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.

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.

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

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.

Novel WFS1 variants are associated with different diabetes phenotypes.

Background: The WFS1 gene encodes the protein wolframin, which is crucial for maintaining endoplasmic reticulum homeostasis. Variants in this gene are predominantly associated with Wolfram syndrome and have been implicated in other disorders such as diabetes mellitus and psychiatric diseases, which increases the rate of clinical misdiagnosis. Methods: Patients were diagnosed with early-onset unclassified diabetes according to their clinical and laboratory data. We performed whole-exome sequencing (WES) in 165 patients, interpreting variants according to the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines. Variant verification was done by Sanger sequencing. In vitro experiments were conducted to evaluate the effects of WFS1 compound heterozygous variants. Results: We identified WFS1 compound heterozygous variants (p.A214fs*74/p.F329I and p.I427S/p.I304T) in two patients with Wolfram Syndrome-Like disorders (WSLD). Both WFS1 compound heterozygous variants were associated with increased ER stress, reduced cell viability, and decreased SERCA2b mRNA levels. Additionally, pathogenic or likely pathogenic WFS1 heterozygous variants were identified in the other three patients. Conclusion: Our results underscore the importance of early genetic testing for diagnosing young-onset diabetes and highlight the clinical relevance of WFS1 variants in increasing ER stress and reducing cell viability. Incorporating these genetic insights into clinical practice can reduce misdiagnoses and improve treatment strategies for related disorders.

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.

Beyond Vision and Hearing: A Case Report of Wolfram Syndrome.

Wolfram syndrome (WFS) is an uncommon autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, diabetes insipidus, optic nerve degeneration, hearing impairment, and other abnormalities. Additionally, a portion of individuals experience neurological, endocrine, behavioral, and urinary tract disorders that make management more challenging. Here, we present a 22-year-old male who was diagnosed with type 1 diabetes at the age of 4 and received treatment with basal-bolus insulin therapy. He had blurring of vision and hearing loss at 13 years of age, and our evaluation revealed optic atrophy and sensorineural hearing loss. He had polydipsia and polyuria (intake/output of 5-6 L/day) despite a fairly controlled blood glucose level. Serum anti-diuretic hormone (ADH) was done, which confirmed the diagnosis of central diabetes insipidus. His sonogram and urinary flow studies revealed bilateral hydroureteronephrosis with reflux uropathy. We diagnosed him with neurogenic bladder disorder with detrusor sphincter dyssynergia. This patient had an early onset urological disorder with involvement of eyes and ears, with diabetes mellitus and diabetes insipidus, which satisfied the criteria of WFS. The genetic test confirmed the diagnosis. He is currently being managed with insulin and desmopressin.

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.

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.

Continuous glycemic monitoring in managing diabetes in adult patients with wolfram syndrome.

AIMS: In this study we evaluated the use of Continuous Glucose Monitoring system in adults with insulin-dependent diabetes in the course of Wolfram syndrome (WFS) in comparison to patients with type 1 diabetes (T1D). METHODS: Individuals with WFS (N = 10) used continuous glucose monitoring for 14 days and were compared with 30 patients with T1D matched using propensity score for age and diabetes duration. Glycemic variability was calculated with Glyculator 3.0. RESULTS: We revealed significant differences in glycemic indices between adults with Wolfram syndrome-related diabetes and matched comparison group. Patients with Wolfram syndrome presented lower mean glucose in 24-h and nighttime records [24h: 141.1 ± 30.4mg/dl (N = 10) vs 164.9 ± 31.3mg/dl (N = 30), p = 0.0427; nighttime: 136.7 ± 39.6mg/dl vs 166.2 ± 32.1mg/dl (N = 30), p = 0.0442]. Moreover, they showed lower standard deviation of sensor glucose over all periods [24h: 50.3 ± 9.2mg/dl (N = 10) vs 67.7 ± 18.7 mg/dl (N = 30), p = 0.0075; daytime: 50.8 ± 8.7mg/dl (N = 10) vs 67.4 ± 18.0mg/dl (N = 30), p = 0.0082; nighttime: 45.1 ± 14.9mg/dl (N = 10) vs 65.8 ± 23.2mg/dl (n = 30), p = 0.0119] and coefficient of variation at night [33.3 ± 5.8% (N = 10) vs 40.5 ± 8.8% (N = 30), p = 0.0210]. Additionally, WFS patients displayed lower time in high-range hyperglycemia (> 250mg/dl) across all parts of day [24h: 4.6 ± 3.8% (N = 10) vs 13.4 ± 10.5% (N = 30), p = 0.0004; daytime: 4.7 ± 3.9% (N = 10) vs 13.8 ± 11.2% (N = 30), p = 0.0005; nighttime: 4.2 ± 5.5% (N = 10) vs 12.1 ± 10.3% (N = 30), p = 0.0272]. CONCLUSIONS: Adult patients with Wolfram syndrome show lower mean blood glucose, less extreme hyperglycemia, and lower glycemic variability in comparison to patients with type 1 diabetes.

