201. Genotype–phenotype interactions in primary dystonias revealed by differential changes in brain structure
- Author
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John Ashburner, Susanne A. Schneider, Michele Tinazzi, Richard S. J. Frackowiak, Stefan Klöppel, Mattia Gambarin, Kailash P. Bhatia, Bogdan Draganski, and Mirta Fiorio
- Subjects
Adult ,Male ,Heterozygote ,Pathology ,medicine.medical_specialty ,Genotype ,Cognitive Neuroscience ,Statistics as Topic ,DYT1 ,Polymorphism, Single Nucleotide ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Genotype-phenotype distinction ,Basal ganglia ,Humans ,Medicine ,Genetic Predisposition to Disease ,Cervical dystonia ,Primary dystonia ,Aged ,030304 developmental biology ,Dystonia ,0303 health sciences ,business.industry ,Brain ,Voxel-based morphometry ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Penetrance ,Ashkenazi jews ,Intermediate phenotype ,Neurology ,Female ,business ,030217 neurology & neurosurgery ,Molecular Chaperones - 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.
- Published
- 2009