Jump to content

Wolfram syndrome

From Wikipedia, the free encyclopedia
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 (WS), 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 of WS, 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

[edit]

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

[edit]

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

[edit]

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

[edit]

Wolfram Syndrome Type 2 (WFS2) is a subtype of Wolfram Syndrome (WS) 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 and most recently discovered subtype of WS.

Diagnosis

[edit]

Patients past medical history can help diagnosis as it may indicate symptoms such as having diabetes mellitus and then developing vision loss.[2] 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.[14]

Treatment

[edit]

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.[15] Patients with Wolfram syndrome experiencing hearing loss have benefited from the use of cochlear implants and hearing aids.[16] 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.[17] 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. [18]

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. [19]

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.[20] Chemical chaperones are being investigated for their effect on reducing the UPR response and thus delaying disease progression by preventing cell death.[15]  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.[21] 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.[22] 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.[23]  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.[24]  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.[25] 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. [26]

Prognosis

[edit]

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 T1DM 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.[27] The next symptom to appear is often optic atrophy, the wasting of optic nerves, around the age of 11. The first signs of this are loss of colour vision and peripheral vision. The condition worsens over time, and people with optic atrophy are usually blind within 8 years of the first symptoms.[28] 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.[29] However, the progression of sensorineural deafness is relatively slow and initially influenced the high-frequency sounds. As patients with WFS1 mutation have degenerative impairment in the central nervous system, they suffered a more severe deafness than other patients that have hearing loss.[27]

Life expectancy of people suffering from this syndrome is about 30 years.[2]

See also

[edit]

References

[edit]
  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 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. ^ 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.
  4. ^ Cardona M, Ardila A, Gómez JD, Román-González A (2023-07-31). "Wolfram Syndrome 1 in Two Brothers Treated with Insulin Pump". AACE Clinical Case Reports. 9 (4): 125–127. doi:10.1016/j.aace.2023.05.002. PMC 10382610. PMID 37520764.
  5. ^ "Wolfram syndrome - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2024-07-26.
  6. ^ "Wolfram syndrome - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2024-07-26.
  7. ^ "Type 1 diabetes: MedlinePlus Genetics". Medline Plus. U.S. National Library of Medicine. Retrieved 2024-07-23.
  8. ^ "WFS1 gene: MedlinePlus Genetics". Medline Plus. U.S. National Library of Medicine. Retrieved 2024-07-23.
  9. ^ Alías L, López de Heredia M, Luna S, Clivillé N, González-Quereda L, Gallano P, et al. (2022-10-18). "Case report: De novo pathogenic variant in WFS1 causes Wolfram-like syndrome debuting with congenital bilateral deafness". Frontiers in Genetics. 13: 998898. doi:10.3389/fgene.2022.998898. PMC 9623256. PMID 36330437.
  10. ^ "CISD2 gene: MedlinePlus Genetics". Medline Plus. U.S. National Library of Medicine. Retrieved 2024-07-23.
  11. ^ Delvecchio M, Iacoviello M, Pantaleo A, Resta N (2021-04-30). "Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype–Phenotype Correlations". International Journal of Environmental Research and Public Health. 18 (9): 4796. doi:10.3390/ijerph18094796. ISSN 1661-7827. PMC 8124476. PMID 33946243.
  12. ^ Rosanio FM, Di Candia F, Occhiati L, Fedi L, Malvone FP, Foschini DF, et al. (January 2022). "Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum". International Journal of Environmental Research and Public Health. 19 (2): 835. doi:10.3390/ijerph19020835. PMC 8776149. PMID 35055657.
  13. ^ Delvecchio M, Iacoviello M, Pantaleo A, Resta N (2021-04-30). "Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype–Phenotype Correlations". International Journal of Environmental Research and Public Health. 18 (9): 4796. doi:10.3390/ijerph18094796. ISSN 1661-7827. PMC 8124476. PMID 33946243.
  14. ^ Ito S, Sakakibara R, Hattori T (February 2007). "Wolfram syndrome presenting marked brain MR imaging abnormalities with few neurologic abnormalities". AJNR. American Journal of Neuroradiology. 28 (2): 305–306. PMC 7977398. PMID 17297000.
  15. ^ a b Rigoli L, Caruso V, Salzano G, Lombardo F (March 2022). "Wolfram Syndrome 1: From Genetics to Therapy". International Journal of Environmental Research and Public Health. 19 (6): 3225. doi:10.3390/ijerph19063225. PMC 8949990. PMID 35328914.
  16. ^ Karzon R, Narayanan A, Chen L, Lieu JE, Hershey T (June 2018). "Longitudinal hearing loss in Wolfram syndrome". Orphanet Journal of Rare Diseases. 13 (1): 102. doi:10.1186/s13023-018-0852-0. PMC 6020390. PMID 29945639.
  17. ^ Chaussenot A, Bannwarth S, Rouzier C, Vialettes B, Mkadem SA, Chabrol B, et al. (March 2011). "Neurologic features and genotype-phenotype correlation in Wolfram syndrome". Annals of Neurology. 69 (3): 501–508. doi:10.1002/ana.22160. PMID 21446023.
  18. ^ de Heredia ML, Clèries R, Nunes V (July 2013). "Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype". Genetics in Medicine. 15 (7): 497–506. doi:10.1038/gim.2012.180. PMID 23429432.
  19. ^ Urano F (March 2014). "Wolfram syndrome iPS cells: the first human cell model of endoplasmic reticulum disease". Diabetes. 63 (3): 844–846. doi:10.2337/db13-1809. PMC 3931391. PMID 24556864.
  20. ^ 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.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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. PMID 31673100.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ a b Rigoli L, Caruso V, Salzano G, Lombardo F (March 2022). "Wolfram Syndrome 1: From Genetics to Therapy". International Journal of Environmental Research and Public Health. 19 (6): 3225. doi:10.3390/ijerph19063225. PMC 8949990. PMID 35328914.
  28. ^ "Wolfram syndrome". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 3 February 2016.
  29. ^ 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.

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


[edit]
Wikimedia Commons has media related to Wolfram syndrome.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Wolfram_syndrome&oldid=1236858619"