The genetics of dystonia: new twists in an old tale

Abstract

Dystonia is a common movement disorder seen by neurologists in clinic. Genetic forms of the disease are important to recognize clinically and also provide valuable information about possible pathogenic mechanisms within the wider disorder. In the past few years, with the advent of new sequencing technologies, there has been a step change in the pace of discovery in the field of dystonia genetics. In just over a year, four new genes have been shown to cause primary dystonia (CIZ1, ANO3, TUBB4A and GNAL), PRRT2 has been identified as the cause of paroxysmal kinesigenic dystonia and other genes, such as SLC30A10 and ATP1A3, have been linked to more complicated forms of dystonia or new phenotypes. In this review, we provide an overview of the current state of knowledge regarding genetic forms of dystonia-related to both new and well-known genes alike-and incorporating genetic, clinical and molecular information. We discuss the mechanistic insights provided by the study of the genetic causes of dystonia and provide a helpful clinical algorithm to aid clinicians in correctly predicting the genetic basis of various forms of dystonia.

Keywords: clinical phenotype; dystonia; genetics; molecular mechanisms.

Figure 1

A workable strategy for identifying the likely genetic basis for some of the major forms of dystonia. Mutational screening for some genes is currently only available on a research basis.

Figure 2

Schematic illustration of the pathways for the synthesis of catecholamines and serotonin. Breakdown products are indicated by broken arrows. Enzymes in which defects cause DOPA-responsive dystonia are shown in red with the gene symbol in brackets. Tetrahydrobiopterin is a key cofactor in some enzymatic reactions.