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Primary dystonia: molecules and mechanisms

Abstract

Primary dystonia is characterized by abnormal, involuntary twisting and turning movements that reflect impaired motor system function. The dystonic brain seems normal, in that it contains no overt lesions or evidence of neurodegeneration, but functional brain imaging has uncovered abnormalities involving the cortex, striatum and cerebellum, and diffusion tensor imaging suggests the presence of microstructural defects in white matter tracts of the cerebellothalamocortical circuit. Clinical electrophysiological studies show that the dystonic CNS exhibits aberrant plasticity—perhaps related to deficient inhibitory neurotransmission—in a range of brain structures, as well as the spinal cord. Dystonia is, therefore, best conceptualized as a motor circuit disorder, rather than an abnormality of a particular brain structure. None of the aforementioned abnormalities can be strictly causal, as they are not limited to regions of the CNS subserving clinically affected body parts, and are found in seemingly healthy patients with dystonia-related mutations. The study of dystonia-related genes will, hopefully, help researchers to unravel the chain of events from molecular to cellular to system abnormalities. DYT1 mutations, for example, cause abnormalities within the endoplasmic reticulum–nuclear envelope endomembrane system. Other dystonia-related gene products traffic through the endoplasmic reticulum, suggesting a potential cell biological theme underlying primary dystonia.

Key Points

  • Primary dystonia is defined as an illness in which dystonic movements occur as an isolated sign in the absence of an identifiable neuropathological lesion or exogenous cause

  • Secondary dystonia refers to dystonic movements that result from a lesion to the motor system, and is typically accompanied by additional neurological signs

  • Dystonia seems to be a motor system or motor circuit disorder rather than dysfunction of a particular motor structure

  • Abnormalities of inhibition, sensory processing and plasticity have been identified in patients with dystonia, but might not be sufficient for the development of dystonic movements

  • The genetic basis of many inherited forms of dystonia is now known, and the study of dystonia-related genes should provide important mechanistic insights leading to novel therapeutic strategies

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Figure 1: Clinical examples of primary dystonia.
Figure 2: Motor circuit abnormalities associated with DYT1 genotype and clinical symptom manifestation.

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Acknowledgements

Given the editorial constraint on the number of permitted citations, we apologize to the authors of many seminal papers for not being able to reference them in this Review. We thank the NIH (R01 NS050528), the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia and Parkinson Foundation and the Parkinson's Disease Foundation for supporting the authors. We also thank Paul Greene and Pietro Mazzoni for their careful reading of the manuscript and helpful comments, and Paul Greene for providing the patient photographs for Figure 1.

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Tanabe, L., Kim, C., Alagem, N. et al. Primary dystonia: molecules and mechanisms. Nat Rev Neurol 5, 598–609 (2009). https://doi.org/10.1038/nrneurol.2009.160

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