Wolfram syndrome: what is it, symptoms, treatment, prognosis

What is Wolfram Syndrome?

Tungsten syndrome is a hereditary disease that is usually associated with childhood-onset insulin-dependent diabetes mellitus and progressive optic nerve atrophy. In addition, many patients with Wolfram syndrome also develop diabetes insipidus and sensorineural hearing loss. Another name for the syndrome is DIDMOAD (pronounced Didmoad, - the abbreviation stands for Diabetes Insipidus, Diabetes Mellitus - diabetes insipidus; Optic Atrophy - optic disc atrophy; Deafness - hearing loss). Most cases of Wolfram syndrome are caused by changes (mutations) in a gene WFS-1. Less serious mutations in a gene WFS-1 cause disorders associated with WFS1in which the victim has only some of the signs of Wolfram syndrome, such as sensorineural hearing loss without diabetes or other disorders.

Signs and symptoms

The symptoms and rate of progression of Wolfram syndrome can be very varied. The main symptoms of Wolfram syndrome (

diabetes, optic nerve atrophy, diabetes insipidus and hearing loss) can manifest at different ages and change at different rates. If some of these symptoms never appear, the patient's condition will be referred to as a disorder associated with WFS1.

Most patients with Wolfram syndrome develop insulin-dependent diabetes mellitus before the age of 16 (87%). Starch and sugar (carbohydrates) in the food we eat is usually converted by the digestive system into glucose, which circulates in the blood as one source of energy for bodily functions. A hormone produced by pancreas (insulin), allows muscle and fat cells to absorb glucose. In diabetes mellitus, the pancreas does not produce enough insulin, so cells cannot metabolize glucose normally, and blood sugar gets too high. With diabetes mellitus caused by the Wolfram gene, the patient needs daily injections of insulin to control blood sugar levels. Diabetes symptoms can include:

• frequent urination;
• excessive thirst;
• increased appetite;
• weight loss;
• blurred vision.

In addition, it is believed that almost all people with Wolfram syndrome have primary atrophy. optic nerve and subsequent visual impairment of varying severity before the age of 16 (80%). The optic nerve transmits visual information to the brain for processing. Loss of nerve fibers and / or their isolation (myelin) leads to color blindness and blurred vision, usually beginning in childhood and progressing with age, although some cases progress rapidly and others slowly.

Some patients with Wolfram syndrome also develop diabetes insipidus (42%). It is not related to diabetes or insulin. The only thing it has in common with diabetes is symptoms of excessive thirst and urination. This condition results in the discharge of large amounts of very watery urine and excessive thirst due to that the brain does not produce enough of the hormone (vasopressin) that causes the kidneys to keep water. Patients tend to drink large amounts of fluids and urinate very often. Other symptoms may include:

• dehydration;
• weakness;
• dry mouth;
• and sometimes constipation.

Symptoms can develop quickly if fluid loss is not constantly replenished.

Diabetes insipidus can be treated with hormone replacement therapy, the drug Desmopressin acetate.

Hearing loss is the fourth major symptom of Wolfram syndrome and occurs in about 48% of patients. This symptom can occur at any age and can be partial or complete. Hearing loss occurs due to the loss of perception of sound transmitted along the nerves (sensorineural). Symptoms may include loss of intensity or pitch, or loss of the ability to hear high tones.

Some of the following additional symptoms may develop:

• Urinary tract abnormalities (33%) - most often this is a problem associated with the fact that the bladder does not empty properly, so a person needs to empty frequently. This symptom can be caused by both advanced and complicated diabetes insipidus.
• Neurological symptoms such as bad odor, imbalance, clumsiness, unbalanced gait (ataxia) and central sleep apnea. In addition, brain imaging shows that patients with Wolfram syndrome have less volume brainstem and cerebellum, and smaller optic nerves than in patients without the syndrome Tungsten. These differences can increase over time.
• Psychiatric and behavioral problems such as depression, anxiety and fatigue, can occur in patients with Wolfram syndrome (26%). These symptoms can be associated with changes in the nervous system caused by Wolfram syndrome itself, or with the psychological and quality of life burdens caused by the consequences of the disease.
• Sleep disturbance can be a problem and can be caused by sleep apnea or waking up frequently to urinate.

Other problems that may arise:

• Decreased testosterone production (hypogonadism) in men (6%).
• Gastrointestinal disorders (5%), including constipation, trouble swallowing (dysphagia), suffocation, diarrhea.
• Bilateral opacity of the lens of the eye (cataract) (1%).
• Impaired body thermoregulation (eg, fever).

Causes

Wolfram syndrome is caused by mutations in WFS1 (most common) or WFS2 (CISD2) genes that are inherited in an autosomal recessive pattern in most affected individuals, although dominant forms of the disorder also exist.

