The pathophysiological basis of dystonias

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Abstract

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.

References

  1. 1

    Fahn, S. Concept and classification of dystonia. Adv. Neurol. 50, 1–8 (1988).

  2. 2

    Tarsy, D. & Simon, D. K. Dystonia. N. Engl. J. Med. 355, 818–829 (2006).

  3. 3

    Geyer, H. L. & Bressman, S. B. The diagnosis of dystonia. Lancet Neurol. 5, 780–790 (2006).

  4. 4

    Klein, C., Ozelius, L. J. & Breakefield, X. O. Genetic evaluation in primary dystonia, in Handbook of Dystonia (ed. Stacy, M.) 21–44 (Taylor & Francis Group, New York, 2007).

  5. 5

    Risch, N., Bressman, S., Senthil, G. & Ozelius, L. Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. Am. J. Hum. Genet. 80, 1188–1193 (2007).

  6. 6

    Edwards, M., Wood, N. & Bhatia, K. Unusual phenotypes in DYT1 dystonia: a report of five cases and a review of the literature. Mov. Disorder 18, 706–711 (2003).

  7. 7

    Saint Hilaire, M. H., Burke, R. E., Bressman, S. B., Brin, M. F. & Fahn, S. Delayed-onset dystonia due to perinatal or early childhood asphyxia. Neurology 41, 216–222 (1991).

  8. 8

    Dobyns, W. B. et al. Rapid-onset dystonia-parkinsonism. Neurology 43, 2596–2602 (1993).

  9. 9

    Lee, H. Y. et al. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum. Mol. Genet. 13, 3161–3170 (2004).

  10. 10

    Augood, S. J. et al. Distribution of the mRNAs encoding torsinA and torsinB in the normal adult human brain. Ann. Neurol. 46, 761–769 (1999).

  11. 11

    Pisani, A., Bernardi, G., Ding, J. & Surmeier, D. J. Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci. 30, 545–553 (2007). This review describes the emerging role of cholinergic interneurons in movement disorders, with reference to reference 73, which describes abnormal cholinergic responses to dopaminergic input in the striatum in a transgenic model of DYT1 dystonia.

  12. 12

    Goto, S. et al. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann. Neurol. 58, 7–17 (2005).

  13. 13

    Wagner, M. L., Fedak, M. N., Sage, J. I. & Mark, M. H. Complications of disease and therapy: a comparison of younger and older patients with Parkinson's disease. Ann. Clin. Lab. Sci. 26, 389–395 (1996).

  14. 14

    Bressman, S. B. et al. The DYT1 phenotype and guidelines for diagnostic testing. Neurology 54, 1746–1752 (2000).

  15. 15

    Hedreen, J. C., Zweig, R. M., DeLong, M. R., Whitehouse, P. J. & Price, D. L. Primary dystonias: a review of the pathology and suggestions for new directions of study. Adv. Neurol. 50, 123–132 (1988).

  16. 16

    Rostasy, K. et al. TorsinA protein and neuropathology in early onset generalized dystonia with GAG deletion. Neurobiol. Dis. 12, 11–24 (2003).

  17. 17

    McNaught, K. S. et al. Brainstem pathology in DYT1 primary torsion dystonia. Ann. Neurol. 56, 540–547 (2004).

  18. 18

    Ozelius, L. J. et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nature Genet. 17, 40–48 (1997). This paper identified the gene and mutation responsible for most cases of early-onset torsion dystonia and described the protein responsible, torsinA, as an AAA+ protein.

  19. 19

    Xiao, J., Gong, S., Zhao, Y. & LeDoux, M. S. Developmental expression of rat torsinA transcript and protein. Brain Res. Dev. Brain Res. 152, 47–60 (2004).

  20. 20

    Vasudevan, A., Breakefield, X. O. & Bhide, P. Developmental patterns of torsinA and torsinB expression. Brain Res. 1073–1074, 139–145 (2006).

  21. 21

    Siegert, S. et al. TorsinA expression is detectable in human infants as young as 4 weeks old. Brain Res. Dev. Brain Res. 157, 19–26 (2005).

