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Wolfram syndrome

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Wolfram syndrome
Other namesDiabetes insipidus-diabetes mellitus-optic atrophy-deafness syndrome
Photographic image of the eye showing optic atrophy without retinopathy; from Manaviat et al., 2009[1]
SpecialtyMedical genetics, neurology Edit this on Wikidata

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. Symptoms can start to appear as early as childhood to adult years (2-11 years old).[2][3][4][5]

It was first described in four siblings in 1938 by Dr. Don J. Wolfram, M.D. In 1995, diagnostic criteria were created based on the profiles of 45 patients.[2] The disease affects the central nervous system (especially the brainstem). There are two subtypes – Wolfram Syndrome Type 1 (WFS1) and Wolfram Syndrome Type 2 (WFS2), that are distinguished by their causative gene.

Less than 5,000 people in the US have this disease, with WFS1 being more common than WFS2.[6]

Causes

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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 (ER) dysfunction.[2]

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

WFS1

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The WFS1 or wolframin gene provides instructions for making the wolframin protein.[2] 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.[7]

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.[8]

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.[9]

Other disorders - caused by mutations in the WFS1 gene

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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]

WFS2

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Wolfram Syndrome Type 2 (WFS2) is a subtype of Wolfram Syndrome caused by a mutation in the CDGSH iron-sulfur domain-containing protein 2 gene (CISD2 gene). CISD2 is a protein coding gene that is found on the endoplasmic reticulum (ER) and outer mitochondrial membrane. Mutation of this gene effects the protein folding of the ER and functions of the mitochondria, which leads to the signs and symptoms seen in those with WFS2.[10][11]

Clinical features of both WFS1 and WFS2 are diabetes mellitus, optic atrophy/neuropathy, sensorineural deafness, and genitourinary problems. Although both types have some overlapping symptoms, there are some differences that help us distinguish between the two. WFS2, it is not associated with diabetes insipidus or psychiatric disorders but is instead associated with higher bleed risks and peptic ulcers.[12]

CISD2 gene consists of 3 exons on chromosome 4q24, which encodes the protein NAF-1 (nutrient deprivation autophagy factor-1). Therefore, if WFS2 were suspected in a patient, it may help to do a gene sequencing of the three exons and their intronic regions for a genetic analysis.[13]

WFS2 is the rarest and most recently discovered subtype of Wolfram syndrome.

Diagnosis

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The diagnosis of Wolfram syndrome is multifaceted, involving clinical evaluation, genetic testing, laboratory investigations, and imaging studies. Clinical evaluation typically begins with a detailed medical history and physical examination, where patients often present with juvenile-onset diabetes mellitus followed by progressive optic atrophy. Other symptoms such as diabetes insipidus, sensorineural hearing loss, and neurological abnormalities like ataxia or myoclonus may also be observed[14][15]. The progression of symptoms, starting with type 1 diabetes and subsequent vision loss within the first decade of life, is a critical diagnostic clue ..[2]

Imaging studies are crucial in assessing the extent of brain and optic nerve damage. Magnetic resonance imaging (MRI) can detect brainstem and cerebellar atrophy as well as optic nerve atrophy, which are characteristic features of Wolfram syndrome [16]. Optical coherence tomography (OCT) is used to measure retinal nerve fiber layer thickness, aiding in the assessment of optic atrophy and monitoring disease progression .

Blood tests can assist with diagnosis as they determine systems within the body are being affected.

Other diagnostic tools include audiological tests to identify sensorineural hearing loss, a common feature of Wolfram syndrome, and psychiatric evaluations to address cognitive or behavioral issues arising from the neurodegenerative nature of the disease . Combining these diagnostic approaches ensures a comprehensive understanding and management of Wolfram syndrome[17].

Treatment

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There is no known direct treatment. Current treatment efforts focus on managing the complications of Wolfram syndrome. Intranasal or oral desmopressin has been shown to improve symptoms for the treatment of diabetes insipidus caused by Wolfram syndrome.[18] Patients with Wolfram syndrome experiencing hearing loss have benefited from the use of cochlear implants and hearing aids.[19] While there are no therapies currently available to slow the progression of neurological manifestations, swallowing therapy and esophagomyotomy have been shown to be useful in alleviating some of the neurological symptoms.[20] Anticholinergic medications, clean intermittent catheterizations, electrical stimulation, and physiotherapy have been shown to be effective at managing urological abnormalities due to Wolfram syndrome such as neurogenic bladder and upper urinary tract dilation.[21]

While there are no direct treatments, many therapies are currently being investigated for their efficacy at treating Wolfram syndrome. Gene and regenerative therapies are currently being studied for their efficacy in replacing damaged tissues due to Wolfram syndrome, such as pancreatic β-cells, neuronal, and retinal cells.[22]

WFS1 mutations cause proteins in the ER to fold improperly, leading to ER stress. ER stress stimulates the unfolded protein response (UPR), which causes cell apoptosis for pancreatic β-cells.[23] Chemical chaperones are being investigated for their effect on reducing the UPR response and thus delaying disease progression by preventing cell death.[18]  The FDA has approved 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as chemical chaperones to reduce ER stress to delay neurodegeneration in patients with Wolfram syndrome.[24] As of 2023, sodium valproate—an anti-epileptic drug—is being investigated as a therapy for Wolfram syndrome due to studies showing its ability to inhibit ER stress-induced apoptosis, reducing neurodegeneration.[25] Liraglutide—a glucagon-like peptide-1 receptor (GLP 1-R) antagonist—has been hypothesized to be an effective therapy, as it has been shown to improve diabetes mellitus, reduce cell death due to ER stress, reduce neuroinflammation, protect retinal ganglion cell death, and prevent optic nerve degeneration.[26]  Dipeptidyl peptidase-4 (DPP-4) inhibitors have also been hypothesized to be efficacious in the treatment of Wolfram syndrome due to their ability to deactivate GLP 1-R, similar to liraglutide.[27]  However, the efficacy and safety of using liraglutide and DPP-4 inhibitors for the treatment of Wolfram syndrome has not been well studied yet.

