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Dystonia

An Author Correction to this article was published on 19 October 2018

This article has been updated

Abstract

Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. Dystonia can be the manifesting neurological sign of many disorders, either in isolation (isolated dystonia) or with additional signs (combined dystonia). The main focus of this Primer is forms of isolated dystonia of idiopathic or genetic aetiology. These disorders differ in manifestations and severity but can affect all age groups and lead to substantial disability and impaired quality of life. The discovery of genes underlying the mendelian forms of isolated or combined dystonia has led to a better understanding of its pathophysiology. In some of the most common genetic dystonias, such as those caused by TOR1A, THAP1, GCH1 and KMT2B mutations, and idiopathic dystonia, these mechanisms include abnormalities in transcriptional regulation, striatal dopaminergic signalling and synaptic plasticity and a loss of inhibition at neuronal circuits. The diagnosis of dystonia is largely based on clinical signs, and the diagnosis and aetiological definition of this disorder remain a challenge. Effective symptomatic treatments with pharmacological therapy (anticholinergics), intramuscular botulinum toxin injection and deep brain stimulation are available; however, future research will hopefully lead to reliable biomarkers, better treatments and cure of this disorder.

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Fig. 1: History of dystonia.
Fig. 2: Phenotype–genotype correlations.
Fig. 3: Highly simplified representation of the basal ganglia circuit.
Fig. 4: Pathophysiology of dystonia.
Fig. 5: Diagnostic approach.
Fig. 6: Treatment algorithm for dystonia.

Change history

  • 19 October 2018

    The affiliation for Enza Maria Valente and Antonio Pisani at IRCCS Santa Lucia Foundation, Rome, Italy, has been amended to remove the laboratory designation. Additionally, in Figure 3a, the subthalamic nucleus was incorrectly included in the anatomy of the brain shown and this has been amended.

References

  1. Fahn, S., Bressman, S. B. & Marsden, C. D. Classification of dystonia. Adv. Neurol. 78, 1–10 (1998).

    CAS  Article  PubMed  Google Scholar 

  2. Albanese, A. et al. Phenomenology and classification of dystonia: a consensus update. Mov. Disord. 28, 863–873 (2013). This is a consensus update that contains the definition of dystonia and its clinical manifestations and the new classification of dystonia.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Jankovic, J. Treatment of hyperkinetic movement disorders. Lancet Neurol. 8, 844–856 (2009).

    CAS  Article  PubMed  Google Scholar 

  4. Steeves, T. D., Day, L., Dykeman, J., Jette, N. & Pringsheim, T. The prevalence of primary dystonia: a systematic review and meta-analysis. Mov. Disord. 27, 1789–1796 (2012). This is a systematic review and meta-analysis of the prevalence of isolated dystonia.

    Article  PubMed  Google Scholar 

  5. Das, S. K. et al. Community survey of primary dystonia in the city of Kolkata, India. Mov. Disord. 22, 2031–2036 (2007).

    Article  PubMed  Google Scholar 

  6. Muller, J. et al. The prevalence of primary dystonia in the general community. Neurology 59, 941–943 (2002).

    CAS  Article  PubMed  Google Scholar 

  7. Ichinose, H. et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat. Genet. 8, 236–242 (1994).

    CAS  Article  PubMed  Google Scholar 

  8. Williams, L. et al. Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland. Eur. J. Neurol. 24, 73–81 (2017).

    CAS  Article  PubMed  Google Scholar 

  9. Asgeirsson, H., Jakobsson, F., Hjaltason, H., Jonsdottir, H. & Sveinbjornsdottir, S. Prevalence study of primary dystonia in Iceland. Mov. Disord. 21, 293–298 (2006).

    Article  PubMed  Google Scholar 

  10. Soland, V. L., Bhatia, K. P. & Marsden, C. D. Sex prevalence of focal dystonias. J. Neurol. Neurosurg. Psychiatry 60, 204–205 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Ozelius, L. J. et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat. Genet. 17, 40–48 (1997). This paper describes the identification of a single GAG in-frame deletion in TOR1A as the genetic cause of DYT1 dystonia, which is the most frequent genetic cause of childhood-onset generalized dystonia in the Ashkenazi Jewish population.

    CAS  Article  PubMed  Google Scholar 

  12. Risch, N. et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat. Genet. 9, 152–159 (1995).

    CAS  Article  PubMed  Google Scholar 

  13. Valente, E. M. et al. The role of DYT1 in primary torsion dystonia in Europe. Brain 121, 2335–2339 (1998). This work establishes the relevance and the high mutational frequency of the common TOR1A pathogenic mutation in the European, non-Ashkenazi Jewish, population, extending the importance of screening for this mutation to all patients with generalized dystonia.

    Article  PubMed  Google Scholar 

  14. Lee, W. W., Ahn, T. B., Chung, S. J. & Jeon, B. S. Phenotypic differences in Dyt1 between ethnic groups. Curr. Neurol. Neurosci. Rep. 12, 341–347 (2012).

    Article  PubMed  Google Scholar 

  15. Fasano, A. et al. Non-DYT1 early-onset primary torsion dystonia: comparison with DYT1 phenotype and review of the literature. Mov. Disord. 21, 1411–1418 (2006).

    Article  PubMed  Google Scholar 

  16. Grundmann, K. et al. Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia. Arch. Neurol. 60, 1266–1270 (2003).

    Article  PubMed  Google Scholar 

  17. Bressman, S. B. et al. Diagnostic criteria for dystonia in DYT1 families. Neurology 59, 1780–1782 (2002).

    CAS  Article  PubMed  Google Scholar 

  18. Frederic, M. et al. First determination of the incidence of the unique TOR1A gene mutation, c.907delGAG, in a Mediterranean population. Mov. Disord. 22, 884–888 (2007).

    Article  PubMed  Google Scholar 

  19. Fuchs, T. et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat. Genet. 41, 286–288 (2009).

    CAS  Article  PubMed  Google Scholar 

  20. Bressman, S. B. et al. Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol. 8, 441–446 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Djarmati, A. et al. Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol. 8, 447–452 (2009).

    CAS  Article  PubMed  Google Scholar 

  22. Blanchard, A. et al. DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. Hum. Mutat. 32, 1213–1224 (2011).

    CAS  Article  PubMed  Google Scholar 

  23. LeDoux, M. S. et al. Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism Relat. Disord. 18, 414–425 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  24. Fuchs, T. et al. Mutations in GNAL cause primary torsion dystonia. Nat. Genet. 45, 88–92 (2013).

