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Wolfram Syndrome in Pediatric Age
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Wolfram Syndrome in Pediatric Age

A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601). This special issue belongs to the section "Health Behavior, Chronic Disease and Health Promotion".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 27094

Special Issue Editor

Prof. Dr. Fortunato Lombardo

E-Mail Website
Guest Editor
Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98124 Messina, Italy
Interests: pediatric diabetes; type 1 diabetes; monogenic diabetes; technology and diabetes

Special Issue Information

Dear colleagues,

Wolfram syndrome 1 (WS1; OMIM 222300) is a rare, autosomal recessive, neurodegenerative, and progressive disease, also known by the acronym DIDMOAD (diabetes insipidus DI, diabetes mellitus DM, optic atrophy OA, and deafness D). WS1 is an autosomal-recessive disorder usually diagnosed in childhood when non-autoimmune, insulin-dependent diabetes is associated with optic atrophy. Additional clinical manifestations include ureterohydronephrosis, neuropsychiatric and endocrinological impairment, and cataract. WS1 prevalence in the general population has been reported to be from 1/770,000 individuals to 1/54,478 in different ethnic groups.

WS1 is caused by mutations in the WFS1 gene located on 4p16.1 which encodes wolframin, an 890-amino-acid glycoprotein which is involved in the regulation of endoplasmic reticulum (ER) stress responses.

The aims of this Special Issue are:

  • To evaluate the prevalence of Wolfram syndrome in pediatric populations in different ethnic groups;
  • To identify the wide spectrum of clinical manifestations of Wolfram syndrome in children and adolescents;
  • To report genotype–phenotype correlations;
  • To identify early pathognomonic clinical signs of Wolfram syndrome in pediatric patients with non-autoimmune diabetes;
  • To critically evaluate cases of DIDMOAD previously diagnosed as type 1 diabetes.

Dr. Fortunato Lombardo
Guest Editor

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Keywords

  • WS Wolfram syndrome
  • DIDMOAD diabetes insipidus, diabetes mellitus, optic atrophy, and deafness
  • DM diabetes mellitus
  • OA optic atrophy
  • DI diabetes insipidus
  • D deafness

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Published Papers (7 papers)

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Research

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9 pages, 314 KiB  
Article
Clinical Peculiarities in a Cohort of Patients with Wolfram Syndrome 1
by Giuseppina Salzano, Luciana Rigoli, Mariella Valenzise, Roberto Chimenz, Stefano Passanisi and Fortunato Lombardo
Int. J. Environ. Res. Public Health 2022, 19(1), 520; https://doi.org/10.3390/ijerph19010520 - 4 Jan 2022
Cited by 4 | Viewed by 2522
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)

