Genetics of dystonia

In recent years, the identification of several new dystonia genes has improved our understanding of the etiology of the rare monogenic forms and of dystonia in general, and has provided important insights into the nature of this clinically and genetically heterogeneous disorder. In the current dystonia genetics nomenclature, 23 different chromosomal regions are termed DYT (to denote their putative link to dystonia), and numbered in chronological order of their identification (DYT1-23; with DYT5a/DYT14; DYT9/DYT18 being identical, and DYT5b being a separate locus). The monogenic dystonia forms with a DYT designation are clinico-genetically grouped as i) ‘isolated dystonias’ (DYT1, DYT2, DYT4, DYT6, DYT7, DYT13, DYT17, DYT21, DYT23, DYT24, and DYT25), and ii) ‘combined dysonias’ that can have a persistent (DYT3, DYT5, DYT11, DYT12, DYT16, and DYT15) or paroxysmal (episodic) temporal pattern (DYT8-10 and DYT18-20). For 13 of these forms causative genes have been unequivocally identified, thereby providing insight into disease mechanisms. In addition to the causative gene mutations, genetic modifiers also seem to play an important role in the etiology of dystonia. In this chapter we will summarize the current knowledge and understanding of the genetics of dystonia and review proposed molecular mechanisms leading to the familial forms of the disease. In addition, we will explain current methods for the identification of dystonia genes, and consider implications for genetic testing.