    CAS  Article  PubMed  Google Scholar 

  25. Vemula, S. R. et al. Role of Gα(olf) in familial and sporadic adult-onset primary dystonia. Hum. Mol. Genet. 22, 2510–2519 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Charlesworth, G. et al. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am. J. Hum. Genet. 91, 1041–1050 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Miltgen, M. et al. Novel heterozygous mutation in ANO3 responsible for craniocervical dystonia. Mov. Disord. 31, 1251–1252 (2016).

    CAS  Article  PubMed  Google Scholar 

  28. Xiao, J. et al. Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann. Neurol. 71, 458–469 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Dufke, C. et al. Mutations in CIZ1 are not a major cause for dystonia in Germany. Mov. Disord. 30, 740–743 (2015).

    Article  PubMed  Google Scholar 

  30. Martino, D. et al. Extragenetic factors and clinical penetrance of DYT1 dystonia: an exploratory study. J. Neurol. 260, 1081–1086 (2013).

    CAS  Article  PubMed  Google Scholar 

  31. Bressman, S. B. et al. Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann. Neurol. 26, 612–620 (1989).

    CAS  Article  PubMed  Google Scholar 

  32. Kramer, P. L. et al. The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews. Am. J. Hum. Genet. 55, 468–475 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Argyelan, M. et al. Cerebellothalamocortical connectivity regulates penetrance in dystonia. J. Neurosci. 29, 9740–9747 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Charlesworth, G. et al. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am. J. Hum. Genet. 96, 657–665 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Cai, X. et al. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci. Rep. 6, 25834 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Zech, M. et al. Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. Am. J. Hum. Genet. 96, 883–893 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Carecchio, M. et al. DYT2 screening in early-onset isolated dystonia. Eur. J. Paediatr. Neurol. 21, 269–271 (2017).

    Article  PubMed  Google Scholar 

  39. Lohmann, K. et al. The role of mutations in COL6A3 in isolated dystonia. J. Neurol. 263, 730–734 (2016).

    CAS  Article  PubMed  Google Scholar 

  40. Masuho, I. et al. Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol. Genet. 2, e78 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  41. Schneider, S. A. et al. Homozygous THAP1 mutations as cause of early-onset generalized dystonia. Mov. Disord. 26, 858–861 (2011).

    Article  PubMed  Google Scholar 

  42. Houlden, H. et al. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 74, 846–850 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Balint, B. & Bhatia, K. P. Isolated and combined dystonia syndromes - an update on new genes and their phenotypes. Eur. J. Neurol. 22, 610–617 (2015). This review outlines the genetic forms of isolated and combined dystonia.

    CAS  Article  PubMed  Google Scholar 

  44. Fung, V. S., Jinnah, H. A., Bhatia, K. & Vidailhet, M. Assessment of patients with isolated or combined dystonia: an update on dystonia syndromes. Mov. Disord. 28, 889–898 (2013). This is an excellent paper on the approach of isolated and combined dystonia in view of the new classification of dystonia.

    PubMed  PubMed Central  Article  Google Scholar 

  45. Paudel, R., Hardy, J., Revesz, T., Holton, J. L. & Houlden, H. Review: genetics and neuropathology of primary pure dystonia. Neuropathol. Appl. Neurobiol. 38, 520–534 (2012).

    CAS  Article  PubMed  Google Scholar 

  46. Paudel, R. et al. DYT6 dystonia: a neuropathological study. Neurodegener. Dis. 16, 273–278 (2016).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  49. Standaert, D. G. Update on the pathology of dystonia. Neurobiol. Dis. 42, 148–151 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  50. Prudente, C. N. et al. Neuropathology of cervical dystonia. Exp. Neurol. 241, 95–104 (2013).

    CAS  Article  PubMed  Google Scholar 

  51. Batla, A. et al. The role of cerebellum in patients with late onset cervical/segmental dystonia? — evidence from the clinic. Parkinsonism Relat. Disord. 21, 1317–1322 (2015).

    CAS  Article  PubMed  Google Scholar 

  52. Bhatia, K. P. & Marsden, C. D. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain: J. Neurol. 117, 859–876 (1994).

    Article  Google Scholar 

  53. Jinnah, H. A., Neychev, V. & Hess, E. J. The anatomical basis for dystonia: the motor network model. Tremor Other Hyperkinet. Mov. 7, 506 (2017).

    CAS  Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  55. Pantano, P. et al. A transverse and longitudinal MR imaging voxel-based morphometry study in patients with primary cervical dystonia. AJNR Am. J. Neuroradiol. 32, 81–84 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Granert, O. et al. Manual activity shapes structure and function in contralateral human motor hand area. Neuroimage 54, 32–41 (2011).

    Article  PubMed  Google Scholar 

  57. Poston, K. L. & Eidelberg, D. Functional brain networks and abnormal connectivity in the movement disorders. Neuorimage 62, 2261–2270 (2012).

    Article  Google Scholar 

  58. Neumann, W. J. et al. A localized pallidal physiomarker in cervical dystonia. Ann. Neurol. 82, 912–924 (2017).

    CAS  Article  PubMed  Google Scholar 

  59. Vitek, J. L. Deep brain stimulation: how does it work? Cleve. Clin. J. Med. 75 (Suppl. 2), 59–65 (2008).

    Article  Google Scholar 

  60. Connolly, A. T. et al. Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator. J. Neural Eng. 12, 066012 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  61. Brittain, J. S. & Brown, P. Oscillations and the basal ganglia: motor control and beyond. Neuroimage 85, 637–647 (2014).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  63. Berardelli, A. et al. Consensus paper on short-interval intracortical inhibition and other transcranial magnetic stimulation intracortical paradigms in movement disorders. Brain Stimul. 1, 183–191 (2008).

    Article  PubMed  Google Scholar 

  64. Lozeron, P. et al. Contribution of TMS and rTMS in the understanding of the pathophysiology and in the treatment of dystonia. Front. Neural Circuits 10, 90 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. Calabresi, P. et al. Hyperkinetic disorders and loss of synaptic downscaling. Nat. Neurosci. 19, 868–875 (2016).

    CAS  Article  PubMed  Google Scholar 

  66. Martella, G. et al. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine. Brain 132, 2336–2349 (2009). This is the first demonstration of an impaired synaptic plasticity in a dystonia model, which recapitulates the alterations found in patients.

