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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2019

Open Access 01-12-2019 | Review

Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses

Authors: Amjad Samara, Rachel Rahn, Olga Neyman, Ki Yun Park, Ahmad Samara, Bess Marshall, Joseph Dougherty, Tamara Hershey

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

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Abstract

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration.
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Metadata
Title
Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses
Authors
Amjad Samara
Rachel Rahn
Olga Neyman
Ki Yun Park
Ahmad Samara
Bess Marshall
Joseph Dougherty
Tamara Hershey
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1260-9

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