Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

Abstract

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.

Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics

“…However, it is interesting to note that NEET proteins have been associated with different pathological conditions in which MT morphology as well as ER‐MT contact‐sites alterations appear to be a frequent signature: metabolic disorders, neurological, cancer (Erpapazoglou et al , 2017; Naia et al , 2017; Tubbs & Rieusset, 2017; Doghman‐Bouguerra & Lalli, 2019), and now infections. Importantly, we show here that chemical‐mediated alteration of NEET proteins' biological function via Mito‐C increases the ER‐mitochondria contact sites, a situation previously reported in patients with a mutated form of NAF‐1 (Rouzier et al , 2017) and suffering from Wolfram syndrome (Pallota et al , 2019).…”

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

“…The prevalence of WS is approximately 1:100,000 in North America, 1:770,000 in the United Kingdom, and 1:710,000 in Japan [8]. The highest frequencies occur in Lebanon (1:68,000) and a small Sicilian population (1:55,000), likely due to higher rates of consanguinity [2, 4, 6, 8].…”

“…Wolfram syndrome-1 (WS1) is caused by homozygous or compound heterozygous pathogenic variants in the gene encoding wolframin, WFS1, on chromosome 4p16. Wolfram syndrome-2 (WFS2) is caused by variants in the CISD2 gene (CDGSH iron-sulfur domain-containing protein 2) on chromosome 4q22-q24 [3, 4]. Variants in CISD2 are much less common, and patients typically do not develop diabetes insipidus or psychiatric disorders, but do have defective platelet aggregation and upper intestinal ulcers [4, 8].…”

Autosomal‐dominant WFS1‐related disorder—Report of a novel WFS1 variant and review of the phenotypic spectrum of autosomal recessive and dominant forms

“…Wolfram syndrome (OMIM 222300) was initially described by Wolfram and Wagener in 1938, in four siblings with diabetes mellitus (DM) and optic atrophy (OA), as an autosomal recessive (AR) condition. It has been characterized by diabetes insipidus (DI), childhood onset DM, gradual progression of OA, and deafness (D)—therefore, it was given the acronym DIDMOAD (Pallotta et al, 2019). Two genes have been identified to be associated with Wolfram syndrome type 1 (WFS1 ) and type 2 (WFS2 ), respectively (Amr et al, 2007; Inoue et al, 1998).…”