Wolfram syndrome is a rare genetic spectrum disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, accompanied by other variable clinical manifestations. At ...present, the prognosis of this syndrome is very poor, the specific molecular mechanism is not clear, effective treatments are lacking to delay, prevent or reverse the development of Wolfram syndrome, and many patients die prematurely due to severe neurological dysfunction. This increases the urgency of the research on the pathogenic molecular mechanism related to Wolfram syndrome and the development of new therapies. This article summarizes the research progress on the pathogenic molecular mechanism and treatment status of Wolfram syndrome, in order to provide reference for the further mechanism research, prevention and treatment of Wolfram syndrome.
Pancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new ...treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS β-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed β-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with β-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.
Wolfram Syndrome (WS) is a rare autosomal recessive neurodegenerative disorder caused by mutations in WFS1 or CISD2 (WFS2). We present a rare case report of pregnancy with WFS1 spectrum disorder ...(WFS1-SD) in our hospital and reviewed literature to provide the management of pregnancy in these patients through multi-disciplinary cooperation.
A 31-year-old (gravida 6, para 1) woman with WFS1-SD conceived naturally. During the pregnancy, she adjusted insulin intermittently to control blood glucose and monitored intraocular pressure changes under the guidance of doctors without any complications. Cesarean section was delivered at 37+4 weeks of gestation due to breech position and uterine scar and the neonatal weight was 3200 g. Apgar score 10 at 1 min, 10 at 5-min and 10 at 10 min, respectively. This rare case had a good maternal and infant outcome under multidisciplinary management.
WS is an extremely rare disease. Limited information is available on the impact and management of WS on maternal physiologic adaptation and fetal outcome. This case provide a guide for clinicians to raise awareness of this rare disease and strengthen the management of pregnancy in these patients.
Die vergleichende Analyse von Wolframs von Eschenbach Willehalm und der Hystoria von dem wirdigen ritter sant Wilhelm ist auf die Formen und Funktionen der Erzählerstimme und der Figurenrede ...fokussiert, wobei die inquit-Formeln eingehender untersucht werden. Erzählerstimme und Figurenrede haben angesichts der modifizierten Rezeptionsbedingungen und des Ãbergangs von Vers zu Prosa erhebliche Veränderungen erfahren. Schlüsselwörter: Wolfram von Eschenbach, Willehalm, Hystoria von dem wirdigen ritter sant Wilhelm, Erzählerstimme, Figurenrede, inquit-Formel, Versroman, Prosaroman Komparativna analiza Willehalma Wolframa von Eschenbacha in njegove priredbe Hysteria von dem wirdigen ritter sant Wilhelm se osredinja na oblike in funkcije glasu pripovedovalca in govora likov; pri tem avtorica vecjo pozornost posveca spremnim stavkom. Glede na razlicne pogoje recepcije in prehoda z verza na prozo sta se pripovedovalcev glas in govor likov bisrveno spremenila. Kljucne besede: Wolfram von Eschenbach, Willehalm, Hysteria von dem wirdigen ritter sant Wilhelm, glas pripovedovalca, govor likov, spremni stavek, roman v verzih, roman v prozi
Metabolic Treatment of Wolfram Syndrome Iafusco, Dario; Zanfardino, Angela; Piscopo, Alessia ...
International journal of environmental research and public health,
02/2022, Letnik:
19, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Wolfram Syndrome (WS) is a very rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Usually, the first clinical sign is non-autoimmune diabetes even if ...other clinical features (optic subatrophy, neurosensorial deafness, diabetes insipidus) may be present in an early state and may be diagnosed after diabetes' onset. Prognosis is poor, and the death occurs at the median age of 39 years as a consequence of progressive respiratory impairment, secondary to brain atrophy and neurological failure. The aim of this paper is the description of the metabolic treatment of the WS. We reported the experience of long treatment in patients with this syndrome diagnosed in pediatric age and followed also in adult age. It is known that there is a correlation between metabolic control of diabetes, the onset of other associated symptoms, and the progression of the neurodegenerative alterations. Therefore, a multidisciplinary approach is necessary in order to prevent, treat and carefully monitor all the comorbidities that may occur. An extensive understanding of WS from pathophysiology to novel possible therapy is fundamental and further studies are needed to better manage this devastating disease and to guarantee to patients a better quality of life and a longer life expectancy.
Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency ...affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.
Wolfram syndrome (WS) is a rarely seen autosomal recessive multisystem neurodegenerative disorder caused by mutations in the
gene.
Three sisters with WS had diabetes mellitus (DM) at 4 years of age ...and optic atrophy. In addition, the first case had hearing impairment, and the second case had diabetes insipidus and urinary incontinence. Linagliptin was administered to the first case as add-on therapy to intensive insulin treatment 15 years after the onset of DM, and her insulin need showed a dramatic decrease. The third case had a remission phase one month after the onset of DM.
Even in cases with the same mutation, symptoms and findings may widely vary in WS. Remission of diabetes has rarely been reported in WS. Also, this report describes the first trial of a dipeptidyl peptidase-4 inhibitor in a patient with WS which provided a decrease in exogenous insulin need.
Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously ...shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.
Aims/hypothesis
Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the
WFS1
gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve ...atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons.
Methods
The effect of the GLP-1R agonists dulaglutide and exenatide was examined in
Wfs1
knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome
,
and humanised mice.
Results
Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons.
Conclusions/interpretation
Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome.
Graphical abstract
We studied 45 patients with Wolfram syndrome 1 (WS1) to describe their clinical history and to search for possible genotype-phenotype correlations.
Clinical criteria contributing to WS1 diagnosis ...were analyzed. The patients were classified into three genotypic classes according to type of detected mutations.
WS1 prevalence in Italy is 0.74/1,000,000. All four manifestations of DIDMOAD were found in 46.7% of patients. Differently combined WS1 clinical features were detected in 53.3% of patients. We found 35 WFS1 different mutations and a novel missense mutation, c.1523A>G. WS1 patients were homozygotes or compound heterozygotes for WFS1 mutations except for 2 heterozygote patients (4.5%). Each genotypic group exhibited a different age onset of DM, D, and DI but not of OA. Genotypic Group 2 patients manifested a lower number of clinical manifestations compared to Groups 1 and 3. Moreover, genotypic Group 1 patients tended to have a shorter survival time than the other groups. No differences were found regarding type of clinical pictures.
Our study suggested that molecular WFS1 typing is a useful tool for early assessment of clinical history, follow-up, and prognosis of WS1.
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