    PubMed  PubMed Central  Article  Google Scholar 

  67. Martella, G. et al. Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia. Neurobiol. Dis. 65, 124–132 (2014).

    CAS  Article  PubMed  Google Scholar 

  68. Calabresi, P. & Tambasco, N. Movement disorders in 2016: from genes to phenotypes. Lancet Neurol. 16, 9–10 (2017).

    Article  PubMed  Google Scholar 

  69. Quartarone, A. et al. Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain 126, 2586–2596 (2003).

    Article  PubMed  Google Scholar 

  70. Sadnicka, A., Hamada, M., Bhatia, K. P., Rothwell, J. C. & Edwards, M. J. A reflection on plasticity research in writing dystonia. Mov. Disord. 29, 980–987 (2014).

    Article  PubMed  Google Scholar 

  71. Quartarone, A. et al. Abnormal sensorimotor plasticity in organic but not in psychogenic dystonia. Brain 132, 2871–2877 (2009).

    CAS  PubMed  Article  Google Scholar 

  72. Kang, J. S., Terranova, C., Hilker, R., Quartarone, A. & Ziemann, U. Deficient homeostatic regulation of practice-dependent plasticity in writer’s cramp. Cereb. Cortex 21, 1203–1212 (2011).

    Article  PubMed  Google Scholar 

  73. Ashkan, K., Rogers, P., Bergman, H. & Ughratdar, I. Insights into the mechanisms of deep brain stimulation. Nat. Rev. Neurol. 13, 548–554 (2017). This is an excellent review on possible mechanisms of action of DBS in dystonia and Parkinson disease.

    Article  PubMed  Google Scholar 

  74. Ruge, D. et al. Deep brain stimulation effects in dystonia: time course of electrophysiological changes in early treatment. Mov. Disord. 26, 1913–1921 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  75. Ruge, D. et al. Shaping reversibility? Long-term deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms. Brain 134, 2106–2115 (2011).

    Article  PubMed  Google Scholar 

  76. Tinazzi, M. et al. Aristotle’s illusion reveals interdigit functional somatosensory alterations in focal hand dystonia. Brain 136, 782–789 (2013).

    Article  PubMed  Google Scholar 

  77. Nelson, A. J., Blake, D. T. & Chen, R. Digit-specific aberrations in the primary somatosensory cortex in writer’s cramp. Ann. Neurol. 66, 146–154 (2009).

    Article  PubMed  Google Scholar 

  78. Ganos, C. et al. Cortical inhibitory function in cervical dystonia. Clin. Neurophysiol. 129, 466–472 (2017).

    Article  PubMed  Google Scholar 

  79. Kojovic, M. et al. Secondary and primary dystonia: pathophysiological differences. Brain 136, 2038–2049 (2013).

    Article  PubMed  Google Scholar 

  80. Macerollo, A. et al. Abnormal movement-related suppression of sensory evoked potentials in upper limb dystonia. Eur. J. Neurol. 23, 562–568 (2016).

    CAS  Article  PubMed  Google Scholar 

  81. Langbour, N. et al. The cortical processing of sensorimotor sequences is disrupted in writer’s cramp. Cereb. Cortex 27, 2544–2559 (2017).

    CAS  PubMed  Google Scholar 

  82. Naumann, M., Magyar-Lehmann, S., Reiners, K., Erbguth, F. & Leenders, K. L. Sensory tricks in cervical dystonia: perceptual dysbalance of parietal cortex modulates frontal motor programming. Ann. Neurol. 47, 322–328 (2000).

    CAS  Article  PubMed  Google Scholar 

  83. Gomez-Wong, E. et al. The ‘geste antagonistique’ induces transient modulation of the blink reflex in human patients with blepharospasm. Neurosci. Lett. 251, 125–128 (1998).

    CAS  Article  PubMed  Google Scholar 

  84. Brighina, F. et al. Effects of cerebellar TMS on motor cortex of patients with focal dystonia: a preliminary report. Exp. Brain Res. 192, 651–656 (2009).

    CAS  Article  PubMed  Google Scholar 

  85. Kaji, R., Bhatia, K. & Graybiel, A. M. Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J. Neurol. Neurosurg. Psychiatry 89, 488–492 (2017).

    PubMed  Article  Google Scholar 

  86. Sadnicka, A. et al. All in the blink of an eye: new insight into cerebellar and brainstem function in DYT1 and DYT6 dystonia. Eur. J. Neurol. 22, 762–767 (2015).

    CAS  Article  PubMed  Google Scholar 

  87. Carbon, M. et al. Increased cerebellar activation during sequence learning in DYT1 carriers: an equiperformance study. Brain 131, 146–154 (2008).

    Article  PubMed  Google Scholar 

  88. Carbon, M. et al. Abnormal striatal and thalamic dopamine neurotransmission: genotype-related features of dystonia. Neurology 72, 2097–2103 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Katschnig-Winter, P. et al. Motor sequence learning and motor adaptation in primary cervical dystonia. J. Clin. Neurosci. 21, 934–938 (2014).

    Article  PubMed  Google Scholar 

  90. Sadnicka, A. et al. Normal motor adaptation in cervical dystonia: a fundamental cerebellar computation is intact. Cerebellum 13, 558–567 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  91. Perlmutter, J. S. & Mink, J. W. Dysfunction of dopaminergic pathways in dystonia. Adv. Neurol. 94, 163–170 (2004).

    PubMed  Google Scholar 

  92. Wichmann, T. Commentary: dopaminergic dysfunction in DYT1 dystonia. Exp. Neurol. 212, 242–246 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Ichinose, H., Inagaki, H., Suzuki, T., Ohye, T. & Nagatsu, T. Molecular mechanisms of hereditary progressive dystonia with marked diurnal fluctuation, Segawa’s disease. Brain Dev. 22 (Suppl. 1), 107–110 (2000).

    Article  Google Scholar 

  94. 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).

    CAS  Article  PubMed  Google Scholar 

  95. van den Heuvel, L. P. et al. A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population. Hum. Genet. 102, 644–646 (1998).

    Article  PubMed  Google Scholar 

  96. Thony, B. & Blau, N. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum. Mut. 27, 870–878 (2006).

    CAS  Article  PubMed  Google Scholar 

  97. Teo, J. T., Edwards, M. J. & Bhatia, K. Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis. Mov. Disord. 27, 1205–1215 (2012).

    Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  99. Berman, B. D., Hallett, M., Herscovitch, P. & Simonyan, K. Striatal dopaminergic dysfunction at rest and during task performance in writer’s cramp. Brain 136, 3645–3658 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  100. Black, K. J. et al. Spatial reorganization of putaminal dopamine D2-like receptors in cranial and hand dystonia. PLOS ONE 9, e88121 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. Karimi, M. et al. Striatal dopamine D1-like receptor binding is unchanged in primary focal dystonia. Mov. Disord. 28, 2002–2006 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Simonyan, K., Cho, H., Hamzehei Sichani, A., Rubien-Thomas, E. & Hallett, M. The direct basal ganglia pathway is hyperfunctional in focal dystonia. Brain 140, 3179–3190 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  103. Goodchild, R. E., Grundmann, K. & Pisani, A. New genetic insights highlight ‘old’ ideas on motor dysfunction in dystonia. Trends Neurosci. 36, 717–725 (2013).

    CAS  Article  PubMed  Google Scholar 

  104. Mencacci, N. E. et al. De novo mutations in PDE10A cause childhood-onset chorea with bilateral striatal lesions. Am. J. Hum. Genet. 98, 763–771 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Diggle, C. P. et al. Biallelic mutations in PDE10A lead to loss of striatal PDE10A and a hyperkinetic movement disorder with onset in infancy. Am. J. Hum. Genet. 98, 735–743 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Herve, D. et al. G(olf) and Gs in rat basal ganglia: possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase. J. Neurosci. 13, 2237–2248 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Herve, D. et al. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum. J. Neurosci. 21, 4390–4399 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Chen, Y. Z. et al. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. Ann. Neurol. 75, 542–549 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Herve, D. Identification of a specific assembly of the g protein golf as a critical and regulated module of dopamine and adenosine-activated cAMP pathways in the striatum. Front. Neuroanat. 5, 48 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Corvol, J. C., Studler, J. M., Schonn, J. S., Girault, J. A. & Herve, D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. J. Neurochem. 76, 1585–1588 (2001).

    CAS  Article  PubMed  Google Scholar 

  111. Corvol, J. C. et al. Quantitative changes in Galphaolf protein levels, but not D1 receptor, alter specifically acute responses to psychostimulants. Neuropsychopharmacology 32, 1109–1121 (2007).

    CAS  Article  PubMed  Google Scholar 

  112. Alcacer, C. et al. Gα(olf) mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in L-3,4-dihydroxyphenylalanine-induced dyskinesia. J. Neurosci. 32, 5900–5910 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Li, Q. et al. Conserved properties of Drosophila insomniac link sleep regulation and synaptic function. PLOS Genet. 13, e1006815 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. Tzingounis, A. V., Kobayashi, M., Takamatsu, K. & Nicoll, R. A. Hippocalcin gates the calcium activation of the slow afterhyperpolarization in hippocampal pyramidal cells. Neuron 53, 487–493 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Pfeiffenberger, C. & Allada, R. Cul3 and the BTB adaptor insomniac are key regulators of sleep homeostasis and a dopamine arousal pathway in Drosophila. PLOS Genet. 8, e1003003 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Mencacci, N. E. et al. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am. J. Hum. Genet. 96, 938–947 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Chen, K.-F., Lamaze, A., Kratschmer, P. & Jepson, J. E. C. Neurocalcin acts in a clock- and light-modulated dopaminergic pathway to promote night sleep in Drosophila. Preprint at https://www.biorxiv.org/content/early/2017/11/13/159772 (2017).

  118. Meyer, E. et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat. Genet. 49, 223–237 (2017).

    CAS  Article  PubMed  Google Scholar 

  119. Napolitano, F. et al. Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia. Neurobiol. Dis. 38, 434–445 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Zhang, L., Yokoi, F., Parsons, D. S., Standaert, D. G. & Li, Y. Alteration of striatal dopaminergic neurotransmission in a mouse model of DYT11 myoclonus-dystonia. PLOS ONE 7, e33669 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Yokoi, F., Dang, M. T., Li, J., Standaert, D. G. & Li, Y. Motor deficits and decreased striatal dopamine receptor 2 binding activity in the striatum-specific Dyt1 conditional knockout mice. PLOS ONE 6, e24539 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Maltese, M. et al. Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition. Neurobiol. Dis. 108, 128–139 (2017).

    CAS  Article  PubMed  Google Scholar 

  123. Eskow Jaunarajs, K. L., Bonsi, P., Chesselet, M. F., Standaert, D. G. & Pisani, A. Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia. Prog. Neurobiol. 127–128, 91–107 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Maltese, M. et al. Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors. Mov. Disord. 29, 1655–1665 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Dang, M. T. et al. An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 DeltaGAG knock-in mice. Behav. Brain Res. 226, 465–472 (2012).

    CAS  Article  PubMed  Google Scholar 

  126. Helassa, N., Antonyuk, S. V., Lian, L. Y., Haynes, L. P. & Burgoyne, R. D. Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. Hum. Mol. Genet. 26, 2426–2435 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Kustedjo, K., Bracey, M. H. & Cravatt, B. F. Torsin A and its torsion dystonia-associated mutant forms are lumenal glycoproteins that exhibit distinct subcellular localizations. J. Biol. Chem. 275, 27933–27939 (2000).

    CAS  Article  PubMed  Google Scholar 

  129. Goodchild, R. E. & Dauer, W. T. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc. Natl Acad. Sci. USA 101, 847–852 (2004). This paper reports the finding that the mutant torsin A1 protein relocalizes from the endoplasmic reticulum to the nuclear envelope, suggesting that abnormal function of these subcellular structures is critical in DYT1 dystonia pathogenesis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. Hewett, J. W. et al. Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proc. Natl Acad. Sci. USA 104, 7271–7276 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Chen, P. et al. The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress response. Hum. Mol. Genet. 19, 3502–3515 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Nery, F. C. et al. TorsinA participates in endoplasmic reticulum-associated degradation. Nat. Commun. 2, 393 (2011).

    PubMed  Article  CAS  Google Scholar 

  133. Liang, C. C., Tanabe, L. M., Jou, S., Chi, F. & Dauer, W. T. TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration. J. Clin. Invest. 124, 3080–3092 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Grillet, M. et al. Torsins are essential regulators of cellular lipid metabolism. Dev. Cell 38, 235–247 (2016).

    CAS  Article  PubMed  Google Scholar 

  135. Rittiner, J. E. et al. Functional genomic analyses of mendelian and sporadic disease identify impaired eIF2alpha signaling as a generalizable mechanism for dystonia. Neuron 92, 1238–1251 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Di Prisco, G. V. et al. Translational control of mGluR-dependent long-term depression and object-place learning by eIF2alpha. Nat. Neurosci. 17, 1073–1082 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Trinh, M. A. et al. The eIF2alpha kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression. Learn. Mem. 21, 298–304 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Vaughn, L. S. et al. Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT. J. Biol. Chem. 290, 22543–22557 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Bessiere, D. et al. Structure-function analysis of the THAP zinc finger of THAP1, a large C2CH DNA-binding module linked to Rb/E2F pathways. J. Biol. Chem. 283, 4352–4363 (2008).