  22. 22

    Shashidharan, P., Kramer, B. C., Walker, R. H., Olanow, C. W. & Brin, M. F. Immunohistochemical localization and distribution of torsinA in normal human and rat brain. Brain Res. 853, 197–206 (2000).

  23. 23

    Neuwald, A. F., Aravind, L., Spouge, J. L. & Koonin, E. V. AAA+: A class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genomic Res. 9, 27–43 (1999).

  24. 24

    Hanson, P. I. & Whiteheart, S. W. AAA+ proteins: have engine, will work. Nature Rev. Mol. Cell Biol. 6, 519–529 (2005).

  25. 25

    Naismith, T. V., Heuser, J. E., Breakefield, X. O. & Hanson, P. I. TorsinA in the nuclear envelope. Proc. Natl Acad. Sci. USA 101, 7612–7617 (2004).

  26. 26

    Goodchild, R. E., Kim, C. E. & Dauer, W. T. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48, 923–932 (2005). Together with reference 25, this paper established the involvement of torsinA in events in the nuclear envelope.

  27. 27

    Hewett, J. W., Tannous, B., Niland, B. P., Nery, F. C. & Breakefield, X. O. Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proc. Natl Acad. Sci. USA 104, 7271–7276 (2007).

  28. 28

    Cao, S., Gelwix, C. C., Caldwell, K. A. & Caldwell, G. A. Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J. Neurosci. 25, 3801–3812 (2005).

  29. 29

    Torres, G. E., Sweeney, A. L., Beaulieu, J. M., Shashidharan, P. & Caron, M. G. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Proc. Natl Acad. Sci. USA 101, 15650–15655 (2004).

  30. 30

    Goodchild, R. E. & Dauer, W. T. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. J. Cell Biol. 168, 855–862 (2005).

  31. 31

    Kock, N. et al. Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier. Hum. Mol. Genet. 15, 1355–1364 (2006).

  32. 32

    Pham, P., Frei, K. P., Woo, W. & Truong, D. D. Molecular defects of the dystonia-causing torsinA mutation. Neuroreport 17, 1725–1728 (2006).

  33. 33

    Konakova, M. & Pulst, S. M. Dystonia-associated forms of torsinA are deficient in ATPase activity. J. Mol. Neurosci. 25, 105–117 (2005).

  34. 34

    Lee, L. V., Munoz, E. L., Tan, K. T. & Reyes, M. T. Sex linked recessive dystonia parkinsonism of Panay, Philippines (XDP). Mol. Pathol. 54, 362–368 (2001).

  35. 35

    Makino, S. et al. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am. J. Hum. Genet. 80, 393–406 (2007).

  36. 36

    Nolte, D., Niemann, S. & Muller, U. Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. Proc. Natl Acad. Sci. USA 100, 10347–10352 (2003).

  37. 37

    Segawa, M. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 1, S65–80 (2000).

  38. 38

    Ichinose, H. et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nature Genet. 8, 236–242 (1994). This landmark paper identified the defect in dopa-responsive dystonia and revealed the central role of altered dopamine biosynthesis in this syndrome.

  39. 39

    Maita, N., Hatakeyama, K., Okada, K. & Hakoshima, T. Structural basis of biopterin-induced inhibition of GTP cyclohydrolase I by GFRP, its feedback regulatory protein. J. Biol. Chem. 279, 51534–51540 (2004).

  40. 40

    Levine, R. A., Miller, L. P. & Lovenberg, W. Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis. Science 214, 919–921 (1981).

  41. 41

    Ludecke, B., Dworniczak, B. & Bartholome, K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum. Genet. 95, 123–125 (1995).

  42. 42

    Knappskog, P. M., Flatmark, T., Mallet, J., Ludecke, B. & Bartholome, K. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum. Mol. Genet. 4, 1209–1212 (1995).

  43. 43

    Swaans, R. J. et al. Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism. Ann. Hum. Genet. 64, 25–31 (2000).

  44. 44

    Royo, M., Daubner, S. C. & Fitzpatrick, P. F. Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein. Proteins 58, 14–21 (2005).

  45. 45

    Friedman, J. & Standaert, D. G. Neurogenetics of dystonia and paroxysmal dyskinesias, in Neurogenetics: Clinical and Scientific Advances (ed. Lynch, D. R.) 403–426 (Marcel Dekker, Inc., New York, 2005).

