INTRODUCTION:

Wolfram syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an infrequent neurological disorder that is distinguished by four principal symptoms: deafness¹, diabetes mellitus, optic atrophy, diabetes insipidus. It was originally identified in 1938 by Wagener and Wolfram and follows an autosomal recessive pattern of derivation. The disorder is quite rare, with a carrier frequency of 1 in 354 and a prevalence degree of 1 in 770,000 live births^2,3.

Alterations in two definite genes, CISD2 and WFS1, are responsible for causing Wolfram syndrome^4-6. These genes encrypt a bilayer protein and an endosomal intermembrane protein, correspondingly. It is noteworthy that in certain cases, alterations in WFS1 can be acquired in an autosomal dominant manner⁷. It is generally observed that individuals afflicted with this ailment have a life expectancy that concludes in the third or fourth decade of existence. Individuals who suffer from WFS1 typically encounter a diverse range of symptoms, such as diabetes that manifests early in life, optic nerve atrophy, and gradual neurodegeneration, which could eventually result in severe debilitation or even fatality. Furthermore, affected individuals may also exhibit hearing loss, urinary tract complications, and mental health issues such as depression⁷.

WS1 is a genetic abnormality that has different types, including CIDS2. It is illustrated by a later commencement of diabetes, less severe neurological engagement, and reduced ocular involvement. As a result, individuals with CIDS2 experience slower disease progression and less disability compared to other types, such as type 1. Furthermore, those with CIDS2 tend to have a longer lifetime than those with type¹⁷.

To diagnose Wolfram syndrome, two criteria must be present: early appearance diabetes (usually before 15 years old) and progressive bilateral osteoarthritis, with diabetes developing at 6 years old and osteoarthritis at 11 years old⁸. The complex symptom presentations in Wolfram syndrome (WS) make a differential diagnosis and therapy challenging. WS type 2 is characterized by an increased risk of bleeding, absence of diabetic insipidus, and intestinal ulcers, while WS type 1 is associated with a median period of death around 30 years old and central respiratory distress due to brain stem deterioration. Although no effective therapies exist to delay or reverse the progression of Wolfram syndrome. careful clinical observation and adjunctive therapy can alleviate exhausting symptoms. These findings are reported by⁹.

CAUSES:

WS1 is a genetic abnormality caused by alterations in the WFS1 gene, which encrypts the WFS1 protein (wolframin) localized in the endoplasmic reticulum (ER). ER stress arises during protein synthesis, and the unfolded protein response (UPR) usually improves and supports ER function. However, since WFS1 is a component of the UPR, alterations in WFS1 can lead to uncertain ER stress and necrobiosis, which are underlying causes of WS symptoms¹⁰. This disorder arises from alterations in the WFS1 gene, which is situated at 4p16¹¹. The appearance of WFS1 alterations on both alleles indicates that WS is an autosomal recessive defect. Wolframin is crucial for the ER stress mechanism and intracellular calcium control and exhibits extensive expression in the muscles, brain, pancreas, and heart, with minimal expression in the liver and kidneys ^12-14.

WFS1 pathologic alterations have been detected in 75–90% of WS1 patients, creating excessive ER stress and significant modifications in pancreatic and neurological cells, leading to necrobiosis¹⁵. frameshift, nonsense, missense, and splice alterations in exon 8 of WFS1 can cause WS1¹⁶. Individuals presenting WS1-like symptoms are either homozygotes or compound heterozygotes for WFS1 alterations. However, heterozygous patients, i.e., monoallelic carriers of WFS1 alterations, may have a higher risk of psychiatric problems, suicide, DM, and sensorineural D¹⁶.

Wolframin is essential in controlling the unfolded protein response and plays a crucial role in neuronal degeneration and beta necrobiosis^17-20. WS is an orphan disease caused by alterations in the gene encoding the ER IFN stimulator (ERIS) protein, CISD2²¹. This protein plays a vital part in enduring the structural and functional integrity of the ER and mitochondria²².

