User:HanDinh2026/Wolfram syndrome

Wolfram syndrome, also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration.

It was first described in four siblings in 1938 by Dr. Don J. Wolfram, M.D. The disease is estimated to affect 1 in about 160,000-700,000 and mainly involved the central nervous system (especially the brainstem).

Wolfram syndrome was initially thought to be caused by mitochondrial dysfunction due to several reports of mitochondrial DNA mutations. However, it has now been established that Wolfram syndrome is caused by a congenital endoplasmic reticulum dysfunction.

Two forms have been described: Wolfram syndrome 1 (WFS1), and Wolfram syndrome 2 (WFS2).

The WFS1 or wolframin gene provides instructions for making the wolframin protein. The WFS1 gene is active in cells throughout the body, with strong activity in the heart, brain, lungs, inner ear, and pancreas. The pancreas provides enzymes that help digest food, and it also produces the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy.

Within cells, wolframin is located in a structure called the endoplasmic reticulum. Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape to function properly. The endoplasmic reticulum also helps transport proteins, fats, and other materials to specific sites within the cell or to the cell surface. The function of wolframin is unknown. Based on its location in the endoplasmic reticulum, however, it may play a role in protein folding or cellular transport. In the pancreas, wolframin may help fold a protein precursor of insulin (called proinsulin) into the mature hormone that controls blood glucose levels. Research findings also suggest that wolframin may help maintain the correct cellular level of charged calcium atoms (calcium ions) by controlling how much is stored in the endoplasmic reticulum. In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing. Mutation is the WFS1 lead to ER stress due to an increase in the accumulation of misfolded proteins. As there is a high level of misfolded protein, unfolded protein response (UPR) is stimulated and lead to transcriptional and translational process that can restore ER homeostasis, However, if the ER stress is present persistently due to physiological or pathophysiological events, the UPR will induce apoptosis.^[1]

More than 30 WFS1 mutations have been identified in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA6. Individuals with DFNA6 deafness cannot hear low tones (low-frequency sounds), such as a tuba or the "m" in moon. DFNA6 hearing loss is unlike most forms of nonsyndromic deafness that affect high tones (high-frequency sounds), such as birds chirping, or all frequencies of sound. Most WFS1 mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. One mutation deletes an amino acid from wolframin. WFS1 mutations probably alter the 3-dimensional shape of wolframin, which could affect its function. Because the function of wolframin is unknown, however, it is unclear how WFS1 mutations cause hearing loss. Some researchers suggest that altered wolframin disturbs the balance of charged particles in the inner ear, which interferes with the hearing process.

Mutations in the WFS1 gene cause Wolfram syndrome, which is also known by the acronym DIDMOAD. This syndrome is characterised by childhood-onset diabetes mellitus (DM), which results from the improper control of glucose due to the lack of insulin; a gradual loss of vision caused by optic atrophy (OA), in which the nerve that connects the eye to the brain wastes away; and deafness (D). This syndrome can sometimes cause diabetes insipidus (DI), a condition in which the kidneys cannot conserve water. Other complications that affect the bladder and nervous system may also occur. Researchers have identified more than 100 WFS1 mutations that cause Wolfram syndrome. Some mutations delete or insert DNA from the WFS1 gene. As a result, little or no wolframin is present in cells. Other mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. These mutations appear to reduce wolframin activity dramatically. Researchers suggest that the loss of wolframin disrupts the production of insulin, which leads to poor glucose control and diabetes mellitus. It is unclear how WFS1 mutations lead to other features of Wolfram syndrome.^{[citation needed]}

The mutation of the CISD2 gene can cause WFS2.

Patients past medical history can help diagnosis as it may indicate symptoms such as having diabetes mellitus and then developing vision loss. Blood tests can assist with diagnosis as they determine systems within the body are being affected. MRI scans can also help diagnose and determine the level of damage to the brain and body systems.^{[citation needed]}

There is no known direct treatment. Current treatment efforts focus on managing the complications of Wolfram syndrome, such as diabetes mellitus and diabetes insipidus. However a number of symptoms can be managed to improve quality of life. These include: insulin for diabetes alongside other medications for this. Desmopressin to treat diabetes insipidus, antibiotics for UTI, hearing aids of cochlear implants for hearing loss and supportive aids for visual loss such as magnifying glasses. New treatment advances include research evaluating ER calcium stabilizers and repurposed drugs/small molecules to reduce ER stress and reduce apoptosis, thus slowing progression of Wolfram syndrome.^{[citation needed]}

A three tiered approach toward the treatment of Wolfram syndrome includes stopping disease progression, protecting and regrowing remaining tissue, and replacing and repairing pathogenic genes.

