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Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington Universi...
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... The identification of causative WFS1 genetic mutations has allowed for a genetic rather than purely clinical diagnosis of Wolfram syndrome. Observations of genetically diagnosed Wolfram syndrome individuals indicate that the disease phenotype is indeed much more variable than classically understood, extending to loss of taste and smell [13][14][15], bladder and bowel dysfunction [16][17][18], gait and balance issues [19,20], and mental health disorders [13,21]. Wolfram syndrome is associated with early brain structural alterations such as reduced or stalled white matter development [22][23][24][25]. ...
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
... Wolfram-like syndrome, also caused by mutations in WFS1, is an additional autosomal dominant condition that can cause hearing impairment (De Muijnck et al., 2023). However, WS patients show deficits in vibration sensation (Marshall et al., 2013), and smell identification and smell sensitivity deficits appear to progress with age (Alfaro et al., 2023(Alfaro et al., , 2020. In addition, trigeminal neuralgia-like headaches are observed in WS patients (Stone et al., 2021;Urano, 2016) but the cause and underlying pathophysiology is unknown. ...
... WS is a rare, incurable, genetic disorder (de Heredia et al., 2013). Increasingly, sensory deficits are being recognised in WS: patients complain of trigeminal-like pain (Urano, 2016) and show deficits in vibration sensation (Marshall et al., 2013), smell (Alfaro et al., 2023(Alfaro et al., , 2020 and hearing (Serbis et al., 2023). Hearing impairments are also common in patients with Wolfram-like syndrome, a condition caused by autosomal dominant mutations in WFS1 (De Muijnck et al., 2023), which may be related to the role of WFS1 in maintaining correct targeting of the beta 1 subunit of the Na + /K + ATPase (Richard et al., 2023). ...
... Our current data highlight a profound impairment of the trigeminal system in WS and the critical importance of Wfs1 and lysosomes for normal function of sensory neurons in WS. In the clinic, WS patients are known to complain of trigeminal neuralgia-like pain (Stone et al., 2021;Urano, 2016) and patients also show reduced vibration sensation (Marshall et al., 2013). Heterozygous mutations in WFS1 also cause sensory disturbances, such as hearing loss (De Muijnck et al., 2023;Lim et al., 2023). ...
Wolfram syndrome (WS) is a rare condition caused by homozygous or compound heterozygous mutations in the WFS1 gene primarily. It is diagnosed on the basis of early-onset diabetes mellitus and optic nerve atrophy. Patients complain of trigeminal-like migraines and show deficits in vibration sensation, but the underlying cause is unknown. Using accurate cell models and two separate, accurate rodent models of WS that show excellent face and construct validity, here we have examined trigeminus, sensation and sensory neuronal function in WS. Analysis of ex vivo and in vivo MRI sequences revealed profound trigeminal atrophy in each rodent model, a novel finding in WS. Optic nerve atrophy is a diagnostic sign in WS, and trigeminal atrophy occurred at the time of earliest loss of optic nerve volume. We also observed deficits in mechanical sensation in our mouse WS model, and pathological analysis revealed extensive inflammation in trigeminal sensory nucleus, both of which are novel findings in WS. Sensory neurons (dorsal root ganglia) showed impaired calcium handling upon depolarisation and reduced mitochondrial membrane potential. Finally, lysosomes were smaller, soma lysosome content was decreased and importantly, lysosome acidity was impaired in sensory neurons, all of which are novel findings in WS. We validated these findings using two separate publicly available datasets, both from WS patient fibroblast-derived neural stem cells. We observed a highly significant functional enrichment of GO cellular component lysosome-related terms among the differentially expressed proteins and genes, with the majority of lysosome-related proteins being downregulated. These data reveal extensive impairments in the trigeminal pathway and nociceptive neurons in WS that may contribute to trigeminal and sensory symptoms observed in patients. Moreover, we note that mutations in WFS1 are relatively common and, given the importance of WFS1 for sensory function, our data may also shed light on sensory impairments in general.
... Two WS patient derived induced pluripotent stem cell (iPSC) lines (kindly provided by Prof. F. Urano, Washington University School of Medicine), and their genetically corrected isogenic controls made by adenosine base editing [51], have been used in this study: patient 1, with a homozygous point mutation at c.2002 C > T [p.Q668X], and patient 2, with compound heterozygous mutations at c.376G > A [p.A126T] and c.1838G > A [p.W613X]. Phenotypic characteristics of these patients have previously been described in [45]. ...
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.
... The criteria for the clinical diagnosis of WFS are the coexistence of insulin-dependent diabetes mellitus with optic nerve atrophy accompanied by diabetes insipidus and deafness. Other symptoms include neurological, urodynamic, and endocrine disorders [1][2][3]. In WFS the clinical manifestation of diabetes mellitus occurs early, usually at the age of 4-7 years and is the first symptom of the syndrome. ...
