Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.
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.
Draganski
B
B
Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, UK. draganski@mpg.cbs.de
Schneider
S A
SA
Fiorio
M
M
Klöppel
S
S
Gambarin
M
M
Tinazzi
M
M
Ashburner
J
J
Bhatia
K P
KP
Frackowiak
R S J
RS
D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D004421:Dystonia / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013223:Statistics as Topic; D055815:Young Adult
D018832:Molecular Chaperones; C108175:TOR1A protein, human