{"paper_id":"0e92d1be-216c-49d7-aa90-c8a54732aa3e","body_text":"New variants of Wolfram syndrome (WS) in an Ecuadorian population. The “Valdivia Project”. A Cross-Sectional Study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article New variants of Wolfram syndrome (WS) in an Ecuadorian population. The “Valdivia Project”. A Cross-Sectional Study. Josefa Palacio, Maria Verdesoto, Noemí Bautista, Abigail Segura, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7544843/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Apr, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 6 You are reading this latest preprint version Abstract Objective: This study aims to document the first genetically confirmed cases of WS in Ecuador. Design and Methods: A Cross-Sectional study was conducted among individuals with early-onset insulin-dependent diabetes, residing in Santa Elena Province, Ecuador. A detailed clinical history and family tree were obtained along with laboratory and imaging diagnostics. A genetic whole exome sequencing was performed to confirm WS or not (NSW). Results: This Ecuadorian cohort included 38 participants (19 males) aged <35 years with an average diabetes onset at 3 years old. Eight are siblings, and 5 are first cousins. Genetic studies tested positive for WS in 26(69%) patients, which yields a prevalence of 1/12,000 inhabitants and the presence of two previously undescribed variants located in exon 8. Twenty-three were homozygous. Positive antibody testing was reported in 3/26 WS and in 4/11 NSW patients. High prevalence of severe and early neurological complications: optic atrophy, deafness and urinary disorders were documented. No patient had diabetes insipidus. Conclusions: Findings suggest the highest WS prevalence worldwide and two novel WS1 variants. In addition, there is high consanguinity and frequency of severe, early clinical complications among WS patients. Only 11% were diagnosed with type 1 diabetes. Must be phenotyping patients with early onset diabetes. Wolfram syndrome type 1 diabetes optic atrophy sensorineural deafness new variant Figures Figure 1 Article Highlights Why did we undertake this study? We identified a cohort of young people with type 1 diabetes and severe and early neurodegenerative complications. What is the specific question(s) we wanted to answer? Could these neurodegenerative complications be linked to Wolfram syndrome? What did we find? We identified two new variants of WS. All patients presented with early-onset diabetes, with an average age of onset of three years. There was a high prevalence of severe and early neurological complications, including optic atrophy (92%), deafness (80%), and urinary disorders (72%). What are the implications of our findings? Ecuadorian patients under the age of 16 with non-autoimmune diabetes and optic atrophy should be investigated for WS to ensure they receive appropriate treatment. INTRODUCTION Wolfram syndrome (WS) is a rare, autosomal recessive, neurodegenerative genetic disorder characterized by diabetes insipidus, early-onset non-autoimmune diabetes, optic atrophy, and sensorineural deafness, classically known by the acronym DIDMOAD [ 1 ]. This is often accompanied by urological disorders such as bladder dysfunction and loss of sphincter control, which is why some authors propose extending the term to DIDMOADUD [ 2 ]. WS is caused by mutations in two main genes: WFS1, located on chromosome 4p16.1; and the WFS2 gene located on chromosome 4q22-24, reported in families of Jordanian descent and characterized by the absence of diabetes insipidus and gastrointestinal manifestations such as ulcers and bleeding [ 3 ]. The estimated prevalence of WS worldwide is 1 per 55,000 to 1 per 770,000 inhabitants, although it varies considerably depending on the population [ 4 ]. Rates of 1/1,000,000 have been reported in Spain [ 4 ]; 1/770,000 in the United Kingdom [ 5 ], 1/100,000 in North America; 1/68,000 in the Lebanese population and 1/54,478 in Sicily [ 2 ]. In Ecuador, at the time of this study, no epidemiological data or clinically confirmed cases of this disease had been reported. Mutations in the WFS1 gene affect the production and function of wolframin, an 890-amino acid transmembrane protein expressed mainly in the endoplasmic reticulum (ER) of cells in the central nervous system, pancreatic β cells, heart, and skeletal muscle [ 6 – 8 ]. Wolframin participates in maintaining calcium homeostasis, controlling ER stress, and regulating apoptosis [ 6 , 9 ]. More than 200 mutations have been identified in the WFS1 gene, most of them in exon 8, which encodes the C-terminal transmembrane domain, causing significant cellular dysfunction, especially in pancreatic β cells, leading to an early form of diabetes mellitus, and in neurons, causing progressive autosomal neurosensory degeneration [ 8 ]. Wolfram Syndrome entails a limited life expectancy, with an average around 30 years and a range from 25 to 49 years, depending on the severity of neurological involvement [ 5 ]. The most common cause of death is central respiratory failure, a direct consequence of progressive brainstem atrophy [ 8 ]. This study aims to document for the first time clinically confirmed cases of Wolfram Syndrome in Ecuador and to report the possible identification of two new genetic variants, thereby contributing to the epidemiological and molecular understanding of this disease in Latin America. METHODOLOGY This article was written following the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist for reporting observational studies [ 10 ]. This is a Cross-Sectional study conducted among individuals with early-onset insulin-dependent diabetes, residing in the Santa Elena Province, Ecuador. All participants with a prior diagnosis of type 1 diabetes (aged < 35) were included in the study. Descriptive variables included age, gender, occupation, income, personal and family medical history, BMI, nutritional status, and blood pressure. Data collection was carried out by trained personnel from March 2023 to March 2025. At the start of the study, participants were evaluated for demographic, anthropometric, and nutritional characteristics. A detailed clinical history and family tree were obtained. Laboratory studies included: complete blood count, blood chemistry, lipid profile, liver function tests, electrolytes, HbA1c, C-peptide, antibodies (tyrosine phosphatase 2, islet cell or GAD-65), thyroid function tests, serum osmolarity, serum cortisol, IGF1, general urine analysis, albumin/creatinine ratio, FSH, LH, estradiol, testosterone, vitamin D3 and B12. In addition, genetic testing was performed: ORION (Whole Exome Sequencing - WES) using Massively Parallel Sequencing (Next Generation Sequencing) to determine whether participants had WS or not (Non-WS/NSW). Specialty evaluations included ophthalmological exam (visual fields, visual acuity, intraocular pressure, fundus exam, biomicroscopy, Ishihara test, macular tomography, optic nerve tomography (OCT), and orbital MRI); audiological study (otoscopy, bioimpedance testing, tympanometry, audiometry); cardiology evaluation and ECG; psychology, and nephrology (reno-vesical ultrasound and hand X-ray). Follow-up visits for each patient included an endocrinologist every 3 months, and with other specialists as needed. No formal sample size calculation was conducted. The study used non-probabilistic convenience sampling, involving all type 1 diabetes patients treated at the health clinic of the non-profit organization “Fundación de diabetes juvenil del Ecuador” and “Futuro Valdivia”, who agreed to participate and signed assent/informed consent. Descriptive statistics were used to compare genetic status (WS vs. NSW) by sex, and by age. Categorical variables were analyzed using the Pearson Chi-square test. To assess differences in continuous variables between WS and NSW patients, the Student’s t-test was utilized. Univariate and multivariate logistic regression was employed to determine Odds Ratios (ORs) or predictive values for the presence of