  46. 46

    Rainier, S. et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch. Neurol. 61, 1025–1029 (2004).

  47. 47

    Saunders-Pullman, R., Ozelius, L. & Bressman, S. B. Inherited myoclonus-dystonia. Adv. Neurol. 89, 185–191 (2002a).

  48. 48

    Saunders-Pullman, R. et al. Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence. Neurology 58, 242–245 (2002b).

  49. 49

    Asmus, F. et al. Myoclonus-dystonia due to genomic deletions in the epsilon-sarcoglycan gene. Ann. Neurol. 58, 792–797 (2005).

  50. 50

    Piras, G. et al. Zac1 (Lot1), a potential tumor suppressor gene, and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines. Mol. Cell Biol. 20, 3308–3315 (2000).

  51. 51

    Yokoi, F., Dang, M. T., Mitsui, S. & Li, Y. Exclusive paternal expression and novel alternatively spliced variants of epsilon-sarcoglycan mRNA in mouse brain. FEBS Lett. 579, 4822–4828 (2005).

  52. 52

    Muller, B. et al. Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia. Am. J. Hum. Genet. 71, 1303–1311 (2002).

  53. 53

    Zimprich, A. et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nature Genet. 29, 66–69 (2001). This study identified the gene responsible for DYT11 dystonia with supporting evidence for maternal inheritance and a potential insight into dystrophin–glycoprotein complexes in the brain.

  54. 54

    Esapa, C. T. et al. SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA. Hum. Mol. Genet. 16, 327–342 (2007).

  55. 55

    Xiao, J. & LeDoux, M. S. Cloning, developmental regulation and neural localization of rat epsilon-sarcoglycan. Brain Res. Mol. Brain Res. 119, 132–143 (2003).

  56. 56

    Chan, P. et al. Epsilon-sarcoglycan immunoreactivity and mRNA expression in mouse brain. J. Comp. Neurol. 482, 50–73 (2005).

  57. 57

    Leung, J. C. et al. Novel mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and polymorphisms in dystonia and early onset parkinsonism. Neurogenetics 3, 133–143 (2001).

  58. 58

    Klein, C. et al. Epsilon-sarcoglycan mutations found in combination with other dystonia gene mutations. Ann. Neurol. 52, 675–679 (2002).

  59. 59

    Brashear, A. et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 130, 828–835 (2007).

  60. 60

    de Carvalho Aguiar, P. et al. Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 43, 169–175 (2004).

  61. 61

    Rodacker, V., Toustrup-Jensen, M. & Vilsen, B. Mutations Phe785Leu and Thr618Met in Na+, K+-ATPase, associated with familial rapid-onset dystonia parkinsonism, interfere with Na+ interaction by distinct mechanisms. J. Biol. Chem. 281, 18539–18548 (2006).

  62. 62

    Cannon, S. C. Pathomechanisms in channelopathies of skeletal muscle and brain. Annu. Rev. Neurosci. 29, 387–415 (2006).

  63. 63

    Evinger, C. Animal models of focal dystonia. NeuroRx 2, 513–524 (2005).

  64. 64

    Jinnah, H. A. et al. Animal models for drug discovery in dystonia. Expert Opin. Drug Disc. 3, 83–97 (2008).

  65. 65

    Koh, Y. H., Rehfeld, K. & Ganetzky, B. A Drosophila model of early onset torsion dystonia suggests impairment in TGF-beta signaling. Hum. Mol. Genet. 13, 2019–2030 (2004).

  66. 66

    Muraro, N. I. & Moffat, K. G. Down-regulation of torp4a, encoding the Drosophila homologue of torsinA, results in increased neuronal degeneration. J. Neurobiol. 66, 1338–1353 (2006).

  67. 67

    Byl, N. N. Learning-based animal models: task-specific focal hand dystonia. ILAR J 48, 411–431 (2007). Summarizes an elegant series of experiments linking changes in sensory maps in the brain to the pathogenesis of focal dystonia, emphasizing the role of sensorimotor plasticity in dystonia.

  68. 68

    Sharma, N. et al. Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation. J. Neurosci. 25, 5351–5355 (2005).

