1932

Abstract

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., , ), calcium homeostasis (e.g., , ), striatal dopamine signaling (e.g., ), endoplasmic reticulum stress response (e.g., , , ), autophagy (e.g., ), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.

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2024-01-24
2024-06-13
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Literature Cited

  1. 1.
    Newby RE, Thorpe DE, Kempster PA, Alty JE. 2017. A history of dystonia: ancient to modern. Mov. Disord. Clin. Pract. 4:447885
    [Google Scholar]
  2. 2.
    Klein C, Fahn S. 2013. Translation of Oppenheim's 1911 paper on dystonia. Mov. Disord. 28:785162
    [Google Scholar]
  3. 3.
    Oppenheim H. 1911. Über eine eigenartige Krampfkrankheit des kindlichen und jugendlichen Alters (Dysbasia lordotica lordotica progressive, Dystonia musculorum deformans). Neurol. Cent. 30:1090107
    [Google Scholar]
  4. 4.
    Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S et al. 2013. Phenomenology and classification of dystonia: a consensus update. Mov. Disord. 28:786373
    [Google Scholar]
  5. 5.
    Ichinose H, Ohye T, Takahashi E, Seki N, Hori T et al. 1994. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat. Genet. 8:323642
    [Google Scholar]
  6. 6.
    Albanese A, Di Giovanni M, Lalli S. 2019. Dystonia: diagnosis and management. Eur. J. Neurol. 26:1517
    [Google Scholar]
  7. 7.
    Dressler D, Altenmüller E, Giess R, Krauss JK, Adib Saberi F. 2022. The epidemiology of dystonia: the Hannover epidemiology study. J. Neurol. 269:12648393
    [Google Scholar]
  8. 8.
    Medina A, Nilles C, Martino D, Pelletier C, Pringsheim T. 2022. The prevalence of idiopathic or inherited isolated dystonia: a systematic review and meta-analysis. Mov. Disord. Clin. Pract. 9:786068
    [Google Scholar]
  9. 9.
    Marras C, Lohmann K, Lang A, Klein C. 2012. Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. Neurology 78:13101624
    [Google Scholar]
  10. 10.
    Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ et al. 2016. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force. Mov. Disord. 31:443657
    [Google Scholar]
  11. 11.
    Lange LM, Gonzalez-Latapi P, Rajalingam R, Tijssen MAJ, Ebrahimi-Fakhari D et al. 2022. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force—an update. Mov. Disord. 37:590535
    [Google Scholar]
  12. 12.
    Genet. Nomencl. Mov. Disord. Study Group 2022. Revision to nomenclature of genetically determined movement disorders—updated complete list of hereditary dystonia https://www.movementdisorders.org/MDS/About/Committees–Other-Groups/Study-Groups/Genetic-Nomenclature-in-Movement-Disorders.htm
    [Google Scholar]
  13. 13.
    Lange LM, Junker J, Loens S, Baumann H, Olschewski L et al. 2021. Genotype-phenotype relations for isolated dystonia genes: MDSGene systematic review. Mov. Disord. 36:51086103
    [Google Scholar]
  14. 14.
    Thomsen M, Lange LM, Klein C, Lohmann K. 2023. MDSGene: extending the list of isolated dystonia genes by VPS16, EIF2AK2, and AOPEP. Mov. Disord. 38:35078
    [Google Scholar]
  15. 15.
    Weissbach A, Pauly MG, Herzog R, Hahn L, Halmans S et al. 2022. Relationship of genotype, phenotype, and treatment in dopa-responsive dystonia: MDSGene review. Mov. Disord. 37:223752
    [Google Scholar]
  16. 16.
    Balint B, Mencacci NE, Valente EM, Pisani A, Rothwell J et al. 2018. Dystonia. Nat. Rev. Dis. Primers 4:125
    [Google Scholar]
  17. 17.
    Jinnah HA, Albanese A, Bhatia KP, Cardoso F, Da Prat G et al. 2018. Treatable inherited rare movement disorders. Mov. Disord. 33:12135
    [Google Scholar]
  18. 18.
    Jankovic J. 2017. Botulinum toxin: state of the art. Mov. Disord. 32:8113138
    [Google Scholar]
  19. 19.
    Jankovic J. 2009. Treatment of hyperkinetic movement disorders. Lancet Neurol. 8:984456
    [Google Scholar]
  20. 20.
    Burke RE, Fahn S, Marsden CD. 1986. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 36:216064
    [Google Scholar]
  21. 21.
    Lumsden DE, Kaminska M, Tomlin S, Lin J-P. 2016. Medication use in childhood dystonia. Eur. J. Paediatr. Neurol. 20:462529
    [Google Scholar]
  22. 22.
    Moro E, LeReun C, Krauss JK, Albanese A, Lin J-P et al. 2017. Efficacy of pallidal stimulation in isolated dystonia: a systematic review and meta-analysis. Eur. J. Neurol. 24:455260
    [Google Scholar]
  23. 23.
    Tsuboi T, Cauraugh JH, Wong JK, Okun MS, Ramirez-Zamora A. 2020. Quality of life outcomes after globus pallidus internus deep brain stimulation in idiopathic or inherited isolated dystonia: a meta-analysis. J. Neurol. Neurosurg. Psychiatry 91:993844
    [Google Scholar]
  24. 24.
    Mok KY, Schneider SA, Trabzuni D, Stamelou M, Edwards M et al. 2014. Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel. Mov. Disord. 29:224551
    [Google Scholar]
  25. 25.
    Sun YV, Li C, Hui Q, Huang Y, Barbano R et al. 2021. A multi-center genome-wide association study of cervical dystonia. Mov. Disord. 36:122795801
    [Google Scholar]
  26. 26.
