Author(s):
Bhagya Sree Lekha Annamneedi, Abhiram Sorra, Vinod Kumar Mugada, Srinivasa Rao Yarguntla
Email(s):
bhagyasreelekha@gmail.com
DOI:
10.52711/2321-5836.2023.00031 
Address:
Bhagya Sree Lekha Annamneedi1*, Abhiram Sorra1, Vinod Kumar Mugada1, Srinivasa Rao Yarguntla2
1Department of Pharmacy Practice, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.
2Department of Pharmaceutics, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.
*Corresponding Author
Published In:
Volume - 15,
Issue - 4,
Year - 2023
ABSTRACT:
Wolfram syndrome is a rare neurological disorder characterised by four main symptoms: diabetes mellitus, optic atrophy, deafness, and diabetes insipidus. It is caused by alterations in the CISD2 and WFS1 genes, which encode important proteins involved in cellular processes. Wolfram syndrome type 1 (WS1) has an earlier onset of diabetes and more severe neurological and ocular involvement compared to WS2. The diagnosis of Wolfram syndrome is based on the presence of early-onset diabetes and progressive optic atrophy. Genetic analysis, such as sequencing of the WFS1 gene, is used to confirm the diagnosis. The prevalence of Wolfram syndrome varies across populations, with a carrier frequency of 1 in 354. Individuals with Wolfram syndrome may experience a range of complications, including neurological abnormalities, urinary tract problems, depression, and an increased risk of suicide. The pathophysiology of Wolfram syndrome involves endoplasmic reticulum stress and unfolded protein responses, leading to cellular dysfunction and apoptosis. A differential diagnosis includes other genetic and mitochondrial disorders with similar symptoms. Although there is no cure for Wolfram syndrome, careful clinical observation and supportive therapy can help manage the symptoms and improve the quality of life for affected individuals.
Cite this article:
Bhagya Sree Lekha Annamneedi, Abhiram Sorra, Vinod Kumar Mugada, Srinivasa Rao Yarguntla. Wolfram Syndrome: A Rare Genetic disorder affecting Multiple Organ Systems. Research Journal of Pharmacology and Pharmacodynamics.2023;15(4):172-8. doi: 10.52711/2321-5836.2023.00031
Cite(Electronic):
Bhagya Sree Lekha Annamneedi, Abhiram Sorra, Vinod Kumar Mugada, Srinivasa Rao Yarguntla. Wolfram Syndrome: A Rare Genetic disorder affecting Multiple Organ Systems. Research Journal of Pharmacology and Pharmacodynamics.2023;15(4):172-8. doi: 10.52711/2321-5836.2023.00031 Available on: https://rjppd.org/AbstractView.aspx?PID=2023-15-4-5
REFERENCES:
1. Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diabetes Rep. 2016;16(1):6.
2. Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458-1463.
3. Cano A, Molines L, Valero R, Simonin G, Paquis-Flucklinger V, Vialettes B. Microvascular Diabetes Complications in Wolfram Syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness [DIDMOAD]): An age- and duration-matched comparison with common type 1 diabetes. Diabetes Care. 2007;30(9):2327-2330.
4. Yamamoto H, Hofmann S, Hamasaki DI, Yamamoto H, Kreczmanski P, Schmitz C, Parel J-M, Schmidt-Kastner R. Wolfram syndrome 1 (WFS1) protein expression in retinal ganglion cells and optic nerve glia of the cynomolgus monkey. Exp Eye Res. 2006;83(5):1303-1306.
5. Kawano J, Tanizawa Y, Shinoda K. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J Comp Neurol. 2008;510(1):SPC1-SPC1.
6. Schmidt-Kastner R, Kreczmanski P, Preising M, Diederen R, Schmitz C, Reis D, Blanks J, Dorey CK. Expression of the diabetes risk gene wolframin (WFS1) in the human retina. Exp Eye Res. 2009;89(4):568-574.
7. Delvecchio M, Iacoviello M, Pantaleo A, Resta N. Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype–Phenotype Correlations. Int J Environ Res Public Health. 2021;18(9):4796.
8. Ghirardello S, Dusi E, Castiglione B, Fumagalli M, Mosca F. Congenital central diabetes insipidus and optic atrophy in a Wolfram newborn: is there a role for WFS1 gene in neurodevelopment? Ital J Pediatr. 2014;40(1).
9. Urano F. Wolfram Syndrome iPS Cells: The First Human Cell Model of Endoplasmic Reticulum Disease. Diabetes. 2014;63(3):844-846.
10. Morikawa S, Tajima T, Nakamura A, Ishizu K, Ariga T. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome. Pediatr Diabetes. 2017;18(8):934-941.