comorbidities (dependent variables) relative to the independent variable (WS/NSW). A p-value < 0.05 or ORs with 95% confidence intervals not including 1 were considered statistically significant. Approval was obtained from the Human Research Ethics Committee of Hospital Clínica Kennedy in Guayaquil, Ecuador, under code HCK-CEISH-2024-001 [ 11 ]. RESULTS In the cohort of 38 participants (19 males) under 35 years old with a prior diagnosis of type 1 diabetes, genetic studies tested positive for WS in 26 patients. Among them, 8 (4 pairs) are siblings, and 5 are first cousins. Two patients were excluded: a 16-year-old female who met all clinical criteria for WS—diabetes, blindness, deafness, chronic kidney disease due to bilateral hydronephrosis, cerebellar ataxia, and psychiatric disorders—died prematurely and did not undergo genetic testing; and another patient was excluded for being only a carrier. Table 1 (supplemental material) shows the genetic variants and their characteristics. Table 1 Genetic Description of Patients with Wolfram Syndrome Type 1 Gene Exon/Intron Number Variant Nomenclature Genomic Nomenclature Zygosity Number Classification Inheritance New Variant WFS1 Exon 8 c.1135dupp.Asp379Glyfser164 [Depth-83X/83X] chr4:g.6302657dup Homozygous 23 Probably pathogenic Autosomal recessive Yes WFS1 Exon 8 c.2192T > Ap.Met731Lys [Depth-19X/57X] chr4:g.6303714T > A Heterozygous 1* Uncertain meaning Recessive Yes WFS1 Exon 4 c.397G > Ap.Ala133Thr [Depth-61X/133X] chr4:g.6290795G > A Heterozygous 1* Probably pathogenic Recessive No WFS1 Exon 8 c.1181A > Tp.Glu394Val [Depth- 64X/117X] chr4:g.6302703A > T Heterozygous 1 Uncertain significance Recessive No *Compound heterozygotes. Summary of Genetic Findings Twenty-five patients presented a new mutation in exon 8 classified as pathogenic. Of these, 23 were homozygous and 2 compound heterozygotes (both male). This new variant causes a frameshift mutation at codon 379 (aspartic acid to glycine), resulting in a premature STOP codon at position 164 (p.Asp379GlyfsTer164). Loss-of-function mutations in this gene are known to be pathogenic [ 12 ]. One compound heterozygote presented an additional new variant in exon 8, previously unreported. A third heterozygous patient had a variant of uncertain significance and was reported only as a carrier. Table 2 (supplemental material) describes the population characteristics by confirmed WS diagnosis vs. non-SW. Table 2 Population Characteristics SW n (%) NSW n (%) Number of participants 25 11 Male 15(60.0) 3 (27.3) Female 10(40.0) 8 (72.7) Average Age (years) 17.5 18.0 ≥ 2 Positive Antibodies: (Tyrosine-phosphatase 2; islet cell antibodies; GDA-65) 3(12) 4(36) Diabetes 25(100) 11(100) Diabetic Retinopathy 2(8) 1(9) ACR (ml/min/1.73 m²) 6(24) 1(9) CRD < 60 3(12) 0 (0) SW NSW Years with diabetes 14.5 5.8 BMI (kg/m 2 ) 20.1 22.2 Early-onset Diabetes (years) 3.0 11.5 C-peptide (ng/ml) 0.14 1.05 HbA1c (A1C DCCT) (%), (mmol/mol) 9.3 78 8.7 72 GFT (ml/min/1.73 m²) 123.32 138.8 Triglycerides (mg/dl) 104.9 157.8 LDL (mg/dl) 110.7 133.2 HDL (mg/dl) 51.8 53.2 ACR (mg/g) 150.2 24.03 US-PCR (mg/L) 1.05 0.4 Urinary osmolarity (mOsml/L) 288.6 287 GDA = glutamic acid decarboxylase; GFT = glomerular filtration rate; ACR = albuminuria/creatinine ratio; US-PCR = ultra-sensitive reactive protein C; ERC = chronic renal disease. Clinical and Biochemical Differences WS was genetically confirmed in 69% of the cohort. Among the remaining Non-WS (NSW) group, only 4 patients had typical type 1diabetes (positive antibodies and low C-peptide). Average age was similar (17.5 years vs. 18 years), but WS patients were diagnosed with diabetes significantly earlier (3 ± 1.8 years vs. 11.5 ± 2.1 years). WS patients had significantly lower C-peptide levels and fewer positive antibodies (12% vs. 36%). Duration of diabetes was twice as long in WS; WS patients had lower BMI and lipid levels. WS group also showed higher albumin/creatinine ratio (150.2 mg/g vs. 24.03 mg/g) and elevated high-sensitivity CRP (1.05 mg/L vs. 0.4 mg/L). Diabetic nephropathy with GFR < 60 was found only in WS (12%). Albuminuria was 24% in WS vs. 9% in NSW. Table 3 (supplemental material) shows WS manifestations by gender over time. Table 3 WS Manifestations and Timeline Variable All n (%) Male n (%) Female n (%) Average Age of Diagnosis (years) Diabetes 25(100) 15 (60) 10 (40) 3 (1–7) Optic Atrophy 22(91.7) 15(68.2) 7(31.8) 12 (8–17) Neurosensorial Deafness 20(80.0) 13(65) 7(35) 12 (9–22) Urological Complications 18(72.2) 13(72.2) 5(27.8) 17.5 (9–32) Neurological Alterations 9(36.0) 4(44.4) 5(55.5) Not reported Cataracts 5(20.0) 3(60) 2(40) Not reported Hypothyroidism 5(20) 2(40.0) 3 (60.0) Not reported Hypogonadism 6(24.0) 6(100.0) 0 Not reported Diabetes Insipidus 0 0 0 Clinical Features All patients had early-onset diabetes, average onset at 3 years. HbA1c averaged 9.3% (78 mmol/mol), with only 12% under 7.5% (58 mmol/mol) and 48% over 9% (75 mmol/mol). Optic atrophy appeared in 92% at an average age of 12 years. Sensorineural deafness occurred in 80%, mostly in males. Urological tract issues affected 72%, mainly males, with both structural and functional findings. No patient showed signs of diabetes insipidus. Serum osmolality was normal at the start (288.6 mOsm/L) and end (291.7 mOsm/L) of the study. Hypothyroidism occurred in 20% (more common in females), exclusively in homozygotes. Hypogonadism (24%) was seen in heterozygous males. Neurological symptoms (cognitive decline, sensory neuropathy, sleep issues, etc.) were present in 36%. Two compound heterozygotes reported depression and suicide attempts. Two homozygous participants showed significant joint deformities and pain. The frequency of clinical complications is showed in Fig. 1 (supplemental material) . DISCUSSION This study found a prevalence of 1 in 12,000 inhabitants in a relatively small coastal area in the province of Santa Elena, Ecuador—higher than reported rates in Sicily (1/54,478). The Ecuadorian population shows substantial degree of consanguinity: four sibling pairs and five first cousins, alike to the population profile describes in Sicily [ 2 ] a finding similar to that observed in Ecuador. This study reports two previously undescribed variants, both located in exon 8: the first, c.1135dupp.Asp379GlyfsTer164 [Depth-83X/83X], was found in 100% of patients with SW, causing a mutation in the frameshift of codon 379 of aspartic acid by glycine residue, which causes a premature stop in the sequential flow at codon 164 p.Asp379GlyfsTer164. Loss-of-function variants in this gene are recognized as pathogenic [ 12 ]. The second new variant c.2192T > Ap.Met731Lys[Depth-19X/57X], previously unreported in the literature, is of undetermined clinical significance and was found in a compound heterozygous male patient carrying both new variants [ 13 ]. In addition, two known variants are described, one in exon 4 class 4 (probably pathogenic) in a compound heterozygote and another in exon 8 class 3 (clinical significance undetermined) [ 13 ]. These two known variants are among the more than 200 mutations published in the scientific literature in patients with SW, most of which are located in exon 8 [ 8 , 13 ]. In the Ecuadorian cohort, no cases of diabetes insipidus (DI) were found – a feature of these new variants –. In contrast, the UK cohort reported DI in 73% of 45 WS patients [ 5 ]. This cohort exhibited very early onset of diabetes (age 3), followed by optic atrophy in 92%, sensorineural hearing loss in 80%, urinary tract issues in 72%, neurological disorders in 36%, hypogonadism in 24%, hypothyroidism in 20%, and cataracts in 20%. The UK cohort reported non-autoimmune diabetes at an average age of 6, followed by optic atrophy (100%), sensorineural hearing loss (62%), urinary tract issues (58%), neurological disorders (62%), and diabetes insipidus (73%) [ 5 ]. A strength of this study is the antibody testing (tyrosine phosphatase 2, islet cell, and GAD-65). In the Ecuadorian WS group, 12% tested positive for antibodies, consistent with a German