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, 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.
Highlights
Wolfram syndrome 1 (WS1; MIM 222300) is a rare autosomal recessive neurodegenerative disease first described in 1938 by Wolfram and Wagener [1]
Zmyslowska et al found that in pediatric insulin-dependent diabetes mellitus (DM) populations, WS1 was diagnosed with a delay of at least 7 years as WS1 patients were initially misdiagnosed as having type 1 DM [13]
unfolded protein response (UPR) activates three transmembrane proteins located in the endoplasmic reticulum (ER) that function as sensors of stress: inositol-requiring protein 1 (IRE1), protein kinase RNA (PKR) -like ER kinase (PERK), and activating transcription factor 6 (ATF6)
Summary
Wolfram syndrome 1 (WS1; MIM 222300) is a rare autosomal recessive neurodegenerative disease first described in 1938 by Wolfram and Wagener [1]. The main clinical features are diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and deafness (D), the acronym DIDMOAD. OA are key clinical criteria for the diagnosis of WS1 [1]. WS1 is a rare type of DM and has been included in subcategory 5A16.1 of the International Classification of Disease (ICD-11) [4]. As the clinical course of WS1 is rapidly progressive and leads to a premature death of patients at the mean age of 30 years (25–49 years). The main cause of death is respiratory failure due to brainstem atrophy [5,6]. Careful clinical follow-up and supportive care can be helpful for relieving severe and progressive symptoms of WS1
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