SIGNS AND SYMPTOMS:

Wolfram syndrome is a disease with symptoms that emerge at different life phases. In the first decade, patients typically develop non-autoimmune and non-HLA-associated optic atrophy and diabetes mellitus. During the 2nd decagon, patients may develop diabetes insipidus and sensorineural stone deaf. In the early 3rd decagon, patients may experience renal tract anomalies, while in the early fourth decade, they may develop multiple congenital anomalies, such as myoclonus, cerebellar ataxia, and mental illness. Disease progression may supremacy to brain stem atrophy, ensuing in central respiratory decline during the third or fourth decade. Diabetes mellitus is the max prevalent symptom and is usually diagnosed around age 6^23,24.

WS is a complex condition with a range of symptoms that appear at different stages of life. Common symptoms include sensorineural deafness, diabetes insipidus, optic nerve atrophy, urinary tract difficulties, and neurogenic symptoms. There are 2 types of WS: WFS1 and WFS2, caused by different genes. WFS2 is characterized by abnormal platelet aggregation and bleeding upper intestine ulcers, while WFS1 is associated with psychological issues and diabetes insipidus. The findings have been reported in studies by different researchers, and Figure 1a lists the symptoms experienced by people with Wolfram syndrome^23,24.

Figure 1: Major and common signs and symptoms of WS

Major symptoms	Common symptoms
Diabetes mellitus	Fatigue, hypersomnolence
Optic nerve atrophy	Neurological: Apnea, dysphagia, headache, decreased ability to detect odors, decreased ability to taste
Central diabetes insipidus	Psychiatric: Anxiety, panic attacks, depression, mood swings
Sensorineural deafness	Autotomic dysfunction: Problems regulating temperature, dizziness when standing up, constipation, diarrhea, excessive sweating
Ataxia	Endocrine: Hypogonadism Hyponatremia
Urinary tract problems: Neurogenic bladder Bladder incontinence Urinary tract infections

Source: Urano, 2016¹

Diagnosis:

Diagnosis of Wolfram syndrome (WS) primarily relies on a patient's medical history and clinical symptoms. In particular, the presence of optic nerve atrophy ensuring the conclusion of juvenile diabetes before 16 years old is a significant concern¹. However, genetic analysis is beneficial in confirming the investigation²⁵. Sanger sequencing of the WFS1 gene is often employed for this purpose, although exome sequencing and genome sequencing can also be utilized to verify or exclude a WS1 examination. Furthermore, additional hereditary variations can contribute to the manifestation of WS-related symptoms. For example, the patient in question possessed a novel homozygous intragenic excision of CISD2, which was not present in her parents' heterozygous genes, which manifested in subclinical platelet aggregation problems²⁶.

Despite long iterations of homozygosity evaluation from SNP-array evidence failing to reveal any maternal connection, microsatellite research confirmed the notion of a common ancestor. The genetic basis of WS is the deleterious homozygous mutation in the WFS gene, which is anticipated to result in the loss of a single amino acid residue (p.Phe414del). Testing of both parents confirmed that they are carriers for the alteration (F414del), and the patient herself was homozygous for this alteration. Additionally, both the father (heterozygous) and the patient (homozygous) have c.1832A>G (R611H) rs734312, which is linked with a higher risk for suicidal tendencies²⁷.

Finally, the patient's brain MRI exposed neuroradiological variations commonly observed in individuals with established pathologic WFS1 alterations, including the absence of claimed usual neuro hypophyseal hyper signal, atrophy of the optic nerve, brainstem, and cerebellum²⁸.

PREVALENCE:

WS1 is a unique and complex neurological condition whose prevalence rates vary across different populations. Several studies have attempted to quantify the occurrence of this disorder, revealing a frequency of 1 / 770,000 in the UK ², 1/ 500,000 in children²⁹, 1/100,000 in North America³⁰, 1/710,000 in Japan³¹, and 0.74/1,000,000 in Italy³². Notably, the Lebanese population has shown the highest incidence of WS1, with a prevalence rate of 1/68,000²³. Likewise, a minuscule fraction of Sicily exhibits a prevalence of 1/ 54,478³³, likely attributable to high rates of consanguinity in both communities. Despite the numerous studies conducted on WS1, its carrier frequency remains largely unknown. Nevertheless, a population study in the UK estimated it to be approximately 1/354². Typically, WS1 presents as non-autoimmune diabetes mellitus and insulin-dependent with prevalence rates ranging from 0.57% in the UK²⁴ to 4.8% in the population of Lebanon. In pediatric insulin-dependent DM populations, WS1 is often primarily confounded as type 1 DM, leading to a delay of seven years in diagnosis. Additionally, a study discovered the ubiquity of WS1 in 30-year-old Sicilians with insulin-dependent juvenile-onset DM to be 1 in 22.3³³.