multicenter study reporting 10% [ 14 ]. In the NSW group, 36% were antibody-positive, while the same study reported 86% [ 14 ]. This is crucial for identifying other diabetes types that may require different treatment. Optic atrophy, the second major clinical feature of WS, was found in 92% of this cohort, with average onset at age 12 however, it is important to note that two participants, due to their young age, do not yet have a conclusive diagnosis. Most patients first noticed a loss of color vision around age 11 [ 1 ]. This aligns with the UK cohort, which had an average onset at age 11 [ 5 ]. Sensorineural hearing loss was present in 80% of participants, with an average onset at 11.5 years. Literature reports rates between 62% and 65%, with onset ranging from 12.5 [ 2 , 5 ] to 16 years [ 2 , 8 ]. Hearing loss can be congenital or develop during adolescence [ 1 ]. Urinary tract complications—including glomerular hyperfiltration, hydronephrosis, tenesmus, and neurogenic bladder—were found in 73% of patients, appearing at an average age of 17 (range: 9–32 years). Similar rates (60–90%) have been reported in the literature [ 1 ], with onset around age 20 [ 9 ]. This high prevalence has prompted some to propose redefining the condition as DIDMOADUD [ 2 , 15 ]. Neurological disorders—such as epilepsy, ataxia, severe depression, psychosis, impulsivity, smell disturbances, sleep issues, aggression, and central apnea—tend to appear later in WS patients [ 9 ]. In this cohort, 36% had symptoms such as epilepsy, cognitive decline, nystagmus, ptosis, corticospinal syndrome, daytime hypersomnia, headache, and sensory neuropathy. These may increase over time. Literature reports similar rates between 32% [ 15 ] to 72% [ 1 ]. Severe psychiatric illnesses are significantly more common in heterozygous carriers, who have a 26-fold higher risk of hospitalization and increased suicide risk compared to spousal controls [ 16 ]. Psychiatric issues typically emerge between ages 17 and 23 [ 9 ]. Two heterozygous patients in our cohort presented depression at age 25, and another had two suicide attempts at age 20. Other findings include primary hypogonadism in 24% of male participants consistent with literature [ 2 , 17 ] and hypothyroidism, cataracts, and delayed menarche [ 2 ] in one out of five female patients. Compound heterozygous patients had better glycemic control (lower HbA1c), fewer clinical manifestations, and a higher risk of psychiatric disorders than homozygous patients, as seen in other studies [ 16 ]. Most studies report lower incidence of microvascular complications in WS compared to type 1 diabetes [ 18 ]. However, in this cohort, WS patients had higher rates of proteinuria (24% vs. 9%) and nephropathy (12% vs. 0%) than NSW. Retinopathy was slightly lower in WS (8%) vs. NSW (9%). Glycemic control was worse in WS (HbA1c 9.3% 78 mmol/mol) vs. NSW (8.7% 72 mmol/mol). This contrasts with a French study where WS patients had better control (7.7% 61mmol/mol) than type 1 diabetes (8.9% 74mmol/mol), and fewer complications (retinopathy 8% vs. 27%; proteinuria 8% vs. 19%; nephropathy 8% vs. 27%)[ 18 ]. The earlier onset of diabetes in the Ecuadorian cohort leads to greater deterioration of pancreatic beta cells mediated by ER stress, which could be the determining factor in the higher and earlier prevalence of microvascular complications observed. CONCLUSIONS The presence of two new variants of WS1 has been demonstrated for the first time in a relatively small coastal area of Ecuador, making it the area with the highest reported prevalence of SW in the world and with the earliest onset of non-autoimmune diabetes. Patients have a high prevalence of severe and early neurodegenerative features, as well as a higher percentage of microvascular complications. SW should be investigated in the presence of non-autoimmune diabetes and optic atrophy in patients under 16 years of age. Given that only 11% of patients meet the diagnostic criteria for type 1 diabetes, it is imperative to phenotype diabetes in populations residing in the coastal area of Ecuador and provide appropriate treatment. RECOMMENDATIONS Further research is needed to genetically profile the relatives of the cohort studied, as well as to provide genetic counseling to families. The implementation of technology for better diabetes control is recommended, reducing the risk of hypoglycemia and the development of microvascular complications. The development of a protocol for the diagnosis and management of SW is a necessity in populations residing in the studied areas. Although no drugs are currently available to slow the progression of the disease, the main objective is to provide comprehensive support to patients and their caregivers, conforming multidisciplinary teams that include social organizations, members of the scientific community, health professionals, and government authorities, to improve the quality of life of those living with this condition. Declarations Acknowledgments. We would like to thank the patients involved in the study and their families who participated in the study, as well as Fundación Diabetes Juvenil del Ecuador, Futuro Valdivia, Junta de Beneficencia de Guayaquil, Interlab, Funcrisa, Proaudio, and the multidisciplinary team of physician who took part in the study. The authors would also like to thank María Fernanda Ruiz and Aimmera Gilces for their dedication as study coordinators, and Schwarmann R., Crespo H., Mosquera N., Alvarez N., Amancha M., for their contributions in various areas of medical expertise. Guarantor statement: Dr. Juan Carlos Zevallos is the guarantor of this work. As such, he had full access to all the data in the study. He takes responsibility for the integrity and accuracy of the data analysis. Funding. This study was supported by the Research Center of the Universidad Espiritu Santo (CIN-UEES) Conflict of Interest. No potential conflict of interest relevant to this article were reported. Contribution statement. J.P.: conceptualization, investigation, methodology, data curation, formal analysis, writing original draft, writing-review & editing. J.Z.: conceptualization, investigation, methodology, data curation, formal analysis, writing original draft, project administration, funding acquisition, writing-review & editing. N.F.: drafting and approval by the ethics committee, investigation, methodology, data curation, formal analysis, writing original draft, writing-review & editing M.V.: conceptualization, data curation, writing original draft, resources. N.B., A.S, R.C.: conceptualization, data curation, resources. Prior Presentation. Parts of this study were presented in abstract form at the American Diabetes Association's 85th Scientific Sessions, June 20-23, 2025 in Chicago, Illinois. https://www.abstractsonline.com/dashboard/login.asp?aId=318&targetMKey=491c7de7-cf6e-4a71-9343-a25943b25ad2&targetMod=notifyMessages References Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. 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Supplementary Files Graphicalabstract.pdf Cite Share Download PDF Status: Published Journal Publication published 17 Apr, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 01 Feb, 2026 Reviewers agreed at journal 24 Nov, 2025 Reviewers invited by journal 23 Nov, 2025 Editor invited by journal 14 Sep, 2025 Editor assigned by journal 11 Sep, 2025 First submitted to journal 08 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7544843\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":549490855,\"identity\":\"fb473d81-cae1-47b2-8e09-35982f4c26d9\",\"order_by\":0,\"name\":\"Josefa 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13:43:18\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7544843/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7544843/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s13023-026-04344-z\",\"type\":\"published\",\"date\":\"2026-04-17T15:58:14+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":97119208,\"identity\":\"041fbda1-abbf-4567-b947-58caaf915b98\",\"added_by\":\"auto\",\"created_at\":\"2025-12-01 07:43:18\",\"extension\":\"xml\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"acdc-reference\",\"size\":10742,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"ojrdOJRDD2501328.xml\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7544843/v1/6130fa2b71ff1dceeed0645b.xml\"},{\"id\":97119207,\"identity\":\"deba5285-eef5-4390-98ec-a058978002a1\",\"added_by\":\"auto\",\"created_at\":\"2025-12-01 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07:43:18\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":164468,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePercentage of clinical complications found in patients with Wolfram síndrome. It also indicates the average reported age of onset and the age range in the Ecuadorian cohort.