    CAS  Article  PubMed  Google Scholar 

  140. Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).

    CAS  Article  PubMed  Google Scholar 

  141. Kaiser, F. J. et al. The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Ann. Neurol. 68, 554–559 (2010).

    CAS  Article  PubMed  Google Scholar 

  142. Ruiz, M. et al. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia. Hum. Mol. Genet. 24, 7159–7170 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Zhao, Y., Xiao, J., Gong, S., Clara, J. A. & Ledoux, M. S. Neural expression of the transcription factor THAP1 during development in rat. Neuroscience 231, 282–295 (2013).

    CAS  Article  PubMed  Google Scholar 

  144. Aguilo, F. et al. THAP1: role in mouse embryonic stem cell survival and differentiation. Stem Cell Rep 9, 92–107 (2017).

    CAS  Article  Google Scholar 

  145. Sitburana, O., Wu, L. J., Sheffield, J. K., Davidson, A. & Jankovic, J. Motor overflow and mirror dystonia. Parkinsonism Relat. Disord. 15, 758–761 (2009).

    Article  PubMed  Google Scholar 

  146. Stamelou, M., Edwards, M. J., Hallett, M. & Bhatia, K. P. The non-motor syndrome of primary dystonia: clinical and pathophysiological implications. Brain 135, 1668–1681 (2012).

    Article  PubMed  Google Scholar 

  147. Patel, N., Hanfelt, J., Marsh, L. & Jankovic, J. Alleviating manoeuvres (sensory tricks) in cervical dystonia. J. Neurol. Neurosurg. Psychiatry 85, 882–884 (2014).

    PubMed  Article  Google Scholar 

  148. Rubio-Agusti, I. et al. Tremulous cervical dystonia is likely to be familial: clinical characteristics of a large cohort. Parkinsonism Relat. Disord. 19, 634–638 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  150. Stamelou, M. et al. The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov. Disord. 29, 928–934 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Wijemanne, S. & Jankovic, J. Dopa-responsive dystonia—clinical and genetic heterogeneity. Nat. Rev. Neurol. 11, 414–424 (2015).

    CAS  Article  PubMed  Google Scholar 

  152. Camargos, S. et al. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 7, 207–215 (2008).

    CAS  Article  PubMed  Google Scholar 

  153. Dos Santos, C. O. et al. The prevalence of PRKRA mutations in idiopathic dystonia. Parkinsonism Relat. Disord. 48, 93–96 (2018).

    Article  PubMed  Google Scholar 

  154. Quadri, M. et al. PRKRA mutation causing early-onset generalized dystonia-parkinsonism (DYT16) in an Italian family. Mov. Disord. 31, 765–767 (2016).

    CAS  Article  PubMed  Google Scholar 

  155. Aneichyk, T. et al. Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly. Cell 172, 897–909 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 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).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  158. Rosewich, H. et al. Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol. 11, 764–773 (2012).

    CAS  Article  PubMed  Google Scholar 

  159. Heinzen, E. L. et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat. Genet. 44, 1030–1034 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. Heinzen, E. L. et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol. 13, 503–514 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Zech, M. et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am. J. Hum. Genet. 99, 1377–1387 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Zech, M. et al. KMT2B rare missense variants in generalized dystonia. Mov. Disord. 32, 1087–1091 (2017).

    CAS  Article  PubMed  Google Scholar 

  163. Zimprich, A. et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat. Genet. 29, 66–69 (2001).

    CAS  Article  PubMed  Google Scholar 

  164. Chen, D. H. et al. ADCY5-related dyskinesia: broader spectrum and genotype-phenotype correlations. Neurology 85, 2026–2035 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Mencacci, N. E. et al. ADCY5 mutations are another cause of benign hereditary chorea. Neurology 85, 80–88 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. Chang, F. C. et al. Phenotypic insights into ADCY5-associated disease. Mov. Disord. 31, 1033–1040 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. Balint, B. & Bhatia, K. P. Dystonia: an update on phenomenology, classification, pathogenesis and treatment. Curr. Opin. Neurol. 27, 468–476 (2014).

    CAS  Article  PubMed  Google Scholar 

  168. Jinnah, H. A. et al. Treatable inherited rare movement disorders. Mov. Disord. 33, 21–35 (2017). This is a comprehensive review of specific therapeutic approaches in hereditary dystonias.

    PubMed  PubMed Central  Article  Google Scholar 

  169. Edwards, M. J., Stamelou, M., Quinn, N. & Bhatia, K. P. Parkinson’s Disease and Other Movement Disorders (Oxford Univ. Press, 2016).

  170. Erro, R. et al. The clinical syndrome of paroxysmal exercise-induced dystonia: diagnostic outcomes and an algorithm. Mov. Disord. Clin. Pract. 1, 57–61 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  171. De Giorgis, V. & Veggiotti, P. GLUT1 deficiency syndrome 2013: current state of the art. Seizure 22, 803–811 (2013).

    Article  PubMed  Google Scholar 

  172. Frei, K., Truong, D. D., Fahn, S., Jankovic, J. & Hauser, R. A. The nosology of tardive syndromes. J. Neurol. Sci. 389, 10–16 (2018).

    Article  PubMed  Google Scholar 

  173. Vijayakumar, D. & Jankovic, J. Drug-induced dyskinesia, part 2: treatment of tardive dyskinesia. Drugs 76, 779–787 (2016).

    CAS  Article  PubMed  Google Scholar 

  174. Thenganatt, M. A. & Jankovic, J. Treatment of dystonia. Neurotherapeutics 11, 139–152 (2014).

    CAS  Article  PubMed  Google Scholar 

  175. Pietracupa, S. et al. Scales for hyperkinetic disorders: a systematic review. J. Neurol. Sci. 358, 9–21 (2015).

    Article  PubMed  Google Scholar 

  176. Jankovic, J. Botulinum toxin: state of the art. Mov. Disord. 32, 1131–1138 (2017). Botulinum toxin has revolutionized the treatment of focal dystonia. This paper summarizes the current knowledge and state of the art strategy for the use of botulinum toxin in dystonia and beyond.

