Dystonia
Advances in Our Understanding of Dystonia – Pathophysiology and Treatment Options
Naomi Lubarr1 and Susan Bressman2
1. Attending Neurologist, Division of Pediatric Neurology and Division of Movement Disorders, Department of Neurology, Beth Israel Medical Center; 2. Alan and Joan Mirken Chair, Department of Neurology, Beth Israel Medical Center and Professor of Neurology, Albert Einstein College of Medicine
Abstract Although the pathophysiology of dystonia remains incompletely understood, advances in two major areas of research over the past two decades have led to important insights into the mechanisms of dystonia. First, with the identification of dystonia genes, investigations using cellular and animal models of dystonia have become possible. Second, advances in functional neuroimaging have led to the possibility of identification of distinct functional, anatomical and neurochemical abnormalities in dystonia patients. Dystonia is currently conceptualised as a neurofunctional disorder characterised by alterations at various levels and multiple points along the sensorimotor circuit. There are multiple causes of these disruptions, and lesions along different points in interconnected pathways can yield similar motor dysfunction. The existence of dystonia endophenotypes in genetic forms of dystonia suggests that it may be a ‘second hit’ disorder, in which genetically predisposed brains can be thrown into an unbalanced dystonic state by environmental or genetic factors. Ultimately, a more complete understanding of the pathophysiology of dystonia should lead to better, more rational, targeted therapies.
Keywords
Dystonia, pathophysiology, genetics, neurophysiology, fluorodeoxyglucose positron emission tomography (FDG-PET), transmagnetic stimulation (TMS), treatment
Disclosure: The authors have no conflicts of interest to declare. Received: 9 August 2010 Accepted: 1 November 2010 Citation: European Neurological Review, 2011;6(2):121–7 Correspondence: Susan Bressman, Beth Israel Medical Center, Department of Neurology, Phillips Ambulatory Care Center, 10 Union Square East, Suite 5H, New York, NY 10003, US. E:
sbressma@chpnet.org
Dystonia is characterised by involuntary muscle contractions causing twisting movements and abnormal postures.1
It is clinically and
aetiologically heterogeneous and is most usefully classified by aetiology as either primary or secondary dystonia. In primary dystonias, dystonia is the only neurological sign (except for tremor), and there is no evidence of an acquired cause or of any neurodegenerative process. In secondary dystonias, dystonia occurs together with other neurological symptoms and is due to acquired causes or neurodegenerative disease. An intermediary category is termed ‘dystonia plus syndromes,’ and consists of disorders in which there is no acquired aetiology or neurodegeneration, but in which there are neurologic symptoms other than dystonia. This category includes dopa-responsive dystonia (DRD/DYT5), myoclonus dystonia (MD/DYT11) and rapid-onset dystonia-parkinsonism (RDP/DYT12) (see Table 1). Primary dystonia is subdivided into early-onset and adult-onset forms. Early-onset primary dystonias typically initially affect a limb and subsequently spread, frequently becoming generalised. Genes have been identified in two forms of early-onset primary dystonia: DYT1 and DYT6. Late-onset primary dystonia typically occurs in either cervical, cranial or brachial muscles, and remains focal or segmental. Adult-onset focal dystonia (with cervical dystonia as the most common form) is far more common than early-onset primary dystonia.
Although the pathophysiology of dystonia remains incompletely understood, advances in two major areas of research over the past
© TOUCH BRIEFINGS 2011
two decades have led to important insights into mechanisms of dystonia.
First, with the identification of dystonia genes, investigations using cellular and animal models of dystonia have become possible. In addition, clinical studies can take advantage of the reduced penetrance in primary dystonia, whereby only approximately 30 % of gene mutation carriers manifest dystonia, by performing clinical investigations in dystonia patients (manifesting carriers) as well as in gene carriers without dystonia (non-manifesting carriers), providing insight into the question of which abnormalities are inherent to the gene mutation (endophenotypes or trait features) regardless of clinical status versus which abnormalities occur in association with clinical dystonia. Second, advances in functional neuroimaging have led to the possibility of in vivo identification of distinct functional, anatomical and neurochemical abnormalities in dystonia patients and in non-manifesting gene carriers.
Historically, the principal cause of dystonia has been thought to be dysfunction of the basal ganglia, which arose from the concept of the basal ganglia as the brain region responsible for integrating motor control, together with the fact that secondary dystonia is most commonly due to lesions of the basal ganglia, specifically the putamen or globus pallidus. However, the absence of neurodegeneration in primary dystonia, as well as observations that lesions of brain regions
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