Diabetes is a common condition that affects the way the body uses blood sugar or blood glucose.
Although rare, some cases of diabetes can have a genetic component.
The Wolfram syndrome is one such case. Below, we discuss Wolfram syndrome and its relationship with diabetes.
What is Wolfram syndrome?
Wolfram syndrome is a serious but rare genetic disorder that affects different organs and systems in a patient’s body.
The condition may cause a wide range of symptoms and complications that lead to the premature death of the patient. The estimated prevalence of Wolfram syndrome is one in 100,000 people.
The symptoms of Wolfram syndrome often depend on the type of the condition, i.e., whether a patient has Wolfram type 1 or type 2.
Wolfram type 1 is also referred to as DIDMOAD syndrome, an acronym based on the main symptoms:
- Diabetes insipidus – a disorder that causes an imbalance of fluids in the body. Patients with this rare condition produce large amounts of urine and often feel thirsty
- Juvenile-onset diabetes mellitus – a condition wherein a child’s body doesn’t produce insulin; it is also known as insulin-dependent diabetes mellitus.
- Gradual bilateral optic atrophy-caused vision loss – a condition that affects the optic nerve that carries impulses from the eyes to the patient’s brain. Optic atrophy is not a disease on its own but is usually a symptom of a more serious medical disorder.
- Deafness – total or partial inability to hear sounds. Loss of hearing usually starts in adolescence. First, it affects higher frequencies and gradually worsens. A patient may develop total sensorineural deafness eventually.
Numbers show most patients (65%) with Wolfram syndrome will experience all the abovementioned symptoms, but others may develop related health problems only.
Patients with Wolfram type 1 could also experience the following symptoms:
- Abnormalities with the urinary tract such as bladder dysfunction
- Cerebellar ataxia (balance and coordination problems)
- Loss of gag reflex
- Losing sense of smell
- Gastrointestinal problems
- Myoclonus i.e., muscle spasms
- Peripheral neuropathy (reduced sensation in certain areas of the body)
- Hypogonadism (in men, low testosterone)
- Intellectual disability
- Central respiratory failure and central apnea (breathing irregularity due to reduced ability by the brain to regulate breathing)
- Aggressiveness or impulsive behavior
Persons with Wolfram type 2 condition may experience all symptoms associated with Wolfram type 1, but they may also develop:
- Ulcers in the intestines or stomach
- Excessive bleeding after injuries
Wolfram syndrome is a genetic disorder, but there’s still a lot to learn about it and why it happens. Mutations of certain genes lead to the development of this disorder.
About 90% of Wolfram syndrome type 1 cases occur due to the gene WFS1 mutation. This particular gene encodes a protein called wolframin, which is vital for the adequate function of the area of the cell that participates in the production of protein and its transport and processing.
This area is called the endoplasmic reticulum (ER). The ER dysfunction contributes to a wide range of complications linked with this condition. Wolframin is also necessary for the regulation and homeostasis of cytosolic calcium.
Calcium homeostasis is necessary for proper cellular function. When mutations develop on the WFS1 gene, wolframin becomes unable to do its “job.”
This leads to apoptosis, cell death, or self-destruction. When these cells die, the consequences are felt in different organs, and symptoms of Wolfram syndrome develop.
It is useful to mention homozygous missense mutation in the WFS1 gene is less frequently observed in patients with this condition.
As far as Wolfram syndrome type 2 is concerned, the main cause is a variation in the gene CISD2. The precise function of the CISD2 gene is unclear.
The theory is that the CISD2 gene functions to provide instruction for producing a protein found in the mitochondria’s outer membrane. In other words, CISD2 could be important for maintaining the normal function of mitochondria.
When we’re discussing the cause of the Wolfram syndrome, it’s also useful to mention in some cases, variations in mitochondrial DNA are the culprit. Mitochondrial DNA mutation is a rare but possible cause of Wolfram syndrome.
Further studies are necessary to evaluate these and potential novel mutation cases linked to this disease and the genotype-phenotype correlation.
Diagnosis of this condition requires genetic analysis. The doctor may order this analysis in the presence of symptoms such as childhood diabetes and congenital cataract.
Considering Wolfram syndrome is a genetic and progressive disease, no cure would eliminate it entirely. Also, there is no treatment to stop the disease progression.
That said, some treatments can help decrease the intensity of symptoms associated with this condition and improve a patient’s quality of life.
Some of these treatments include:
- Oral or nasal desmopressin to manage diabetes insipidus
- Magnifying glasses and supportive aids to treat visual loss
- Cochlear implants or hearing aids for sensorineural hearing loss
- Antibiotics to treat urinary tract infection
Wolfram patients should go to checkups regularly because monitoring is crucial here. More precisely, a multidisciplinary team of health professionals can help improve a patient’s quality of life.
Living with Wolfram syndrome can be challenging, which is why a patient may need psychological support, and so do their caregivers.
Many clinical trials are still ongoing, and their main purpose is to strive and repurpose medications for other conditions and evaluate their impact on problems with the endoplasmic reticulum.
The link between diabetes and Wolfram syndrome
Diabetes mellitus is the first symptom of Wolfram syndrome. However, it’s not the same as type 1 or type 2 diabetes.
In this condition, diabetes mellitus has a strictly genetic cause. Besides excessive thirst or urination, diabetes mellitus can cause other symptoms to Wolfram syndrome patients if not treated properly. These symptoms may range from increased appetite and blurred vision to weight loss and coma.
Studies show defective insulin secretion could contribute to the early onset of diabetes in patients with Wolfram syndrome. Interestingly, progression of diabetes toward complete insulin deficiency tends to occur at a slower rate in the Wolfram syndrome than in patients with type 1 diabetes.
For that reason, clinicians may suspect a patient has this genetic disorder if diabetes develops without diabetic ketoacidosis in preschool children with a long remission period and negative autoantibodies.
While some research says gene mutations that cause Wolfram syndrome can actually protect from classic diabetes-related complications, other pieces of evidence show otherwise.
In one study, the overall incidence of neuropathy, diabetic retinopathy, and nephropathy in patients with this condition isn’t lower than the incidence of these complications in persons with autoimmune type 1 diabetes.
As seen above, gene mutations associated with this condition act on the endoplasmic reticulum (ER). This is important because ER stress can contribute to the pathogenesis of diabetes.
The connection between the Wolfram syndrome and diabetes becomes more apparent if we bear in mind WFS1 expression has a major influence on the function of the pancreas.
As a reminder, insulin is produced in the pancreas. You see, wolframin (WFS1 protein) is highly expressed in pancreatic cells, and it works to fold proinsulin (a protein precursor of insulin) into a mature hormone. This hormone regulates blood glucose levels, as you already know.
Basically, WFS1 regulates the secretion and regulation of insulin and the survival of beta cells. Deficiency in wolframin and mutations of the WFS1 gene can lead to the loss of these beta cells and thereby impair glucose tolerance and progression of the cell cycle.
Wolfram syndrome is a rare and genetic disorder with serious symptoms and severe neurological disabilities. The first symptom that usually occurs is diabetes.
Unlike “regular” types of diabetes, in persons with Wolfram syndrome, the genetic mutations cause inadequate glucose balance and impaired insulin function.
While there is no cure for Wolfram syndrome, some treatment options can help manage symptoms and improve a patient’s quality of life.