In Wolfram syndrome (WFS), due to the loss of wolframin function, there is increased ER stress and, as a result, progressive neurodegenerative disorders, accompanied by insulin-dependent diabetes. The aim of the study was to evaluate the oral microbiome and metabolome in WFS patients compared with patients with type 1 diabetes mellitus (T1DM) and controls. The buccal and gingival samples were collected from 12 WFS patients, 29 HbA1c-matched T1DM patients (p = 0.23), and 17 healthy individuals matched by age (p = 0.09) and gender (p = 0.91). The abundance of oral microbiota components was obtained by Illumina sequencing the 16S rRNA gene, and metabolite levels were measured by gas chromatography–mass spectrometry. Streptococcus (22.2%), Veillonella (12.1%), and Haemophilus (10.8%) were the most common bacteria in the WFS patients, while comparisons between groups showed significantly higher abundance of Olsenella, Dialister, Staphylococcus, Campylobacter, and Actinomyces in the WFS group (p < 0.001). An ROC curve (AUC = 0.861) was constructed for the three metabolites that best discriminated WFS from T1DM and controls (acetic acid, benzoic acid, and lactic acid). Selected oral microorganisms and metabolites that distinguish WFS patients from T1DM patients and healthy individuals may suggest their possible role in modulating neurodegeneration and serve as potential biomarkers and indicators of future therapeutic strategies.
... Among NSHL patients that received a molecular diagnosis, 10/26 were affected by an isolated AR form of HL, underlining how recessive HL is the most common hereditary deafness, in line with previous studies reported in the literature [23]. These cases are represented by Patients 16,19,20,21,24,27,29,32,38,and 39. Alongside the frequent forms of AR NSHL, such as MYO15Aand TMPRSS3-related [24], variants in rarely mutated genes were also identified, as the cases of Patient 21, carrying a homozygous splicing variant in the LRTOMT gene, and Patient 27, presenting two compound heterozygous variants in the CLDN14 gene. ...
... Patient 46, affected by congenital bilateral profound sensorineural HL and retinitis pigmentosa, was a carrier both of the most frequent variants associated with NSHL (c.35delG, p.(Gly12Valfs * 2) in the GJB2 gene [28]) and of a novel heterozygous frameshift variant in the RPGR gene, which is causative of X-linked retinitis pigmentosa 3 (MIM: #300029). WES analysis of Patient 50, presenting severe bilateral sensorineural HL and cutaneous signs of pseudoxanthoma elasticum, highlighted the presence of a known heterozygous variant in the WFS1 gene [29], associated with Deafness, autosomal dominant 6/14/38 (MIM: # 600965) and an already-reported homozygous variant in the ABCC6 gene [30], causative of pseudoxanthoma elasticum (MIM: # 264800). ...
Hearing loss is the most frequent sensorineural disorder, affecting approximately 1:1000 newborns. Hereditary forms (HHL) represent 50–60% of cases, highlighting the relevance of genetic testing in deaf patients. HHL is classified as non-syndromic (NSHL—70% of cases) or syndromic (SHL—30% of cases). In this study, a multistep and integrative approach aimed at identifying the molecular cause of HHL in 102 patients, whose GJB2 analysis already showed a negative result, is described. In NSHL patients, multiplex ligation probe amplification and long-range PCR analyses of the STRC gene solved 13 cases, while whole exome sequencing (WES) identified the genetic diagnosis in 26 additional ones, with a total detection rate of 47.6%. Concerning SHL, WES detected the molecular cause in 55% of cases. Peculiar findings are represented by the identification of four subjects displaying a dual molecular diagnosis and eight affected by non-syndromic mimics, five of them presenting Usher syndrome type 2. Overall, this study provides a detailed characterisation of the genetic causes of HHL in the Italian population. Furthermore, we highlighted the frequency of Usher syndrome type 2 carriers in the Italian population to pave the way for a more effective implementation of diagnostic and follow-up strategies for this disease.
... Hallmark clinical symptoms of Wolfram syndrome include insulin-dependent diabetes , diabetes insipidus, neurodegeneration (Lugar et al. 2019), loss of vision , and loss of audition (Karzon et al. 2018). Wolfram syndrome is also associated with smell dysfunction (Marshall et al. 2013;Bischoff et al. 2015). ...
... The cohort of participants with Wolfram syndrome (n = 36) examined attended the Wolfram Research Clinic during the summer of 2019. Data from a subset of individuals (n = 21/36) who had attended the clinic before 2019 have been published (Marshall et al. 2013;Bischoff et al. 2015;Alfaro et al. 2020). Participants in the healthy control group were recruited via flyers and newsletter emails posted at the University of Illinois at Urbana-Champaign campus, Urbana, IL during the span of 2020-2021. ...
