scholarly journals Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Maryam Sobhani ◽  
Mohammad Amin Tabatabaiefar ◽  
Soudeh Ghafouri-Fard ◽  
Asadollah Rajab ◽  
Asal Hojjat ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Neurodegenerative Disorder ◽  
Autoimmune Diabetes ◽  
Wolfram Syndrome ◽  
Clinical Diagnostics ◽  
Genetic Linkage Analysis ◽  
Diabetes Type Ii ◽  
Pathogenic Variants ◽  
High Prevalence ◽  
Syndromic Hearing Loss

Abstract Background Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM. Case presentation In this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene. Conclusions The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.

scholarly journals GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kadri Seppa ◽  
Maarja Toots ◽  
Riin Reimets ◽  
Toomas Jagomäe ◽  
Tuuliki Koppel ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Optic Nerve ◽  
Rat Model ◽  
Receptor Agonist ◽  
Neurodegenerative Disorder ◽  
Ganglion Cells ◽  
Neuroprotective Effect ◽  
Wolfram Syndrome ◽  
Retinal Ganglion ◽  
Knock Out

Abstract Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.

scholarly journals Functional assessment of variants associated with Wolfram syndrome

2019 ◽  
Vol 28 (22) ◽  
pp. 3815-3824
Author(s):  
Melissa Riachi ◽  
Sebahat Yilmaz ◽  
Erdal Kurnaz ◽  
Zehra Aycan ◽  
Semra Çetinkaya ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Molecular Genetic ◽  
Wolfram Syndrome ◽  
Neurological Complications ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Genetic Mechanisms ◽  
Allelic Variations

Abstract Wolfram syndrome (WS) is a heterogeneous multisystem neurodegenerative disorder with two allelic variations in addition to a separate subtype known as WS type 2. The wide phenotypic spectrum of WS includes diabetes mellitus and optic atrophy which is often accompanied by diabetes insipidus, deafness, urological and neurological complications in combination or in isolation. To date, the understanding of the genotype-phenotype relationship in this complex syndrome remains poorly understood. In this study, we identified and explored the functionality of rare and novel variants in the two causative WS genes WFS1 and CISD2 by assessing the effects of the mutations on the encoded proteins Wolframin and ERIS, in a cohort of 12 patients with autosomal recessive WS, dominant WS and WS type 2. The identified pathogenic variants included missense changes, frameshift deletions and insertions in WFS1 and an exonic deletion in CISD2 which all altered the respective encoded protein in a manner that did not correlate to the phenome previously described. These observations suggest the lack of genotype-phenotype correlation in this complex syndrome and the need to explore other molecular genetic mechanisms. Additionally, our findings highlight the importance of functionally assessing variants for their pathogenicity to tackle the problem of increasing variants of unknown significance in the public genetic databases.

scholarly journals Clinical Peculiarities in a Cohort of Patients with Wolfram Syndrome 1

2022 ◽  
Vol 19 (1) ◽  
pp. 520
Author(s):  
Giuseppina Salzano ◽  
Luciana Rigoli ◽  
Mariella Valenzise ◽  
Roberto Chimenz ◽  
Stefano Passanisi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Respiratory Failure ◽  
Diabetes Insipidus ◽  
Cause Of Death ◽  
Autoimmune Diabetes ◽  
Heart Diseases ◽  
Wolfram Syndrome ◽  
Clinical Approach ◽  
Large Patient ◽  
The Mean

Wolfram syndrome 1 is a rare, autosomal recessive, neurodegenerative, progressive disorder. Insulin-dependent, non-autoimmune diabetes mellitus and bilateral progressive optic atrophy are both sensitive and specific criteria for clinical diagnosis. The leading cause of death is central respiratory failure resulting from brainstem atrophy. We describe the clinical features of fourteen patients from seven different families followed in our Diabetes Center. The mean age at Wolfram syndrome 1 diagnosis was 12.4 years. Diabetes mellitus was the first clinical manifestation, in all patients. Sensorineural hearing impairment and central diabetes insipidus were present in 85.7% of patients. Other endocrine findings included hypogonadotropic hypogonadism (7.1%), hypergonadotropic hypogonadism (7.1%), and Hashimoto’s thyroiditis (21.4%). Neuropsychiatric disorders were detected in 35.7% of patients, and urogenital tract abnormalities were present in 21.4%. Finally, heart diseases were found in 14.2% of patients. Eight patients (57.1%) died at the mean age of 27.3 years. The most common cause of death was respiratory failure which occurred in six patients. The remaining two died due to end-stage renal failure and myocardial infarction. Our data are superimposable with those reported in the literature in terms of mean age of onset, the clinical course of the disease, and causes of death. The frequency of deafness and diabetes insipidus was higher in our patients. The incidence of urogenital diseases was lower although it led to the death of one patient. Long-term follow-up studies including large patient cohorts are necessary to establish potential genotype-phenotype correlation in order to personalize the most suitable clinical approach for each patient.

