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Journal Article

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


Draganski,  Bogdan
Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, United Kingdom;
Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society;

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Draganski, B., Schneider, S. A., Fiorio, M., Klöppel, S., Gambarin, M., Tinazzi, M., et al. (2009). Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure. NeuroImage, 47(4), 1141-1147. doi:10.1016/j.neuroimage.2009.03.057.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0010-B7D0-D
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. © 2009 Elsevier Inc.