    CAS  Article  PubMed  Google Scholar 

  177. Pirio Richardson, S., Wegele, A. R., Skipper, B., Deligtisch, A. & Jinnah, H. A. Dystonia treatment: patterns of medication use in an international cohort. Neurology 88, 543–550 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. Pirazzini, M., Rossetto, O., Eleopra, R. & Montecucco, C. Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol. Rev. 69, 200–235 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. Simpson, D. M. et al. Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 86, 1818–1826 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. Hallett, M. et al. Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders. Toxicon 67, 94–114 (2013).

    CAS  Article  PubMed  Google Scholar 

  181. Contarino, M. F. et al. Clinical practice: evidence-based recommendations for the treatment of cervical dystonia with botulinum toxin. Front. Neurol. 8, 35 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  182. Comella, C. et al. A phase 2, open-label, dose-escalating study to evaluate the safety and preliminary efficacy of daxibotulinumtoxina for injection (RT002) in isolated cervical dystonia. Neurology 88 (Suppl. 16), P3.021 (2017).

    Google Scholar 

  183. Contarino, M. F., Smit, M., van den Dool, J., Volkmann, J. & Tijssen, M. A. Unmet needs in the management of cervical dystonia. Front. Neurol. 7, 165 (2016).

    PubMed  PubMed Central  Google Scholar 

  184. De Pauw, J. et al. The effectiveness of physiotherapy for cervical dystonia: a systematic literature review. J. Neurol. 261, 1857–1865 (2014).

    Article  PubMed  Google Scholar 

  185. Counsell, C. et al. A randomized trial of specialized versus standard neck physiotherapy in cervical dystonia. Parkinsonism Relat. Disord. 23, 72–79 (2016).

    Article  PubMed  Google Scholar 

  186. Boyce, M. J. et al. Active exercise for individuals with cervical dystonia: a pilot randomized controlled trial. Clin. Rehabil. 27, 226–235 (2013).

    Article  PubMed  Google Scholar 

  187. Tassorelli, C. et al. Botulinum toxin and neuromotor rehabilitation: an integrated approach to idiopathic cervical dystonia. Mov. Disord. 21, 2240–2243 (2006).

    Article  PubMed  Google Scholar 

  188. Bleton, J. P. et al. Baseline Features Influencing the Effectiveness of Retraining Therapy for Writer’s Cramp. Mov. Disord. Clin. Pract. 2, 232–236 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  189. Priori, A., Pesenti, A., Cappellari, A., Scarlato, G. & Barbieri, S. Limb immobilization for the treatment of focal occupational dystonia. Neurology 57, 405–409 (2001).

    CAS  Article  PubMed  Google Scholar 

  190. Pirio Richardson, S. et al. Research priorities in limb and task-specific dystonias. Front. Neurol. 8, 170 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  191. Cho, H. J. & Hallett, M. Non-invasive brain stimulation for treatment of focal hand dystonia: update and future direction. J. Mov. Disord. 9, 55–62 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  192. Erro, R., Tinazzi, M., Morgante, F. & Bhatia, K. P. Non-invasive brain stimulation for dystonia: therapeutic implications. Eur. J. Neurol. 24, 1228 (2017).

    CAS  Article  PubMed  Google Scholar 

  193. Burke, R. E., Fahn, S. & Marsden, C. D. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 36, 160–164 (1986).

    CAS  Article  PubMed  Google Scholar 

  194. Lumsden, D. E., Kaminska, M., Tomlin, S. & Lin, J. P. Medication use in childhood dystonia. Eur. J. Paediatr. Neurol. 20, 625–629 (2016).

    Article  PubMed  Google Scholar 

  195. Alfradique-Dunham, I. & Jankovic, J. Available treatment options for dystonia. Expert Opin. Orphan Drugs 5, 707–716 (2017).

    CAS  Article  Google Scholar 

  196. Vijayakumar, D. & Jankovic, J. Drug-induced dyskinesia, part 1: treatment of levodopa-induced dyskinesia. Drugs 76, 759–777 (2016).

    CAS  Article  PubMed  Google Scholar 

  197. Jankovic, J. Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin. Pharmacother. 17, 2461–2470 (2016).

    CAS  Article  PubMed  Google Scholar 

  198. Solmi, M., Pigato, G., Kane, J. M. & Correll, C. U. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des. Devel. Ther. 12, 1215–1238 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. Monbaliu, E. et al. Clinical presentation and management of dyskinetic cerebral palsy. Lancet Neurol. 16, 741–749 (2017).

    Article  PubMed  Google Scholar 

  200. Motta, F. & Antonello, C. E. Analysis of complications in 430 consecutive pediatric patients treated with intrathecal baclofen therapy: 14-year experience. J. Neurosurg. Pediatr. 13, 301–306 (2014).

    Article  PubMed  Google Scholar 

  201. Turner, M., Nguyen, H. S. & Cohen-Gadol, A. A. Intraventricular baclofen as an alternative to intrathecal baclofen for intractable spasticity or dystonia: outcomes and technical considerations. J. Neurosurg. Pediatr. 10, 315–319 (2012).

    Article  PubMed  Google Scholar 

  202. Hainque, E. et al. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia. Neurology 86, 1729–1735 (2016).

    CAS  Article  PubMed  Google Scholar 

  203. Bomalaski, M. N., Claflin, E. S., Townsend, W. & Peterson, M. D. Zolpidem for the treatment of neurologic disorders: a systematic review. JAMA Neurol. 74, 1130–1139 (2017).

    Article  PubMed  Google Scholar 

  204. Liow, N. Y. et al. Gabapentin can significantly improve dystonia severity and quality of life in children. Eur. J. Paediatr. Neurol. 20, 100–107 (2016).

    Article  PubMed  Google Scholar 

  205. Vijayakumar, D., Wijemanne, S. & Jankovic, J. Treatment of blepharospasm with apraclonidine. J. Neurol. Sci. 372, 57–59 (2017).

    CAS  Article  PubMed  Google Scholar 

  206. Moro, E. et al. Efficacy of pallidal stimulation in isolated dystonia: a systematic review and meta-analysis. Eur. J. Neurol. 24, 552–560 (2017). This is a comprehensive meta-analysis with a systematic review of the literature on DBS in dystonia. This paper provides strong clinical evidence of the efficacy of DBS of the GPi in isolated inherited or idiopathic dystonia.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 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).

    Article  PubMed  Google Scholar 

  208. Volkmann, J. et al. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol. 11, 1029–1038 (2012).

    Article  PubMed  Google Scholar 

  209. Volkmann, J. et al. Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial. Lancet Neurol. 13, 875–884 (2014).

    Article  PubMed  Google Scholar 

  210. Reese, R. et al. Long-term clinical outcome in meige syndrome treated with internal pallidum deep brain stimulation. Mov. Disord. 26, 691–698 (2011).

