Wolfram Syndrome Research Articles

SID/SIEDP expert consensus on optimizing clinical strategies for early detection and management of wolfram syndrome.

Wolfram Syndrome (WFS) is a rare, multisystemic, degenerative disease leading to premature death. Clinical and genetic heterogeneity makes WFS diagnosis and management challenging. The Italian Society of Diabetes (SID) and the Italian Society for Pediatric Endocrinology and Diabetology (SIEDP) convened an expert panel of professional healthcare practitioners to provide up-to-date knowledge about the pathophysiology, clinical presentation and treatment of WFS, and recommendations for the earlydetection and optimal disease management. The consensus recommends the revision of diagnostic protocols to include genetic testing and comprehensive multidisciplinary evaluations to ensure accurate diagnosis of WFS, advocates for personalized management plans tailored to the unique needs of each patient, with an emphasis on exploring new potential drug therapies. A holistic care model that addresses the medical, psychological, and social challenges faced by patients with WFS and their families is strongly endorsed. The opinion underscores the importance of educating healthcare professionals about WFS to enhance early diagnosis and intervention, aiming to improve outcomes for patients through practical and evidence-based clinical strategies.

A WFS1 variant disrupting acceptor splice site uncovers the impact of alternative splicing on beta cell apoptosis in a patient with Wolfram syndrome.

Wolfram syndrome 1 (WS1) is an inherited condition mainly manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy. The causative gene, WFS1, encodes wolframin, a master regulator of several cellular responses, and the gene's mutations associate with clinical variability. Indeed, nonsense/frameshift variants correlate with more severe symptoms than missense/in-frame variants. As achieving a genotype-phenotype correlation is crucial for dealing with disease outcome, works investigating the impact of transcriptional and translational landscapes stemming from such mutations are needed. Therefore, we sought to elucidate the molecular determinants behind the pathophysiological alterations in a WS1 patient carrying compound heterozygous mutations in WFS1: c.316-1G>A, affecting the acceptor splice site (ASS) upstream of exon 4; and c.757A>T, introducing a premature termination codon (PTC) in exon 7. Bioinformatic analysis was carried out to infer the alternative splicing events occurring after disruption of ASS, followed by RNA-seq and PCR to validate the transcriptional landscape. Patient-derived induced pluripotent stem cells (iPSCs) were used as an in vitro model of WS1 and to investigate the WFS1 alternative splicing isoforms in pancreatic beta cells. CRISPR/Cas9 technology was employed to correct ASS mutation and generate a syngeneic control for the endoplasmic reticulum stress induction and immunotoxicity assays. We showed that patient-derived iPSCs retained the ability to differentiate into pancreatic beta cells. We demonstrated that the allele carrying the ASS mutation c.316-1G>A originates two PTC-containing alternative splicing transcripts (c.316del and c.316-460del), and two open reading frame-conserving mRNAs (c.271-513del and c.316-456del) leading to N-terminally truncated polypeptides. By retaining the C-terminal domain, these isoforms sustained the endoplasmic reticulum stress response in beta cells. Otherwise, PTC-carrying transcripts were regulated by the nonsense-mediated decay (NMD) in basal conditions. Exposure to cell stress inducers and proinflammatory cytokines affected expression levels of the NMD-related gene SMG7 (>twofold decrease; p<0.001) without eliciting a robust unfolded protein response in WFS1 beta cells. This resulted in a dramatic accumulation of the PTC-containing isoforms c.316del (>100-fold increase over basal; p<0.001) and c.316-460del (>20-fold increase over basal; p<0.001), predisposing affected beta cells to undergo apoptosis. Cas9-mediated recovery of ASS retrieved the canonical transcriptional landscape, rescuing the normal phenotype in patient-derived beta cells. This study represents a new model to study wolframin, highlighting how each single mutation of the WFS1 gene can determine dramatically different functional outcomes. Our data point to increased vulnerability of WFS1 beta cells to stress and inflammation and we postulate that this is triggered by escaping NMD and accumulation of mutated transcripts and truncated proteins. These findings pave the way for further studies on the molecular basis of genotype-phenotype relationship in WS1, to uncover the key determinants that might be targeted to ameliorate the clinical outcome of patients affected by this rare disease. The in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of WFS1 are available in the SRA database (BioProject PRJNA1109747).