  69. 69

    Shashidharan, P. et al. Transgenic mouse model of early-onset DYT1 dystonia. Hum. Mol. Genet. 14, 125–133 (2005).

  70. 70

    Grundmann, K. et al. Overexpression of human wildtype torsinA and human DeltaGAG torsinA in a transgenic mouse model causes phenotypic abnormalities. Neurobiol. Dis. 27, 190–206 (2007).

  71. 71

    Dang, M. T. et al. Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia. Exp. Neurol. 196, 452–463 (2005). Together with references 26 and 76, this paper establishes that the DYT1-associated GAG deletion renders torsinA nonfunctional in the setting of a homozygous knock-in mouse.

  72. 72

    Balcioglu, A. et al. Dopamine release is impaired in a mouse model of DYT1 dystonia. J. Neurochem. 102, 783–788 (2007).

  73. 73

    Pisani, A. et al. Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia. Neurobiol. Dis. 24, 318–325 (2006).

  74. 74

    Ghilardi, M. F. et al. Impaired sequence learning in carriers of the DYT1 dystonia mutation. Ann. Neurol. 54, 102–109 (2003).

  75. 75

    Yokoi, F., Dang, M. T., Mitsui, S., Li, J. & Li, Y. Motor deficits and hyperactivity in cerebral cortex-specific Dyt1 conditional knockout mice. J. Biochem. 143, 39–47 (2007).

  76. 76

    Dang, M. T., Yokoi, F., Pence, M. A. & Li, Y. Motor deficits and hyperactivity in Dyt1 knockdown mice. Neurosci. Res. 56, 470–474 (2006).

  77. 77

    Hyland, K., Gunasekara, R. S., Munk-Martin, T. L., Arnold, L. A. & Engle, T. The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency. Ann. Neurol. 6, S46–48 (2003).

  78. 78

    Yokoi, F., Dang, M. T., Li, J. & Li, Y. Myoclonus, motor deficits, alterations in emotional responses and monoamine metabolism in epsilon-sarcoglycan deficient mice. J. Biochem. (Tokyo) 140, 141–146 (2006). This mouse model of DYT11 dystonia most accurately reflects symptoms seen in patients with myoclonus dystonia, as compared to other rodent models of dystonia.

  79. 79

    Moseley, A. E. et al. Deficiency in Na, K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice. J. Neurosci. 27, 616–26 (2007).

  80. 80

    Brown, A., Bernier, G., Mathieu, M., Rossant, J. & Kothary, R. The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1. Nature Genet. 10, 301–306 (1995).

  81. 81

    Liu, J. J. et al. Retrolinkin, a membrane protein, plays an important role in retrograde axonal transport. Proc. Natl Acad. Sci. USA 104, 2223–2228 (2007).

  82. 82

    Young, K. G., Pinheiro, B. & Kothary, R. A Bpag1 isoform involved in cytoskeletal organization surrounding the nucleus. Exp. Cell Res. 312, 121–134 (2006).

  83. 83

    Berardelli, A. et al. The pathophysiology of primary dystonia. Brain 121, 1195–1212 (1998).

  84. 84

    Richter, A. The genetically dystonic hamster: an animal model of paroxysmal dystonia, in Animal Models of Movement Disorders (ed. LeDoux, M.) 459–466 (Elsevier Academic Press, San Diego, 2005).

  85. 85

    Sander, S. E. & Richter, A. Effects of intrastriatal infections of glutamate receptor antagonists on the severity of paroxysmal dystonia in the dtsz mutant. Eur. J. Pharmacol. 563, 102–108 (2007).

  86. 86

    LeDoux, M. Animal Models Movement Disorders, 241–252 (Elsevier Academic Press, Burlington, Massachusetts, 2005).

  87. 87

    Xiao, J., Gong, S. & LeDoux, M. S. Caytaxin deficiency disrupts signaling pathways in cerebellar cortex. Neuroscience 144, 439–461 (2007).

  88. 88

    Buschdorf, J. P. et al. Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels. J. Cell Sci. 119, 3337–3350 (2006).

  89. 89

    Defazio, G., Berardelli, A. & Hallett, M. Do primary adult-onset focal dystonias share aetiological factors? Brain 130, 1183–1193 (2007).

