Wolfram syndrome is a rare and serious autosomal recessive neurodegenerative disease. Wolfram syndrome is also known by the abbreviation “DIDMOAD” because of four fairly classic common symptoms (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). Diagnosing this rare condition is often not an easy task. In most patients, it takes years before a doctor confirms the diagnosis of Wolfram Syndrome. The morbidity and mortality of this syndrome are high and there is no immediate treatment. J. Don Wolfram, an American physician, first described Wolfram syndrome (WFS) in 1938.
- Epidemiology Wolfram syndrome
- Causes, heredity and types of neurodegenerative disease
- Symptoms of neurodegenerative disease
- Diagnosis
- Therapy
- Prognosis condition
Epidemiology Wolfram syndrome
The estimated prevalence of Wolfram syndrome type 1 is 1 in 500,000 patients worldwide. About 200 cases have been described in the scientific literature. Only a few Jordanian families have Wolfram syndrome type 2. Wolfram syndrome affects men and women equally.
Causes, heredity and types of neurodegenerative disease
There are two types of Wolfram syndrome with many overlapping symptoms. The difference lies in their genetic cause. In addition to the usual symptoms of Wolfram syndrome, patients with Wolfram syndrome type 2 have stomach or duodenal ulcers and bleed excessively after an injury. This causes abnormal bleeding in the gastrointestinal tract. Patients with Wolfram syndrome type 2 do not develop diabetes insipidus (condition with symptoms of excessive thirst (polydipsia), frequent urination and large amounts of urination). Some patients with Wolfram syndrome are affected by Wolfram syndrome from an unknown cause.
Wolfram Syndrome Type 1 (WFS1)
In more than 90% of all patients, mutations in the WFS1 gene are the cause of type Wolfram syndrome 1. This gene produces the protein “Wolframin” that regulates the amount of calcium in the cells. With WFS1 gene mutations there is too little or no production of the wolframin protein. The Wolframin protein is found in many different tissues, such as the pancreas, brain, heart, bones, muscles, lungs, liver and kidneys. For example, without proper Wolframin function, the production of the hormone insulin in the pancreas is not possible, causing people to develop diabetes mellitus. Wolframin is also important for the eyes. Because the optic nerve slowly dies without Wolframin protein, affected patients become completely blind. Cell death probably also causes various signs and symptoms of Wolfram syndrome type 1 elsewhere in the body.
Wolfram Syndrome Type 2 (WFS2)
The CISD2 gene mutation causes WFS2. This gene ensures the production of a protein that is located in the outer membrane of cell structures (mitochondria). Mitochondria ensure energy production from nutrients. The gene mutation creates an abnormally small, non-functional CISD2 protein. The mitochondria then supply less energy to the cells, causing them to die. Cells with high energy requirements such as nerve cells in the brain, eye or gastrointestinal tract are most susceptible to cell death due to reduced energy. It is not known why patients with CISD2 gene mutations have ulcers and blood problems in addition to the usual Wolfram Syndrome symptoms.
Symptoms of neurodegenerative disease
Wolfram syndrome is a condition that affects many parts of the body. A whole range of symptoms is possible. Usually, but not always, the following four main symptoms are present:
- diabetes insipidus,
- diabetes mellitus,
- optic atrophy and
- deafness.
In patients with Wolfram syndrome, the pituitary gland often does not work properly, resulting in the excretion of large amounts of urine in combination with a constant great thirst , which, for example, results in renewed bed-wetting. In other words, pituitary dysfunction leads to diabetes inspididus, which occurs in approximately 70% of patients with Wolfram syndrome. Pituitary dysfunction causes hypogonadism in men. The lack of testosterone, which occurs with hypogonadism (insufficient development of gonads), hinders growth and sexual development.
High blood sugar levels (the medical term for this is “hyperglycemia”) due to a deficiency of the hormone insulin (diabetes mellitus) is usually the first symptom that appears in children between the ages of 5 and 15.
Ophthalmologically, there are many symptoms that start around the age of 11. The patient has progressive vision loss due to degeneration of the optic nerves . This optic atrophy is usually bilateral (in both eyes) with patients usually completely blind within 10 years of diagnosis. The iris in the eye reacts slowly, which is often the first demonstrable symptom of the WFS. In addition, color blindness occurs in WFS patients. Less frequent eye abnormalities related to Wolfram syndrome include nystagmus (uncontrollable random eye tremors), cataract, macular degeneration, retinopathy (retinal disease), and glaucoma.
The syndrome also affects hearing. Approximately 65% of patients with Wolfram syndrome suffer from sensorineural hearing loss that varies in severity. This usually starts at birth with no or minor hearing loss that worsens in adolescence, causing a loss of high tones . This is progressive. Some people are completely deaf from birth.
In addition, about 60 to 90% of all patients with Wolfram syndrome develop urinary tract problems . Some examples of urinary tract problems include blocked ureters between the kidneys and bladder (ureters), a large bladder that does not empty normally, improper urination (lack of proper cooperation between the bladder and sphincter) and incontinence.
Finally, approximately 60% of patients with Wolfram syndrome develop a neurological or psychiatric condition such as coordination and balance problems (ataxia). These often start in young adulthood. Mental disorders associated with Wolfram syndrome include psychosis (loss of reality with delusions and hallucinations), episodes of major depression, and impulsive and aggressive behavior.
Various other symptoms have also been reported:
- anorexia,
- vomit,
- chronic fatigue,
- convulsions (convulsions: uncontrollable physical movements and changes in consciousness),
- gastrointestinal disorders such as fecal incontinence (involuntary loss of bowel movements) and stomach and/or duodenal ulcers,
- dementia,
- diarrhea,
- epilepsy
- jaundice,
- no sense of smell (anosmia),
- neutropenia (decreased number of neutrophils (type of white blood cells)): This condition often makes the patient more susceptible to infections, fungi and bacteria,
- kidney abnormalities: This results from the pressure of urinary retention (inability to (completely) empty the bladder),
- irregular breathing: This is because the brain is unable to balance breathing sufficiently (central apnea),
- hypersensitive to high environmental temperatures: This has been shown by excessive sweating (hyperhidrosis), hyperthermia (abnormally high body temperature) or heat-induced metabolic shock,
- sideroblastic anemia: The bone marrow produces fewer red blood cells, leading to breathing problems
- swallowing problems,
- muscle spasms (myoclonus),
- Thrombocytopenia: This causes a patient to experience excessive bleeding in the skin or mucous membranes,
- enlargement of the liver (hepatomegaly) and spleen (splenomegaly),
- reduced sensation in the lower limbs (peripheral neuropathy: damage to peripheral nerves with pain, weakness, numbness and tingling especially in the hands and feet) and
- mental disability.
Diagnosis
The diagnosis is not easy. Doctors usually do not know about this syndrome. In addition, the disease is progressive and degenerative, so the mild symptoms are initially not linked to Wolfram syndrome.
Therapy
There is no proven effective treatment available. Therefore, doctors try to control the complications of Wolfram syndrome, such as diabetes mellitus and diabetes insipidus. Naturally, the treatment is multidisciplinary and addresses the different aspects of this condition. People with hearing loss often benefit from hearing aids. For visually impaired and blind people, there are all kinds of aids, adjustments, guidance techniques and tips that the patient obtains through blind aftercare work.
Prognosis condition
Patients often die in middle age from complications of the condition’s many symptoms, such as health problems related to diabetes mellitus or neurological problems. The life expectancy of patients suffering from this syndrome is approximately 30 years. However, this is linked to the severity of the symptoms.
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