Recessive genetic disorders occur when a person inherits two copies of an altered gene for the same trait, one from each parent. If a person inherits one normal gene and one gene for the disease, they will carry the disease but are usually asymptomatic. The risk for two carrier parents of passing on the altered gene and having a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents is 25%. The risk is the same for men and women.

Parents who are close relatives (blood relatives) are more likely than unrelated parents, have the same altered (mutated) gene, which increases the risk of having children with a recessive genetic disease.

Dominant genetic disorders occur when only one copy of an altered gene is needed to cause disease. The altered gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in an affected person. The risk of passing the altered gene from the affected parent to the offspring is 50% with every pregnancy. The risk is the same for men and women. In some people, the disease occurs due to a spontaneous (new) gene mutation that occurs in an egg or sperm cell. In such situations, the disorder is not inherited from the parents.

Affected populations

Because diabetes mellitus and optic nerve atrophy usually begin before the age of 16, Wolfram syndrome is usually diagnosed in childhood and adolescence. However, in some patients, the onset of key symptoms or genetic confirmation may occur much later. Wolfram syndrome affects men and women equally and is equally widespread throughout the world.

Symptomatic disorders

The following disorders have similar symptoms to some of the symptoms of Wolfram syndrome:

• Leber hereditary optic neuropathy (Leber optic atrophy) is a rare hereditary eye disorder characterized by a relatively slow, painless, and progressive loss of vision. Leber optic atrophy and optic atrophy in Wolfram syndrome may look the same and have the same symptoms. Leber's hereditary optic neuropathy can begin in one or both eyes, but usually both eyes are affected within six months. In most patients, vision loss is irreversible. Leber's hereditary optic neuropathy is a genetic disorder that results from a mutation in mitochondrial DNA inherited from the mother, or arises as a new sporadic mutation of mitochondrial DNA.
• Thiamine-dependent megaloblastic anemia - an autosomal recessive disorder with features that include megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Megaloblastic anemia - a blood disease characterized by anemicin which red blood cells are larger than normal, usually as a result of a folate deficiency or vitamin B-12. Sensorineural hearing loss and diabetes mellitus in this disease can look the same as hearing loss and diabetes in Wolfram syndrome.

Other disorders that can be confused with Wolfram syndrome include Alstrom's syndrome; Friedreich's ataxia; Kearns-Sayre syndrome; Lawrence-Moon syndrome; Refsum disease; autosomal dominant optic nerve atrophy; X-linked Charcot-Marie-Tooth disease 5 types; hearing loss, dystonia, optic neuropathy syndrome; mitochondrial DNA abnormalities and Bardet-Biedl syndrome.

Diagnostics

Wolfram syndrome is difficult to diagnose. In many cases, patients with this disorder and their doctors may not be aware that the various symptoms and complaints are related and indicate a specific disorder. Initially, attention may be focused on one symptom, usually diabetes mellitus, and its treatment. Other symptoms may appear later. Wolfram syndrome should be considered in anyone with diabetes mellitus and optic nerve atrophy; anyone with low-frequency sensorineural / sensorineural hearing loss; any person with diabetes mellitus or optic atrophy in addition to hearing loss, diabetes insipidus, bladder dysfunction or loss of smell, or a family member with the syndrome Tungsten.

Molecular genetic testing for mutations in genes is available to confirm the diagnosis. WFS1 and WFS2.

Standard treatments

Treatment for Wolfram syndrome is symptomatic and supportive. A multidisciplinary effort is required to manage various aspects of this condition. In the presence of diabetes mellitus, the patient needs insulin treatment. Diabetes insipidus is difficult to diagnose and may require treatment with intranasal or oral dDAVP (Desmopressin Acetate). Treating diabetes insipidus in Wolfram syndrome can be very difficult, as a person can also have diabetes and bladder dysfunction.

Hearing aids or cochlear implants, as well as other devices for those with hearing loss, may be helpful for people with hearing loss. All patients should be closely monitored by an eye doctor (ophthalmologist) and may require glasses or other visually impaired devices. Occupational therapy can help in some cases.

Regular bladder exams are important to detect poor bladder emptying. Psychological evaluation and nurturing are important to many, especially in matters of school performance. Treatment for constipation, diarrhea, and swallowing problems may be needed. Sleep should be monitored and sleep apnea considered. Patients may not tolerate high or low temperatures and may need an air conditioning or heating device.

Genetic counseling is recommended for patients with Wolfram syndrome and their families.

Forecast

The first symptom is often diabetes mellitus, which is usually diagnosed around age 6. The next symptom that often appears is optic atrophy, depletion of the optic nerves, around the age of 11. The first signs of this are loss of color vision and peripheral vision. The condition worsens over time, and patients with optic atrophy usually go blind within 8 years after the first symptoms appear. The life expectancy of patients suffering from this syndrome is about 30 years.