  90. 90

    Chase, T. N., Tamminga, C. A. & Burrows, H. Positron emission tomographic studies of regional cerebral glucose metabolism in idiopathic dystonia. Adv. Neurol. 50, 237–241 (1988).

  91. 91

    Perlmutter, J. S. et al. Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia. J. Neurosci. 17, 843–850 (1997). This study provided the first direct neural (as opposed to clinical) evidence that dopaminergic abnormalities might be involved in some human forms of dystonia.

  92. 92

    Asanuma, K. et al. Decreased striatal D2 receptor binding in non-manifesting carriers of the DYT1 dystonia mutation. Neurology 64, 347–349 (2005).

  93. 93

    Rinne, J. O. et al. Striatal dopaminergic system in dopa-response dystonia: a multi-tracer PET study shows increased D2 receptors. J. Neural. Transm. 111, 59–67 (2004).

  94. 94

    Eidelberg, D. et al. Functional brain networks in DYT1 dystonia. Ann. Neurol. 44, 303–312 (1998). This fMRI study established dystonia as a network disorder and set the design and interpretation of future functional imaging studies, highlighting that dystonia patients, even at rest, do not have the same functional neural baseline as healthy controls. It provided a means to distinguish the brain regions involved in dystonic symptoms themselves (movement-related regions) from those which may underlie more fundamental endophenotypic traits of the disorder (movement-free regions).

  95. 95

    Ceballos-Baumann, A. O. et al. Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia. Ann. Neurol. 37, 363–372 (1995).

  96. 96

    Ibanez, V., Sadato, N., Karp, B., Deiber, M. P. & Hallett, M. Deficient activation of the motor cortical network in patients with writer's cramp. Neurology 53, 96–105 (1999).

  97. 97

    Dresel, C., Haslinger, B., Castrop, F., Wohlschlaeger, A. M. & Ceballos-Baumann, A. O. Silent event-related fMRI reveals deficient motor and enhanced somatosensory activation in orofacial dystonia. Brain 129, 36–46 (2006).

  98. 98

    Blood, A. J. et al. Basal ganglia activity remains elevated after movement in focal hand dystonia. Ann. Neurol. 55, 744–748 (2004).

  99. 99

    Pujol, J. et al. Brain cortical activation during guitar-induced hand dystonia studied by functional MRI. Neuroimage 12, 257–267 (2000).

  100. 100

    Ikoma, K., Samii, A., Mercuri, B., Wassermann, E. M. & Hallett, M. Abnormal cortical motor excitability in dystonia. Neurology 46, 1371–1376 (1996). This study was key to establishing the idea that abnormal excitability of motor-system neural function could be a physiological mechanism underlying dystonia.

  101. 101

    DeLong, M. R. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13, 281–285 (1990).

  102. 102

    Carbon, M. et al. Microstructural white matter changes in carriers of the DYT1 gene mutation. Ann. Neurol. 56, 283–286 (2004).

  103. 103

    Colosimo, C. et al. Diffusion tensor imaging in primary cervical dystonia. J. Neurol. Neurosurg. Psychiatry 76, 1591–1593 (2005).

  104. 104

    Blood, A. J. et al. White matter abnormalities in dystonia normalize after botulinum toxin treatment. Neuroreport 17, 1251–1255 (2006).

  105. 105

    Draganski, B., Thun-Hohenstein, C., Bogdahn, U., Winkler, J. & May, A. “Motor circuit” gray matter changes in idiopathic cervical dystonia. Neurology 61, 1228–1231 (2003).

  106. 106

    Garraux, G. et al. Changes in brain anatomy in focal hand dystonia. Ann. Neurol. 55, 736–739 (2004).

  107. 107

    Delmaire, C. et al. Structural abnormalities in the cerebellum and sensorimotor circuit in writer's cramp. Neurology 69, 376–380 (2007).

  108. 108

    Etgen, T., Muhlau, M., Gaser, C. & Sander, D. Bilateral grey-matter increase in the putamen in primary blepharospasm. J. Neurol. Neurosurg. Psychiatry 77, 1017–1020 (2006).

  109. 109

    Egger, K. et al. Voxel based morphometry reveals specific gray matter changes in primary dystonia. Mov. Disord. 22, 1538–1542 (2007).