Review

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18 pages, 780 KiB  
Review
Wolfram Syndrome 1: From Genetics to Therapy
by Luciana Rigoli, Valerio Caruso, Giuseppina Salzano and Fortunato Lombardo
Int. J. Environ. Res. Public Health 2022, 19(6), 3225; https://doi.org/10.3390/ijerph19063225 - 9 Mar 2022
Cited by 32 | Viewed by 6399
Abstract
Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, [...] Read more.
Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the WFS1 gene located on chromosome 4p16 that encodes a transmembrane protein named wolframin. Many studies have shown that wolframin regulates some mechanisms of ER calcium homeostasis and therefore plays a role in cellular apoptosis. More than 200 mutations are responsible for WS1. However, abnormal phenotypes of WS with or without DM, inherited in an autosomal dominant mode and associated with one or more WFS1 mutations, have been found. Furthermore, recessive Wolfram-like disease without DM has been described. The prognosis of WS1 is poor, and the death occurs prematurely. Although there are no therapies that can slow or stop WS1, a careful clinical monitoring can help patients during the rapid progression of the disease, thus improving their quality of life. In this review, we describe natural history and etiology of WS1 and suggest criteria for a most pertinent approach to the diagnosis and clinical follow up. We also describe the hallmarks of new therapies for WS1. Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)
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10 pages, 328 KiB  
Review
Metabolic Treatment of Wolfram Syndrome
by Dario Iafusco, Angela Zanfardino, Alessia Piscopo, Stefano Curto, Alda Troncone, Antonietta Chianese, Assunta Serena Rollato, Veronica Testa, Fernanda Iafusco, Giovanna Maione, Alessandro Pennarella, Lucia Boccabella, Gulsum Ozen, Pier Luigi Palma, Cristina Mazzaccara, Nadia Tinto and Emanuele Miraglia del Giudice
Int. J. Environ. Res. Public Health 2022, 19(5), 2755; https://doi.org/10.3390/ijerph19052755 - 27 Feb 2022
Cited by 10 | Viewed by 3699
Abstract
Wolfram Syndrome (WS) is a very rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Usually, the first clinical sign is non-autoimmune diabetes even if other clinical features (optic subatrophy, neurosensorial deafness, diabetes insipidus) may be present in an [...] Read more.
Wolfram Syndrome (WS) is a very rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Usually, the first clinical sign is non-autoimmune diabetes even if other clinical features (optic subatrophy, neurosensorial deafness, diabetes insipidus) may be present in an early state and may be diagnosed after diabetes’ onset. Prognosis is poor, and the death occurs at the median age of 39 years as a consequence of progressive respiratory impairment, secondary to brain atrophy and neurological failure. The aim of this paper is the description of the metabolic treatment of the WS. We reported the experience of long treatment in patients with this syndrome diagnosed in pediatric age and followed also in adult age. It is known that there is a correlation between metabolic control of diabetes, the onset of other associated symptoms, and the progression of the neurodegenerative alterations. Therefore, a multidisciplinary approach is necessary in order to prevent, treat and carefully monitor all the comorbidities that may occur. An extensive understanding of WS from pathophysiology to novel possible therapy is fundamental and further studies are needed to better manage this devastating disease and to guarantee to patients a better quality of life and a longer life expectancy. Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)
12 pages, 736 KiB  
Review
Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum
by Francesco Maria Rosanio, Francesca Di Candia, Luisa Occhiati, Ludovica Fedi, Francesco Paolo Malvone, Davide Fortunato Foschini, Adriana Franzese and Enza Mozzillo
Int. J. Environ. Res. Public Health 2022, 19(2), 835; https://doi.org/10.3390/ijerph19020835 - 12 Jan 2022
Cited by 7 | Viewed by 3461
Abstract
Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary [...] Read more.
Background: Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928). Methods: A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form. Conclusion: WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers. Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)
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16 pages, 583 KiB  
Review
Urinary Tract Involvement in Wolfram Syndrome: A Narrative Review
by Alberto La Valle, Gianluca Piccolo, Mohamad Maghnie and Giuseppe d’Annunzio
Int. J. Environ. Res. Public Health 2021, 18(22), 11994; https://doi.org/10.3390/ijerph182211994 - 15 Nov 2021
Cited by 5 | Viewed by 3346
Abstract
Wolfram Syndrome (WS) is a rare neurodegenerative disease with autosomal recessive inheritance and characterized by juvenile onset, non-autoimmune diabetes mellitus and later followed by optic atrophy leading to blindness, diabetes insipidus, hearing loss, and other neurological and endocrine dysfunctions. A wide spectrum of [...] Read more.
Wolfram Syndrome (WS) is a rare neurodegenerative disease with autosomal recessive inheritance and characterized by juvenile onset, non-autoimmune diabetes mellitus and later followed by optic atrophy leading to blindness, diabetes insipidus, hearing loss, and other neurological and endocrine dysfunctions. A wide spectrum of neurodegenerative abnormalities affecting the central nervous system has been described. Among these complications, neurogenic bladder and urodynamic abnormalities also deserve attention. Urinary tract dysfunctions (UTD) up to end stage renal disease are a life-threatening complication of WS patients. Notably, end stage renal disease is reported as one of the most common causes of death among WS patients. UTD have been also reported in affected adolescents. Involvement of the urinary tract occurs in about 90% of affected patients, at a median age of 20 years and with peaks at 13, 21 and 33 years. The aim of our narrative review was to provide an overview of the most important papers regarding urological impairment in Wolfram Syndrome. A comprehensive search on PubMed including Wolfram Syndrome and one or more of the following terms: chronic renal failure, bladder dysfunction, urological aspects, and urinary tract dysfunction, was done. The exclusion criteria were studies not written in English and not including urinary tract dysfunction deep evaluation and description. Studies mentioning general urologic abnormalities without deep description and/or follow-up were not considered. Due to the rarity of the condition, we considered not only papers including pediatric patients, but also papers with pediatric and adult case reports Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)
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12 pages, 1213 KiB  
Review
Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype–Phenotype Correlations
by Maurizio Delvecchio, Matteo Iacoviello, Antonino Pantaleo and Nicoletta Resta
Int. J. Environ. Res. Public Health 2021, 18(9), 4796; https://doi.org/10.3390/ijerph18094796 - 30 Apr 2021
Cited by 28 | Viewed by 3916
Abstract
Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may [...] Read more.
Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may be incomplete. The syndrome is progressive, and thus, the clinical picture may change during follow-up. Currently, two different subtypes of this syndrome have been described, and they are associated with two different disease-genes, wolframin (WFS1) and CISD2. These genes encode a transmembrane protein and an endoplasmic reticulum intermembrane protein, respectively. These genes are detected in different organs and account for the pleiotropic features of this syndrome. In this review, we describe the phenotypes of both syndromes and discuss the most pertinent literature about the genotype–phenotype correlation. The clinical presentation of Wolfram syndrome type 1 suggests that the pathogenic variant does not predict the phenotype. There are few papers on Wolfram syndrome type 2 and, thus, predicting the phenotype on the basis of genotype is not yet supported. We also discuss the most pertinent approach to gene analysis. Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)
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Other

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6 pages, 599 KiB  
Case Report
An Atypical Case of Late-Onset Wolfram Syndrome 1 without Diabetes Insipidus
by Luciana Rigoli, Valerio Caruso, Concetta Aloi, Alessandro Salina, Mohamad Maghnie, Giuseppe d'Annunzio, Olga Lamacchia, Giuseppina Salzano, Fortunato Lombardo and Giuseppe Picca
Int. J. Environ. Res. Public Health 2022, 19(4), 2473; https://doi.org/10.3390/ijerph19042473 - 21 Feb 2022
Cited by 2 | Viewed by 2719
Abstract
Wolfram syndrome 1, a rare autosomal recessive neurodegenerative disease, is caused by mutations in the WFS1 gene. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), and other clinical manifestations such as urological and neurological disorders. Here we described [...] Read more.
Wolfram syndrome 1, a rare autosomal recessive neurodegenerative disease, is caused by mutations in the WFS1 gene. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), and other clinical manifestations such as urological and neurological disorders. Here we described the case of a patient with an atypical late-onset Wolfram syndrome 1 without DI. Our WS1 patient was a c.1620_1622delGTG (p.Trp540del)/c.124 C > T (p.Arg42*) heterozygous compound. The p.Arg42* nonsense mutation was also found in heterozygosity in his sister and niece, both suffering from psychiatric disorders. The p.Arg42* nonsense mutation has never been found in WS1 and its pathogenicity is unclear so far. Our study underlined the need to study a greater number of WS1 cases in order to better understand the clinical significance of many WFS1 variants. Full article
(This article belongs to the Special Issue Wolfram Syndrome in Pediatric Age)
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