    Lohmann K, Schmidt A, Schillert A, Winkler S, Albanese A et al. 2014. Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?. Mov. Disord. 29:792127
    [Google Scholar]
  27. 27.
    Nibbeling E, Schaake S, Tijssen MA, Weissbach A, Groen JL et al. 2015. Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia. J. Neurol. 262:5134043
    [Google Scholar]
  28. 28.
    Kumar KR, Davis RL, Tchan MC, Wali GM, Mahant N et al. 2019. Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat. Disord. 69:11118
    [Google Scholar]
  29. 29.
    Gómez-Garre P, Huertas-Fernández I, Cáceres-Redondo MT, Alonso-Canovas A, Bernal-Bernal I et al. 2014. Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study. Mov. Disord. 29:14182528
    [Google Scholar]
  30. 30.
    Ohlei O, Dobricic V, Lohmann K, Klein C, Lill CM, Bertram L. 2018. Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia. Parkinsonism Relat. Disord. 57:5057
    [Google Scholar]
  31. 31.
    Sharma N. 2019. Neuropathology of dystonia. Tremor Other Hyperkinet. Mov. 9:569
    [Google Scholar]
  32. 32.
    Bhatia KP, Marsden CD. 1994. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117:485976
    [Google Scholar]
  33. 33.
    DeLong MR. 1990. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13:728185
    [Google Scholar]
  34. 34.
    Neychev VK, Gross RE, Lehéricy S, Hess EJ, Jinnah HA. 2011. The functional neuroanatomy of dystonia. Neurobiol. Dis. 42:2185201
    [Google Scholar]
  35. 35.
    Jinnah HA, Neychev V, Hess EJ. 2017. The anatomical basis for dystonia: the motor network model. Tremor Other Hyperkinet. Mov. 7:506
    [Google Scholar]
  36. 36.
    Poston KL, Eidelberg D. 2012. Functional brain networks and abnormal connectivity in the movement disorders. NeuroImage 62:4226170
    [Google Scholar]
  37. 37.
    Stefanova N, Puschban Z, Fernagut P-O, Brouillet E, Tison F et al. 2003. Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy). Acta Neuropathol. 106:215766
    [Google Scholar]
  38. 38.
    Fernagut PO, Diguet E, Stefanova N, Biran M, Wenning GK et al. 2002. Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57Bl/6 mice: behavioural and histopathological characterisation. Neuroscience 114:4100517
    [Google Scholar]
  39. 39.
    Pizoli CE, Jinnah HA, Billingsley ML, Hess EJ. 2002. Abnormal cerebellar signaling induces dystonia in mice. J. Neurosci. 22:17782533
    [Google Scholar]
  40. 40.
    White JJ, Sillitoe RV. 2017. Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat. Commun. 8:14912
    [Google Scholar]
  41. 41.
    Calderon DP, Fremont R, Kraenzlin F, Khodakhah K. 2011. The neural substrates of rapid-onset dystonia-parkinsonism. Nat. Neurosci. 14:335765
    [Google Scholar]
  42. 42.
    Latorre A, Rocchi L, Bhatia KP. 2020. Delineating the electrophysiological signature of dystonia. Exp. Brain Res. 238:7/8168592
    [Google Scholar]
  43. 43.
    Morigaki R, Miyamoto R, Matsuda T, Miyake K, Yamamoto N, Takagi Y. 2021. Dystonia and cerebellum: from bench to bedside. Life 11:8776
    [Google Scholar]
  44. 44.
    Yoshida J, Oñate M, Khatami L, Vera J, Nadim F, Khodakhah K. 2022. Cerebellar contributions to the basal ganglia influence motor coordination, reward processing, and movement vigor. J. Neurosci. 42:45840615
    [Google Scholar]
  45. 45.
    Shetty AS, Bhatia KP, Lang AE. 2019. Dystonia and Parkinson's disease: What is the relationship?. Neurobiol. Dis. 132:104462
    [Google Scholar]
  46. 46.
    Ribot B, Aupy J, Vidailhet M, Mazère J, Pisani A et al. 2019. Dystonia and dopamine: from phenomenology to pathophysiology. Prog. Neurobiol. 182:101678
    [Google Scholar]
  47. 47.
    Keller Sarmiento IJ, Mencacci NE. 2021. Genetic dystonias: update on classification and new genetic discoveries. Curr. Neurol. Neurosci. Rep. 21:38
    [Google Scholar]
  48. 48.
    Mastrangelo M, Tolve M, Artiola C, Bove R, Carducci C et al. 2023. Phenotypes and genotypes of inherited disorders of biogenic amine neurotransmitter metabolism. Genes 14:2263
    [Google Scholar]
  49. 49.
    Hervé D. 2011. 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
    [Google Scholar]
  50. 50.
    Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D et al. 2013. Mutations in GNAL cause primary torsion dystonia. Nat. Genet. 45:18892
    [Google Scholar]
  51. 51.
    Kumar KR, Lohmann K, Masuho I, Miyamoto R, Ferbert A et al. 2014. Mutations in GNAL: a novel cause of craniocervical dystonia. JAMA Neurol. 71:449094
    [Google Scholar]
  52. 52.
    Mori A. 2020. How do adenosine A2A receptors regulate motor function?. Parkinsonism Relat. Disord. 80:S1320
    [Google Scholar]
  53. 53.
    Doyle T, Hayes M, Chen D, Raskind W, Watts V. 2019. Functional characterization of AC5 gain-of-function variants: impact on the molecular basis of ADCY5-related dyskinesia. Biochem. Pharmacol. 163:16977
    [Google Scholar]
  54. 54.