  110. 110

    Hallett, M. Pathophysiology of dystonia. J. Neural. Transm. 70, S485–S488 (2006).

  111. 111

    Quartarone, A., Siebner, H. R. & Rothwell, J. C. Task-specific hand dystonia: can too much plasticity be bad for you? Trends Neurosci. 29, 192–199 (2006). This article summarises recent results concerning abnormalities of plasticity in dystonia and explains how abnormal plasticity can give rise to dystonia. Although the discussion is most appropriate to focal hand dystonia, the ideas are generalizable to other forms of dystonia.

  112. 112

    Weise, D. et al. The two sides of associative plasticity in writer's cramp. Brain 129, 2709–2721 (2006).

  113. 113

    Bara-Jimenez, W., Catalan, M. J., Hallett, M. & Gerloff, C. Abnormal somatosensory homunculus in dystonia of the hand. Ann. Neurol. 44, 828–831 (1998).

  114. 114

    Byl, N. N., McKenzie, A. & Nagarajan, S. S. Differences in somatosensory hand organization in a healthy flutist and a flutist with focal hand dystonia: a case report. J. Hand Ther. 13, 302–309 (2000).

  115. 115

    Meunier, S. et al. Human brain mapping in dystonia reveals both endophenotypic traits and adaptive reorganization. Ann. Neurol. 50, 521–527 (2001).

  116. 116

    Thickbroom, G. W., Byrnes, M. L., Stell, R. & Mastaglia, F. L. Reversible reorganisation of the motor cortical representation of the hand in cervical dystonia. Mov. Disord. 18, 395–402 (2003).

  117. 117

    Fiorio, M., Tinazzi, M. & Aglioti, S. M. Selective impairment of hand mental rotation in patients with focal hand dystonia. Brain 129, 47–54 (2006).

  118. 118

    Sanger, T. D., Tarsy, D. & Pascual-Leone, A. Abnormalities of spatial and temporal sensory discrimination in writer's cramp. Mov. Disord. 16, 94–99 (2001).

  119. 119

    Rosenkranz, K., Altenmuller, E., Siggelkow, S. & Dengler, R. Alteration of sensorimotor integration in musician's cramp: impaired focusing of proprioception. Clin. Neurophysiol. 111, 2040–2045 (2000).

  120. 120

    Hallett, M. Dystonia: abnormal movements result from loss of inhibition. Adv. Neurol. 94, 1–9 (2004).

  121. 121

    Espay, A. J. et al. Cortical and spinal abnormalities in psychogenic dystonia. Ann. Neurol. 59, 825–834 (2006).

  122. 122

    Jankovic, J. Treatment of dystonia. Lancet Neurol. 5, 864–872 (2006).

  123. 123

    Curra, A., Trompetto, C., Abbruzzese, G. & Berardelli, A. Central effects of botulinum toxin type A: evidence and supposition. Mov. Disorder. 19, S60–64 (2004).

  124. 124

    Tagliati, M., Shils, J., Sun, C. & Alterman, R. Deep brain stimulation for dystonia. Expert Rev. Med. Devices 1, 33–41 (2004).

  125. 125

    Vidailhet, M. et al. Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet Neurol. 6, 223–229 (2007).

  126. 126

    Alterman, R. L. & Snyder, B. J. Deep brain stimulation for torsion dystonia. Acta Neurochir Suppl, 97, 191–199 (2007).

  127. 127

    Zhang, J. G., Zhang, K., Wang, Z. C., Ge, M. & Ma, Y. Deep brain stimulation in the treatment of secondary dystonia. Chin. Med. J. (Eng) 119, 2069–2074 (2006).

  128. 128

    Arnon, S. S. et al. Botulinum toxin as a biological weapon. JAMA 285, 1059–1070 (2001).

  129. 129

    Sharma, N. & Richman, E. Parkinson's Disease and the Family, A New Guide, (Harvard University Press Family Health Guides, USA, 2005).

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Acknowledgements

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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Glossary

Paroxysmal dystonia

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

Dyskinesia

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

Chorea

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

Monogenic

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.

Dominant-negative

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.

Haploinsufficiency

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

Endophenotype

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.

Somatotopy

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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