Defects of WFS1-mediated peptide hormones secretion contribute to the manifestations of Wolfram syndrome

AimsThe study aims to investigate whether WFS1 is involved in the regulation of the exportation and secretion of other peptide hormones, as well as to elucidate the precise molecular mechanisms underlying WS caused by pathogenic mutations in the WFS1 gene. Materials and methodsThe plasma proteome from the WS patients (n = 2, male) and WFS1-deficient mice (n = 5, male) were analyzed using liquid-chromatography tandem mass spectrometry (LC-MS/MS), while age- and gender-matched healthy individuals and wildtype (WT) mice serve as controls. WFS1-deficient mice were intraperitoneally injected with IGF1 starting from 4 weeks of age. Body weight was monitored every 2 days, fasting blood glucose and glucose tolerance test were performed on the day 30 and day 40 after injection of IGF1, respectively. BiFC (bimolecular fluorescence complementation) and Co-immunoprecipitation (IP) were used to analyze the interaction between WFS1 and peptide hormones. Confocal microscopy was employed to analyze the colocalization of IGF1 with ER and Golgi. Key findingsPeptide hormones are deficient in both the plasma of WS patients and WFS1-deficient mice. WFS1 binds to and mediates the secretion of these peptide hormones, suggesting that WFS1 serves as a general COPII vesicular receptor for sorting peptide hormones. Interestingly, the WFS1 pathogenic mutations significantly disrupt its interaction with these peptide hormones. Furthermore, intraperitoneal administration of IGF1 partially attenuates high blood glucose levels in WFS1-deficient male mice. SignificanceThis study suggests that WS is characterized by defective peptide hormone secretion and proposes administration of these deficient peptide hormones as a promising treatment regimen for WS.

A novel (-)-(2S)-7,4'-dihydroxyflavanone compound for treating age-related diabetes mellitus through immunoinformatics-guided activation of CISD3.

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as "(-)-(2S)-7,4'-Dihydroxyflavanone", has the potential to counteract telomere shortening and improve metabolic pathways.

Assessment of Neuroradiological Features of Wolfram Syndrome (DIDMOD)

Assessment of Neuroradiological Features of Wolfram Syndrome (DIDMOD)

Characteristics of autosomal dominant WFS1-associated optic neuropathy and its comparability to OPA1-associated autosomal dominant optic atrophy

This study aims to describe the ophthalmic characteristics of autosomal dominant (AD) WFS1-associated optic atrophy (AD WFS1-OA), and to explore phenotypic differences with dominant optic atrophy (DOA) caused by mutations in the OPA1-gene. WFS1-associated diseases, or ‘wolframinopathies’, exhibit a spectrum of ocular and systemic phenotypes, of which the autosomal recessive Wolfram syndrome has been the most extensively studied. AD mutations in WFS1 also cause various phenotypical changes including OA. The most common phenotype in AD WFS1-associated disease, the combination of OA and hearing loss (HL), clinically resembles the ‘plus’ phenotype of DOA. We performed a comprehensive medical record review across tertiary referral centers in the Netherlands and Belgium resulting in 22 patients with heterozygous WFS1 variants. Eighteen (82%) had HL in addition to OA. Diabetes mellitus was found in 7 (32%). Four patients had isolated OA. One patient had an unusual phenotype with anterior chamber abnormalities and malformations of the extremities. Compared to DOA, AD WFS1-OA patients had different color vision abnormalities (red-green vs blue-yellow in DOA), abnormal OPL lamination on macular OCT (absent in DOA), more generalized thinning of the retinal nerve fiber layer, and more reduced and delayed pattern reversal visual evoked potentials.

Assessment Of Neuroradiological Features Of Wolfram Syndrome

The WOLFRAM syndrome is a rare hereditary neurodegenerative disorder described for the first time in 1938 as the coexistence of a diabetes mellitus and optic atrophy to which join frequently a diabetes insipidus and a bilateral deafness. Here we report cranial MRI findings in a 20 year old patient who presented with diabetes mellitus, decreased visual loss since 3 years with progressive loss of hearing since 6 months. We reviewed the brain MR images to determine the frequency and characteristics of common neuroradiologic findings. Imaging findings include absence of the normal high signal of the neurohypophysis, atrophy of visual pathways, the brainstem, cerebellum and cerebral cortex and abnormal signal changes in pons

8656 A Case of Wolfram Syndrome Accompanied by Growth Hormone Deficiency

8656 A Case of Wolfram Syndrome Accompanied by Growth Hormone Deficiency

Insights from a Wolfram syndrome cohort: clinical and molecular findings from a specialized diabetes reference center.