    Wirth T, Garone G, Kurian MA, Piton A, Millan F et al. 2022. Highlighting the dystonic phenotype related to GNAO1. Mov. Disord. 37:7154754
    [Google Scholar]
  55. 55.
    Lohmann K, Masuho I, Patil DN, Baumann H, Hebert E et al. 2017. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans. Hum. Mol. Genet. 26:6107886
    [Google Scholar]
  56. 56.
    Khan SM, Sleno R, Gora S, Zylbergold P, Laverdure J-P et al. 2013. The expanding roles of Gβγ subunits in G protein–coupled receptor signaling and drug action. Pharmacol. Rev. 65:254577
    [Google Scholar]
  57. 57.
    van der Weijden MCM, Rodriguez-Contreras D, Delnooz CCS, Robinson BG, Condon AF et al. 2021. A gain-of-function variant in dopamine D2 receptor and progressive chorea and dystonia phenotype. Mov. Disord. 36:372939
    [Google Scholar]
  58. 58.
    Downs AM, Fan X, Kadakia RF, Donsante Y, Jinnah HA, Hess EJ. 2021. Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of TOR1A dystonia. Neurobiol. Dis. 155:105369
    [Google Scholar]
  59. 59.
    Napolitano F, Pasqualetti M, Usiello A, Santini E, Pacini G et al. 2010. Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia. Neurobiol. Dis. 38:343445
    [Google Scholar]
  60. 60.
    Frederick NM, Pooler MM, Shah P, Didonna A, Opal P. 2021. Pharmacological perturbation reveals deficits in D2 receptor responses in Thap1 null mice. Ann. Clin. Transl. Neurol. 8:1223028
    [Google Scholar]
  61. 61.
    Chen K-F, Lowe S, Lamaze A, Krätschmer P, Jepson J. 2019. Neurocalcin regulates nighttime sleep and arousal in Drosophila. eLife 8:e38114
    [Google Scholar]
  62. 62.
    Li Q, Kellner DA, Hatch HAM, Yumita T, Sanchez S et al. 2017. Conserved properties of Drosophila insomniac link sleep regulation and synaptic function. PLOS Genet. 13:5e1006815
    [Google Scholar]
  63. 63.
    Pfeiffenberger C, Allada R. 2012. Cul3 and the BTB adaptor insomniac are key regulators of sleep homeostasis and a dopamine arousal pathway in Drosophila. PLOS Genet. 8:10e1003003
    [Google Scholar]
  64. 64.
    Mencacci NE, Reynolds R, Ruiz SG, Vandrovcova J, Forabosco P et al. 2020. Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders. Brain 143:9277187
    [Google Scholar]
  65. 65.
    Campagne S, Muller I, Milon A, Gervais V. 2012. Towards the classification of DYT6 dystonia mutants in the DNA-binding domain of THAP1. Nucleic Acids Res. 40:19992740
    [Google Scholar]
  66. 66.
    Lohmann K, Uflacker N, Erogullari A, Lohnau T, Winkler S et al. 2012. Identification and functional analysis of novel THAP1 mutations. Eur. J. Hum. Genet. 20:217175
    [Google Scholar]
  67. 67.
    Osmanovic A, Dendorfer A, Erogullari A, Uflacker N, Braunholz D et al. 2011. Truncating mutations in THAP1 define the nuclear localization signal. Mov. Disord. 26:8156567
    [Google Scholar]
  68. 68.
    Hollstein R, Reiz B, Kötter L, Richter A, Schaake S et al. 2017. Dystonia-causing mutations in the transcription factor THAP1 disrupt HCFC1 cofactor recruitment and alter gene expression. Hum. Mol. Genet. 26:15297583
    [Google Scholar]
  69. 69.
    Sengel C, Gavarini S, Sharma N, Ozelius LJ, Bragg DC. 2011. Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain. J. Neurochem. 118:61087100
    [Google Scholar]
  70. 70.
    Frederick NM, Shah PV, Didonna A, Langley MR, Kanthasamy AG, Opal P. 2019. Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes. Hum. Mol. Genet. 28:8134356
    [Google Scholar]
  71. 71.
    Baumann H, Ott F, Weber J, Trilck-Winkler M, Münchau A et al. 2021. Linking penetrance and transcription in DYT-THAP1: insights from a human iPSC-derived cortical model. Mov. Disord. 36:6138191
    [Google Scholar]
  72. 72.
    Diaw SH, Ganos C, Zittel S, Plötze-Martin K, Kulikovskaja L et al. 2022. Mutant WDR45 leads to altered ferritinophagy and ferroptosis in β-propeller protein-associated neurodegeneration. Int. J. Mol. Sci. 23:179524
    [Google Scholar]
  73. 73.
    Staege S, Kutschenko A, Baumann H, Glaß H, Henkel L et al. 2021. Reduced expression of GABAA receptor alpha2 subunit is associated with disinhibition of DYT-THAP1 dystonia patient-derived striatal medium spiny neurons. Front. Cell Dev. Biol. 9:650586
    [Google Scholar]
  74. 74.
    Yellajoshyula D, Liang C-C, Pappas SS, Penati S, Yang A et al. 2017. The DYT6 dystonia protein THAP1 regulates myelination within the oligodendrocyte lineage. Dev. Cell 42:15267.e4
    [Google Scholar]
  75. 75.
    Ruiz M, Perez-Garcia G, Ortiz-Virumbrales M, Méneret A, Morant A et al. 2015. Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia. Hum. Mol. Genet. 24:25715970
    [Google Scholar]
  76. 76.
    Gavarini S, Cayrol C, Fuchs T, Lyons N, Ehrlich ME et al. 2010. A direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann. Neurol. 68:454953
    [Google Scholar]
  77. 77.
