Wolfram syndrome

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Wolfram syndrome
Other namesDiabetes insipidus-diabetes mellitus-optic atrophy-deafness syndrome
Photographic image of the patient right eye showing optic atrophy without diabetic retinopathy Wolfram syndrome.jpg
Photographic image of the eye showing optic atrophy without retinopathy; from Manaviat et al., 2009 [1]
Specialty Medical genetics, neurology   OOjs UI icon edit-ltr-progressive.svg

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. [2] [3] [4]

Contents

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).

Causes

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]

Autorecessive.svg

Two forms have been described: Wolfram syndrome 1 (WFS1), [2] [5] and Wolfram syndrome 2 (WFS2). [2] [6]

WFS1

The WFS1 or wolframin gene [7] 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. [8]

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. [9]

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. [10]

Other disorders - caused by mutations in the WFS1 gene

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

Wolfram Syndrome Type 2 (WFS2) is caused by a mutation in the CDGSH iron-sulfur domain-containing protein 2 gene (CISD2 gene). CISD2 is a protein-coding gene that provides instructions for proteins found in the mitochondria. Mutation of this gene causes it to lose its function, which affects the mitochondria. The mitochondria is vital for cell energy, and the gradual loss of sufficient cell function can lead to the signs and symptoms of WFS2. [11]

Clinical features of both WFS1 and WFS2 are diabetes mellitus, optic atrophy/neuropathy, sensorineural deafness, and genitourinary problems. It can be hard to differentiate between the two but the main differences is that in WFS2, it is not associated with diabetes insipidus or psychiatric disorders but is instead associated with higher bleed risks and peptic ulcers. [12]

Diagnosis

Patients past medical history can help diagnosis as it may indicate symptoms such as having diabetes mellitus and then developing vision loss. [13] 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 ]

Treatment

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

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. [18]

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. [19] Chemical chaperones are being investigated for their effect on reducing the UPR response and thus delaying disease progression by preventing cell death. [14]  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. [20] 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. [21] 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. [22]  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. [23]  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. [24] 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. [25]

Prognosis

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. [26] 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. [27] 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. [28] 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. [26]

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

See also

Related Research Articles

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. Along with neonatal diabetes, MODY is a form of the conditions known as monogenic diabetes. While the more common types of diabetes involve more complex combinations of causes involving multiple genes and environmental factors, each forms of MODY are caused by changes to a single gene (monogenic). GCK-MODY and HNF1A-MODY are the most common forms.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Dominant optic atrophy (DOA), or autosomal dominant optic atrophy (ADOA), (Kjer's type) is an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. However, the disease can seem to re-present a second time with further vision loss due to the early onset of presbyopia symptoms (i.e., difficulty in viewing objects up close). DOA is characterized as affecting neurons called retinal ganglion cells (RGCs). This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers. The RGCs axons form the optic nerve. Therefore, the disease can be considered of the central nervous system. Dominant optic atrophy was first described clinically by Batten in 1896 and named Kjer’s optic neuropathy in 1959 after Danish ophthalmologist Poul Kjer, who studied 19 families with the disease. Although dominant optic atrophy is the most common autosomally inherited optic neuropathy (i.e., disease of the optic nerves), it is often misdiagnosed.

<span class="mw-page-title-main">Alström syndrome</span> Rare genetic disorder involving childhood obesity and multiple organ dysfunction

Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early-onset type 2 diabetes, cone-rod dystrophy resulting in blindness, sensorineural hearing loss and dilated cardiomyopathy. Endocrine disorders typically also occur, such as hypergonadotrophic hypogonadism and hypothyroidism, as well as acanthosis nigricans resulting from hyperinsulinemia. Developmental delay is seen in almost half of people with Alström syndrome.

<span class="mw-page-title-main">Diabetes and deafness</span> Medical condition

Diabetes and deafness (DAD) or maternally inherited diabetes and deafness (MIDD) or mitochondrial diabetes is a subtype of diabetes which is caused from a mutation in mitochondrial DNA, which consists of a circular genome. It is associated with the genes MT-TL1, MT-TE, and MT-TK. The point mutation at position 3243A>G, in gene MT-TL1 encoding tRNA leucine 1, is most common. Because mitochondrial DNA is contributed to the embryo by the oocyte and not by spermatozoa, this disease is inherited from maternal family members only. As indicated by the name, MIDD is characterized by diabetes and sensorineural hearing loss. Some individuals also experience more systemic symptoms including eye, muscle, brain, kidney, heart, and gastrointestinal abnormalities, similar to other mitochondrial diseases.

