The focal dystonias: current views and challenges for future research

Abstract

The most common forms of dystonia are those that develop in adults and affect a relatively isolated region of the body. Although these adult-onset focal dystonias are most prevalent, knowledge of their etiologies and pathogenesis has lagged behind some of the rarer generalized dystonias, in which the identification of genetic defects has facilitated both basic and clinical research. This summary provides a brief review of the clinical manifestations of the adult-onset focal dystonias, focusing attention on less well understood clinical manifestations that need further study. It also provides a simple conceptual model for the similarities and differences among the different adult-onset focal dystonias as a rationale for lumping them together as a class of disorders while at the same time splitting them into subtypes. The concluding section outlines some of the most important research questions for the future. Answers to these questions are critical for advancing our understanding of this group of disorders and for developing novel therapeutics.

Keywords: blepharospasm; cervical dystonia; focal dystonia; focal hand dystonia; spasmodic dysphonia.

Figure 1

Conceptual model for similarities and differences among different dystonias. A simplified scheme for pathogenesis begins with a specific etiology and proceeds through a series of downstream processes in the pathogenesis of dystonia (A). Etiologically different types of dystonia may share a similar molecular pathway and similar subsequent pathogenesis (B). Alternatively, etiologically different types of dystonia may differ at the molecular level, yet disrupt the same neuronal population (C). Etiologically different types of dystonia instead may disrupt a common anatomical circuit (D). Ultimately, all may share some similar biological defect at the systems level to result in the patterns of muscle activity that define dystonia.

Figure 2

Example model for shared mechanisms of pathogenesis at different biological levels. A simplified scheme for pathogenesis begins with a specific etiology and proceeds through a series of downstream processes in the pathogenesis of dystonia (A). Some disorders are known to disrupt a common molecular pathway involving dopamine synthesis via different molecular mechanisms (B). Two gene defects (GCH1 and PTPS) affect dopamine synthesis by disrupting biopterin metabolism, while two other gene defects (TH and AADC) affect other steps in dopamine synthesis. All 4 of these disorders disrupt nigrostriatal dopamine neuron function, signaling in basal ganglia circuits, and alter systems physiology to produce dystonia. Nigrostriatal dopamine neurons may be affected via other genetic mechanisms (C: HPRT) or exposure to dopamine receptor antagonists(D) to cause dystonia. Damage may also occur to basal ganglia circuits more directly, as in some mitochondrial disorders, glutaric aciduria, biotin-responsive basal ganglia disease, 3-nitropropionic acid exposure (E).