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Genetic causes have long been suspected in many subtypes of dystonia. The earliest descriptions of early-onset primary dystonia in the first decades of the 20th century contained important clues to its genetic etiology. In recent decades, advances in molecular biology have led to the identification of an increasing number of genes for both primary and secondary dystonia subtypes. The identification of dystonia genes has, in turn, led to a clearer understanding of dystonia and to important changes in both clinical and basic science approaches to dystonia. With the advent of gene discovery, further investigations into the basic pathogenic mechanisms of dystonia using cellular and animal models have become possible, our understanding of the phenotypic spectrum of gene expression has been broadened, and the way that neurologists diagnose and counsel patients with dystonia has been altered. Ultimately, a more complete understanding of the genetic causes of dystonia and their mechanisms holds the promise of rational, targeted therapies.
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Dystonia is a clinically defined movement disorder characterized by involuntary sustained postures and repetitive movements that result from co-contraction of agonist and antagonist muscles.1 Dystonia is a clinically and etiologically heterogeneous condition. The clinical spectrum of dystonia is very broad, ranging from generalized, disabling contractions, which are much more common in those with early-onset disease, to localized or focal involvement, most commonly seen in those with adult-onset symptoms; focal adult-onset dystonia typically affects the cervical muscles (e.g., torticollis), cranial muscles (e.g., blepharospasm, hemifacial spasm, spasmodic dysphonia), or the arm (e.g., writer's cramp).
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Dystonia can be classified according to age of onset (early-onset versus late-onset), distribution (focal, segmental, multifocal, or generalized), and etiology (primary or secondary). When classified by etiology, dystonia is divided into the two broad categories: primary torsion dystonia (PTD, previously named idiopathic torsion dystonia), and secondary (nonprimary) dystonia. PTD is defined as a syndrome in which dystonia is the only neurological clinical sign (except for tremor), and in which there is no evidence of a neurodegenerative process or an acquired cause. The primary dystonias include both early-onset and adult-onset forms. Early-onset dystonia typically first affects a limb and then spreads, whereas late-onset dystonia typically starts in the cervical, cranial, or brachial muscles and usually remains focal or segmental. Adult-onset dystonia (which most commonly affects the cervical muscles) constitutes the great majority of primary dystonia. The PTDs were previously termed “idiopathic torsion dystonia” because of the lack of etiology or consistent pathological or neurochemical abnormality. However, with the determination of genetic etiologies of “idiopathic” dystonia, beginning with the identification of the DYT1 gene in 1997, the term “primary” has since replaced “idiopathic.”
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Secondary dystonias include all nonprimary dystonia subtypes; many have neurological signs other than dystonia and anatomic or biochemical changes involving the basal ganglia. The secondary dystonias can be subdivided into those with acquired etiologies, due to inherited neurodegenerative diseases, and the dystonia plus syndromes, due to hereditary nondegenerative neurological disorders that differ from primary dystonia because there are ...