Wolfram syndrome is a rare disease characterized by diabetes, neurodegeneration, loss of vision, and audition. We recently found, in a young sample of participants (mean age 15 yrs), that Wolfram syndrome was associated with impairment in smell identification with normal smell sensitivity and whole-mouth taste function. However, these senses were assessed separately, and it is unknown whether smell-taste interactions are altered in Wolfram syndrome, which was the focus of this study. Participants with Wolfram syndrome (n=36; 18.2 ± 6.8 years) and sex-age equivalent healthy controls (n=34) were assessed with a battery of sensory tests. Using sip-and-spit methods, participants tasted solutions containing gustatory and olfactory stimuli (sucrose with strawberry extract, citric acid with lemon extract, sodium chloride in vegetable broth, and coffee) with and without nose clips, and rated perceived taste and retronasal smell intensities using the general Labeled Magnitude Scale. Participants also completed n-butanol detection thresholds and the University of Pennsylvania Smell Identification Test (UPSIT). Retronasal smell increased taste intensity of sucrose, sodium chloride, and coffee solutions similarly in both groups (P values <0.03). Compared to the control group, participants in the Wolfram group had lower UPSIT scores and reduced smell sensitivity, retronasal intensity, and saltiness (P values <0.03), but rated other taste intensities similarly when wearing the nose clip. Despite impairments in orthonasal smell identification, odor-induced taste enhancement was preserved in participants with Wolfram syndrome who still had some peripheral olfactory function. This finding suggests that odor-induced taste enhancement may be preserved in the presence of reduced olfactory intensity.
... The abovementioned reproducible genes identified in transcriptomic and proteomic datasets fit well the functional pathways revealed by GSEA. For example, "sensory perception of smell" and "olfactory receptor activity" are consistent with the involvement of Wfs1 in olfaction [169][170][171]. This finding is in good agreement with neuroanatomical anomalies in olfactory bulbs [98,100] and low capacity for odor discrimination in BTBR mice [172][173][174]. ...
Animal models of psychopathologies are of exceptional interest for neurobiologists because these models allow us to clarify molecular mechanisms underlying the pathologies. One such model is the inbred BTBR strain of mice, which is characterized by behavioral, neuroanatomical, and physiological hallmarks of schizophrenia (SCZ) and autism spectrum disorders (ASDs). Despite the active use of BTBR mice as a model object, the understanding of the molecular features of this strain that cause the observed behavioral phenotype remains insufficient. Here, we analyzed recently published data from independent transcriptomic and proteomic studies on hippocampal and corticostriatal samples from BTBR mice to search for the most consistent aberrations in gene or protein expression. Next, we compared reproducible molecular signatures of BTBR mice with data on postmortem samples from ASD and SCZ patients. Taken together, these data helped us to elucidate brain-region-specific molecular abnormalities in BTBR mice as well as their relevance to the anomalies seen in ASDs or SCZ in humans.
... Diabetes in Wolfram syndrome presents in patients around six years of age, and optic nerve atrophy manifests around age ten. Diabetes insipidus, neurogenic bladder, obstructive sleep apnea, and deafness may also develop in the next two decades of life, along with brainstem symptoms and cerebellar atrophy, such as dysphagia, ataxia, and central sleep apnea [62,[64][65][66][67][68]. ...
The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of “poorly folded proteins”, namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction.
... 189 Other reported features, including sensorineural deafness, central diabetes insipidus, urinary tract dysfunction, and neurological symptoms that develop later in a variable order even within the same family. [190][191][192] Many individuals with WFS are initially diagnosed as having T1D and subsequent loss of vision, which occurs 4 years after diabetes diagnosis, may be misdiagnosed as diabetic retinopathy. 193,194 Persons with WFS die at a median age of 30 years, mainly from neurodegenerative complications. ...
... Recent clinical and brain MRI data from our group's ongoing natural history study of Wolfram syndrome in children, adolescents and young adults describe an early neurophenotype of ophthalmologic deficits, impaired balance, smell identification, and hearing. Brain MRI analyses from our study and case studies of adults with Wolfram syndrome reveal reduced volumes in ventral pons, cerebellar white matter, thalamus, optic nerve, and total ICV (Rando et al., 1992;Saiz et al., 1995;Barrett et al., 1997;Hadidy et al., 2004;Pakdemirli et al., 2005;Yang et al., 2005;Ito et al., 2007;Mathis et al., 2007;Nickl-Jockschat et al., 2008;Waschbisch et al., 2011;Hershey et al., 2012;Pickett et al., 2012a,b;Karzon and Hullar, 2013;Marshall et al., 2013;Hoekel et al., 2014;Bischoff et al., 2015;Lugar et al., 2016;Zmyslowska et al., 2019;Samara et al., 2020), among other regions, even early in the disease progression (Hershey et al., 2012;Lugar et al., 2016Lugar et al., , 2019. Over time and age in children, adolescents and young adults, white matter volume increases in controls but specific white matter volumes (brainstem and ventral pons) decrease in Wolfram syndrome (Lugar et al., 2019). ...
Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8–13.9) pg/mL] relative to controls [5.6 (4.5–7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.