scholarly journals Diabetes Mellitus and Optic Atrophy: A Study of Wolfram Syndrome in the Lebanese Population

2004 ◽  
Vol 89 (4) ◽  
pp. 1656-1661 ◽  
Author(s):  
R. Medlej ◽  
J. Wasson ◽  
P. Baz ◽  
S. Azar ◽  
I. Salti ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetes Insipidus ◽  
Optic Atrophy ◽  
Neurodegenerative Disorder ◽  
Sensorineural Deafness ◽  
Microvascular Disease ◽  
Insulin Dependent Diabetes Mellitus ◽  
Wolfram Syndrome ◽  
Dependent Diabetes Mellitus ◽  
Number Of Patients

Abstract Wolfram syndrome (WFS) is a rare hereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). WFS seems to be a heterogeneous disease that has not yet been fully characterized in terms of clinical features and pathophysiological mechanisms because the number of patients in most series was small. In this study we describe 31 Lebanese WFS patients belonging to 17 families; this, to our knowledge, is the largest number of patients reported in one series so far. Criteria for diagnosis of WFS were the presence of insulin-dependent diabetes mellitus and optic atrophy unexplained by any other disease. Central diabetes insipidus was found in 87% of the patients, and sensorineural deafness confirmed by audiograms was present in 64.5%. Other less frequent features included neurological and psychiatric abnormalities, urodynamic abnormalities, limited joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotropic hypogonadism in males, and diabetic microvascular disease. New features, not reported in previous descriptions, such as heart malformations and anterior pituitary dysfunction, were recognized in some of the patients and participated in the morbidity and mortality of the disease. Genetic analysis revealed WFS1 gene mutations in three families (23.5%), whereas no abnormalities were detected in mitochondrial DNA. In conclusion, WFS is a devastating disease for the patients and their families. More information about WFS will lead to a better understanding of this disease and hopefully to improvement in means of its prevention and treatment.

Efficacy of GLP-1 Agonist Therapy in Autosomal Dominant WFS1-Related Disorder: A Case Report

2020 ◽  
pp. 1-6
Author(s):  
Kevin J. Scully ◽  
Joseph I. Wolfsdorf
Keyword(s):  
Diabetes Mellitus ◽  
Autosomal Dominant ◽  
Neurodegenerative Disorder ◽  
Low Frequency ◽  
Sensorineural Deafness ◽  
Indirect Evidence ◽  
Wolfram Syndrome ◽  
Related Disorder ◽  
History Of ◽  
Congenital Strabismus

<b><i>Background:</i></b> Wolfram syndrome is a rare neurodegenerative disorder, characterized by the presence of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness. The majority of cases are due to autosomal recessive biallelic variants in the <i>WFS1</i> gene; however, pathogenic autosomal dominant (AD) mutations have also been described. Glucagon-like peptide (GLP-1) agonists have been studied in both animal models and humans with classic Wolfram syndrome. <b><i>Case:</i></b> We present a 15-year-old female with a personal and family history of congenital strabismus, bilateral cataracts, low-frequency sensorineural hearing loss, and diabetes mellitus. Trio whole exome sequencing revealed a previously unknown maternally inherited heterozygous variant in exon 8 of the <i>WFS1</i> gene c.2605_2616del12 <i>p</i>.Ser869_His872del, leading to the diagnosis of AD WFS1-related disorder. Treatment with a GLP-1 agonist resulted in marked improvement in glycemic control and discontinuation of insulin therapy. This patient’s response to a GLP-1 agonist provides suggestive indirect evidence for a role of WFS1 on β-cell endoplasmic reticulum stress and suggests that treatment with a GLP-1 agonist should be considered in patients with dominant forms of WS.

scholarly journals Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome

2020 ◽  
Vol 117 (29) ◽  
pp. 17389-17398 ◽  
Author(s):  
Lien D. Nguyen ◽  
Tom T. Fischer ◽  
Damien Abreu ◽  
Alfredo Arroyo ◽  
Fumihiko Urano ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Calcium Homeostasis ◽  
Single Gene ◽  
Wolfram Syndrome ◽  
Calpain Inhibitor ◽  
Multisystem Disease ◽  
Drug Candidates ◽  
Cell Functions ◽  
Pathogenic Variants ◽  
Glucose Stimulated Insulin Secretion

Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic β cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1’s interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.

