Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders.

Objective: Wolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately. Approach: Patient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants. Missense/in-frame variants were further classified as transmembrane or non-transmembrane based on whether they affected amino acid residues predicted to be in transmembrane domains of WFS1. Statistical analysis was performed using Wilcoxon rank-sum tests with multiple test adjustment applied via the Bonferonni correction. Results: A greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by diabetes mellitus and optic atrophy emerging significantly earlier in patients with two nonsense/frameshift variants compared with zero or one nonsense/frameshift variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy among patients with either one or two in-frame variants. Summary/Conclusion: The results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

Genotype and Clinical Characteristics of Patients with Wolfram Syndrome and WFS1-related Disorders.

Objective: Wolfram syndrome (WFS) is an autosomal recessive disorder associated with juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss. We sought to elucidate the relationship between genotypic and phenotypic presentations of Wolfram syndrome which would assist clinicians in classifying the severity and prognosis of Wolfram syndrome more accurately. Approach: Patient data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and patient case reports were analyzed to select for patients with two recessive mutations in the WFS1 gene. Mutations were classified as being either nonsense/frameshift variants or missense/in-frame insertion/deletion variants and statistical analysis was performed using unpaired and paired t-tests and one- and two-way ANOVA with Tukey's or Dunnett's tests. Results: A greater number of genotype variants correlated with earlier onset and a more severe presentation of Wolfram syndrome. Secondly, non-sense and frameshift variants had more severe phenotypic presentations than missense variants, as evidenced by optic atrophy emerging significantly earlier in patients with 2 nonsense/frameshift alleles compared with 0 missense transmembrane variants. In addition, the number of transmembrane in-frame variants demonstrated a statistically significant dose-effect on age of onset of diabetes mellitus and optic atrophy. Summary / Conclusions: The results contribute to our current understanding of the genotype-phenotype relationship of Wolfram syndrome, suggesting that alterations in coding sequences result in significant changes in the presentation and severity of Wolfram. The impact of these findings is significant, as the results will aid clinicians in predicting more accurate prognoses and pave the way for personalized treatments for Wolfram syndrome.

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome.

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.

Longitudinal progression of diabetes mellitus in Wolfram syndrome: The Washington University Wolfram Research Clinic experience.

OBJECTIVE: (1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder, which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. (2) Determine whether C-peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome. METHODS: N = 44 (25F/19M) participants with genetically confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010 to 2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta-cell function was assessed by determination of C-peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C-peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C-peptide decline during an intervention trial. RESULTS: 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C-peptide significantly decreased with increasing duration of diabetes mellitus (p < 0.0001); an optimal break point in C-peptide decline was identified to occur between 0.1 and 2.3 years after diabetes mellitus diagnosis. Twenty patients per group (active vs. control) were estimated to be needed to detect a 60% slowing of C-peptide decline during the first 2.3 years following diabetes diagnosis. CONCLUSION: C-peptide declines over time in Wolfram syndrome and could potentially be used as a marker of diabetes progression in interventional studies for Wolfram syndrome, especially within the first 2 years after diabetes diagnosis.

Insights from an Intervention to Support Early Career Faculty with Extraprofessional Caregiving Responsibilities.

Background: Insufficient support for balancing career and family responsibilities hinders retention of physician-scientists. Programs to improve retention of this important group of faculty are crucial. Understanding the experiences of program implementers is key to refining and improving program offerings. Methods: We conducted an interpretive, descriptive, and qualitative study as part of an ongoing evaluation of the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists (FRCS) awards. We conducted telephone interviews with 12 program directors representing all 10 US medical schools who received the Doris Duke funding in 2016. Results: Of the 12 participants, 10 were women (83.3%). Participating program directors perceived the FRCS award as capable of producing paradigmatic changes regarding how responsibilities at home and work in academic medicine are viewed and integrated by early-career faculty members. The main qualitative themes that captured directors' experiences implementing the program were as follows: (1) championing a new paradigm of support, (2) lessons learned while implementing the new paradigm, (3) results of the new paradigm, and (4) sustaining the paradigm. Conclusions: These findings may help to inform development of similar programs to retain and support the career progress of physician-scientists with extraprofessional caregiving responsibilities. The interviews illuminate ways in which the Doris Duke FRCS award has driven institutional culture change by normalizing discussion and prompted reassessment of extraprofessional challenges and how best to aid early-career faculty members in overcoming these challenges.

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome.

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic ß cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, ß cell functions were not significantly improved, but there was a significant correlation between baseline ß cell functions and change in ß cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1ß, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Management and Appropriate Use of Diazoxide in Infants and Children with Hyperinsulinism.

