Molecular Genetics of Dystonia

Abstract

Abstract Dystonia is a clinically and genetically highly heterogeneous, rare movement disorder that is characterised by sustained or intermittent muscle contractions causing abnormal movements and/or postures. Dystonic syndromes can manifest from early infancy to late adulthood and display diverse anatomical expressivity. Phenotypically, dystonias are classified as isolated, combined (in combination with another movement disorder) or complex dystonia (usually as one of several disease manifestations in a complex syndrome). Over 100 dystonia genes have been identified including pathogenic genomic variants (mutations) in TOR1A , THAP1 , GNAL , GCH1 , ATP1A3 , PRKRA , SGCE , TUBB4A , ADCY5 and GNB1 . The encoded proteins do not seem to belong to a common pathway but rather affect diverse cellular functions including, for instance, dopamine biosynthesis, signal transduction as ion channels or G proteins as well as transcriptional regulation. Key Concepts Dystonias represent a heterogeneous group of movement disorders. Over 100 genes have been linked to dystonic features. Owing to the advent of next‐generation sequencing many novel dystonia genes have been reported but their role needs to be confirmed. Dystonia can affect all age groups. In some cases, it starts in early childhood and then often generalises. The most common form of dystonia is late‐onset, focal dystonia. Diverse pathways are affected by dystonia‐causing mutations.