Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives.
Adolescent
Adult
Child
Child, Preschool
Clinical Trials as Topic
Diabetes Mellitus, Type 1
/ complications
Disease Progression
Drug Development
Drug Repositioning
Endoplasmic Reticulum
/ metabolism
Female
Genes, Recessive
Humans
Infant
Interdisciplinary Communication
Male
Membrane Proteins
/ genetics
Neurodegenerative Diseases
/ complications
Prognosis
Quality of Life
Wolfram Syndrome
/ complications
Young Adult
Deafness
Diabetes insipidus
Optic atrophy
Type 1 diabetes
WFS1
WFS2
Wolfram syndrome
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
23 07 2019
23 07 2019
Historique:
received:
22
01
2019
accepted:
17
07
2019
entrez:
25
7
2019
pubmed:
25
7
2019
medline:
10
7
2020
Statut:
epublish
Résumé
Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions. WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction. Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.
Sections du résumé
BACKGROUND
Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions.
MAIN BODY
WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction.
CONCLUSIONS
Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.
Identifiants
pubmed: 31337416
doi: 10.1186/s12967-019-1993-1
pii: 10.1186/s12967-019-1993-1
pmc: PMC6651977
doi:
Substances chimiques
Membrane Proteins
0
wolframin protein
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
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