Mechanisms Involved in Glycemic Control Promoted by Exercise in Diabetics

2019 ◽  
Vol 15 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Eric Francelino Andrade ◽  
Víviam de Oliveira Silva ◽  
Débora Ribeiro Orlando ◽  
Luciano José Pereira
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Disease ◽  
Skeletal Muscle ◽  
Glycemic Control ◽  
Sedentary Lifestyle ◽  
World Population ◽  
Pharmacological Interventions ◽  
High Prevalence ◽  
The World ◽  
Main Factors

Introduction: Diabetes mellitus is a metabolic disease characterized by high glycemic levels for long periods. This disease has a high prevalence in the world population, being currently observed an increase in its incidence. This fact is mainly due to the sedentary lifestyle and hypercaloric diets. Non-pharmacological interventions for glycemic control include exercise, which promotes changes in skeletal muscle and adipocytes. Thus, increased glucose uptake by skeletal muscle and decreased insulin resistance through modulating adipocytes are the main factors that improve glycemic control against diabetes. Conclusion: It was sought to elucidate mechanisms involved in the improvement of glycemic control in diabetics in front of the exercise.

Knowledge, awareness and perceptions of diabetes mellitus among the Saudi population

2020 ◽  
Vol 9 (6) ◽  
pp. 413-422
Author(s):  
Muhammad H Mujammami ◽  
Abdulaziz A Alodhayani ◽  
Mohammad Ibrahim AlJabri ◽  
Ahmad Alhumaidi Alanazi ◽  
Sultan Sayyaf Alanazi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Social Media ◽  
Risk Factor ◽  
Healthcare Workers ◽  
Health Workers ◽  
Saudi Population ◽  
Limited Data ◽  
High Prevalence ◽  
Associated Risk Factors

Background: High prevalence of undiagnosed cases of diabetes mellitus (DM) has increased over the last two decades, most patients with DM only become aware of their condition once they develop a complication. Limited data are available regarding the knowledge and awareness about DM and the associated risk factors, complications and management in Saudi society. Aim: This study aimed to assess knowledge of DM in general Saudi society and among Saudi healthcare workers. Results: Only 37.3% of the participants were aware of the current DM prevalence. Obesity was the most frequently identified risk factor for DM. Most comparisons indicated better awareness among health workers. Conclusion: A significant lack of knowledge about DM in Saudi society was identified. Social media and educational curriculum can improve knowledge and awareness of DM.

Premature ovarian ageing following heterozygous loss of Senataxin

2020 ◽  
Author(s):  
G N Subramanian ◽  
M Lavin ◽  
H A Homer
Keyword(s):  
Dna Damage ◽  
Neurodegenerative Disorder ◽  
Dna Helicase ◽  
Dna Integrity ◽  
Ovarian Activity ◽  
Homozygous Mutation ◽  
Female Mice ◽  
Mating Trial ◽  
High Prevalence

Abstract Premature loss of ovarian activity before 40 years of age is known as primary ovarian insufficiency (POI) and occurs in ∼1% of women. A more subtle decline in ovarian activity, known as premature ovarian ageing (POA), occurs in ∼10% of women. Despite the high prevalence of POA, very little is known regarding its genetic causation. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage. Homozygous mutation of SETX leads to the neurodegenerative disorder, ataxia oculomotor apraxia type 2 (AOA2). There have been reports of POI in AOA2 females suggesting a link between SETX and ovarian ageing. Here, we studied female mice lacking either one (Setx+/−) or both (Setx−/−) copies of SETX over a 12- to 14-month period. We find that DNA damage is increased in oocytes from 8-month-old Setx+/− and Setx−/− females compared with Setx+/+ oocytes leading to a marked reduction in all classes of ovarian follicles at least 4 months earlier than typically occurs in female mice. Furthermore, during a 12-month long mating trial, Setx+/− and Setx−/− females produced significantly fewer pups than Setx+/+ females from 7 months of age onwards. These data show that SETX is critical for preventing POA in mice, likely by preserving DNA integrity in oocytes. Intriguingly, heterozygous Setx loss causes an equally severe impact on ovarian ageing as homozygous Setx loss. Because heterozygous SETX disruption is less likely to produce systemic effects, SETX compromise could underpin some cases of insidious POA.

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