    Kaiser FJ, Osmanoric A, Rakovic A, Erogullari A, Uflacker N et al. 2010. The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Ann. Neurol. 68:455459
    [Google Scholar]
  78. 78.
    Muramoto T, Müller I, Thomas G, Melvin A, Chubb JR. 2010. Methylation of H3K4 is required for inheritance of active transcriptional states. Curr. Biol. 20:5397406
    [Google Scholar]
  79. 79.
    Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K et al. 2014. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158:367388
    [Google Scholar]
  80. 80.
    Glaser S, Lubitz S, Loveland KL, Ohbo K, Robb L et al. 2009. The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenet. Chromatin 2:5
    [Google Scholar]
  81. 81.
    Meyer E, Carss KJ, Rankin J, Nichols JME, Grozeva D et al. 2017. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat. Genet. 49:222337
    [Google Scholar]
  82. 82.
    Ciolfi A, Foroutan A, Capuano A, Pedace L, Travaglini L et al. 2021. Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile. Clin. Epigenet. 13:1157
    [Google Scholar]
  83. 83.
    Lee S, Ochoa E, Barwick K, Cif L, Rodger F et al. 2022. Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders. Epigenomics 14:953747
    [Google Scholar]
  84. 84.
    Mirza-Schreiber N, Zech M, Wilson R, Brunet T, Wagner M et al. 2022. Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset. Brain 145:264454
    [Google Scholar]
  85. 85.
    Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J et al. 2008. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:720576670
    [Google Scholar]
  86. 86.
    Douillet D, Sze CC, Ryan C, Piunti A, Shah AP et al. 2020. Uncoupling histone H3K4 trimethyl-ation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation. Nat. Genet. 52:661525
    [Google Scholar]
  87. 87.
    Ferng A, Thulin P, Walsh E, Weissbrod PA, Friedman J. 2022. YY1: a new gene for childhood onset dystonia with prominent oromandibular-laryngeal involvement?. Mov. Disord. 37:122728
    [Google Scholar]
  88. 88.
    Gabriele M, Vulto-van Silfhout AT, Germain P-L, Vitriolo A, Kumar R et al. 2017. YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction. Am. J. Hum. Genet. 100:690725
    [Google Scholar]
  89. 89.
    Yellajoshyula D, Rogers AE, Kim AJ, Kim S, Pappas SS, Dauer WT. 2022. A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding. Hum. Mol. Genet. 31:71096104
    [Google Scholar]
  90. 90.
    Domingo A, Amar D, Grütz K, Lee LV, Rosales R et al. 2016. Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism. Cell. Mol. Life Sci. 73:16320515
    [Google Scholar]
  91. 91.
    Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K et al. 2007. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am. J. Hum. Genet. 80:3393406
    [Google Scholar]
  92. 92.
    Ito N, Hendriks WT, Dhakal J, Vaine CA, Liu C et al. 2016. Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells. Dis. Model. Mech. 9:445162
    [Google Scholar]
  93. 93.
    Gudmundsson S, Wilbe M, Filipek-Górniok B, Molin A-M, Ekvall S et al. 2019. TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish. Sci. Rep. 9:10730
    [Google Scholar]
  94. 94.
    Jambaldorj J, Makino S, Munkhbat B, Tamiya G. 2012. Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice. Biochem. Biophys. Res. Commun. 425:227377
    [Google Scholar]
  95. 95.
    O'Rawe JA, Wu Y, Dörfel MJ, Rope AF, Au PYB et al. 2015. TAF1 variants are associated with dysmorphic features, intellectual disability, and neurological manifestations. Am. J. Hum. Genet. 97:692232
    [Google Scholar]
  96. 96.
    Aneichyk T, Hendriks WT, Yadav R, Shin D, Gao D et al. 2018. Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly. Cell 172:5897909.e21
    [Google Scholar]
  97. 97.
    Groenendyk J, Agellon LB, Michalak M. 2021. Calcium signaling and endoplasmic reticulum stress. Int. Rev. Cell Mol. Biol. 363:120
    [Google Scholar]
  98. 98.
    Kinoshita PF, Orellana AMM, Nakao VW, de Souza Port's NM, Quintas LEM et al. 2022. The Janus face of ouabain in Na+/K+-ATPase and calcium signalling in neurons. Br. J. Pharmacol. 179:8151224
    [Google Scholar]
  99. 99.
    Karagas NE, Venkatachalam K. 2019. Roles for the endoplasmic reticulum in regulation of neuronal calcium homeostasis. Cells 8:101232
    [Google Scholar]
  100. 100.
    Rossi A, Pizzo P, Filadi R. 2019. Calcium, mitochondria and cell metabolism: a functional triangle in bioenergetics. Biochim. Biophys. Acta Mol. Cell Res. 1866:7106878
    [Google Scholar]
  101. 101.
    Ghaoui R, Sue CM. 2018. Movement disorders in mitochondrial disease. J. Neurol. 265:5123040
    [Google Scholar]
  102. 102.
    Ng HWY, Ogbeta JA, Clapcote SJ. 2021. Genetically altered animal models for ATP1A3-related disorders. Dis. Model. Mech. 14:10dmm048938
    [Google Scholar]
  103. 103.
    Prasuhn J, Göttlich M, Grosser SS, Reuther K, Ebeling B et al. 2022. In vivo brain sodium disequilibrium in ATP1A3-related rapid-onset dystonia-parkinsonism. Mov. Disord. 37:487779
    [Google Scholar]
  104. 104.
    Murata K, Kinoshita T, Ishikawa T, Kuroda K, Hoshi M, Fukazawa Y. 2020. Region- and neuronal-subtype-specific expression of Na,K-ATPase alpha and beta subunit isoforms in the mouse brain. J. Comp. Neurol. 528:16265478
    [Google Scholar]
  105. 105.
