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Abstract Background Wolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic atrophy, sensorineural deafness, and diabetes as the main features. Owing to clinical phenotypic heterogeneity, the misdiagnosis rate is high. However, early accurate diagnosis and comprehensive management are key to improving quality of life and prolonging life. Results Eleven patients from seven WS pedigrees with 10 mutation sites (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, c.G2105A, and c.G1393C) in the WFS1 gene were included. We conducted further expert department analysis to clarify the diagnosis and analyze the correlation between genes and phenotypes. Conclusions The genotypes of these patients were closely associated with their phenotypes. The clinical data of the patients were analyzed to provide a basis for the diagnosis and clinical management of the disease.

Abstract Background Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by juvenile onset diabetes, optic nerve atrophy and other systemic manifestations. Symptoms of the disease arise mostly in early childhood with a high mortality rate due to severe neurological complications. Two causative genes have been identifed in this syndrome; the classical form is caused by autosomal recessive mutations of the WFS1 gene, and a smaller portion of patients has mutations in the CIDS2 gene, which are responsible for autosomal recessive Wolfram syndrome 2. Case presentation We report the case of a 28-year-old Moroccan boy born from consanguineous parents referred to the department of medical genetics at the National Institute of Health in Rabat. The diagnosis of Wolfram syndrome was made based on insulin-dependent diabetes, optic nerve atrophy, sensorineural deafness, urological abnormalities and psychiatric illness. To establish the diagnosis at a molecular level, we performed next-generation sequencing in the index patient, which revealed compound heterozygous WFS1 mutations: c.1113G > A (p.Trp371Ter) and c.1223_1224insGGAACCACCTGGAGCCCTATGCCCATTT (p.Phe408fs). This second variant has never been described in patients with Wolfram syndrome. Conclusion The identification of the genetic substrate in our patient confirmed the clinical diagnosis of Wolfram syndrome and allowed us to provide him an appropriate management and genetic counseling to his family.

Abstract Background Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Mutations in Wolfram syndrome 1 (WFS1) gene may cause dysregulated endoplasmic reticulum (ER)-stress and cell apoptosis, contributing to WS symptoms. The aim of this study was to identify the molecular etiology of a case of WS and to explore the functional consequence of the mutant WFS1 gene in vitro. Methods A 27 years-old Chinese man was diagnosed as wolfram syndrome type 1 based on clinical data and laboratory data. DNA sequencing of WFS1 gene and mitochondrial m.3337G > A, m.3243A > G mutations were performed in the patient and his 4 family members. Functional analysis was performed to assessed the in vitro effect of the newly identified mutant. ER stress were evaluated by ER stress response element (ERSE)-luciferase assay. Cell apoptosis were performed by CCK-8, TUNEL staining and flow cytometric analysis. Results A novel heterozygous 10-base deletion (c. 2067_2076 del10, p.W690fsX706) was identified in the patient. In vitro studies showed that mutant p.W690fsX706 increased ERSE reporter activity in the presence or absence of thapsigargin instead of wild type WFS1. Knockdown of WFS1 activated the unfolded protein response (UPR) pathway and increased the cell apoptosis, which could not be restored by transfection with WFS1 mutant (p.W690fsX706) comparable to the wild type WFS1. Conclusions A novel heterozygous mutation of WFS1 detected in the patient resulted in loss-of-function of wolframin, thereby inducing dysregulated ER stress signaling and cell apoptosis. These findings increase the spectrum of WFS1 gene mutations and broaden our insights into the roles of mutant WFS1 in the pathogenesis of WS.

Abstract Background Wolfram syndrome (WS), caused by mutations of the Wolfram syndrome 1 (WFS1) gene on chromosome 4p16.1, is an autosomal recessive disorder characterized by diabetes insipidus (DI), neuro-psychiatric disorders, hearing deficit, and urinary tract anomalies. Case presentation Here we report a 11-year-old Chinese boy who presented with visual loss, was suspected with optic neuritis (ON) or neuromyelitis optica (NMO) and referred to our department for further diagnosis. Finally he was diagnosed with WS because of diabetes mellitus (DM) and optic atrophy (OA). Eight exons and flanking introns of WFS1 gene were analyzed by sequencing. A novel mutation c.1760G > A in WFS1 gene of exon 8 was identified. Conclusion This report reviews a case of WS associated with a novel mutation, c.1760G > A in WFS1 gene of exon 8, and emphasizes that WS should be taken into account for juveniles with visual loss and diabetes mellitus.