The pathophysiological basis of dystonias

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Dystonias comprise a group of movement disorders that are characterized by involuntary movements and postures. Insight into the nature of neuronal dysfunction has been provided by the identification of genes responsible for primary dystonias, the characterization of animal models and functional evaluations and in vivo brain imaging of patients with dystonia. The data suggest that alterations in neuronal development and communication within the brain create a susceptible substratum for dystonia. Although there is no overt neurodegeneration in most forms of dystonia, there are functional and microstructural brain alterations. Dystonia offers a window into the mechanisms whereby subtle changes in neuronal function, particularly in sensorimotor circuits that are associated with motor learning and memory, can corrupt normal coordination and lead to a disabling motor disorder.

Key Points

  • Dystonia is a common and disabling movement disorder in humans. It encompasses a variety of different symptoms including torticollis, limb and trunk dystonia, writer's cramp, blepharospasm and spastic dysphonia.

  • Dystonia can arise in the absence of other apparent neurological disease (primary dystonia) or as a result of brain injury, drug treatment or neurodegenerative disease (secondary dystonia).

  • A large number of dystonias appear to have a strong genetic component. Fourteen monogenic forms of dystonia have been identified, most of which are autosomal dominant with incomplete penetrance. The proteins encoded are involved in a wide range of cellular functions including dopamine synthesis, organelle transport, neuronal development, membrane transport and toxin metabolism.

  • Both genotypic and phenotypic animal models of dystonia that provide insights into the pathophysiological basis of the disorder are available. These models can be used as platform for therapeutic testing.

  • Neuroimaging studies in humans and non-human primates have provided insight into the systems-level disturbances that are responsible for dystonia. These indicate a central role for abnormal plasticity, affecting the sensorimotor system, leading to distortion of sensory fields in the sensorimotor cortex and abnormal signalling in the basal ganglia.

  • Current treatment of the dystonias relies on drugs acting at dopaminergic, cholinergic and γ-aminobutyric acid (GABA)ergic receptors, but in most cases they are only partially effective. Some forms of dystonia respond remarkably well to deep brain stimulation of the globus pallidus, indicating that the movement abnormalities are potentially reversible.

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Figure 1: Images of patients with different forms of dystonia.
Figure 2: Changes in proteins that cause dystonia.
Figure 3: Brain circuitry affected in dystonia.
Figure 4: Functional and microstructural basal ganglia abnormalities in dystonia.
Figure 5: Modes of symptomatic therapy for dystonia.


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We thank S. McDavitt for skilled editorial assistance. Funding was provided by the Bachmann-Strauss Dystonia and Parkinson Foundation (X.O.B., Y.L. and D.G.S.), the Jack Fasciana Fund for Support of Dystonia Research (X.O.B.), the Dystonia Medical Research Foundation (A.B. and Y.L.), National Institute of Neurological Disorders and Stroke (NINDS) NS37409 (X.O.B. and D.G.S.), NS047692 (Y.L.), NS050717 (P.I.H.) and NINDS intramural funding (M.H.).

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Correspondence to Xandra O. Breakefield.

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Paroxysmal dystonia

Type of dystonia characterized by a sudden onset of symptoms of brief duration followed by remission.


Excessive and uncontrolled movements, which may be dystonic, repetitive or choreiform.


Involuntary movements involving limbs, torso or facial muscles with a writhing, continuous character.


A hereditary disease caused by a defect in one or both alleles of a single gene.

Autosomal dominant

A disease in which a mutation in one of two alleles for a gene on an autosome (any chromosome other than the X and Y chromosomes) gives rise to the syndrome.

Reduced penetrance

Hereditary diseases in which only some carriers of the mutant gene are affected.

Homo-oligomeric complex

Protein complexes which are made up of multiple identical subunits.


A mutant form of a protein which itself lacks normal function but can suppress the functions of the wild-type gene product.

Founder mutation

A mutation that occurs in an isolated population, with in-breeding leading to an increased frequency in that population.

Ballistic movement

Involuntary or flinging projectile movements of the limbs, a violent form of chorea.

Maternal imprinting

The process by which the maternally inherited allele of a gene is silenced during embryogenesis so that only the paternal allele of that gene is expressed in the offspring.

Receptive field

The area of the brain that responds to sensory input.

Sequence learning

The process of learning motor skills in which a series of tasks must be executed in the proper sequence.


Partial deficiency of a protein, resulting from a loss-of-function mutation in one of the two alleles encoding the protein.


A characteristic of an individual that is not immediately apparent, but which might be revealed by a biochemical or imaging test and used to classify the individual in a genetic study.

Paired associative stimulation

A transcranial magnetic stimulation (TMS) paradigm in which peripheral nerve stimulation is combined with TMS over the contralateral motor cortex, leading to an increase or a decrease in cortical excitability, depending on the interval between the two stimulations; the technique is meant to simulate long-term potentiation or depression in electrophysiological studies.


The mapping of neuronal connections from body structures onto a physical representation of those structures in the cerebral cortex.

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Breakefield, X., Blood, A., Li, Y. et al. The pathophysiological basis of dystonias. Nat Rev Neurosci 9, 222–234 (2008) doi:10.1038/nrn2337

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