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7544843/v1/40b1bade739ce6b35ce62182.png\"},{\"id\":107350877,\"identity\":\"a9f00d5b-8607-4496-b238-5701e249d585\",\"added_by\":\"auto\",\"created_at\":\"2026-04-20 16:06:13\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":592574,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7544843/v1/268190db-89ac-4d39-96d2-8b4a80df6329.pdf\"},{\"id\":97119216,\"identity\":\"d7b63274-f1f1-4f42-b6a4-f6baad5166f6\",\"added_by\":\"auto\",\"created_at\":\"2025-12-01 07:43:18\",\"extension\":\"pdf\",\"order_by\":6,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":1077845,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Graphicalabstract.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7544843/v1/769347340e834cce86d431ed.pdf\"}],\"financialInterests\":\"\",\"formattedTitle\":\"New variants of Wolfram syndrome (WS) in an Ecuadorian population. The “Valdivia Project”. A Cross-Sectional Study.\",\"fulltext\":[{\"header\":\"Article Highlights\",\"content\":\"\\u003cul\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eWhy did we undertake this study?\\u003c/strong\\u003e\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eWe identified a cohort of young people with type 1 diabetes and severe and early neurodegenerative complications.\\u003c/p\\u003e\\n\\u003cul\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eWhat is the specific question(s) we wanted to answer?\\u003c/strong\\u003e\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eCould these neurodegenerative complications be linked to Wolfram syndrome?\\u003c/p\\u003e\\n\\u003cul\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eWhat did we find?\\u003c/strong\\u003e\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eWe identified two new variants of WS. All patients presented with early-onset diabetes, with an average age of onset of three years. There was a high prevalence of severe and early neurological complications, including optic atrophy (92%), deafness (80%), and urinary disorders (72%).\\u003c/p\\u003e\\n\\u003cul\\u003e\\n \\u003cli\\u003e\\u003cstrong\\u003eWhat are the implications of our findings?\\u003c/strong\\u003e\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003eEcuadorian patients under the age of 16 with non-autoimmune diabetes and optic atrophy should be investigated for WS to ensure they receive appropriate treatment.\\u003c/p\\u003e\"},{\"header\":\"INTRODUCTION\",\"content\":\"\\u003cp\\u003eWolfram syndrome (WS) is a rare, autosomal recessive, neurodegenerative genetic disorder characterized by diabetes insipidus, early-onset non-autoimmune diabetes, optic atrophy, and sensorineural deafness, classically known by the acronym DIDMOAD [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. This is often accompanied by urological disorders such as bladder dysfunction and loss of sphincter control, which is why some authors propose extending the term to DIDMOADUD [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. WS is caused by mutations in two main genes: WFS1, located on chromosome 4p16.1; and the WFS2 gene located on chromosome 4q22-24, reported in families of Jordanian descent and characterized by the absence of diabetes insipidus and gastrointestinal manifestations such as ulcers and bleeding [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThe estimated prevalence of WS worldwide is 1 per 55,000 to 1 per 770,000 inhabitants, although it varies considerably depending on the population [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. Rates of 1/1,000,000 have been reported in Spain [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]; 1/770,000 in the United Kingdom [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e], 1/100,000 in North America; 1/68,000 in the Lebanese population and 1/54,478 in Sicily [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. In Ecuador, at the time of this study, no epidemiological data or clinically confirmed cases of this disease had been reported.\\u003c/p\\u003e\\u003cp\\u003eMutations in the WFS1 gene affect the production and function of wolframin, an 890-amino acid transmembrane protein expressed mainly in the endoplasmic reticulum (ER) of cells in the central nervous system, pancreatic β cells, heart, and skeletal muscle [\\u003cspan additionalcitationids=\\\"CR7\\\" citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. Wolframin participates in maintaining calcium homeostasis, controlling ER stress, and regulating apoptosis [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. More than 200 mutations have been identified in the WFS1 gene, most of them in exon 8, which encodes the C-terminal transmembrane domain, causing significant cellular dysfunction, especially in pancreatic β cells, leading to an early form of diabetes mellitus, and in neurons, causing progressive autosomal neurosensory degeneration [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eWolfram Syndrome entails a limited life expectancy, with an average around 30 years and a range from 25 to 49 years, depending on the severity of neurological involvement [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. The most common cause of death is central respiratory failure, a direct consequence of progressive brainstem atrophy [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThis study aims to document for the first time clinically confirmed cases of Wolfram Syndrome in Ecuador and to report the possible identification of two new genetic variants, thereby contributing to the epidemiological and molecular understanding of this disease in Latin America.\\u003c/p\\u003e\"},{\"header\":\"METHODOLOGY\",\"content\":\"\\u003cp\\u003eThis article was written following the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) checklist for reporting observational studies [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThis is a Cross-Sectional study conducted among individuals with early-onset insulin-dependent diabetes, residing in the Santa Elena Province, Ecuador. All participants with a prior diagnosis of type 1 diabetes (aged\\u0026thinsp;\\u0026lt;\\u0026thinsp;35) were included in the study.\\u003c/p\\u003e\\u003cp\\u003eDescriptive variables included age, gender, occupation, income, personal and family medical history, BMI, nutritional status, and blood pressure. Data collection was carried out by trained personnel from March 2023 to March 2025. At the start of the study, participants were evaluated for demographic, anthropometric, and nutritional characteristics. A detailed clinical history and family tree were obtained. Laboratory studies included: complete blood count, blood chemistry, lipid profile, liver function tests, electrolytes, HbA1c, C-peptide, antibodies (tyrosine phosphatase 2, islet cell or GAD-65), thyroid function tests, serum osmolarity, serum cortisol, IGF1, general urine analysis, albumin/creatinine ratio, FSH, LH, estradiol, testosterone, vitamin D3 and B12. In addition, genetic testing was performed: ORION (Whole Exome Sequencing - WES) using Massively Parallel Sequencing (Next Generation Sequencing) to determine whether participants had WS or not (Non-WS/NSW). Specialty evaluations included ophthalmological exam (visual fields, visual acuity, intraocular pressure, fundus exam, biomicroscopy, Ishihara test, macular tomography, optic nerve tomography (OCT), and orbital MRI); audiological study (otoscopy, bioimpedance testing, tympanometry, audiometry); cardiology evaluation and ECG; psychology, and nephrology (reno-vesical ultrasound and hand X-ray). Follow-up visits for each patient included an endocrinologist every 3 months, and with other specialists as needed.