COMPLICATIONS:

Neurological abnormalities and urinary tract issues are the preeminent etiologies of morbidity and mortality among personals with WS³⁴. The persistence of the condition and the amount of injections administered to patients are contributory factors to an elevated risk of despondency, suicide attempts, suicidal ideation, and completions, with a prevalence rate of 10%–20%. Notably, the incidence of depression and parasuicides is greater, with approximately 30% and 25% of WS patients affected, respectively³⁵.

Urine tract problems, including hydroureter, urinary incontinence, and recurrent infections, are projected to affect nearly two-thirds of WS patients³⁶. Incontinence and ureteral obstruction are prevalent diseases of the urinary tract, with almost half of WS patients displaying urinary tract dilatation due to persistent high urine flow rate or neurogenesis³⁷.

The medial age of mortality in individuals with WS is 30, with renal failure due to infection and central respiratory failure being the primary causes of death³⁸. Though not a key symptom of WS, several individuals with the disease have presented with cataracts. The study reported congenital cataracts in five WS families, all of which exhibited heterozygous or compound heterozygous WFS1 alterations. Similarly, another study stated solitary cataracts result from heterozygous WFS1 alterations (p.E462G).Neurological complications such as ataxia, neurogenic bladder, and central respiratory failure constitute a significant proportion of the morbidity and mortality in individuals with WS^34,39

PATHOPHYSIOLOGY:

ER membrane is a critical cellular structure that plays a vital role in protein folding, post-translational modification, and transportation. It contains a protein known as wolframin, which is crucial for the proper fold and post-translation of secretor and endoplasmic reticulam (Er) transmembrane proteins^40,41,15.

However, alterations in WFS1 have been established to cause misfolding of proteins, leading to ER stress, which is illustrated by the aggregation of misfolded proteins in the ER lumen. ER stress triggers the unfolded protein response (UPR), which is a complex signaling path that aims to recover cellular homeostasis. The UPR is activated by 3 transmembrane proteins, namely inositol-requiring protein 1 (IRE 1), activating transcription factor 6 (ATF6), and protein kinase RNA (PKR) -like (ER) kinase. These transducers are critical in initiating transcriptional and translational mechanisms that recover ER equilibrium, promote cell survival, and induce apoptosis when necessary. Under normal physiological conditions, ER attendants such as immunoglobulin-binding protein (BIP) remain inactive. Still, when ER stress occurs, BIP helps in the proper folding of accumulating proteins^42,43.

IRE1 is responsible for splicing X-binding protein 1 mRNA, resulting in a transcriptionally active mRNA that is modified into the transcription factor X-BP1. This transcription factor translocates to the nucleus, where it up-regulates a subset of UPR target genes to restore protein homeostasis and activate cellular defense. IRE1 also enhances cell homeostasis and increases proinsulin production in response to hyperglycemia. However, excessive activation of IRE1 can lead to apoptosis⁴⁴.

On one hand, protein kinase RNA-like endoplasmic reticulum kinase (PERK) promotes the phosphorylation of eIF2alpha, which inhibits the activity of ER biosynthesis. On the other hand, it stimulates the translation of ATF4 transcription factor and apoptosis-antagonism transcription factor (AATF) mRNAs.ATF4 is responsible for promoting gene expression related to amino acid transport and glutathione production, metabolism, and antioxidant responses. However, when continuously activated in high ER stress conditions, the ATF4-ATF3-CHOP axis leads to apoptosis. AATF, on the other hand, promotes cell survival. One of the three most important regulators of the UPR response is ATF6. Its activation occurs when ER stress-induced dissociation of BIP leads to its translocation to the Golgi apparatus. Proteases then cleave ATF6, generating an active cytosolic transcription factor that translocates to the nucleus. Here, it stimulates ER transcriptional equilibrium factors to optimize processing, protein folding, and degradation activity. In addition, ATF6 regulates lipid production^45-47.