<span class="mw-page-title-main">WFS1</span> Protein-coding gene in the species Homo sapiens

Wolframin is a protein that in humans is encoded by the WFS1 gene.

<span class="mw-page-title-main">TIMM8A</span> Protein-coding gene in humans

Mitochondrial import inner membrane translocase subunit Tim8 A, also known as deafness-dystonia peptide or protein is an enzyme that in humans is encoded by the TIMM8A gene. This translocase has similarity to yeast mitochondrial proteins that are involved in the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in deafness-dystonia syndrome and it is postulated that MTS/DFN-1 is a mitochondrial disease caused by a defective mitochondrial protein import system.

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Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

<span class="mw-page-title-main">Wolcott–Rallison syndrome</span> Medical condition

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<span class="mw-page-title-main">Johanson–Blizzard syndrome</span> Medical condition

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<span class="mw-page-title-main">Neonatal diabetes</span> Medical condition

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<span class="mw-page-title-main">Cranio-lenticulo-sutural dysplasia</span> Medical condition

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<span class="mw-page-title-main">SERAC1</span> Protein-coding gene in the species Homo sapiens

Serine active site-containing protein 1, or Protein SERAC1 is a protein in humans that is encoded by the SERAC1 gene. The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.

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<span class="mw-page-title-main">Wolfram-like syndrome</span> Medical condition

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References

  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. 1 2 3 4 5 6 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. ↑ OMIM 222300 (WFS1)
  6. ↑ OMIM 604928 (WFS2)
  7. ↑ OMIM 606201 (WFS1 gene)
  8. ↑ "Type 1 diabetes: MedlinePlus Genetics". medlineplus.gov. Retrieved 2024-07-23.
  9. ↑ "WFS1 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2024-07-23.
  10. ↑ 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.
  11. ↑ "CISD2 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2024-07-23.
  12. ↑ Rosanio FM, Di Candia F, Occhiati L, Fedi L, Malvone FP, Foschini DF, et al. (2022-01). "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. ISSN   1660-4601.{{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  13. ↑ "Wolfram Syndrome - Symptoms, Causes, Treatment | NORD". rarediseases.org. Retrieved 2024-07-22.
  14. 1 2 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.
  15. ↑ Karzon R, Narayanan A, Chen L, Lieu JE, Hershey T (2018-06-27). "Longitudinal hearing loss in Wolfram syndrome". Orphanet Journal of Rare Diseases. 13 (1): 102. doi:10.1186/s13023-018-0852-0. ISSN   1750-1172. PMC   6020390 . PMID   29945639.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ↑ Chaussenot A, Bannwarth S, Rouzier C, Vialettes B, Mkadem SA, Chabrol B, et al. (2011-03). "Neurologic features and genotype‐phenotype correlation in Wolfram syndrome". Annals of Neurology. 69 (3): 501–508. doi:10.1002/ana.22160. ISSN   0364-5134.{{cite journal}}: Check date values in: |date= (help)
  17. ↑ de Heredia ML, Clèries R, Nunes V (2013-07-01). "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. ISSN   1098-3600.
  18. ↑ Urano F (2014-03). "Wolfram Syndrome iPS Cells: The First Human Cell Model of Endoplasmic Reticulum Disease". Diabetes. 63 (3): 844–846. doi:10.2337/db13-1809. ISSN   0012-1797. PMC   3931391 . PMID   24556864.{{cite journal}}: Check date values in: |date= (help)
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Seppa K, Toots M, Reimets R, Jagomäe T, Koppel T, Pallase M, et al. (2019-10-31). "GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome". Scientific Reports. 9 (1): 15742. doi:10.1038/s41598-019-52295-2. ISSN   2045-2322.
  23. ↑ Deacon CF (2020-11). "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. ISSN   1759-5037.{{cite journal}}: Check date values in: |date= (help)
  24. ↑ 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.
  25. ↑ 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.
  26. 1 2 Rigoli L, Caruso V, Salzano G, Lombardo F (2022-03-09). "Wolfram Syndrome 1: From Genetics to Therapy". International Journal of Environmental Research and Public Health. 19 (6): 3225. doi:10.3390/ijerph19063225. ISSN   1661-7827. PMC   8949990 . PMID   35328914.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  27. ↑ "Wolfram syndrome". ghr.nlm.nih.gov. Retrieved 3 February 2016.
  28. ↑ Urano F (2016). "Wolfram Syndrome: Diagnosis, Management, and Treatment". Current Diabetes Reports. 16: 6. doi:10.1007/s11892-015-0702-6. ISSN   1534-4827. PMC   4705145 . PMID   26742931.
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