Considering the rarity and clinical and molecular diversity of Wolfram syndrome (WS), the objective of this study was to identify patients with a clinical presentation suggestive of WS following up at a single Brazilian diabetes service and analyze their clinical and molecular characteristics. The study included all patients with a clinical presentation of WS following up between 1991 and 2022 with early-onset diabetes mellitus and other WS signs and symptoms. A retrospective analysis was conducted, including patients' age, sex, consanguinity, age at symptom onset, diagnosis of diabetes mellitus, optic atrophy, diabetes insipidus, neurological and psychiatric disorders, hearing loss, urinary disorders, hypogonadism, and WFS1 molecular analysis. Eight patients were identified, all of whom were diagnosed with diabetes mellitus at an average age of 3.7 years. Optic atrophy, diabetes insipidus, and hearing loss were common, while psychiatric and neurological alterations were observed in some cases. Genetic analysis revealed pathogenic variants in homozygosity or compound heterozygosity. The most frequent variant was p. Val412Serfs29, present in five of the seven families. This study represents the second-largest Brazilian sample of WS and is the first cohort from a single center in Southeast Brazil. The patients had an early, severe, and complete clinical presentation. The genetic variants identified were consistent with previous literature descriptions. The variant p. Val412Serfs29 was particularly common in this cohort, highlighting its relevance in the region.

Does real time continuous glucose monitoring improve glycaemic control in patients with Wolfram syndrome and insulin dependent diabetes mellitus?

Does real time continuous glucose monitoring improve glycaemic control in patients with Wolfram syndrome and insulin dependent diabetes mellitus?

Images in sleep medicine sleep-disordered breathing in Wolfram's syndrome - A near-fatal event

Wolfram syndrome (WS) is a rare autosomal-recessive genetic disorder. The authors report a case of a patient with WS and undiagnosed/untreated obstructive sleep apnea (OSA) associated with prolonged periods of apnea and hypopnea and nocturnal hypoxemia, which may have predisposed him to the development of a near-fatal event during sleep. Addressing sleep-disordered breathing in patients with WS could improve their quality of life and potentially their longevity.

Endoplasmic reticulum-mitochondria lockdown in Wolfram syndrome

Wolfram syndrome (WS) is an incurable autosomal recessive disorder originally described as a mitochondriopathy. In a recent work, Liiv and colleagues found that an impaired endoplasmic reticulum (ER)-to-mitochondria calcium shuttling underlies mitochondrial dysfunction in WS models.

Clinical Trials for Wolfram Syndrome Neurodegeneration: Novel Design, Endpoints, and Analysis Models.

Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome. We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model. Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group. For rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs.

Discovery of a TRMT10A mutation in a case of atypical diabetes: Case report

It is notable that monogenic forms of diabetes are exceedingly uncommon, with only 28 genes thus far identified. Such conditions frequently result in the dysfunction of pancreatic cells responsible for insulin production. Mutation in the TRMT10A gene leads to a rare genetic disease that is associated with endocrine and metabolic disorders, including diabetes and short stature. This article presents a review of the existing literature on the subject, describing the association between TRMT10A gene mutation and diabetes. It also presents the clinical case of a young girl with type 1 diabetes and facial dysmorphia. TRMT10A gene mutation has been linked to syndromic juvenile diabetes in a manner analogous to Wolfram's syndrome. This form of diabetes, which manifests in early childhood and is associated with microcephaly, epilepsy and intellectual disability, is caused by mutations in the gene for homolog A of tRNA methyltransferase 10 (TRMT10A). This emphasizes the importance of using a targeted panel to recognize previously unidentified monogenic diabetes among early-onset non-insulin-dependent diabetes in the absence of obesity and autoimmunity. In view of the aforementioned data, it is recommended that TRMT10A sequencing be considered in children or adults with early-onset diabetes and a history of intellectual disability, microcephaly and epilepsy.