    Article  PubMed  Google Scholar 

  211. Schrader, C. et al. GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia. Neurology 77, 483–488 (2011).

    CAS  Article  PubMed  Google Scholar 

  212. Ostrem, J. L. et al. Subthalamic nucleus deep brain stimulation in isolated dystonia: a 3-year follow-up study. Neurology 88, 25–35 (2017).

    Article  PubMed  Google Scholar 

  213. Mills, K. A., Scherzer, R., Starr, P. A. & Ostrem, J. L. Weight change after globus pallidus internus or subthalamic nucleus deep brain stimulation in Parkinson’s disease and dystonia. Stereotact. Funct. Neurosurg. 90, 386–393 (2012).

    PubMed  Article  Google Scholar 

  214. Baizabal Carvallo, J. F. et al. Deep brain stimulation hardware complications in patients with movement disorders: risk factors and clinical correlations. Stereotact. Funct. Neurosurg. 90, 300–306 (2012).

    Article  PubMed  Google Scholar 

  215. Pouclet-Courtemanche, H. et al. Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia. Neurology 86, 651–659 (2016).

    CAS  Article  PubMed  Google Scholar 

  216. Azoulay-Zyss, J. et al. Bilateral deep brain stimulation of the pallidum for myoclonus-dystonia due to epsilon-sarcoglycan mutations: a pilot study. Arch. Neurol. 68, 94–98 (2011).

    Article  PubMed  Google Scholar 

  217. Panov, F. et al. Deep brain stimulation in DYT1 dystonia: a 10-year experience. Neurosurgery 73, 86–93 (2013).

    Article  PubMed  Google Scholar 

  218. Krause, P. et al. Long-term effect on dystonia after pallidal deep brain stimulation (DBS) in three members of a family with a THAP1 mutation. J. Neurol. 262, 2739–2744 (2015).

    CAS  Article  PubMed  Google Scholar 

  219. Panov, F. et al. Pallidal deep brain stimulation for DYT6 dystonia. J. Neurol. Neurosurg. Psychiatry 83, 182–187 (2012).

    Article  PubMed  Google Scholar 

  220. Ziegan, J. et al. Novel GNAL mutations in two German patients with sporadic dystonia. Mov Disord. 29, 1833–1834 (2014).

    CAS  Article  PubMed  Google Scholar 

  221. Carecchio, M. et al. Novel GNAL mutation with intra-familial clinical heterogeneity: expanding the phenotype. Parkinsonism Relat. Disord. 23, 66–71 (2016).

    Article  PubMed  Google Scholar 

  222. Horisawa, S., Taira, T., Goto, S., Ochiai, T. & Nakajima, T. Long-term improvement of musician’s dystonia after stereotactic ventro-oral thalamotomy. Ann. Neurol. 74, 648–654 (2013).

    Article  PubMed  Google Scholar 

  223. Dallapiazza, R. F. et al. Noninvasive neuromodulation and thalamic mapping with low-intensity focused ultrasound. J. Neurosurg. 128, 875–884 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  224. Allen, N. M., Lin, J. P., Lynch, T. & King, M. D. Status dystonicus: a practice guide. Dev. Med. Child Neurol. 56, 105–112 (2014).

    Article  PubMed  Google Scholar 

  225. Termsarasab, P. & Frucht, S. J. Dystonic storm: a practical clinical and video review. J. Clin. Mov. Disord. 4, 10 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  226. Ben-Shlomo, Y., Camfield, L. & Warner, T. What are the determinants of quality of life in people with cervical dystonia? J. Neurol. Neurosurg. Psychiatry 72, 608–614 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. Marsden, C. D., Marion, M. H. & Quinn, N. The treatment of severe dystonia in children and adults. J. Neurol. Neurosurg. Psychiatry 47, 1166–1173 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  228. Fezza, J. et al. A cross-sectional structured survey of patients receiving botulinum toxin type A treatment for blepharospasm. J. Neurol. Sci. 367, 56–62 (2016).

    CAS  Article  PubMed  Google Scholar 

  229. Benninger, M. S., Gardner, G. & Grywalski, C. Outcomes of botulinum toxin treatment for patients with spasmodic dysphonia. Arch. Otolaryngol. Head Neck Surg. 127, 1083–1085 (2001).

    CAS  Article  PubMed  Google Scholar 

  230. Sheehy, M. P. & Marsden, C. D. Writers’ cramp-a focal dystonia. Brain 105, 461–480 (1982).

    Article  PubMed  Google Scholar 

  231. Conti, A. M., Pullman, S. & Frucht, S. J. The hand that has forgotten its cunning — lessons from musicians’ hand dystonia. Mov. Disord. 23, 1398–1406 (2008).

    Article  PubMed  Google Scholar 

  232. Hwang, W. J. & Tsai, C. F. Motor vehicle accidents and injuries in patients with idiopathic blepharospasm. J. Neurol. Sci. 339, 217–219 (2014).

    Article  PubMed  Google Scholar 

  233. van den Dool, J., Tijssen, M. A., Koelman, J. H., Engelbert, R. H. & Visser, B. Determinants of disability in cervical dystonia. Parkinsonism Relat. Disord. 32, 48–53 (2016).

    Article  PubMed  Google Scholar 

  234. Muller, J. et al. The impact of blepharospasm and cervical dystonia on health-related quality of life and depression. J. Neurol. 249, 842–846 (2002).

    CAS  Article  PubMed  Google Scholar 

  235. Smit, M. et al. Psychiatric co-morbidity is highly prevalent in idiopathic cervical dystonia and significantly influences health-related quality of life: results of a controlled study. Parkinsonism Relat. Disord. 30, 7–12 (2016).

    CAS  Article  PubMed  Google Scholar 

  236. Gundel, H. et al. High psychiatric comorbidity in spasmodic torticollis: a controlled study. J. Nerv. Ment. Dis. 191, 465–473 (2003).

    Article  PubMed  Google Scholar 

  237. Berman, B. D. et al. Psychiatric associations of adult-onset focal dystonia phenotypes. J. Neurol. Neurosurg. Psychiatry 88, 595–602 (2017).

    PubMed  Article  Google Scholar 

  238. Heiman, G. A. et al. Increased risk for recurrent major depression in DYT1 dystonia mutation carriers. Neurology 63, 631–637 (2004).

