Text reviewed by: Renata Curtin, Denise Chaves and Carolina Souza
What is Wolfram Syndrome?
Wolfram Syndrome (WS) is a rare genetic neurodegenerative disease that affects approximately 1 in 500,000 individuals. WS is caused by mutations in the WFS1 or WFS2 gene and, since the genetic inheritance is recessive, the affected individuals inherit two mutated copies (one from the mother and one from the father).
The diagnosis of the disease is extremely difficult because the symptoms appear gradually. The first problem to manifest in the first decade of life is type 1 diabetes mellitus. The patient continues to develop vision symptoms (optic nerve atrophy), hearing symptoms (sensorineural loss) and neurological symptoms. In addition, the disease can also cause loss of sense of smell, problems of balance and coordination, muscle spasms and seizures, problems in the urinary tract and irregular breathing. Nowadays, there is still no specific medication to cure WS. The available treatments are aimed at improving the symptoms associated with the disease such as diabetes, kidney and neurological problems, including the visual changes. Unfortunately, 60% of the patients die before the age of thirty. However, studies and research are being carried out opening doors to possible treatments.
Wolfram Syndrome (WS) was initially characterized as a mitochondrial disease, but currently the syndrome has been established as a prototype of endoplasmic reticulum (ER) dysfunction. ER is a membrane network within our cells responsible for the synthesis and transport of proteins, calcium storage and other important activities for the cells.
Previous studies on WS have shown that beta-pancreatic cells and neuronal cells are particularly sensitive to endoplasmic reticulum dysfunction. These cell types are destroyed as a consequence of the mutations in the WFS1 gene. This gene is given instructions to produce the protein called Wolframine, which regulates the amount of calcium in the cells. The amount of proper calcium is very important for cellular functioning, including cell-to-cell communication, contraction of muscles and protein processing. Wolframine can be found in many different tissues and organs such as: the lung, heart, pancreas, liver, muscles and kidneys.
A small portion of patients have mutations in the WFS2 gene, so this particularity of the syndrome is still unknown by physicians and researchers.
What is known is that nearly 100% of patients with mutations in the WFS2 gene will develop diabetes, but diabetes will be milder and less aggressive. These patients may also present intestinal ulcers and platelet deficiency.
It is important to note that type 1 diabetes mellitus manifests in about 90% of patients with Wolfram syndrome who have dominant mutations of the WFS1 gene or that carry two recessive mutations in WFS1 genes. This type of diabetes usually occurs at the age of six and simulates an atypical and difficult to control type 1 diabetes. About 70% of the patients also develop another type of diabetes called diabetes insipidus.
The optic atrophy caused by the syndrome is often the second symptom to manifest.
It only affects peripheral vision and it is bilateral. Most of the time, it develops before the second decade of life. The first signs of optical atrophy are loss of color perception and loss of peripheral vision. However, the sensorineural hearing loss is a symptom that affects approximately 65% of patients and develops in early adolescence.
One of the main challenges for researchers is the problem in the urinary tract, since about 60% to 90% of patients develop this type of symptom, which includes obstruction of the ducts between the kidneys and the bladder, flaccid bladder, interruption of urine and difficulty to control urinary flow. Approximately 60% of Wolfram’s patients also develop neurological problems, including coordination and balance difficulties, which usually manifest early in adulthood.
The treatment for this disease depends on the problems that the patient presents. Each individual should be treated according to his/her symptoms, as there is no specific treatment or cure for the syndrome. Type 1 diabetes mellitus, for example, is a disease symptom that requires treatment with insulin application and medical monitoring.
Text reviewed by: Carolina Fishenger Souza, M.D. and André Palmini, M.D.
Major Features of WS
Glucose, or blood sugar, is essential for life. Our body uses glucose to produce energy which is essential for the normal functioning of our body and our cells. In order to be used, the glucose must pass from blood to cells. In most situations, this transport into the cells is performed with the help of a very important hormone called insulin. Insulin is normally produced by the pancreas, but when this organ suffers from any kind of injury, insulin may no longer be produced, causing blood sugar to increase and consequently a number of associated clinical complications. When blood sugar level goes up due to low insulin activity this is considered diabetes. There are several types of diabetes, some manifesting in childhood or adolescence and others in adult life. For each type of diabetes there is a cause, but all stem from the lack or low insulin activity.