However, analyses have shown that WFS1 inhibits the activation of the ER stress response element of the ER (ERSE) induced by ATF6. WFS1 also stimulates the stability of E3 ubiquitin ligase HRD1 and suppresses stress signals under conditions of physiological ER stress ⁴⁸.

RELATED DISEASES:

The disorders closely associated with Wolfram syndrome encompass mitochondrial encephalomyopathy and stroke-like episodes, lactic acidosis, and Kearns-Sayre syndrome. Other genetic abnormalities contributing to ocular atrophy comprise Dystonia, optic neuropathy syndrome, X-linked Charcot Marie-Tooth disease type 5, Deafness, Friedreich ataxia, Bardet Biedl syndrome, Congenital rubella syndrome, and Alastrom. It is worth noting that ocular atrophy is intricately connected with Refsum disease, Friedreich's ataxia, Alstrom syndrome, Kearns-Sayre syndrome, Lawrence-Moon syndrome, as well as deafness and diabetes in individuals with the "3243" mitochondrial DNA alterations. Furthermore, diabetes mellitus has been observed to be associated with certain conditions mentioned above⁴⁹.

TREATMENT:

In the realm of medical science, WS represents a unique genetic condition that has yet to be curable, but certain symptoms can be ameliorated with appropriate management techniques. Insulin remains the primary means of managing diabetes mellitus, while vasopressin has been shown to improve the clinical manifestation of diabetes insipidus. Although hearing loss can be addressed with hearing aids, the absence of available treatments for vision loss is a matter of concern. Renal diseases can be treated with catheterization, and certain neurological symptoms can be alleviated using medication^49.

Desmopressin and vasopressin are available therapies for individuals suffering from diabetes insipidus⁵⁰. Desmopressin therapy, either intranasally or orally, has been found to significantly enhance the clinical presentation of diabetes insipidus in a majority of WS1 cases. For effective monitoring of diabetes insipidus in individuals with WS1, regular audiometric testing, and measurement of the auditory brainstem response (ABR) is recommended. In addition, WS1 patients can significantly benefit from therapeutic equipment such as hearing aids and cochlear implants⁵¹. For individuals with type 1 DM, insulin replacement therapy is the primary approach, whereas diet and lifestyle modifications are regarded as the foundation for treating and managing type 2 DM⁵². Metformin, a recognized antidiabetic medication, effectively lowered blood glucose levels when administered at a dosage of 1.4mg/kg⁵³. Currently, Linagliptin has become the preferred first-line treatment for managing type 2 diabetes⁵⁴.

Swallowing therapy represents an effective method for the prevention of serious complications such as aspiration pneumonia. Esophageal dilatation and esophageal myotomy are recommended in some instances. Neurogenic bladder can be treated with anticholinergic drugs and occasional catheterization. In some cases, individuals with WS1 may undergo electrical stimulation and physical therapy¹. The use of natural attendants such as tauroursodeoxycholic acid and 4-phenyl butyric acid has demonstrated promise in clinical trials as potential treatments for WS¹⁶.

To mitigate neurodegeneration in WS1, researchers have identified the awakening of ER stress cells as a potential therapeutic approach. This involves stabilizing the normal conformation of mutant WFS1 proteins during folding, as demonstrated in studies by Pallotta et al., 2019 Other strategies include the use of ER calcium stabilizers such as Calpain inhibitor XI, Ibudilast to normalize resting cytosolic calcium, and the interaction between the suppression of cAMP cleavage and the calcium pathway, as described in analyses by^20,51,55,1.

Various drugs targeting ER stress, including valproic acid, GLP-1R antagonists (e.g., liraglutide, exenatide, semaglutide), and dipeptidyl peptidase-4 inhibitors (e.g., gemigliptin, sitagliptin, vildagliptin), have displayed potential in counteracting ER stress-induced cell death and increasing the expression of WFS1^57-58. In addition, mitochondrial modulators have been demonstrated to reinstate mitochondrial function in WS1 patients⁹. The potential to substitute mutant WFS1 alleles with wild-type WFS1 alleles in WS1 patient cells has been shown through gene therapy, particularly adeno-associated virus (AAV) rescue by wild-type WFS1 transfection, an d CRISPR/Cas9 WFS1 gene editing⁹.

