Evolving concepts in the pathogenesis of dystonia

Abstract

Introduction: The dystonias are a group of disorders defined by over-contraction of muscles leading to abnormal movements and postures. In recent years, enormous advances have been made in elucidating the neurobiological mechanisms responsible for many types of dystonia.

Methods: A literature review was conducted focusing on evolving concepts in dystonia genetics, anatomy and physiology.

Results: The list of genes related to dystonia has grown from a relatively small number to more than 100. Concepts regarding the neuroanatomical basis for dystonia have evolved from a relatively narrow focus on dysfunction of the basal ganglia to a broader motor network model in which the basal ganglia, cerebellum, cerebral cortex, and other brain regions play a key role. Physiologically, our understanding of the core abnormalities has matured; and numerous changes in neural signaling have been revealed in the basal ganglia, cerebellum and cortex.

Conclusion: Although the dystonias share certain clinical aspects such as over-contraction of muscles leading to abnormal movements and postures, they actually comprise a very clinically and etiologically heterogeneous group of disorders. Understanding their neurobiological basis is important for devising rational therapies appropriately targeted for specific subgroups of patients.

Keywords: Neuroanatomy; Neurobiology; Neurogenetics; Neurophysiology; Pathogenesis; Pathophysiology.

Figure 1. Patterns of inheritance

This schematic shows a classification system for genes for monogenic dystonias based on pattern of inheritance. It is not a complete list of all genes and patterns of inheritance; only representative examples are shown. Genes shown in underlined type are those that are commonly associated with dystonia as the only or predominant clinical feature. Those in plain type are those where dystonia is often combined with other clinical features.

Figure 2. Biological pathways

This schematic shows a classification system for genes for monogenic dystonias based on shared biological pathways. It is not a complete list of all genes and their biological pathways. Only representative examples are shown. Genes shown in underlined type are those that are commonly associated with dystonia as the only or predominant clinical feature. Those in plain type are those where dystonia is often combined with other clinical features. Some genes may fall in more than one group when their functions overlap more than one biological mechanism. In many cases the biological pathways are well established, but in some the pathways are suspected but not proven.