate.

Improved diagnosis and management and the prospect of new therapies are improving the outlook.

When should I talk to a healthcare provider about genetic testing?

If you have a family history of Wolfram syndrome, talk to your provider about genetic testing. With a simple blood or saliva test, you can:

• Determine your risk of having a child with the disorder.
• Learn whether your child has Wolfram syndrome before they develop symptoms.

A note from Cleveland Clinic

Although there’s currently no cure for Wolfram syndrome, research and clinical trials are uncovering new potential treatments. If you or a family member have Wolfram syndrome, ask your healthcare provider about clinical trials. Coping with a rare diagnosis like Wolfram syndrome can be difficult. Although it’s a rare condition, you’re never alone. Ask your provider for help finding the support and resources you need — you may be able to connect with others affected by this condition and greatly benefit from that support.