Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.
Détails
ID Serval
serval:BIB_CC89F1E9223C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.
Périodique
NeuroImage
ISSN
1095-9572 (Electronic)
ISSN-L
1053-8119
Statut éditorial
Publié
Date de publication
01/10/2009
Peer-reviewed
Oui
Volume
47
Numéro
4
Pages
1141-1147
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
11/01/2010 14:10
Dernière modification de la notice
18/12/2023 14:02