    Balint B, Guerreiro R, Carmona S, Dehghani N, Latorre A et al. 2020. KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia. Eur. J. Neurol. 27:8147177
    [Google Scholar]
  106. 106.
    Manville RW, Sidlow R, Abbott GW. 2022. Case report: a novel loss-of-function pathogenic variant in the KCNA1 cytoplasmic N-terminus causing carbamazepine-responsive type 1 episodic ataxia. Front. Neurol. 13:975849
    [Google Scholar]
  107. 107.
    Choi K-D, Choi J-H. 2016. Episodic ataxias: clinical and genetic features. J. Mov. Disord. 9:312935
    [Google Scholar]
  108. 108.
    Mencacci NE, Brockmann MM, Dai J, Pajusalu S, Atasu B et al. 2021. Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia. J. Clin. Investig. 131:7e140625
    [Google Scholar]
  109. 109.
    Lipman AR, Fan X, Shen Y, Chung WK. 2022. Clinical and genetic characterization of CACNA1A-related disease. Clin. Genet. 102:428895
    [Google Scholar]
  110. 110.
    Fletcher CF, Tottene A, Lennon VA, Wilson SM, Dubel SJ et al. 2001. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J. 15:7128890
    [Google Scholar]
  111. 111.
    Chen F, Zhang S, Liu T, Yuan L, Wang Y et al. 2022. Preliminary study on pathogenic mechanism of first Chinese family with PNKD. Transl. Neurosci. 13:112533
    [Google Scholar]
  112. 112.
    Tan G-H, Liu Y-Y, Wang L, Li K, Zhang Z-Q et al. 2018. PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum. Cell Res. 28:190110
    [Google Scholar]
  113. 113.
    Harvey S, King MD, Gorman KM. 2021. Paroxysmal movement disorders. Front. Neurol. 12:659064
    [Google Scholar]
  114. 114.
    Fruscione F, Valente P, Sterlini B, Romei A, Baldassari S et al. 2018. PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain 141:4100016
    [Google Scholar]
  115. 115.
    Hamann M, Meisler MH, Richter A. 2003. Motor disturbances in mice with deficiency of the sodium channel gene Scn8a show features of human dystonia. Exp. Neurol. 184:283038
    [Google Scholar]
  116. 116.
    Andrade R, Foehring RC, Tzingounis AV. 2012. The calcium-activated slow AHP: cutting through the Gordian knot. Front. Cell. Neurosci. 6:47
    [Google Scholar]
  117. 117.
    Helassa N, Antonyuk SV, Lian L-Y, Haynes LP, Burgoyne RD. 2017. Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. Hum. Mol. Genet. 26:13242635
    [Google Scholar]
  118. 118.
    Charlesworth G, Angelova PR, Bartolomé-Robledo F, Ryten M, Trabzuni D et al. 2015. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am. J. Hum. Genet. 96:465765
    [Google Scholar]
  119. 119.
    Osypenko DS, Dovgan AV, Kononenko NI, Dromaretsky AV, Matvieienko M et al. 2019. Perturbed Ca2+-dependent signaling of DYT2 hippocalcin mutant as mechanism of autosomal recessive dystonia. Neurobiol. Dis. 132:104529
    [Google Scholar]
  120. 120.
    Charlesworth G, Plagnol V, Holmström KM, Bras J, Sheerin U-M et al. 2012. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am. J. Hum. Genet. 91:6104150
    [Google Scholar]
  121. 121.
    Kim H, Kim E, Lee B-C. 2022. Investigation of phosphatidylserine-transporting activity of human TMEM16C isoforms. Membranes 12:101005
    [Google Scholar]
  122. 122.
    Huang F, Wang X, Ostertag E, Nuwal T, Huang B et al. 2013. TMEM16C facilitates Na+-activated K+ currents in rat primary sensory neurons and regulates pain processing. Nat. Neurosci. 16:9128490
    [Google Scholar]
  123. 123.
    Muntean BS, Marwari S, Li X, Sloan DC, Young BD et al. 2022. Members of the KCTD family are major regulators of cAMP signaling. PNAS 119:1e2119237119
    [Google Scholar]
  124. 124.
    Mencacci NE, Rubio-Agusti I, Zdebik A, Asmus F, Ludtmann MHR et al. 2015. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am. J. Hum. Genet. 96:693847
    [Google Scholar]
  125. 125.
    Iwabuchi S, Koh J-Y, Wang K, Ho KWD, Harata NC. 2013. Minimal change in the cytoplasmic calcium dynamics in striatal GABAergic neurons of a DYT1 dystonia knock-in mouse model. PLOS ONE 8:11e80793
    [Google Scholar]
  126. 126.
    Kutschenko A, Staege S, Grütz K, Glaß H, Kalmbach N et al. 2021. Functional and molecular properties of DYT-SGCE myoclonus-dystonia patient–derived striatal medium spiny neurons. Int. J. Mol. Sci. 22:73565
    [Google Scholar]
  127. 127.
    Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. 2016. The integrated stress response. EMBO Rep. 17:10137495
    [Google Scholar]
  128. 128.
    Donnelly N, Gorman AM, Gupta S, Samali A. 2013. The eIF2α kinases: their structures and functions. Cell. Mol. Life Sci. 70:193493511
    [Google Scholar]
  129. 129.
    Garcia-Ortega MB, Lopez GJ, Jimenez G, Garcia-Garcia JA, Conde V et al. 2017. Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism. Expert Rev. Mol. Med. 19:e9
    [Google Scholar]
  130. 130.
    Kuipers DJS, Mandemakers W, Lu C-S, Olgiati S, Breedveld GJ et al. 2021. EIF2AK2 missense variants associated with early onset generalized dystonia. Ann Neurol. 89:348597
    [Google Scholar]
  131. 131.