BACKGROUND: The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS: We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS: Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.

Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses.

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration.

Pancreatic stone protein/regenerating protein is a potential biomarker for endoplasmic reticulum stress in beta cells.

Endoplasmic reticulum (ER) stress in beta cells is an important pathogenic component of both type 1 and type 2 diabetes mellitus, as well as genetic forms of diabetes, especially Wolfram syndrome. However, there are currently no convenient ways to assess ER stress in beta cells, raising the need for circulating ER stress markers indicative of beta cell health. Here we show that pancreatic stone protein/regenerating protein (PSP/reg) is a potential biomarker for ER stressed beta cells. PSP/reg levels are elevated in cell culture and mouse models of Wolfram syndrome, a prototype of ER stress-induced diabetes. Moreover, PSP/reg expression is induced by the canonical chemical inducers of ER stress, tunicamycin and thapsigargin. Circulating PSP/reg levels are also increased in some patients with Wolfram syndrome. Our results therefore reveal PSP/reg as a potential biomarker for beta cells under chronic ER stress, as is the case in Wolfram syndrome.

Phenotype and response to growth hormone therapy in siblings with B4GALT7 deficiency.

B4GALT7 encodes beta-1,4-galactosyltransferase which links glycosaminoglycans to proteoglycans in connective tissues. Rare, biallelic variants in B4GALT7 have been associated with spondylodysplastic Ehlers-Danlos and Larsen of Reunion Island syndromes. Thirty patients with B4GALT7-related disorders have been reported to date with phenotypic variability. Using whole exome sequencing, we identified male and female siblings with biallelic, pathogenic B4GALT7 variants and phenotypic features of spondylodysplastic Ehlers-Danlos syndrome as well as previously unreported skeletal characteristics. We also provide detailed radiological characterization and describe the siblings' responses to growth hormone treatment. Our report extends the phenotypic spectrum of B4GALT7-associated spondylodysplastic Ehlers-Danlos syndrome and reports results of growth hormone treatment for patients with this rare disorder.

Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11ß-hydroxylase enzyme.

Posaconazole is an antifungal therapy reported to cause incident hypertension. Hypokalemia is also a known side effect. The combination of hypertension and hypokalemia suggests mineralocorticoid excess. We present the case of a 15-year-old adolescent male with hypertensive urgency while on prophylactic posaconazole therapy for a combined immunodeficiency. We identify the mechanism of posaconazole-induced hypertension to be inhibition of the 11ß-hydroxylase enzyme, resulting in elevated levels of the mineralocorticoid receptor activator deoxycorticosterone. Loss of function of the 11ß-hydroxylase enzyme is responsible for a rare form of congenital adrenal hyperplasia and can be associated with life-threatening adrenal crisis.

Lower Urinary Tract Dysfunction and Associated Pons Volume in Patients with Wolfram Syndrome.

PURPOSE: Wolfram syndrome is a neurodegenerative disorder characterized by childhood onset diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing impairment, and commonly bladder and bowel dysfunction. We hypothesized that there is an association between a smaller pons, which contains the pontine micturition center, and abnormal lower urinary tract function. MATERIALS AND METHODS: Patients with genetically confirmed Wolfram syndrome attended an annual multidisciplinary research clinic. Subjects underwent noninvasive urodynamic testing and brain magnetic resonance imaging, and completed validated patient reported outcome measures. Bowel and bladder diaries were completed before visits. Age and gender corrected linear and logistic mixed effects models were used to correlate pons volume, corrected for whole brain size, to urodynamic and patient reported outcomes. RESULTS: A total of 36 patients attended 142 visits between 2010 and 2016. Mean age was 16.9 years (range 7 to 30) and 64% of patients were female. Functional bladder capacity was decreased in 31% of the patients, normal in 54% and increased in 14%. Of the patients 44% and 54% had abnormal uroflowmetry and post-void residual, respectively, on at least 1 occasion. There was no increase through time in incidence of lower urinary tract dysfunction. Decreased pons volume was associated with increased post-void residual (p = 0.048) and higher PinQ (Pediatric Incontinence Questionnaire) score (p = 0.011), indicating lower quality of life and higher levels of dysfunction. CONCLUSIONS: A significant number of children, adolescents and young adults with Wolfram syndrome have objective evidence of lower urinary tract dysfunction. Decreased pons volume is associated with more abnormal urinary function and lower quality of life in patients with Wolfram syndrome.

The effects of disease-related symptoms on daily function in Wolfram Syndrome.