The first symptom is typically diabetes mellitus, which is usually diagnosed around the age of 6. Insulin-dependent diabetes mellitus associate with Wolfram syndrome is differed from type 1 diabetes mellitus by having earlier diagnosis, rarely having positive auto-antibodies and ketoacidosis, having longer remission, needing less daily insulin, having lower average HbA1c level and more frequent hypoglycemia.^[1]

The next symptom to appear is often optic atrophy, the wasting of optic nerves, around the age of 11. The blindness tends to develop a few years after the decrease in visual ability with the loss of color vision.^[1] The third most common clinical manifestation of the disease is diabetes insipidus, which affect around 70% of the patients with WSF1 mutation (WFS2 mutation does not typically associate with diabetes insipidus).^[1][2] It often occur at the age of 14, but the onset can varies greatly as diabetes insipidus is often diagnosed late.^[1]

Approximately 65% of the patient experienced sensorineural deafness which can manifest as deafness at birth or mild hearing loss in adolescence years and progressively worsen.^[3] However, the progression of sensorineural deafness is relatively slow and initially influenced the high-frequency sounds. Patients with WFS1 mutation have degenerative impairment in the central nervous system, as they increased in age they are more likely to suffer a more severe deafness than other patients that have hearing loss.^[1][4]

The majority of patient (>60%) with WSF1 mutation develop neurological symptoms around the age of 40; however, some may experience these symptoms earlier in life. Some most common neurological abnormalities are cerebellar ataxia, peripheral neuropathy, epilepsy, cognitive impairement, dysphagia, dysarthria and diminish sense of taste and smell. In addition, patient can also experienced orthostatic hypotension, gastroparesis, hypothermia/hyperthermia, hypohidrosis or hyperhidrosis, constipation and headache.^[1][2][4]

Urinary tract disorders are also found in more than 90% patient with Wolfram Syndrome, in which neurogenic bladder is the main manifestation of neurological disorder that can lead to urinary incontinence, hydroureter and recurrent infections. These urological abnormalities are usually onset at the age of 20 and can be peaked at 13, 21 and 33 years of age.^[1][4] Furthermore, bladder dysfunction can progress to megacystis over time.^[2]

Endocrine dysfunction is another clinical manifestation of Wolfram syndrome, which include hypogonadism. More specifically, hypogonadism present more frequent in male than female. Male patients are more likely to experience fertility impairment and erectile dysfunction while female patient will encounter some menstrual abnormalities. Additionally, due to the decrease in function of the anterior pituitary gland, patients with Wolfram syndrome can also have short statue, growth hormone deficiency and corticotrophin secretion deficiency.^[1][3][5]

The disease prognosis is very poor which a median mortality rate of 65% before the age of 35 (age range 25-39).^[5] The two main reason for death in patient with Wolfram syndrome are central respiratory failure, due to severe neurological disability, and renal failure secondary to infections.^[6][7] Unfortunately, currently, there is no effective treatment that can delay or reverse the progression of the disease.^[7]

Wolfram syndrome is considered a rare autosomal recessive neurodegenerative disease. According to the draft International Classification of Disease (ICD-11), Wolfram Syndrome is classified as a rare specified diabetes mellitus.^[3] The disease is estimated to affect 1 in 160,000 to 700,00.^[3][8] More specifically, the disease prevalence is 1 in 770,00 in the UK, 1 in 710,000 in Japan, 1 in 100,00 in North America, 0.74 in 1,000,000 in Italy, 1 in 68,000 in Lebanon and the highest prevalence is 1 in 54,478 in a small area of Sicily (Italy).^[1][4][6] It is believed that the populations with high prevalence have high-rate of consanguinity.^[9][10] The frequency of WSF1 mutation carrier is estimated to be 1 in 3,542 and the disease is estimated to affect 1 out of 150 patient with juvenile-onset insulin-independent diabetes mellitus.^[11]

• WFS1
• Chromosome 4 disorders
• Nonsyndromic deafness
• List of rare diseases

5. OMIM 222300 (WFS1)
6. OMIM 604928 (WFS2)
7. OMIM 606201 (WFS1 gene)
11. Role for CISD2 gene in human disease and lifespan control
13. Wolfram Syndrome

Wikimedia Commons has media related to Wolfram syndrome.

• OMIM DIDMOAD search
• Genetics Home Reference WFS1Archived 2010-04-09 at the Wayback Machine