\\u003c/p\\u003e\\u003cp\\u003eNo formal sample size calculation was conducted. The study used non-probabilistic convenience sampling, involving all type 1 diabetes patients treated at the health clinic of the non-profit organization \\u0026ldquo;Fundaci\\u0026oacute;n de diabetes juvenil del Ecuador\\u0026rdquo; and \\u0026ldquo;Futuro Valdivia\\u0026rdquo;, who agreed to participate and signed assent/informed consent.\\u003c/p\\u003e\\u003cp\\u003eDescriptive statistics were used to compare genetic status (WS vs. NSW) by sex, and by age. Categorical variables were analyzed using the Pearson Chi-square test. To assess differences in continuous variables between WS and NSW patients, the Student\\u0026rsquo;s t-test was utilized. Univariate and multivariate logistic regression was employed to determine Odds Ratios (ORs) or predictive values for the presence of comorbidities (dependent variables) relative to the independent variable (WS/NSW). A p-value\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 or ORs with 95% confidence intervals not including 1 were considered statistically significant.\\u003c/p\\u003e\\u003cp\\u003eApproval was obtained from the Human Research Ethics Committee of Hospital Cl\\u0026iacute;nica Kennedy in Guayaquil, Ecuador, under code HCK-CEISH-2024-001 [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e].\\u003c/p\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cp\\u003eIn the cohort of 38 participants (19 males) under 35 years old with a prior diagnosis of type 1 diabetes, genetic studies tested positive for WS in 26 patients. Among them, 8 (4 pairs) are siblings, and 5 are first cousins. Two patients were excluded: a 16-year-old female who met all clinical criteria for WS\\u0026mdash;diabetes, blindness, deafness, chronic kidney disease due to bilateral hydronephrosis, cerebellar ataxia, and psychiatric disorders\\u0026mdash;died prematurely and did not undergo genetic testing; and another patient was excluded for being only a carrier. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e \\u003cb\\u003e(supplemental material)\\u003c/b\\u003e shows the genetic variants and their characteristics.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eGenetic Description of Patients with Wolfram Syndrome Type 1\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"9\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGene\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eExon/Intron Number\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eVariant Nomenclature\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eGenomic Nomenclature\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eZygosity\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eNumber\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eClassification\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eInheritance\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003eNew Variant\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eWFS1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eExon 8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.1135dupp.Asp379Glyfser164\\u003c/p\\u003e\\u003cp\\u003e[Depth-83X/83X]\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003echr4:g.6302657dup\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eHomozygous\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e23\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eProbably pathogenic\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eAutosomal recessive\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eWFS1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eExon 8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.2192T\\u0026thinsp;\\u0026gt;\\u0026thinsp;Ap.Met731Lys\\u003c/p\\u003e\\u003cp\\u003e[Depth-19X/57X]\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003echr4:g.6303714T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eHeterozygous\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e1*\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eUncertain meaning\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eRecessive\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003eYes\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eWFS1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eExon 4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.397G\\u0026thinsp;\\u0026gt;\\u0026thinsp;Ap.Ala133Thr [Depth-61X/133X]\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003echr4:g.6290795G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eHeterozygous\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e1*\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eProbably pathogenic\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eRecessive\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003eNo\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eWFS1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eExon 8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ec.1181A\\u0026thinsp;\\u0026gt;\\u0026thinsp;Tp.Glu394Val\\u003c/p\\u003e\\u003cp\\u003e[Depth- 64X/117X]\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003echr4:g.6302703A\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eHeterozygous\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eUncertain significance\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eRecessive\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003eNo\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"9\\\"\\u003e*Compound heterozygotes.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\n\\u003ch3\\u003eSummary of Genetic Findings\\u003c/h3\\u003e\\n\\u003cp\\u003eTwenty-five patients presented a new mutation in exon 8 classified as pathogenic. Of these, 23 were homozygous and 2 compound heterozygotes (both male). This new variant causes a frameshift mutation at codon 379 (aspartic acid to glycine), resulting in a premature STOP codon at position 164 (p.Asp379GlyfsTer164). Loss-of-function mutations in this gene are known to be pathogenic [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. One compound heterozygote presented an additional new variant in exon 8, previously unreported. A third heterozygous patient had a variant of uncertain significance and was reported only as a carrier. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e \\u003cb\\u003e(supplemental material)\\u003c/b\\u003e describes the population characteristics by confirmed WS diagnosis vs. non-SW.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003ePopulation Characteristics\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"3\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSW\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eNSW\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNumber of participants\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e25\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e11\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMale\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e15(60.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3 (27.3)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eFemale\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e10(40.