OBJECTIVE: To investigate daily function among individuals with Wolfram Syndrome (WFS) and examine whether any limitations are related to disease-related symptoms. METHODS: WFS (n = 31), Type 1 diabetic (T1DM; n = 25), and healthy control (HC; n = 29) participants completed the Pediatric Quality of Life Questionnaire (PEDSQL) Self and Parent Report. PEDSQL domain scores were compared among these groups and between WFS patients with and without specific disease-related symptoms. Relationships between PEDSQL scores and symptom severity as assessed by the Wolfram Unified Rating Scale (WURS) Physical Scale were also examined. RESULTS: Across most domains, the WFS group had lower PEDSQL Self and Parent Report scores than the T1DM and HC groups. WFS participants with urinary, sleep, and temperature regulation problems had lower PEDSQL scores than those without. The WURS Physical Scale correlated with Self and Parent Report PEDSQL domains. WFS group Self and Parent Reports correlated with each other. CONCLUSIONS: The WFS group reported lower daily function compared to T1DM and HC groups. Within WFS, worse symptom severity and the specific symptoms of sleep, temperature regulation, and urinary problems were associated with poorer daily function. These findings provide rationale for an increased emphasis on identifying, treating and understanding these less well-known symptoms of WFS.

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.

Sulfonylurea challenge test in subjects diagnosed with type 1 diabetes mellitus.

BACKGROUND: Patients with early onset diabetes because of defects in glucose-stimulated insulin secretion (GSIS) may respond better to sulfonylureas than insulin treatment. Such patients include those with monogenic disorders, who can be differentiated from autoimmune type 1 diabetes mellitus (T1DM) by genetic testing. Genetic testing is expensive and unknown defects in GSIS would not be diagnosed. AIMS: We propose a sulfonylurea challenge test to identify patients who have been clinically diagnosed with T1DM, but those who maintain a preferentially sulfonylurea-responsive insulin secretion. MATERIALS & METHODS: A total of 3 healthy controls, 2 neonatal diabetes mellitus (NDM) subjects, 3 antibody-positive (Ab+T1DM), and 12 antibody-negative (Ab-T1DM) subjects with type 1 diabetes, were given an intravenous bolus of glucose followed by an oral dose of glipizide. RESULTS: Healthy controls showed a robust C-peptide increase after both glucose and glipizide, but NDM subjects showed a large increase in C-peptide only following glipizide. As expected, 2 of 3 Ab+T1DM, as well as 11 of 12 Ab-T1DM showed no response to either glucose or glipizide. However, 1 Ab-T1DM and 1 Ab+T1DM showed a small C-peptide response to glucose and a marked positive response to glipizide, suggesting defects in GSIS rather than typical autoimmune diabetes. DISCUSSION: These data demonstrate the feasibility of the sulfonylurea challenge test, and suggest that responder individuals may be identified. CONCLUSIONS: We propose that this sulfonylurea challenge test should be explored more extensively, as it may prove useful as a clinical and scientific tool.

Neuroimaging evidence of deficient axon myelination in Wolfram syndrome.

Wolfram syndrome is a rare autosomal recessive genetic disease characterized by insulin dependent diabetes and vision, hearing and brain abnormalities which generally emerge in childhood. Mutations in the WFS1 gene predispose cells to endoplasmic reticulum stress-mediated apoptosis and may induce myelin degradation in neuronal cell models. However, in vivo evidence of this phenomenon in humans is lacking. White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome (n = 21) and healthy and diabetic controls (n = 50). Wolfram patients had lower fractional anisotropy and higher radial diffusivity in major white matter tracts and lower volume in the basilar (ventral) pons, cerebellar white matter and visual cortex. Correlations were found between key brain findings and overall neurological symptoms. This pattern of findings suggests that reduction in myelin is a primary neuropathological feature of Wolfram syndrome. Endoplasmic reticulum stress-related dysfunction in Wolfram syndrome may interact with the development of myelin or promote degeneration of myelin during the progression of the disease. These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.

Selective cognitive and psychiatric manifestations in Wolfram Syndrome.

BACKGROUND: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. METHODS: Individuals with genetically-confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. RESULTS: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. CONCLUSIONS: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well. TRIAL REGISTRATION: Current Clinicaltrials.gov Trial NCT02455414 .

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome.

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and ß cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.

Phenotypic characteristics of early Wolfram syndrome.

BACKGROUND: 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 University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. METHODS: Eighteen subjects (ages 5.9-25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. RESULTS: Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. CONCLUSIONS: WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.