    CAS  Article  PubMed  Google Scholar 

  239. Zoons, E., Dijkgraaf, M. G., Dijk, J. M., van Schaik, I. N. & Tijssen, M. A. Botulinum toxin as treatment for focal dystonia: a systematic review of the pharmaco-therapeutic and pharmaco-economic value. J. Neurol. 259, 2519–2526 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  240. Antelmi, E. et al. Modulation of the muscle activity during sleep in cervical dystonia. Sleep 40, zsx088 (2017).

    Article  Google Scholar 

  241. Paus, S. et al. Impaired sleep quality and restless legs syndrome in idiopathic focal dystonia: a controlled study. J. Neurol. 258, 1835–1840 (2011).

    Article  PubMed  Google Scholar 

  242. Molho, E. S. et al. Impact of cervical dystonia on work productivity: an analysis from a patient registry. Mov Disord. Clin. Pract. 3, 130–138 (2016).

    Article  PubMed  Google Scholar 

  243. Molho, E. S., Agarwal, N., Regan, K., Higgins, D. S. & Factor, S. A. Effect of cervical dystonia on employment: a retrospective analysis of the ability of treatment to restore premorbid employment status. Mov. Disord. 24, 1384–1387 (2009).

    Article  PubMed  Google Scholar 

  244. Skogseid, I. M., Roislien, J., Claussen, B. & Kerty, E. Long-term botulinum toxin treatment increases employment rate in patients with cervical dystonia. Mov. Disord. 20, 1604–1609 (2005).

    Article  PubMed  Google Scholar 

  245. Martikainen, K. K., Luukkaala, T. H. & Marttila, R. J. Working capacity and cervical dystonia. Parkinsonism Relat. Disord. 16, 215–217 (2010).

    Article  PubMed  Google Scholar 

  246. Zech, M. et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls. Mov. Disord. 29, 143–147 (2014).

    CAS  Article  PubMed  Google Scholar 

  247. Zech, M. et al. Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls. Parkinsonism Relat. Disord. 31, 119–123 (2016).

    Article  PubMed  Google Scholar 

  248. Kuhn, A. A. & Volkmann, J. Innovations in deep brain stimulation methodology. Mov. Disord. 32, 11–19 (2017).

    Article  PubMed  Google Scholar 

  249. Munts, A. G. & Koehler, P. J. How psychogenic is dystonia? Views from past to present. Brain 133, 1552–1564 (2010).

    Article  PubMed  Google Scholar 

  250. Marsden, C. D. The problem of adult-onset idiopathic torsion dystonia and other isolated dyskinesias in adult life (including blepharospasm, oromandibular dystonia, dystonic writer’s cramp, and torticollis, or axial dystonia). Adv. Neurol. 14, 259–276 (1976).

    CAS  PubMed  Google Scholar 

  251. Robertson, M. M. et al. Gilles de la Tourette syndrome. Nat. Rev. Dis. Primers 3, 16097 (2017).

    Article  PubMed  Google Scholar 

  252. Charlesworth, G., Bhatia, K. P. & Wood, N. W. The genetics of dystonia: new twists in an old tale. Brain 136, 2017–2037 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  253. Marras, C., Lohmann, K., Lang, A. & Klein, C. Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. Neurology 78, 1016–1024 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

B.B. is supported by a European Academy of Neurology fellowship and the Robert Bosch Foundation.

Reviewer information

Nature Reviews Disease Primers thanks G. Abbruzzese, H. Jinnah, R. Kaji and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

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Contributions

Introduction (B.B. and K.P.B.); Epidemiology (B.B., E.M.V., N.E.M. and K.P.B.); Mechanisms/pathophysiology (N.E.M., E.M.V., J.R. and A.P.); Diagnosis, screening and prevention (B.B. and K.P.B.); Management (J.J. and M.V.); Quality of life (B.B. and K.P.B.); Outlook (B.B., M.V. and K.P.B.); Overview of Primer (B.B. and K.P.B.).

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Correspondence to Kailash P. Bhatia.

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Competing interests

E.M.V. holds research grants from the European Research Council (ERC StG260888), Telethon Foundation Italy (GGP13146), the Italian Ministry of Health (Ricerca Finalizzata 2013 NET-2013-02356160) and the University of Pavia (BlueSky Research Grants), receives a stipend from The BMJ as Associate Editor of the Journal of Medical Genetics and has received financial support to speak and/or attend meetings from Zambon. A.P. receives grants from the Italian Ministry of Education, Universities and Research (MIUR, ref PRIN 2015, 2015FNWP34-002) and the Dystonia Medical Research Foundation and received honoraria and financial support to speak or attend meetings from AbbVie, Teva and Union Chimique Belge. M.V. has received travel grants as faculty from The International Parkinson and Movement Disorder Society and the European Academy of Neurology and holds an unrestricted research grant from Merz. J.J. has received research and/or training grants from Adamas Pharmaceuticals, Allergan, Biotie Therapies, CHDI Foundation, Civitas/Acorda Therapeutics, Dystonia Coalition, Dystonia Medical Research Foundation, F. Hoffmann-La Roche, Huntington Study Group, Kyowa Hakko Kirin Pharma, Medtronic Neuromodulation, Merz Pharmaceuticals, Michael J. Fox Foundation for Parkinson Research, National Institutes of Health, Neurocrine Biosciences, NeuroDerm, Nuvelution, Parkinson Disease Foundation, Parkinson Study Group, Pfizer, Prothena Biosciences, Psyadon Pharmaceuticals, Revance Therapeutics, Sangamo BioSciences, St. Jude Medical and Teva. J.J. has served as a consultant or as an advisory committee member for Adamas Pharmaceuticals, Allergan, Merz Pharmaceuticals, Pfizer, Prothena Biosciences, Revance Therapeutics and Teva and has received royalties or other payments from Cambridge, Elsevier, Future Science Group, Hodder Arnold, Lippincott Williams and Wilkins, MedLink, Neurology and Wiley-Blackwell. K.P.B. holds research grants from the National Institute for Health Research, Research for Patient Benefit (NIHR RfPB), a Medical Research Council Wellcome Strategic grant (WT089698) and a grant from Parkinson’s UK (G-1009) and has received honoraria and/or financial support to speak and/or attend meetings from Allergan, Boehringer-Ingelheim, GSK, Ipsen, Lundbeck, Merz, Orion, Sun Pharma and Teva. K.P.B. receives royalties from the Oxford University Press and a stipend for Movement Disorders Clinical Practice editorship. All other authors declare no competing interests.

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Balint, B., Mencacci, N.E., Valente, E.M. et al. Dystonia. Nat Rev Dis Primers 4, 25 (2018). https://doi.org/10.1038/s41572-018-0023-6

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