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

Clinical Characteristics and Audiological Profiles of Patients with Pathogenic Variants of WFS1.

Background: Mutations in Wolfram syndrome 1 (WFS1) cause Wolfram syndrome and autosomal dominant non-syndromic hearing loss DFNA6/14/38. To date, more than 300 pathogenic variants of WFS1 have been identified. Generally, the audiological phenotype of Wolfram syndrome or DFNA6/14/38 is characterized by low-frequency hearing loss; however, this phenotype is largely variable. Hence, there is a need to better understand the diversity in audiological and vestibular profiles associated with WFS1 variants, as this can have significant implications for diagnosis and management. This study aims to investigate the clinical characteristics, audiological phenotypes, and vestibular function in patients with DFNA6/14/38. Methods: Whole-exome or targeted deafness gene panel sequencing was performed to confirm the pathogenic variants in patients with genetic hearing loss. Results: We identified nine independent families with affected individuals who carried a heterozygous pathogenic variant of WFS1. The onset of hearing loss varied from the first to the fifth decade. On a pure-tone audiogram, hearing loss was symmetrical, and the severity ranged from mild to severe. Notably, either both low-frequency and high-frequency or all-frequency-specific hearing loss was observed. However, hearing loss was non-progressive in all types. In addition, vestibular impairment was identified in patients with DFNA6/14/38, indicating that impaired WFS1 may also affect the vestibular organs. Conclusions: Diverse audiological and vestibular profiles were observed in patients with pathogenic variants of WFS1. These findings highlight the importance of comprehensive audiological and vestibular assessments in patients with WFS1 mutations for accurate diagnosis and management.

Family Planning in Genetic Optic Atrophies in Israel, a Case Series and a Discussion of Ethical Considerations.

Patients with genetic optic atrophies must navigate all stages of life with their visual impairment, including the important milestone of family planning. Advances in genetic testing now allows physicians and affected families to consider medical help with the aim of preventing blindness through preconception, preimplantation, and perinatal methods. This case series presents 4 patients with different genetic optic atrophies (Leber hereditary optic neuropathy [LHON], autosomal dominant optic atrophy, Wolfram syndrome, and papillorenal syndrome) who were followed by the Neuro-Ophthalmology Unit at a tertiary medical center between 2010 and 2023 and were of child-bearing age. The aim of this study was to increase understanding in family planning options for patients with optic atrophies, raise awareness of the solutions available, and provide guidance for clinicians to support their patients. Advances in medicine, genetics, and medical technology allow multidisciplinary teams to assist patients in fulfilling their desire for a genetically healthy offspring. Customized solutions can be designed to meet the specific challenges posed by each type of genetic optic atrophy. The solutions proposed in this series are based on genetic testing done in the parents, which then allows to plan medical and genetic intervention individually. The solutions opted for in this series range from the decision to not have another child until PGD (Preimplantation genetic diagnosis). We describe how genetic advancements have made it possible for patients with the 4 most common hereditary optic atrophies to fulfill their wish to have children without visually threatening genetic mutations. We also review the recent literature on the penetrance of optic atrophy in OA-mutation carriers and raise 2 significant ethical considerations: the reduction of a future life to a non-life-threatening impairment and that of public expenditure for non-life-threatening conditions.

Wolfram Syndrome 1: A Neuropsychiatric Perspective on a Rare Disease.

Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease's progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient's relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1's neurophysiopathology is critical for achieving the goal of improving patients' quality of life and life expectancy.

ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome

Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.

A Case of Wolfram Syndrome from South India: Diabetologist’s Perspective

Wolfram syndrome (WS), also called diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, diabetes insipidus, optic atrophy, and deafness as well as several other disorders including neurodegeneration. It is well documented that genetic mutations in the genes WFS 1, that codes for the protein Wolframin and WFS 2, also known as CISD2, which encodes for a transmembrane protein located in the endoplasmic reticulum, are responsible for wolfram syndrome. It is usually observed in children born of consanguineous marriages, and there are currently no effective therapies to prevent or slow the progression of the condition. Current research focuses on evaluating several possible repurposed drugs and small molecules to reduce endoplasmic reticulum stress in WS and slow progression of the disease. This report describes the case of a 13-year-old female with uncontrolled glycemia and WS.