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.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

“…The control of voluntary movement is governed by interactive neural networks within the brain involving the basal ganglia, sensorimotor cortex, cerebellum and thalamus 1 . Disruption of these pathways can lead to a variety of movement disorders.…”

“…Dystonia is described in a broad spectrum of genetic and acquired disorders, either in isolation or combined with other neurological and systemic features [1][2][3][4][5] . Despite genetic advances, the underlying cause remains elusive for a significant proportion of individuals with childhood-onset dystonia, hindering future prognostication and treatment strategies 6 .…”

Twisting mice move the dystonia field forward

“…7). The DYT1/TOR1A mutation is responsible for around 50% of early onset primary dystonia cases (8). Most often, the genetic mutation in DYT1-related dystonia is an in-frame GAG deletion (termed ΔE mutant), which is thought to result in at least a partial loss of torsinA function.…”

Youngest presenting patient with dystonia 24 and review of the literature

“…This protein belongs to a family of 10 anoctamin proteins that function as calcium‐activated chloride channels of which the most is known about ANO1 and ANO2 6. ANO1 and ANO2 are known to function at the cell surface with roles in sensory transduction, secretion at the epithelial membrane, and smooth muscle contraction 7.…”