Genetics of dystonia: an overview

Abstract

The torsion dystonias encompass a broad collection of etiologic subtypes, often divided into primary and secondary classes. Over the last two decades an increasing number of genetic causes have been identified, including an important genetic cause for early-onset primary torsion dystonia (PTD): a GAG deletion in exon 5 of DYT1, a gene that encodes torsinA. Although the exact function of torsinA remains elusive, evidence suggests aberrant localization and interaction of mutated protein; this may result in an abnormal response to stress or interference with cytoskeletal events and the development of neuronal brain pathways. Identification of DYT1 has also permitted studies of both “manifesting” and “non-manifesting” DYT1 mutation carriers. These investigations have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. Similarly, there has been progress in our understanding of the genetic underpinnings of the “dystonia-plus” syndromes: dopa-responsive dystonia (DRD), myoclonus–dystonia (M-D), and rapid-onset dystonia–parkinsonism (RDP). These advances provide a widened platform for future research.