    Vaughn LS, Bragg DC, Sharma N, Camargos S, Cardoso F, Patel RC. 2015. Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT. J. Biol. Chem. 290:372254357
    [Google Scholar]
  132. 132.
    Burnett SB, Vaughn LS, Sharma N, Kulkarni R, Patel RC. 2020. Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2α signaling leading to a compromised stress response. Neurobiol. Dis. 146:105135
    [Google Scholar]
  133. 133.
    Lemmon ME, Lavenstein B, Applegate CD, Hamosh A, Tekes A, Singer HS. 2013. A novel presentation of DYT 16: acute onset in infancy and association with MRI abnormalities. Mov. Disord. 28:14193738
    [Google Scholar]
  134. 134.
    Pinto MJ, Oliveira A, Rosas MJ, Massano J. 2020. Imaging evidence of nigrostriatal degeneration in DYT-PRKRA. Mov. Disord. Clin. Pract. 7:447274
    [Google Scholar]
  135. 135.
    Rittiner JE, Caffall ZF, Hernández-Martinez R, Sanderson SM, Pearson JL et al. 2016. Functional genomic analyses of Mendelian and sporadic disease identify impaired eIF2α signaling as a generalizable mechanism for dystonia. Neuron 92:6123851
    [Google Scholar]
  136. 136.
    Beauvais G, Rodriguez-Losada N, Ying L, Zakirova Z, Watson JL et al. 2018. Exploring the interaction between eIF2α dysregulation, acute endoplasmic reticulum stress and DYT1 dystonia in the mammalian brain. Neuroscience 371:45568
    [Google Scholar]
  137. 137.
    Zakirova Z, Fanutza T, Bonet J, Readhead B, Zhang W et al. 2018. Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. PLOS Genet. 14:1e1007169
    [Google Scholar]
  138. 138.
    Hanson PI, Whiteheart SW. 2005. AAA+ proteins: have engine, will work. Nat. Rev. Mol. Cell Biol. 6:751929
    [Google Scholar]
  139. 139.
    Gonzalez-Alegre P. 2019. Advances in molecular and cell biology of dystonia: focus on torsinA. Neurobiol. Dis. 127:23341
    [Google Scholar]
  140. 140.
    Bragg DC, Camp SM, Kaufman CA, Wilbur JD, Boston H et al. 2004. Perinuclear biogenesis of mutant torsin-A inclusions in cultured cells infected with tetracycline-regulated herpes simplex virus type 1 amplicon vectors. Neuroscience 125:365161
    [Google Scholar]
  141. 141.
    Nery FC, Armata IA, Farley JE, Cho JA, Yaqub U et al. 2011. TorsinA participates in endoplasmic reticulum–associated degradation. Nat. Commun. 2:393
    [Google Scholar]
  142. 142.
    Jungwirth M, Dear ML, Brown P, Holbrook K, Goodchild R. 2010. Relative tissue expression of homologous torsinB correlates with the neuronal specific importance of DYT1 dystonia-associated torsinA. Hum. Mol. Genet. 19:5888900
    [Google Scholar]
  143. 143.
    Goodchild RE, Dauer WT. 2004. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. PNAS 101:384752
    [Google Scholar]
  144. 144.
    Jokhi V, Ashley J, Noma A, Ito N, Wakabayashi-Ito N et al. 2013. Torsin mediates primary envelopment of large ribonucleoprotein granules at the nuclear envelope. Cell Rep. 3:498895
    [Google Scholar]
  145. 145.
    Naismith TV, Heuser JE, Breakefield XO, Hanson PI. 2004. TorsinA in the nuclear envelope. PNAS 101:20761217
    [Google Scholar]
  146. 146.
    Prophet SM, Rampello AJ, Niescier RF, Gentile JE, Mallik S et al. 2022. Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities. Nat. Cell Biol. 24:11163041
    [Google Scholar]
  147. 147.
    Harrer P, Schalk A, Shimura M, Baer S, Calmels N et al. 2023. Recessive NUP54 variants underlie early-onset dystonia with striatal lesions. Ann. Neurol. 93:233035
    [Google Scholar]
  148. 148.
    Yokoi F, Dang MT, Yang G, Li J, Doroodchi A et al. 2012. Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models. Behav. Brain Res. 227:11220
    [Google Scholar]
  149. 149.
    Phua CS, Kumar KR, Levy S. 2020. Clinical characteristics and diagnostic clues to neurometabolic causes of dystonia. J. Neurol. Sci. 419:117167
    [Google Scholar]
  150. 150.
    Cai X, Chen X, Wu S, Liu W, Zhang X et al. 2016. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci. Rep. 6:25834
    [Google Scholar]
  151. 151.
    Ostrowicz CW, Bröcker C, Ahnert F, Nordmann M, Lachmann J et al. 2010. Defined subunit arrangement and Rab interactions are required for functionality of the HOPS tethering complex. Traffic 11:10133446
    [Google Scholar]
  152. 152.
    Steel D, Zech M, Zhao C, Barwick KES, Burke D et al. 2020. Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities. Ann. Neurol. 88:586777
    [Google Scholar]
  153. 153.
    Pulipparacharuvil S, Akbar MA, Ray S, Sevrioukov EA, Haberman AS et al. 2005. Drosophila Vps16A is required for trafficking to lysosomes and biogenesis of pigment granules. J. Cell Sci. 118:Part 16366373
    [Google Scholar]
  154. 154.
    Wartosch L, Günesdogan U, Graham SC, Luzio JP. 2015. Recruitment of VPS33A to HOPS by VPS16 is required for lysosome fusion with endosomes and autophagosomes. Traffic 16:772742
    [Google Scholar]
  155. 155.