Wolfram Syndrome Type I Case Report and Review-Focus on Early Diagnosis and Genetic Variants.

Background and Objectives: Wolfram syndrome type 1 (OMIM# 222300; ORPHAcode 3463) is an extremely rare autosomal recessive syndrome with a 25% recurrence risk in children. It is characterized by the presence of juvenile-onset diabetes mellitus (DM), progressive optic atrophy (OA), diabetes insipidus (DI), and sensorineural deafness (D), often referred to by the acronym DIDMOAD. It is a severe neurodegenerative disease with a life expectancy of 39 years, with death occurring due to cerebral atrophy. For a positive diagnosis, the presence of diabetes mellitus and optic nerve atrophy is sufficient. The disease occurs because of pathogenic variants in the WFS1 gene. The aim of this article is to present a case report of Wolfram Syndrome Type I, alongside a review of genetic variants, clinical manifestations, diagnosis, therapy, and long-term management. Emphasizing the importance of early diagnosis and a multidisciplinary approach, the study aims to enhance understanding and improve outcomes for patients with this complex syndrome. Materials and Methods: A case of a 28-year-old patient diagnosed with DM at the age of 6 and with progressive optic atrophy at 26 years old is presented. Molecular diagnosis revealed the presence of a heterozygous nonsense variant WFS1 c.1943G>A (p.Trp648*), and a heterozygous missense variant WFS1 c.1675G>C (p.Ala559Pro). Results: The molecular diagnosis of the patient confirmed the presence of a heterozygous nonsense variant and a heterozygous missense variant in the WFS1 gene, correlating with the clinical presentation of Wolfram syndrome type 1. Both allelic variants found in our patient have been previously described in other patients, whilst this combination has not been described before. Conclusions: This case report and review underscores the critical role of early recognition and diagnosis in Wolfram syndrome, facilitated by genetic testing. By identifying pathogenic variants in the WFS1 gene, genetic testing not only confirms diagnosis but also guides clinical management and informs genetic counseling for affected families. Timely intervention based on genetic insights can potentially reduce the progressive multisystem manifestations of the syndrome, thereby improving the quality of life and outcomes for patients.

An adolescent male with persistent urinary symptoms.

An 11-year-old male child who presented with increased frequency of urination, thirst and feeling of incomplete void was initially diagnosed with diabetes mellitus (DM) based on elevated blood sugar. Polyuria and polydipsia were confirmed even after normalisation of blood sugar. A standardised water deprivation test showed presence of central diabetes insipidus (DI) and patient was started on desmopressin. Presence of DM and DI led to suspicion of DIDMOAD/Wolfram syndrome and ophthalmic examination confirmed bilateral optic atrophy. Despite treatment for DM and DI the urinary complaints persisted, and ultrasound showed persistent bilateral hydronephroureterosis. Bladder workup including voiding cystourethrography (VCUG) and urodynamic study reported thickened trabeculated bladder wall along with overactivity, poor compliance and high bladder pressure. Bladder dysfunction has been documented to be associated with Wolfram syndrome and often may lead to chronic kidney disease which can be prevented by early diagnosis and appropriate management. The case highlights the need for comprehensive evaluation of children with urinary symptoms.

