An Overview of Wolfram Syndrome

Wolfram syndrome is a rare and serious genetic medical condition affecting several different organ systems. It leads to premature death. Among its main complications are diabetes mellitus, diabetes insipidus, and vision and hearing symptoms. It is a progressive, neurological illness that usually begins in childhood and is estimated to affect approximately one person in 100,000. It was first described in the 1930s by Dr. Don Wolfram. Though the underlying cause of Wolfram syndrome can’t currently be treated, much can be done to manage the symptoms of the disease.

Symptoms

Wolfram syndrome is also sometimes known by an acronym, “DIDMOAD,” which is composed of some of the condition’s primary characteristics. These are:

• Diabetes Insipidus
• Diabetes Mellitus
• Optic Atrophy
• Deafness

The term “diabetes” originally meant “to pass through" came to be used as a term for a condition causing excessive creation of urine. When most people talk about diabetes, they mean a form of the disease called “diabetes mellitus.” Another medical condition, “diabetes insipidus” is much less common, and it can also cause the creation of excess urine. Diabetes mellitus and diabetes insipidus do not have the same cause, and most people with diabetes mellitus do not have diabetes insipidus. However, Wolfram syndrome is unusual in that the genetic problem causing the condition often eventually causes both diabetes mellitus and diabetes insipidus.

Diabetes mellitus is usually the first problem that occurs in Wolfram syndrome. Unlike type 1 or type 2 diabetes mellitus, diabetes from Wolfram syndrome is thought to come from a strictly genetic cause. In addition to excessive urination and excessive thirst, it can cause other symptoms if untreated, like:

• Increased appetite
• Blurred vision
• Weight loss
• Coma

Diabetes insipidus is a medical condition that causes excessive thirst and urination. In diabetes insipidus caused by Wolfram syndrome, part of the brain cannot release normal amounts of a hormone called vasopressin (also called antidiuretic hormone). This hormone is very important for regulating the amount of water in the body and controlling the concentration of various substances in the blood. When it is not present, the kidneys produce more urine than normal. This can lead to dehydration and other serious problems if not treated.

Atrophy (degeneration) of the optic nerve is another major concern. This nerve sends signals to the brain from the eye. Its degeneration leads to decreasing visual sharpness with loss of color vision and peripheral vision. These symptoms usually begin in childhood. Other eye problems, such as cataracts, can also occur. Most patients eventually go blind.

Hearing loss is one of the most common symptoms associated with Wolfram syndrome. Hearing loss usually begins in adolescence, first affecting the higher frequencies and then slowly worsening over time. This may ultimately lead to total deafness.

Not all of these symptoms affect everyone with Wolfram syndrome, though all are possibilities. For example, only about 70% of people with the syndrome develop diabetes insipidus.

Other Symptoms

In addition to “DIDMOAD,” Wolfram syndrome can cause other problems as well. Some of these may include:

• Urinary tract problems (such as incontinence and repeated urinary tract infections)
• Impaired smell and taste
• Problems with balance and coordination
• Problems regulating temperature
• Problems swallowing
• Nerve pain from peripheral neuropathy
• Seizures
• Severe depression or other psychiatric problems
• Fatigue
• Constipation and diarrhea
• Impaired growth
• Reproductive problems (like skipped periods and infertility)

Progressive damage to part of the brain that regulates respiration may eventually cause a person to stop breathing. This typically results in death before middle adulthood.

Causes

There is still a lot that researchers are learning about the genetics of Wolfram syndrome. In most cases, Wolfram syndrome seems to be an autosomal recessive condition. That means that an affected individual must receive an affected gene from their mother and father to have Wolfram syndrome.

Many cases of the syndrome are caused by a mutation in a gene called WFS1. This gene is inherited from the parents, as part of DNA. This mutation causes a problem in making a protein called wolframin. The protein is found in a part of cells called the endoplasmic reticulum, which plays a variety of roles. These include protein synthesis, calcium storage, and cell signaling.

