Genetics of dystonia: what's known? What's new? What's next?

Abstract

Although all forms of dystonia share the core clinical features of involuntary dystonic dyskinesia, there is not only marked phenotypic but also etiologic heterogeneity. Isolated dystonia can be caused by mutations in TOR1A (DYT1), TUBB4 (DYT4), THAP1 (DYT6), CIZ1 (DYT23), ANO3 (DYT24), and GNAL (DYT25). Combined dystonias (with parkinsonism or myoclonus) are further subdivided into persistent (TAF1 [DYT3], GCHI [DYT5], SGCE [DYT11], ATP1A3 [DYT12]), PRKRA (DYT16), and paroxysmal (MR-1 [DYT8], PRRT2 [DYT10], SLC2A1 [DYT18]. With the advent of next-generation sequencing, an unprecedented number of new dystonia genes have recently been described, including 4 in the past 12 months. Despite the need for independent confirmation, these recent findings raise 2 important questions regarding (1) the role of genetics in dystonia overall and (2) the role of different molecular mechanisms in dystonia pathogenesis. The genetic contribution to dystonia represents a continuum ranging from genetic susceptibility factors of small effect to causative genes with markedly reduced penetrance to those with full penetrance. Equally diverse and complex are the pathways and neuronal function(s) putatively involved in dystonia pathogenesis including dopamine signaling, intracellular transport, cytoskeletal dynamics, transcriptional regulation, cell-cycle control, ion channel function, energy metabolism, signal transduction, and detoxification mechanisms. In the next decade of dystonia research, we expect to see the discovery of additional dystonia genes and susceptibility factors. In this context, it will be of great interest to explore whether the diverse cellular functions of the known dystonia proteins may be linked to shared pathways and thus complete the complex puzzle of dystonia pathogenesis. © 2013 Movement Disorder Society.

Keywords: dystonia; exome sequencing; gene; pathways; penetrance.