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e8 (72.7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAverage Age (years)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e17.5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e18.0\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e\\u0026ge;\\u0026thinsp;2 Positive Antibodies: (Tyrosine-phosphatase 2; islet cell antibodies; GDA-65)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3(12)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4(36)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eDiabetes\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e25(100)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e11(100)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eDiabetic Retinopathy\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e2(8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eACR (ml/min/1.73 m\\u0026sup2;)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e6(24)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1(9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eCRD\\u0026thinsp;\\u0026lt;\\u0026thinsp;60\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3(12)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eSW\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eNSW\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eYears with diabetes\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e14.5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e5.8\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eBMI (kg/m\\u003csup\\u003e2\\u003c/sup\\u003e)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e20.1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e22.2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eEarly-onset Diabetes (years)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3.0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e11.5\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eC-peptide (ng/ml)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0.14\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e1.05\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eHbA1c (A1C DCCT) (%),\\u003c/p\\u003e\\u003cp\\u003e(mmol/mol)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9.3\\u003c/p\\u003e\\u003cp\\u003e78\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e8.7\\u003c/p\\u003e\\u003cp\\u003e72\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGFT (ml/min/1.73 m\\u0026sup2;)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e123.32\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e138.8\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eTriglycerides (mg/dl)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e104.9\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e157.8\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eLDL (mg/dl)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e110.7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e133.2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eHDL (mg/dl)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e51.8\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e53.2\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eACR (mg/g)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e150.2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e24.03\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eUS-PCR (mg/L)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e1.05\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0.4\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eUrinary osmolarity (mOsml/L)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e288.6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e287\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eGDA\\u0026thinsp;=\\u0026thinsp;glutamic acid decarboxylase; GFT\\u0026thinsp;=\\u0026thinsp;glomerular filtration rate; ACR\\u0026thinsp;=\\u0026thinsp;albuminuria/creatinine ratio; US-PCR\\u0026thinsp;=\\u0026thinsp;ultra-sensitive reactive protein C; ERC\\u0026thinsp;=\\u0026thinsp;chronic renal disease.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\n\\u003ch3\\u003eClinical and Biochemical Differences\\u003c/h3\\u003e\\n\\u003cp\\u003eWS was genetically confirmed in 69% of the cohort. Among the remaining Non-WS (NSW) group, only 4 patients had typical type 1diabetes (positive antibodies and low C-peptide). Average age was similar (17.5 years vs. 18 years), but WS patients were diagnosed with diabetes significantly earlier (3\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.8 years vs. 11.5\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.1 years). WS patients had significantly lower C-peptide levels and fewer positive antibodies (12% vs. 36%).\\u003c/p\\u003e\\u003cp\\u003eDuration of diabetes was twice as long in WS; WS patients had lower BMI and lipid levels. WS group also showed higher albumin/creatinine ratio (150.2 mg/g vs. 24.03 mg/g) and elevated high-sensitivity CRP (1.05 mg/L vs. 0.4 mg/L). Diabetic nephropathy with GFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;60 was found only in WS (12%). Albuminuria was 24% in WS vs. 9% in NSW. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e \\u003cb\\u003e(supplemental material)\\u003c/b\\u003e shows WS manifestations by gender over time.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003e\\u003cem\\u003eWS Manifestations and Timeline\\u003c/em\\u003e\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"5\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVariable\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eAll\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMale\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eFemale\\u003c/p\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eAverage Age of Diagnosis (years)\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eDiabetes\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e25(100)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e15 (60)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e10 (40)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3 (1\\u0026ndash;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eOptic Atrophy\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e22(91.7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e15(68.2)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e7(31.8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e12 (8\\u0026ndash;17)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNeurosensorial Deafness\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e20(80.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e13(65)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e7(35)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e12 (9\\u0026ndash;22)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eUrological Complications\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e18(72.2)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e13(72.2)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e5(27.8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e17.5 (9\\u0026ndash;32)\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNeurological Alterations\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9(36.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4(44.4)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e5(55.5)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eNot reported\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eCataracts\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e5(20.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3(60)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e2(40)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eNot reported\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eHypothyroidism\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e5(20)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e2(40.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e3 (60.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eNot reported\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eHypogonadism\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e6(24.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e6(100.