Novel WFS1 Variants in Two Moroccan Families with Wolfram Syndrome.

Background: Wolfram syndrome (WFS) is an autosomal recessive disorder that often leads to diabetes, optic atrophy, and sensorineural hearing loss. The aim of this study was to determine the clinical characteristics and the genetic cause of the first two Moroccan families presenting with WFS. Methods: The clinical features of five members of two WFS families were evaluated. Whole-exome sequencing was conducted to explore the underlying genetic cause in the affected patients. Results: Two homozygous variants in the WFS1 gene were identified, each in one of the two families studied: a missense c.1329C>G variant (p.Ser443Arg) and a nonsense mutation c.1113G>A (p.Trp371Ter). These variants affected conserved amino acid residues, segregated well in the two families, and are absent from genetic databases and in controls of Moroccan origin. Bioinformatics analysis classified the two variants as pathogenic by in silico tools and molecular modeling. Conclusion: Our study identified for the first time two variants in Moroccan patients with WFS that extends the mutational spectrum associated with the disease.

Cardiac Wolframinopathies: A Case Report of Myocarditis and a Literature Review of Cardiac Involvement in Wolfram Syndrome 1.

Purpose: Myocarditis is frequently a sporadic disease, but may also occur in the context of genetic disorders which may increase susceptibility to cardiac inflammation. Cardiac involvement in Wolfram syndrome type 1 (WS1) has been scarcely characterized. To our knowledge, no cases of virus-negative myocarditis have been reported in the WS1 pediatric population. Methods: We report the description of a pediatric case of acute myocarditis in the context of WS1, followed by a literature review of cardiovascular involvement associated with wolframin variants, and discuss potential pathophysiological mechanisms and therapeutic options. Results: A young patient with WS1, treated with insulin and liraglutide, was admitted for acute chest pain. Cardiac magnetic resonance and endomyocardial biopsy were performed to confirm the clinical suspicion of myocarditis. While congenital heart diseases and arrhythmias have been described previously in patients with WS1, this is the first description of virus-negative myocarditis. Conclusions: Myocarditis may represent a possible manifestation of cardiovascular involvement in WS1. Cardiovascular screening may be considered in patients with WS1.

An adolescent with Wolfram syndrome and central sleep apnea.

Wolfram syndrome is a rare autosomal recessive disorder affecting approximately 1 in 500,000 individuals. The disorder is most commonly caused by mutations in the WFS1 gene, which encodes an endoplasmic reticulum protein, wolframin, which is thought to protect against endoplasmic reticulum stress-related apoptosis. The major clinical findings of Wolfram syndrome are diabetes mellitus and optic atrophy, both of which usually appear before 16 years of age. Common additional findings include sensorineural hearing impairment, central diabetes insipidus, nonautoimmune hypothyroidism, delayed puberty, neurogenic bladder, cerebellar ataxia, and psychiatric disorders. Central sleep apnea is an uncommon but serious feature of Wolfram syndrome. However, the clinical details of this manifestation have not been documented. Herein, we report an adolescent with recently diagnosed Wolfram syndrome who demonstrated severe central sleep apnea on polysomnography testing. CITATION: Harris JC, Kenkare JD, Schramm CM. An adolescent with Wolfram syndrome and central sleep apnea. J Clin Sleep Med. 2024;20(7):1205-1208.

Long term clinical follow up of four patients with Wolfram syndrome and urodynamic abnormalities.