    Monfrini E, Cogiamanian F, Salani S, Straniero L, Fagiolari G et al. 2021. A novel homozygous VPS11 variant may cause generalized dystonia. Ann. Neurol. 89:483439
    [Google Scholar]
  156. 156.
    Sanderson LE, Lanko K, Alsagob M, Almass R, Al-Ahmadi N et al. 2021. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking. Brain 144:376980
    [Google Scholar]
  157. 157.
    Monfrini E, Zech M, Steel D, Kurian MA, Winkelmann J, Di Fonzo A. 2021. HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia. Brain 144:9261015
    [Google Scholar]
  158. 158.
    Hinarejos I, Machuca C, Sancho P, Espinós C. 2020. Mitochondrial dysfunction, oxidative stress and neuroinflammation in neurodegeneration with brain iron accumulation (NBIA). Antioxidants 9:101020
    [Google Scholar]
  159. 159.
    Higashimori A, Dong Y, Zhang Y, Kang W, Nakatsu G et al. 2018. Forkhead box F2 suppresses gastric cancer through a novel FOXF2-IRF2BPL-β-catenin signaling axis. Cancer Res. 78:7164356
    [Google Scholar]
  160. 160.
    Ginevrino M, Battini R, Nuovo S, Simonati A, Micalizzi A et al. 2020. A novel IRF2BPL truncating variant is associated with endolysosomal storage. Mol. Biol. Rep. 47:171114
    [Google Scholar]
  161. 161.
    Prilop L, Buchert R, Woerz S, Gerloff C, Haack TB, Zittel S. 2020. IRF2BPL mutation causes nigrostriatal degeneration presenting with dystonia, spasticity and keratoconus. Parkinsonism Relat. Disord. 79:14143
    [Google Scholar]
  162. 162.
    Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P et al. 2016. Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. Am. J. Hum. Genet. 99:373543
    [Google Scholar]
  163. 163.
    Muto V, Flex E, Kupchinsky Z, Primiano G, Galehdari H et al. 2018. Biallelic SQSTM1—mutations in early-onset, variably progressive neurodegeneration. Neurology 91:4e31930
    [Google Scholar]
  164. 164.
    Zúñiga-Ramírez C, de Oliveira LM, Kramis-Hollands M, Algarni M, Soto-Escageda A et al. 2019. Beyond dystonia and ataxia: expanding the phenotype of SQSTM1 mutations. Parkinsonism Relat. Disord. 62:19295
    [Google Scholar]
  165. 165.
    B'chir W, Maurin A-C, Carraro V, Averous J, Jousse C et al. 2013. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41:16768399
    [Google Scholar]
  166. 166.
    Marques ARA, Saftig P. 2019. Lysosomal storage disorders—challenges, concepts and avenues for therapy: beyond rare diseases. J. Cell Sci. 132:2jcs221739
    [Google Scholar]
  167. 167.
    Bonam SR, Wang F, Muller S. 2019. Lysosomes as a therapeutic target. Nat. Rev. Drug Discov. 18:1292348
    [Google Scholar]
  168. 168.
    Ozawa E, Mizuno Y, Hagiwara Y, Sasaoka T, Yoshida M. 2005. Molecular and cell biology of the sarcoglycan complex. Muscle Nerve 32:556376
    [Google Scholar]
  169. 169.
    Xiao J, LeDoux MS. 2003. Cloning, developmental regulation and neural localization of rat ε-sarcoglycan. Brain Res. Mol. Brain Res. 119:213243
    [Google Scholar]
  170. 170.
    Ritz K, van Schaik BD, Jakobs ME, van Kampen AH, Aronica E et al. 2011. SGCE isoform characterization and expression in human brain: implications for myoclonus-dystonia pathogenesis?. Eur. J. Hum. Genet. 19:443844
    [Google Scholar]
  171. 171.
    Nishiyama A, Endo T, Takeda S, Imamura M. 2004. Identification and characterization of ε-sarcoglycans in the central nervous system. Brain Res. Mol. Brain Res. 125:1/2112
    [Google Scholar]
  172. 172.
    Cazurro-Gutiérrez A, Marcé-Grau A, Correa-Vela M, Salazar A, Vanegas MI et al. 2021. ε-Sarcoglycan: unraveling the myoclonus-dystonia gene. Mol. Neurobiol. 58:8393852
    [Google Scholar]
  173. 173.
    Menozzi E, Balint B, Latorre A, Valente EM, Rothwell JC, Bhatia KP. 2019. Twenty years on: myoclonus-dystonia and ε-sarcoglycan—neurodevelopment, channel, and signaling dysfunction. Mov. Disord. 34:111588601
    [Google Scholar]
  174. 174.
    Zhang L, Yokoi F, Parsons DS, Standaert DG, Li Y. 2012. Alteration of striatal dopaminergic neurotransmission in a mouse model of DYT11 myoclonus-dystonia. PLOS ONE 7:3e33669
    [Google Scholar]
  175. 175.
    Washburn S, Fremont R, Moreno-Escobar MC, Angueyra C, Khodakhah K. 2019. Acute cerebellar knockdown of Sgce reproduces salient features of myoclonus-dystonia (DYT11) in mice. eLife 8:e52101
    [Google Scholar]
  176. 176.
    Li J, Liu Y, Li Q, Huang X, Zhou D et al. 2021. Mutation in ε-sarcoglycan induces a myoclonus-dystonia syndrome-like movement disorder in mice. Neurosci. Bull. 37:331122
    [Google Scholar]
  177. 177.
    Lohmann K, Wilcox RA, Winkler S, Ramirez A, Rakovic A et al. 2013. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann. Neurol. 73:453745
    [Google Scholar]
  178. 178.