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eNot reported\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eDiabetes Insipidus\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e0\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\n\\u003ch3\\u003eClinical Features\\u003c/h3\\u003e\\n\\u003cp\\u003eAll patients had early-onset diabetes, average onset at 3 years. HbA1c averaged 9.3% (78 mmol/mol), with only 12% under 7.5% (58 mmol/mol) and 48% over 9% (75 mmol/mol). Optic atrophy appeared in 92% at an average age of 12 years. Sensorineural deafness occurred in 80%, mostly in males. Urological tract issues affected 72%, mainly males, with both structural and functional findings.\\u003c/p\\u003e\\u003cp\\u003eNo patient showed signs of diabetes insipidus. Serum osmolality was normal at the start (288.6 mOsm/L) and end (291.7 mOsm/L) of the study. Hypothyroidism occurred in 20% (more common in females), exclusively in homozygotes. Hypogonadism (24%) was seen in heterozygous males. Neurological symptoms (cognitive decline, sensory neuropathy, sleep issues, etc.) were present in 36%. Two compound heterozygotes reported depression and suicide attempts. Two homozygous participants showed significant joint deformities and pain. The frequency of clinical complications is showed in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e \\u003cb\\u003e(supplemental material)\\u003c/b\\u003e.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eThis study found a prevalence of 1 in 12,000 inhabitants in a relatively small coastal area in the province of Santa Elena, Ecuador\\u0026mdash;higher than reported rates in Sicily (1/54,478). The Ecuadorian population shows substantial degree of consanguinity: four sibling pairs and five first cousins, alike to the population profile describes in Sicily [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e] a finding similar to that observed in Ecuador.\\u003c/p\\u003e\\u003cp\\u003eThis study reports two previously undescribed variants, both located in exon 8: the first, c.1135dupp.Asp379GlyfsTer164 [Depth-83X/83X], was found in 100% of patients with SW, causing a mutation in the frameshift of codon 379 of aspartic acid by glycine residue, which causes a premature stop in the sequential flow at codon 164 p.Asp379GlyfsTer164. Loss-of-function variants in this gene are recognized as pathogenic [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. The second new variant c.2192T\\u0026thinsp;\\u0026gt;\\u0026thinsp;Ap.Met731Lys[Depth-19X/57X], previously unreported in the literature, is of undetermined clinical significance and was found in a compound heterozygous male patient carrying both new variants [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eIn addition, two known variants are described, one in exon 4 class 4 (probably pathogenic) in a compound heterozygote and another in exon 8 class 3 (clinical significance undetermined) [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. These two known variants are among the more than 200 mutations published in the scientific literature in patients with SW, most of which are located in exon 8 [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eIn the Ecuadorian cohort, no cases of diabetes insipidus (DI) were found \\u0026ndash; a feature of these new variants \\u0026ndash;. In contrast, the UK cohort reported DI in 73% of 45 WS patients [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. This cohort exhibited very early onset of diabetes (age 3), followed by optic atrophy in 92%, sensorineural hearing loss in 80%, urinary tract issues in 72%, neurological disorders in 36%, hypogonadism in 24%, hypothyroidism in 20%, and cataracts in 20%. The UK cohort reported non-autoimmune diabetes at an average age of 6, followed by optic atrophy (100%), sensorineural hearing loss (62%), urinary tract issues (58%), neurological disorders (62%), and diabetes insipidus (73%) [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eA strength of this study is the antibody testing (tyrosine phosphatase 2, islet cell, and GAD-65). In the Ecuadorian WS group, 12% tested positive for antibodies, consistent with a German multicenter study reporting 10% [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. In the NSW group, 36% were antibody-positive, while the same study reported 86% [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. This is crucial for identifying other diabetes types that may require different treatment.\\u003c/p\\u003e\\u003cp\\u003eOptic atrophy, the second major clinical feature of WS, was found in 92% of this cohort, with average onset at age 12 however, it is important to note that two participants, due to their young age, do not yet have a conclusive diagnosis. Most patients first noticed a loss of color vision around age 11 [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. This aligns with the UK cohort, which had an average onset at age 11 [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eSensorineural hearing loss was present in 80% of participants, with an average onset at 11.5 years. Literature reports rates between 62% and 65%, with onset ranging from 12.5 [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e] to 16 years [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. Hearing loss can be congenital or develop during adolescence [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eUrinary tract complications\\u0026mdash;including glomerular hyperfiltration, hydronephrosis, tenesmus, and neurogenic bladder\\u0026mdash;were found in 73% of patients, appearing at an average age of 17 (range: 9\\u0026ndash;32 years). Similar rates (60\\u0026ndash;90%) have been reported in the literature [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e], with onset around age 20 [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. This high prevalence has prompted some to propose redefining the condition as DIDMOADUD [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eNeurological disorders\\u0026mdash;such as epilepsy, ataxia, severe depression, psychosis, impulsivity, smell disturbances, sleep issues, aggression, and central apnea\\u0026mdash;tend to appear later in WS patients [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. In this cohort, 36% had symptoms such as epilepsy, cognitive decline, nystagmus, ptosis, corticospinal syndrome, daytime hypersomnia, headache, and sensory neuropathy. These may increase over time. Literature reports similar rates between 32% [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e] to 72% [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eSevere psychiatric illnesses are significantly more common in heterozygous carriers, who have a 26-fold higher risk of hospitalization and increased suicide risk compared to spousal controls [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. Psychiatric issues typically emerge between ages 17 and 23 [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. Two heterozygous patients in our cohort presented depression at age 25, and another had two suicide attempts at age 20.\\u003c/p\\u003e\\u003cp\\u003eOther findings include primary hypogonadism in 24% of male participants consistent with literature [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e] and hypothyroidism, cataracts, and delayed menarche [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e] in one out of five female patients.\\u003c/p\\u003e\\u003cp\\u003eCompound heterozygous patients had better glycemic control (lower HbA1c), fewer clinical manifestations, and a higher risk of psychiatric disorders than homozygous patients, as seen in other studies [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eMost studies report lower incidence of microvascular complications in WS compared to type 1 diabetes [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. However, in this cohort, WS patients had higher rates of proteinuria (24% vs. 9%) and nephropathy (12% vs. 0%) than NSW. Retinopathy was slightly lower in WS (8%) vs. NSW (9%). Glycemic control was worse in WS (HbA1c 9.3% 78 mmol/mol) vs. NSW (8.7% 72 mmol/mol). This contrasts with a French study where WS patients had better control (7.7% 61mmol/mol) than type 1 diabetes (8.9% 74mmol/mol), and fewer complications (retinopathy 8% vs. 27%; proteinuria 8% vs. 19%; nephropathy 8% vs. 27%)[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eThe earlier onset of diabetes in the Ecuadorian cohort leads to greater deterioration of pancreatic beta cells mediated by ER stress, which could be the determining factor in the higher and earlier prevalence of microvascular complications observed.