11. Hofmann S. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003;12(16):2003-2012.
12. Gómez-Zaera M, Strom TM, Rodrı́guezB, Estivill X, Meitinger T, Nunes V. Presence of a Major WFS1 Mutation in Spanish Wolfram Syndrome Pedigrees. Mol Genet Metab. 2001;72(1):72-81.
13. Takeda K. WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet. 2001;10(5):477-484.
14. Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. 2012;24(4):512-517.
15. Fonseca SG, Fukuma M, Lipson KL, et al. WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic β-Cells. J Biol Chem. 2005;280(47):39609-39615.
16. de Heredia ML, Clèries R, Nunes V. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med. 2013;15(7):497-506.
17. Stone SI, Abreu D, McGill JB, Urano F. Monogenic and syndromic diabetes due to endoplasmic reticulum stress. J Diabetes Complications. 2020;34(3):107618.
18. Cagalinec M, Liiv M, Hodurova Z, et al. Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome. PLoS Biol. 2016;14(7):e1002511.
19. Panfili E, Mondanelli G, Orabona C, et al. Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation. Hum Mol Genet. 2021;30(3-4):265-276.
20. Abreu D, Urano F. Current Landscape of Treatments for Wolfram Syndrome. Trends Pharmacol Sci. 2019;40(11):822-838.
21. El-Shanti H, Lidral AC, Jarrah N, Druhan L, Ajlouni K. Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am J Hum Genet. 2000;66(4):1229-1236.
22. Rouzier C, Moore D, Delorme C, et al. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet. 2017;26(9):1599-1611.
23. Medlej R, Wasson J, Baz P, et al. Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population. J Clin Endocrinol Metab. 2004;89(4):1656-1661.
24. Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458-1463.
25. Colosimo A, Guida V, Rigoli L, et al. Molecular detection of novel WFS1 mutations in patients with Wolfram syndrome by a DHPLC-based assay. Hum Mutat. 2003;21(6):622-629. doi:10.1002/humu.10215
26. Mozzillo E, Delvecchio M, Carella M, et al. A novel CISD2 intragenic deletion, optic neuropathy and platelet aggregation defect in Wolfram syndrome type 2. BMC Med Genet. 2014;15:88.
27. Lodha S, Das L, Ramchandani G, Bhansali A. A case of young diabetes and parasuicide. BMJ Case Rep. 2018;2018:bcr-2018-225839.
28. Chaussenot A, Bannwarth S, Rouzier C, et al. Neurologic features and genotype-phenotype correlation in Wolfram syndrome. Ann Neurol. 2010;69(3):501-508.
29. Karzon RK, Hullar TE. Audiologic and vestibular findings in Wolfram syndrome. Ear Hear. 2013;34(6):809-812.
30. Fraser FC, Gunn T. Diabetes mellitus, diabetes insipidus, and optic atrophy. An autosomal recessive syndrome? J Med Genet. 1977;14(3):190-193.
31. Matsunaga K, Tanabe K, Inoue H, et al. Wolfram Syndrome in the Japanese Population; Molecular Analysis of WFS1 Gene and Characterization of Clinical Features. PLoS ONE. 2014;9(9):e106906.
32. Rigoli L, Aloi C, Salina A, et al. Wolfram syndrome 1 in the Italian population: genotype-phenotype correlations. Pediatr Res. 2019;87(3):456-462.
33. Lombardo F, Salzano G, Di Bella C, et al. Phenotypical and genotypical expression of Wolfram syndrome in 12 patients from a Sicilian district where this syndrome might not be so infrequent as generally expected. J Endocrinol Invest. 2014;37(2):195-202.
34. Kinsley BT, Swift M, Dumont RH, Swift RG. Morbidity and mortality in the Wolfram syndrome. Diabetes Care. 1995;18(12):1566-1570.
35. Swift RG, Polymeropoulos MH, Torres R, Swift M. Predisposition of Wolfram syndrome heterozygotes to psychiatric illness. Mol Psychiatry. 1998;3(1):86-91.
36. Seynaeve H, Vermeiren A, Leys A, Dralands L. Four cases of Wolfram syndrome: ophthalmologic findings and complications. Bull Soc Belge Ophtalmol. 1994;252:75-80.
37. Rando TA, Horton JC, Layzer RB. Wolfram syndrome: evidence of a diffuse neurodegenerative disease by magnetic resonance imaging. Neurology. 1992;42(6):1220.
38. Hasan MA, Hazza I, Najada A. Wolfram's (DIDMOAD) syndrome and chronic renal failure. Saudi J Kidney Dis Transpl. 2000;11(1):53-58.
39. Cano A, Rouzier C, Monnot S, et al. Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. Am J Med Genet A. 2007;143A(14):1605-1612.
