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 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.
Highlights
Wolfram syndrome (WS) is a progressive neurodegenerative disorder, which should always be suspected in patients with insulin-dependent diabetes mellitus (DM) and optic atrophy
To consider the pleiotropic manifestations, a multidisciplinary, team approach to the different clinical problems should be used for these patients. This diagnosis should be considered in all the patients with DM and optic atrophy and with an overall absence of type 1 DM autoantibodies
We recommend that this diagnosis should be suspected in patients with non-autoimmune DM who present less frequent clinical findings that are suggestive of WS, such as sensorineural hearing loss or bowel disease
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Wolfram syndrome (WS) is a rare neurodegenerative disorder that is sometimes referred to as Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (DIDMOAD), and it was described for the first time by Wolfram and Wagener in 1938 [1]. They described four siblings who were born to consanguineous parents with diabetes mellitus (DM) and optic atrophy, which are key elements that are used to diagnose this syndrome.
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