The resulting problems with the endoplasmic reticulum seem to impact several different types of cells in the body. Some types of cells are more prone to damage than others. For example, the impaired wolframin seems to cause the death of a certain type of cell in the pancreas that normally makes the hormone insulin (called beta cells). This ultimately leads to the symptoms of diabetes mellitus, as the beta cells cannot produce the insulin needed to bring glucose out of the blood and into cells. Death and malfunction of cells in the brain and nervous system lead to many of the serious problems of Wolfram syndrome.

There is also another type of Wolfram syndrome that seems to be caused by another gene called CISD2. Less is known about this gene, but it may play a role in some similar pathways as the WFS1 gene.

Probability of Disease

People who have only one bad copy of the gene, called carriers, do not usually have symptoms. A full sibling of someone with Wolfram disease has a 25% chance of having the disease. A couple who has previously had a child with the disease has a 25% chance that their next child will also have Wolfram syndrome.

If someone in your family has Wolfram syndrome, you may find it helpful to meet with a genetic counselor as they can let you know what to expect in your particular situation. If Wolfram syndrome is a possibility, it is a good idea to get tested. Prenatal testing may also be helpful for some families.

Types

People with mutations in the WFS1 gene are sometimes described as having Wolfram syndrome 1. Those with the less common CISD2 mutation are sometimes described as having a slightly different version of the syndrome called Wolfram syndrome 2. People with Wolfram syndrome 2 tend to have the same optic nerve atrophy, diabetes mellitus, deafness and decreased lifespan as those with Wolfram syndrome 1, but they don’t usually have diabetes insipidus.

There are also people who have a mutation in the WFS1 gene but who don’t get most of the characteristic symptoms of Wolfram syndrome. For example, you might have hearing loss but none of the other features of the disease. This might be due to a different type of mutation in the WFS1 gene. You may have a WFS1 related disorder but not classic Wolfram syndrome.

Diagnosis

A patient’s medical history and clinical exam provide an important starting point for diagnosis. Blood tests (like tests for diabetes mellitus) can also provide clues about the organ systems involved. Imaging tests (like MRI) can give an idea of the level of damage to the brain and other systems.

You may be diagnosed with a component of Wolfram syndrome (like diabetes mellitus) before an overarching diagnosis is made. Since a condition like diabetes mellitus usually doesn’t arise from a genetic condition like Wolfram, it is easy to initially miss the diagnosis. Many people are first misdiagnosed with type I diabetes before being diagnosed with Wolfram syndrome.

However, it is important for clinicians to be thinking about the possibility of the disease. For example, a child who develops optic nerve atrophy after being diagnosed with diabetes mellitus needs to be checked for Wolfram syndrome. People known to have Wolfram syndrome in their family also need to be screened for the disease. It is important to get a diagnosis as soon as possible, to help provide supportive care.

To confirm a diagnosis of Wolfram syndrome, a specialist familiar with the disease should perform genetic testing.

Treatment

Unfortunately, Wolfram syndrome is a progressive disease, and we don’t currently have treatments that can stop that process. However, there are a number of treatments that can help reduce symptoms from the condition and help individuals lead fuller lives. For example:

• Insulin and other diabetes drugs, to treat diabetes mellitus
• Desmopressin (oral or intranasal) to treat diabetes insipidus
• Antibiotics for urinary tract infection
• Hearing aids or cochlear implants for hearing loss
• Supportive aids for visual loss, such as magnifying glasses

Support should also include regular monitoring by a multidisciplinary team of healthcare providers including specialists in the condition. This should include psychological support, including help for caregivers. Even with these supports, most patients with Wolfram syndrome die prematurely from neurological problems.

Though there currently aren’t any treatments that directly treat the disease, this may change in the future. Researchers are looking at repurposing drugs used for other conditions or developing new drugs to target these problems with the endoplasmic reticulum. Ultimately gene therapy may play a role in treating the disease. You can talk to your medical provider about clinical trials that may be available.

A Word From Verywell

It can be devastating to learn that you someone you care about has Wolfram syndrome. However, know that you aren’t alone. Even though Wolfram syndrome is a rare condition, it is easier than ever to network with other families dealing with the disease. Understanding more about the disease can help you feel empowered to make the best medical choices possible. Your team of healthcare providers will do their utmost to provide you with the support that you need.