40. Osman AA, Saito M, Makepeace C, et al. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. J Biol Chem. 2003;278(52):52755-52762.
41. Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, Maruyama Y, Oka Y. WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. FEBS Lett. 2006;580(24):5635-5640.
42. Bonnet Wersinger D, Benkafadar N, Jagodzinska J, Hamel C, Tanizawa Y, Lenaers G, Delettre C. Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice. PLoS One. 2014;9(5):e97222.
43. S, JS. Roles of endoplasmic reticulum stress in immune responses. Mol Cells. 2018;41(8). doi:10.14348/molcells.2018.0241
44. Lipson KL, Ghosh R, Urano F. The role of IRE1α in the degradation of insulin mRNA in pancreatic β-cells. PLoS One. 2008;3(2):e1648.
45. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11(3):619-633.
46. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999;10(11):3787-3799.
47. Seo H-Y, Kim M-K, Min A-K, Kim H-S, Ryu S-Y, Kim N-K, Lee KM, Kim H-J, Choi H-S, Lee K-U, Park K-G, Lee I-K. Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases cAMP-stimulated hepatic gluconeogenesis via inhibition of CREB. Endocrinology. 2010;151(2):561-568.
48. Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, Hayashi E, Ishihara H, Oka Y, Permutt MA, Urano F. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010;120(3):744-755.
49. Maleki N, Bashardoust B, Zakeri A, Salehifar A, Tavosi Z. Diabetes mellitus, diabetes insipidus, optic atrophy, and deafness: A case of Wolfram (DIDMOAD) syndrome. J Curr Ophthalmol. 2015;27(3-4):132-135.
50. Shivani Chib, Neha Kumari, Sukhbinder. Role of Vasopressin and Desmopressin in Diabetes Insipidus. Int. J. Tech. 2020; 10(1):7-12.
51. Karzon R, Narayanan A, Chen L, Lieu JEC, Hershey T. Longitudinal hearing loss in Wolfram syndrome. Orphanet J Rare Dis. 2018;13(1).
52. M. Sujatha Kumari, M. Kiran Babu, Rehana Sulthana, M. Srinivas, Ch. Prasanthi. Diabetes Mellitus: Present status and Drug therapy Updates. Research J. Pharm. and Tech. 7(1): Jan. 2014; Page 84-94
53. Nwauche Kelechi T., Monago Comfort C., Onwuka Frank. Management of Diabetes Mellitus with Combined Therapy of Reducdyn and Metformin in Streptozotocin-induced Diabetic Rats. Research J. Pharm. and Tech. 7(1): Jan. 2014; Page 39-43.
54. Smita S. Aher, Saroj P. Gajare, Ravindra B. Saudagar. Linagliptin: A Review on Therapeutic Role in Diabetes Mellitus. Research J. Pharm. and Tech. 2017; 10(9): 3233-3236.
55. Nguyen LD, Fischer TT, Abreu D, Arroyo A, Urano F, Ehrlich BE. Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome. Proc Natl Acad Sci U S A. 2020;117(29):17389-17398.
56. Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, Esposito S. Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives. J Transl Med. 2019;17.
57. Kondo M, Tanabe K, Amo-Shiinoki K, Hatanaka M, Morii T, Takahashi H, Seino S, Yamada Y, Tanizawa Y. Activation of GLP-1 receptor signalling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome. Diabetologia. 2018;61(10):2189-2201.
58. Toots M, Seppa K, Jagomäe T, Koppel T, Pallase M, Heinla I, Terasmaa A, Plaas M, Vasar E. Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome. Sci Rep. 2018;8(1).
59. Lu S, Kanekura K, Hara T, Mahadevan J, Spears LD, Oslowski CM, Martínez R, Yamazaki-Inoue M, Toyoda M, Neilson A, Blanner P, Brown CM, Semenkovich C, Marshall B, Hershey T, Umezawa A, Greer P, Urano F. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci U S A.
60. Chan CH. Dantrolene sodium and hepatic injury. Neurology. 1990;40(9):1427-1427.
61. Utili R, Boitnott JK, Zimmerman HJ. Dantrolene-associated hepatic injury. Gastroenterology. 1977;72(4):610-616.
62. Kim JY, Chun S, Bang MS, Shin H-I, Lee S-U. Safety of low-dose oral dantrolene sodium on hepatic function. Arch Phys Med Rehabil. 2011;92(9):1359-1363.
63. Sun XY, Qin HJ, Zhang Z, et al. Valproate attenuates diabetic nephropathy through inhibition of endoplasmic reticulum stress-induced apoptosis. Mol Med Rep. 2015;13(1):661-668.
64. Rakitin A. Does Valproic Acid Have Potential in the Treatment of Diabetes Mellitus? Front Endocrinol (Lausanne). 2017;8.