In type 1 diabetes mellitus, the immune system mistakenly attacks the beta cells responsible for insulin production in the pancreas, so people with the disease end up lacking enough insulin to regulate blood glucose. This causes glucose to stay in circulation and raise the blood sugar level of a patient instead of entering the cells and being used as energy. The main symptoms of this type of diabetes are weakness, excessive thirst and urge to urinate many times throughout the day. When present, these symptoms are alarm signals for a possible diagnosis of type 1 diabetes mellitus. With a little drop of blood, it is possible to know if there is an increase in the blood glucose level. If positive, more accurate tests are required to confirm the diagnosis such as a fasting glucose test or a 2-hour glucose tolerance test. Type 1 diabetes mellitus concentrates between 5% and 10% of the total patients with the disease. So far there is no cure and the treatment requires applications of insulin and general care. It is a chronic disease that requires follow-up with an endocrinologist.
In order to ensure the control of blood glucose levels you should have healthy habits and an active lifestyle, as well as follow medication guidelines, have applications of insulin, do physical activities, eat well and in a planned way. The goal of glucose levels varies according to age, general health conditions and other risk factors. To avoid hypoglycemia and hyperglycemia, in addition to the complications of the disease, patients must maintain glucose levels within the rates set for them.
Diabetic patients may develop serious health risk issues over time, especially when blood glucose control is not adequate. The kidneys, heart, arteries, vision and also the nerves and teeth may be affected. People with diabetes also have a high risk of developing infections. In many countries, diabetes is a major cause of cardiovascular disease, blindness, lower limb amputation and kidney failure. There are also other types of diabetes such as type 2 diabetes mellitus, gestational diabetes, neonatal diabetes, secondary diabetes and mitochondrial diabetes. The diagnosis is always the same regardless of the type of diabetes, but treatment varies between insulin applications and medication.
Wolfram syndrome is a genetic form of diabetes mellitus and simulates type 1 diabetes mellitus, but in an atypical and difficult way to control. This type of diabetes develops in about 90% of patients and usually manifests in the first decade of patient’s life. It is also important to emphasize that patients with the syndrome usually develop only type 1 diabetes mellitus.
Reviewed by: Marcia Puñales, M.D., Carolina Fishenger Souza, M.D. and André Palmini, M.D.
Diabetes insipidus is an uncommon condition of diabetes that occurs when the kidneys are unable to conserve water free. The amount of water stored is controlled by the antidiuretic hormone (ADH). This hormone is produced in a region of the brain called the hypothalamus where it is then stored and released by the pituitary gland.
There are two types of diabetes insipidus: the type caused by lack of antidiuretic hormone called Central Diabetes Insipidus and the other type caused by a failure of the kidneys to respond to the antidiuretic hormone called Nephrogenic Diabetes Insipidus.
The main clinical manifestations of diabetes insipidus are: excessive thirst associated with constant urge to urinate and with very high urinary volume. This contributes to weakening, dehydration, dryness of the mouth and skin.
It is important to note that diabetes insipidus may be a common manifestation among people with Wolfram Syndrome. About 70% of the patients report these symptoms in adolescence or adulthood. In most cases, only central diabetes insipidus is manifested among patients.
Reviewed by: Carolina Fishenger Souza, , M.D. and André Palmini, M.D.
It is important to note that this visual change can not be reversed and limits the optic nerve to transmit the light signals to the brain to assemble the image. The first signs of optical atrophy are the loss of the notion of colors and the reduction of the visual field. The time of evolution of vision loss caused by optic nerve atrophy is quite short, so it is extremely important that the diagnosis be made as early as possible. Unfortunately, there is still no treatment for this symptom, but studies are being conducted with new drugs in order to delay visual loss.
Reviewed by: Carlos Felipe Chicani, M.D. and André Palmini, M.D.
Sensorineural deafness is a type of hearing loss which cause lies in the auditory nerve, the inner ear (cochlea) or the central processor of the brain.
This type of deafness can have several causes. Many diseases such as diabetes, hypertension, otosclerosis and viral and bacterial infections can cause sensorineural hearing loss.
The hearing loss developed in Wolfram Syndrome is a common manifestation originated in the central nervous system, reaching approximately 65% of the patients and usually develops in early adolescence.
Reviewed by André Palmini, M.D.
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