Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Details

Serval ID
serval:BIB_CC89F1E9223C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.
Journal
NeuroImage
Author(s)
Draganski B., Schneider S.A., Fiorio M., Klöppel S., Gambarin M., Tinazzi M., Ashburner J., Bhatia K.P., Frackowiak R.S.
ISSN
1095-9572[electronic]
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
47
Number
4
Pages
1141-1147
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.
Keywords
Adult, Aged, Brain/pathology, Brain/physiopathology, Dystonia/genetics, Dystonia/pathology, Female, Genetic Predisposition to Disease/genetics, Genotype, Heterozygote, Humans, Magnetic Resonance Imaging/methods, Male, Middle Aged, Molecular Chaperones/genetics, Polymorphism, Single Nucleotide/genetics, Statistics as Topic, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
11/01/2010 14:10
Last modification date
20/08/2019 16:47
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