OBJECTIVES: Wolfram syndrome is characterised by insulin-dependent diabetes (IDDM), diabetes insipidus (DI), optic atrophy, sensorineural deafness and neurocognitive disorders. The DIDMOAD acronym has been recently modified to DIDMOAUD suggesting the rising awareness of the prevalence of urinary tract dysfunction (UD). End stage renal disease is the commonest cause of mortality in Wolfram syndrome. We present a case series with main objective of long term follow up in four children having Wolfram syndrome with evaluation of their urodynamic profile. METHODS: A prospective follow up of four genetically proven children with Wolfram syndrome presenting to a tertiary care pediatric diabetes clinic in Pune, India was conducted. Their clinical, and urodynamic parameters were reviewed. RESULTS: IDDM, in the first decade, was the initial presentation in all the four children (three male and one female). Three children had persistent polyuria and polydipsia despite having optimum glycemic control; hence were diagnosed to have DI and treated with desmopressin. All four patients entered spontaneous puberty. All patients had homozygous mutation in WFS1 gene; three with exon 8 and one with exon 6 novel mutations. These children with symptoms of lower urinary tract malfunction were further evaluated with urodynamic studies; two of them had hypocontractile detrusor and another had sphincter-detrusor dyssynergia. Patients with hypocontractile bladder were taught clean intermittent catheterization and the use of overnight drain. CONCLUSIONS: We report a novel homozygous deletion in exon 6 of WFS-1 gene. The importance of evaluation of lower urinary tract malfunction is highlighted by our case series. The final bladder outcome in our cases was a poorly contractile bladder in three patients.

Neuroimaging features in Wolfram syndrome type 1.

Wolfram syndrome type 1 is a rare autosomal recessive genetic disorder which is characterized by the co-existence of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, and hence is also referred to as the acronym DIDMOAD. In this neuroimage, the typical neuroimaging features of a genetically confirmed case of Wolfram syndrome type 1 are presented. The presence of left-sided vestibulocochlear dysplasia is a novel finding in our case which has not been reported previously.

Overlap between ophthalmology and psychiatry - A narrative review focused on congenital and inherited conditions.

A number of congenital and inherited diseases present with both ocular and psychiatric features. The genetic inheritance and phenotypic variants play a key role in disease severity. Early recognition of the signs and symptoms of those disorders is critical to earlier intervention and improved prognosis. Typically, the associations between these two medical subspecialties of ophthalmology and psychiatry are poorly understood by most practitioners so we hope to provide a narrative review to improve the identification and management of these disorders. We conducted a comprehensive review of the literature detailing the diseases with ophthalmic and psychiatric overlap that were more widely represented in the literature. Herein, we describe the clinical features, pathophysiology, molecular biology, diagnostic tests, and the most recent approaches for the treatment of these diseases. Recent studies have combined technologies for ocular and brain imaging such as optical coherence tomography (OCT) and functional imaging with genetic testing to identify the genetic basis for eye-brain connections. Additional work is needed to further explore these potential biomarkers. Overall, accurate, efficient, widely distributed and non-invasive tests that can help with early recognition of these diseases will improve the management of these patients using a multidisciplinary approach.

High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes.

BACKGROUND: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. METHODS: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. RESULTS: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. CONCLUSION: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM.

Wolfram syndrome type 1: a case series.

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.

Wolfram Syndrome: A Curious Case of Repetitive Loss of Consciousness.

Wolfram syndrome is a rare, multisystemic, progressive, and autosomal-recessive genetic disease, characterized by diabetes mellitus and diabetes insipidus, optic nerve atrophy, deafness, and other neurological signs. The diagnosis is usually based on history and clinical manifestations but genetic tests are necessary for confirmation. Currently, there are no treatments available to cure or delay disease progression. This report describes a case of a 23-year-old male diagnosed with Wolfram syndrome who presented to the emergency department with several episodes of loss of consciousness. This case reinforces the need for an early diagnosis of obstructive and central apneas, respiratory failure, and dysphagia, in order to prevent and treat the complications of this disease and to improve patients' quality of life.