    Erro R, Hersheson J, Ganos C, Mencacci NE, Stamelou M et al. 2015. H-ABC syndrome and DYT4: variable expressivity or pleiotropy of TUBB4 mutations?. Mov. Disord. 30:682833
    [Google Scholar]
  179. 179.
    Fertuzinhos S, Legué E, Li D, Liem KF. 2022. A dominant tubulin mutation causes cerebellar neurodegeneration in a genetic model of tubulinopathy. Sci. Adv. 8:7eabf7262
    [Google Scholar]
  180. 180.
    Vulinovic F, Krajka V, Hausrat TJ, Seibler P, Alvarez-Fischer D et al. 2018. Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants. Hum. Mutat. 39:12190115
    [Google Scholar]
  181. 181.
    Krajka V, Vulinovic F, Genova M, Tanzer K, Jijumon AS et al. 2022. H-ABC- and dystonia-causing TUBB4A mutations show distinct pathogenic effects. Sci. Adv. 8:10eabj9229
    [Google Scholar]
  182. 182.
    Hundt N, Preller M, Swolski O, Ang AM, Mannherz HG et al. 2014. Molecular mechanisms of disease-related human β-actin mutations p.R183W and p.E364K. FEBS J. 281:23527991
    [Google Scholar]
  183. 183.
    Skogseid IM, Røsby O, Konglund A, Connelly JP, Nedregaard B et al. 2018. Dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity shows striatal dopaminergic dysfunction and response to pallidal stimulation. J. Neurodev. Disord. 10:17
    [Google Scholar]
  184. 184.
    Straccia G, Reale C, Castellani M, Colangelo I, Orunesu E et al. 2022. ACTB gene mutation in combined dystonia-deafness syndrome with parkinsonism: expanding the phenotype and highlighting the long-term GPi DBS outcome. Parkinsonism Relat. Disord. 104:36
    [Google Scholar]
  185. 185.
    Zech M, Jech R, Boesch S, Škorvánek M, Weber S et al. 2020. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol. 19:1190818
    [Google Scholar]
  186. 186.
    Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BWM et al. 2014. Genome sequencing identifies major causes of severe intellectual disability. Nature 511:750934447
    [Google Scholar]
  187. 187.
    Inzelberg R, Hassin-Baer S, Jankovic J. 2014. Genetic movement disorders in patients of Jewish ancestry. JAMA Neurol. 71:12156772
    [Google Scholar]
  188. 188.
    Grünewald A, Djarmati A, Lohmann-Hedrich K, Farrell K, Zeller JA et al. 2008. Myoclonus-dystonia: significance of large SGCE deletions. Hum. Mutat. 29:233132
    [Google Scholar]
  189. 189.
    Hagenah J, Saunders-Pullman R, Hedrich K, Kabakci K, Habermann K et al. 2005. High mutation rate in dopa-responsive dystonia: detection with comprehensive GCHI screening. Neurology 64:590811
    [Google Scholar]
  190. 190.
    Kumar N, Rizek P, Jog M. 2017. Movement disorders in 18p deletion syndrome: a case report and review of literature. Can. J. Neurol. Sci. 44:444143
    [Google Scholar]
  191. 191.
    Richards S, Aziz N, Bale S, Bick D, Das S et al. 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17:540524
    [Google Scholar]
  192. 192.
    Shah N, Hou Y-CC, Yu H-C, Sainger R, Caskey CT et al. 2018. Identification of misclassified ClinVar variants via disease population prevalence. Am. J. Hum. Genet. 102:460919
    [Google Scholar]
  193. 193.
    Masuho I, Fang M, Geng C, Zhang J, Jiang H et al. 2016. Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol. Genet. 2:3e78
    [Google Scholar]
  194. 194.
    Opladen T, Hoffmann GF, Kühn AA, Blau N. 2013. Pitfalls in phenylalanine loading test in the diagnosis of dopa-responsive dystonia. Mol. Genet. Metab. 108:319597
    [Google Scholar]
  195. 195.
    Atasu B, Hanagasi H, Bilgic B, Pak M, Erginel-Unaltuna N et al. 2018. HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype. Mov. Disord. 33:8135458
    [Google Scholar]
  196. 196.
    Lohmann K, Schlicht F, Svetel M, Hinrichs F, Zittel S et al. 2016. The role of mutations in COL6A3 in isolated dystonia. J. Neurol. 263:473034
    [Google Scholar]
  197. 197.
    Mencacci NE, R'bibo L, Bandres-Ciga S, Carecchio M, Zorzi G et al. 2015. The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort. Hum. Mol. Genet. 24:18532629
    [Google Scholar]
  198. 198.
    Kock N, Naismith TV, Boston HE, Ozelius LJ, Corey DP et al. 2006. Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier. Hum. Mol. Genet. 15:8135564
    [Google Scholar]
  199. 199.
    Risch NJ, Bressman SB, Senthil G, Ozelius LJ. 2007. Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. Am. J. Hum. Genet. 80:6118893
    [Google Scholar]
  200. 200.
    Müller B, Hedrich K, Kock N, Dragasevic N, Svetel M et al. 2002. Evidence that paternal expression of the ε-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia. Am. J. Hum. Genet. 71:6130311
    [Google Scholar]
  201. 201.
    Westenberger A, Reyes CJ, Saranza G, Dobricic V, Hanssen H et al. 2019. A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism. Ann. Neurol. 85:681222
    [Google Scholar]
  202. 202.
    Laabs B-H, Klein C, Pozojevic J, Domingo A, Brüggemann N et al. 2021. Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism. Nat. Commun. 12:13216
    [Google Scholar]
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