\\u003c/p\\u003e\"},{\"header\":\"CONCLUSIONS\",\"content\":\"\\u003cp\\u003eThe presence of two new variants of WS1 has been demonstrated for the first time in a relatively small coastal area of Ecuador, making it the area with the highest reported prevalence of SW in the world and with the earliest onset of non-autoimmune diabetes.\\u003c/p\\u003e\\u003cp\\u003ePatients have a high prevalence of severe and early neurodegenerative features, as well as a higher percentage of microvascular complications.\\u003c/p\\u003e\\u003cp\\u003eSW should be investigated in the presence of non-autoimmune diabetes and optic atrophy in patients under 16 years of age.\\u003c/p\\u003e\\u003cp\\u003eGiven that only 11% of patients meet the diagnostic criteria for type 1 diabetes, it is imperative to phenotype diabetes in populations residing in the coastal area of Ecuador and provide appropriate treatment.\\u003c/p\\u003e\"},{\"header\":\"RECOMMENDATIONS\",\"content\":\"\\u003cp\\u003eFurther research is needed to genetically profile the relatives of the cohort studied, as well as to provide genetic counseling to families.\\u003c/p\\u003e\\u003cp\\u003eThe implementation of technology for better diabetes control is recommended, reducing the risk of hypoglycemia and the development of microvascular complications.\\u003c/p\\u003e\\u003cp\\u003eThe development of a protocol for the diagnosis and management of SW is a necessity in populations residing in the studied areas.\\u003c/p\\u003e\\u003cp\\u003eAlthough no drugs are currently available to slow the progression of the disease, the main objective is to provide comprehensive support to patients and their caregivers, conforming multidisciplinary teams that include social organizations, members of the scientific community, health professionals, and government authorities, to improve the quality of life of those living with this condition.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe would like to thank the patients involved in the study\\u0026nbsp;and their families who participated in the study, as well as Fundaci\\u0026oacute;n Diabetes Juvenil del Ecuador, Futuro Valdivia, Junta de Beneficencia de Guayaquil, Interlab, Funcrisa, Proaudio, and the multidisciplinary team of physician who took part in the study.\\u0026nbsp;The authors would also like to thank Mar\\u0026iacute;a Fernanda Ruiz and Aimmera Gilces for their dedication as study coordinators, and Schwarmann R., Crespo H., Mosquera N., Alvarez N., Amancha M., for their contributions in various areas of medical expertise.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eGuarantor statement: Dr. Juan Carlos Zevallos is the guarantor of this work. As such, he had full access to all the data in the study. He takes responsibility for the integrity and accuracy of the data analysis.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was supported by the Research Center of the Universidad Espiritu Santo (CIN-UEES)\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of Interest.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNo potential conflict of interest relevant to this article were reported.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eContribution statement.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eJ.P.: conceptualization, investigation, methodology, data curation, formal analysis, writing original draft, writing-review \\u0026amp; editing. J.Z.: conceptualization, investigation, methodology, data curation, formal analysis, writing original draft, project administration, funding acquisition, writing-review \\u0026amp; editing. N.F.: drafting and approval by the ethics committee, investigation, methodology, data curation, formal analysis, writing original draft, writing-review \\u0026amp; editing M.V.: conceptualization, data curation, writing original draft, resources. N.B., A.S, R.C.: conceptualization, data curation, resources.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePrior Presentation.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eParts of this study were presented in abstract form at the American Diabetes Association\\u0026apos;s 85th Scientific Sessions, June 20-23, 2025 in Chicago, Illinois. https://www.abstractsonline.com/dashboard/login.asp?aId=318\\u0026amp;targetMKey=491c7de7-cf6e-4a71-9343-a25943b25ad2\\u0026amp;targetMod=notifyMessages\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eUrano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. 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Endocrine. 2020;69:420\\u0026ndash;9. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1007/s12020-020-02320-6\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s12020-020-02320-6\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCano A, Molines L, Val\\u0026eacute;ro R, et al. Microvascular diabetes complications in Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness [DIDMOAD]): an age- and duration-matched comparison with common type 1 diabetes. Diabetes Care. 2007;30:2327\\u0026ndash;30. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.2337/dc07-0380\\u003c/span\\u003e\\u003cspan address=\\\"10.2337/dc07-0380\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"orphanet-journal-of-rare-diseases\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ojrd\",\"sideBox\":\"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/ojrd/default.aspx\",\"title\":\"Orphanet Journal of Rare Diseases\",\"twitterHandle\":\"@bmc\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Wolfram syndrome, type 1 diabetes, optic atrophy, sensorineural deafness, new variant\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7544843/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7544843/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eObjective: \\u003c/strong\\u003eThis study aims to document the first genetically confirmed cases of WS in Ecuador.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDesign and Methods: \\u003c/strong\\u003eA Cross-Sectional study was conducted among individuals with early-onset insulin-dependent diabetes, residing in Santa Elena Province, Ecuador. A detailed clinical history and family tree were obtained along with laboratory and imaging diagnostics. A genetic whole exome sequencing was performed to confirm WS or not (NSW).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults: \\u003c/strong\\u003eThis Ecuadorian cohort included 38 participants (19 males) aged \\u0026lt;35 years with an average diabetes onset at 3 years old. Eight are siblings, and 5 are first cousins. Genetic studies tested positive for WS in 26(69%) patients, which yields a prevalence of 1/12,000 inhabitants and the presence of two previously undescribed variants located in exon 8. Twenty-three were homozygous. Positive antibody testing was reported in 3/26 WS and in 4/11 NSW patients.\\u003c/p\\u003e\\n\\u003cp\\u003eHigh prevalence of severe and early neurological complications: optic atrophy, deafness and urinary disorders were documented. No patient had diabetes insipidus.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions: \\u003c/strong\\u003eFindings suggest the highest WS prevalence worldwide and two novel WS1 variants. In addition, there is high consanguinity and frequency of severe, early clinical complications among WS patients. Only 11% were diagnosed with type 1 diabetes. Must be phenotyping patients with early onset diabetes.\\u003c/p\\u003e\",\"manuscriptTitle\":\"New variants of Wolfram syndrome (WS) in an Ecuadorian population. The “Valdivia Project”. 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