Faculty Opinions recommendation of Lamin B1 duplications cause autosomal dominant leukodystrophy.

Author(s):  
Yosef Gruenbaum
Keyword(s):  
2013 ◽  
Vol 260 (8) ◽  
pp. 2124-2129 ◽  
Author(s):  
Ana Potic ◽  
Aleksandra M. Pavlovic ◽  
Graziella Uziel ◽  
Dusko Kozic ◽  
Jelena Ostojic ◽  
...  

2014 ◽  
Vol 28 (9) ◽  
pp. 3906-3918 ◽  
Author(s):  
Denise Ferrera ◽  
Claudio Canale ◽  
Roberto Marotta ◽  
Nadia Mazzaro ◽  
Marta Gritti ◽  
...  
Keyword(s):  

2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert Laforce ◽  
Martin Roy ◽  
Maxime Descoteaux ◽  
Christian Berthelot ◽  
Jean-Pierre Bouchard

AbstractAutosomal dominant adult-onset leukodystrophy (ADLD) is a progressive hereditary disease caused by duplication of Lamin B1 on chromosome 5q23.2. It is characterized by autonomic dysregulation, pyramidal signs, and cerebellar dysfunction. Since the first description in 1984, no authors have reported on its neurocognitive sequelae or attempted to quantify the severity of white matter changes. Herein we report a case of ADLD presenting with progressive cognitive changes leading to dementia and its associated white matter damage using diffusion MR imaging.


2015 ◽  
Vol 24 (11) ◽  
pp. 3143-3154 ◽  
Author(s):  
Elisa Giorgio ◽  
Daniel Robyr ◽  
Malte Spielmann ◽  
Enza Ferrero ◽  
Eleonora Di Gregorio ◽  
...  

2007 ◽  
Vol 39 (2) ◽  
pp. 276-276 ◽  
Author(s):  
Quasar S Padiath ◽  
Kazumasa Saigoh ◽  
Raphael Schiffmann ◽  
Hideaki Asahara ◽  
Takeshi Yamada ◽  
...  
Keyword(s):  

Author(s):  
Stefano Ratti ◽  
Isabella Rusciano ◽  
Sara Mongiorgi ◽  
Eric Owusu Obeng ◽  
Alessandra Cappellini ◽  
...  

Abstract Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.


2009 ◽  
Vol 17 (4) ◽  
pp. 541-549 ◽  
Author(s):  
A. Brussino ◽  
G. Vaula ◽  
C. Cagnoli ◽  
E. Panza ◽  
M. Seri ◽  
...  
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2020 ◽  
Vol 25 (8) ◽  
pp. 939-949
Author(s):  
Bruce Nmezi ◽  
Laura L. Vollmer ◽  
Tong Ying Shun ◽  
Albert Gough ◽  
Harshvardhan Rolyan ◽  
...  

Autosomal dominant leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by widespread central nervous system (CNS) demyelination and significant morbidity. The late age of onset together with the relatively slow disease progression provides a large therapeutic window for the disorder. However, no treatment exists for ADLD, representing an urgent and unmet clinical need. We have previously shown that ADLD is caused by duplications of the lamin B1 gene causing increased expression of the lamin B1 protein, a major constituent of the nuclear lamina, and demonstrated that transgenic mice with oligodendrocyte-specific overexpression of lamin B1 exhibit temporal and histopathological features reminiscent of the human disease. As increased levels of lamin B1 are the causative event triggering ADLD, approaches aimed at reducing lamin B1 levels and associated functional consequences represent a promising strategy for discovery of small-molecule ADLD therapeutics. To this end, we have created an inducible cell culture model of lamin B1 overexpression and developed high-content analysis in connection with multivariate analysis to define, analyze, and quantify lamin B1 expression and its associated abnormal nuclear phenotype in mouse embryonic fibroblasts (MEFs). The assay has been optimized to meet high-throughput screening (HTS) criteria in multiday variability studies. To control for batch-to-batch variation in the primary MEFs, we have implemented a screening strategy that employs sentinel cells to avoid costly losses during HTS. We posit the assay will identify bona fide suppressors of lamin B1 pathophysiology as candidates for development into potential therapies for ADLD.


2006 ◽  
Vol 38 (10) ◽  
pp. 1114-1123 ◽  
Author(s):  
Quasar S Padiath ◽  
Kazumasa Saigoh ◽  
Raphael Schiffmann ◽  
Hideaki Asahara ◽  
Takeshi Yamada ◽  
...  
Keyword(s):  

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