ER calcium levels have also been identified as a target for Wolfram syndrome therapy. WFS1 mutations increase cytosolic calcium, leading to the activation of cysteine proteases known as calpains. Increased calpains activation is associated which cell death.[28] As of 2021, dantrolene sodium—a medication indicated for the treatment of malignant hyperthermia and muscle spasms—was being investigated in patients with Wolfram syndrome in a phase 2 clinical trial.[29]

Prognosis

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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.[18]

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.[18] 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).[18][12] It often occur at the age of 14, but the onset can varies greatly as diabetes insipidus is often diagnosed late.[18]

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.[2] 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.[3][18]

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.[3][12][18]

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.[3][18] Furthermore, bladder dysfunction can progress to megacystis over time.[12]

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.[2][18][30]

The disease prognosis is very poor with a median mortality rate of 65% before the age of 35 (age range 25-39).[30] 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.[31][32] Unfortunately, currently, there is no effective treatment that can delay or reverse the progression of the disease.[32]

See also

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References

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  1. ^ Manaviat MR, Rashidi M, Mohammadi SM (December 2009). "Wolfram Syndrome presenting with optic atrophy and diabetes mellitus: two case reports". Cases Journal. 2: 9355. doi:10.1186/1757-1626-2-9355. PMC 2804005. PMID 20062605.
  2. ^ a b c d e f g h Urano F (January 2016). "Wolfram Syndrome: Diagnosis, Management, and Treatment". Current Diabetes Reports. 16 (1): 6. doi:10.1007/s11892-015-0702-6. PMC 4705145. PMID 26742931.
  3. ^ a b c d Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, et al. (July 2019). "Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives". Journal of Translational Medicine. 17 (1): 238. doi:10.1186/s12967-019-1993-1. PMC 6651977. PMID 31337416.
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  23. ^ Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y, et al. (November 2005). "WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells". The Journal of Biological Chemistry. 280 (47): 39609–39615. doi:10.1074/jbc.M507426200. PMID 16195229.
  24. ^ Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, et al. (July 2019). "Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives". Journal of Translational Medicine. 17 (1): 238. doi:10.1186/s12967-019-1993-1. PMC 6651977. PMID 31337416.
  25. ^ Serbis A, Rallis D, Giapros V, Galli-Tsinopoulou A, Siomou E (February 2023). "Wolfram Syndrome 1: A Pediatrician's and Pediatric Endocrinologist's Perspective". International Journal of Molecular Sciences. 24 (4): 3690. doi:10.3390/ijms24043690. PMC 9960967. PMID 36835101.
  26. ^ Seppa K, Toots M, Reimets R, Jagomäe T, Koppel T, Pallase M, et al. (October 2019). "GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome". Scientific Reports. 9 (1): 15742. Bibcode:2019NatSR...915742S. doi:10.1038/s41598-019-52295-2. PMC 6823542. PMID 31673100.
  27. ^ Deacon CF (November 2020). "Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus". Nature Reviews. Endocrinology. 16 (11): 642–653. doi:10.1038/s41574-020-0399-8. PMID 32929230.
  28. ^ Lu S, Kanekura K, Hara T, Mahadevan J, Spears LD, Oslowski CM, et al. (December 2014). "A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome". Proceedings of the National Academy of Sciences of the United States of America. 111 (49): E5292–E5301. Bibcode:2014PNAS..111E5292L. doi:10.1073/pnas.1421055111. PMC 4267371. PMID 25422446.
  29. ^ Abreu D, Stone SI, Pearson TS, Bucelli RC, Simpson AN, Hurst S, et al. (August 2021). "A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome". JCI Insight. 6 (15): e145188. doi:10.1172/jci.insight.145188. PMC 8410026. PMID 34185708.
  30. ^ a b La Valle A, Piccolo G, Maghnie M, d'Annunzio G (2021-11-15). "Urinary Tract Involvement in Wolfram Syndrome: A Narrative Review". International Journal of Environmental Research and Public Health. 18 (22): 11994. doi:10.3390/ijerph182211994. ISSN 1661-7827. PMC 8624443. PMID 34831749.
  31. ^ Barrett TG, Bundey SE (October 1997). "Wolfram (DIDMOAD) syndrome". Journal of Medical Genetics. 34 (10): 838–841. doi:10.1136/jmg.34.10.838. ISSN 0022-2593. PMC 1051091. PMID 9350817.
  32. ^ a b Iafusco D, Zanfardino A, Piscopo A, Curto S, Troncone A, Chianese A, et al. (January 2022). "Metabolic Treatment of Wolfram Syndrome". International Journal of Environmental Research and Public Health. 19 (5): 2755. doi:10.3390/ijerph19052755. ISSN 1660-4601.

This article incorporates text from the United States National Library of Medicine ([1]), which is in the public domain.


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