In an investigation, the administration of dantrolene, a medication that hinders the escape of calcium into the cytosol by blocking ryanodine receptors in the endoplasmic reticulum, was found to inhibit the death of brain progenitor cells in individuals with Wolfram Syndrome (WS)⁵⁹. Notably, excessive daily dosages of this drug, exceeding 300 mg, have been linked to fatal hepatotoxicity^60,61. Recent studies have recommended that reduced daily doses, such as 200mg/day, may be safe for individuals without concurrent liver impairment or the use of hepatotoxic drugs^62.

Valproate has been shown to prevent endoplasmic reticulum stress-induced apoptosis in a diabetic nephropathy pattern⁶³, but its underlying molecular mechanisms in endoplasmic reticulum-stress-related illnesses are still under investigation⁶⁴. In the realm of WS treatment, there has been a recent surge in interest in gene-based therapies, such as an adeno-associated virus and Clustered Regularly Interspaced Short Palindromic Repeats technologies¹. Additionally, research is exploring the possibility of utilizing mesencephalic astrocyte-derived neurotrophic factor to enhance the number of existing β-cells and neurons¹.

POTENTIAL IMPLICATIONS:

WS, a genetic condition with no known cure, poses several challenges in terms of treatment. While certain symptoms can be managed with appropriate techniques, such as insulin for diabetes and vasopressin for diabetes insipidus, other issues like vision loss lack effective treatments. Renal diseases and neurological symptoms can be addressed through catheterization and medication, respectively. Optic atrophy, a condition similar to WS, also lacks specific drugs for treatment. However, desmopressin therapy has shown promise in improving diabetes insipidus symptoms in WS1 cases. Swallowing therapy, esophageal treatments, and medication can help manage complications like aspiration pneumonia and neurogenic bladder. Potential treatments for WS include the use of natural attendants and ER stress cell awakening. Normalizing calcium levels, gene therapy, and regenerative medicine strategies using induced pluripotent stem cells are being explored. Drugs targeting ER stress and mitochondrial modulators show potential in countering cell death and restoring mitochondrial function. However, certain medications like dantrolene and thiazolidinediones have associated risks and side effects. GLP-1R agonists and DPP-4 inhibitors have shown promise in inhibiting pancreatic apoptosis. Gene-based therapies and the use of neurotrophic factors are also being investigated.

CONCLUSION:

In summary, Wolfram syndrome is a rare neurological disorder characterised by deafness, diabetes mellitus, optic atrophy, and diabetes insipidus. It follows an autosomal recessive pattern of inheritance and is caused by alterations in the CISD2 and WFS1 genes. The diagnosis of WS relies on the presence of early-onset diabetes and progressive optic atrophy. Genetic analysis, such as Sanger sequencing of the WFS1 gene, is often used for confirmation.WS1 is caused by alterations in the WFS1 gene, leading to ER stress and necrosis in pancreatic and neurological cells. The prevalence of WS1 varies across populations, ranging from 1 in 770,000 to 1 in 100,000 live births. Complications of WS include neurological abnormalities, urinary tract problems, depression, and an increased risk of suicide. The median age of mortality in individuals with WS is around 30 years, primarily due to renal failure and central respiratory failure. Understanding the pathophysiology of WS has revealed the role of the ER and the unfolded protein response in protein folding and cellular homeostasis. A differential diagnosis of WS includes mitochondrial diseases and other genetic abnormalities causing ocular atrophy. While there is currently no cure for WS, careful clinical observation and adjunctive therapy can help alleviate symptoms. Further research is needed to explore potential therapeutic interventions for this complex and debilitating disorder.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

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.

Received on 09.06.2023 Modified on 27.07.2023

Res. J. Pharmacology and Pharmacodynamics.2023;15(4):172-178.

DOI: 10.52711/2321-5836.2023.00031