Abstract
Four genes associated with isolated dystonia are currently well replicated and validated. DYT-THAP1 manifests as young-onset generalized dystonia with predominant craniocervical symptoms; and is associated with mostly deleterious missense variation in the THAP1 gene. De novo and inherited missense and protein truncating variation in GNAL as well as primarily missense variation in ANO3 cause isolated focal and/or segmental dystonia with preference for the upper half of the body and older ages at onset. The GAG deletion in TOR1A is associated with generalized dystonia with onset in childhood in the lower limbs. Rare variation in these genes causes monogenic sporadic and inherited forms of isolated dystonia; common variation may confer risk and imply that dystonia is a polygenic trait in a subset of cases. Although candidate gene screens have been successful in the past in detecting gene-disease associations, recent application of whole-genome and whole-exome sequencing methods enable unbiased capture of all genetic variation that may explain the phenotype. However, careful variant-level evaluation is necessary in every case, even in genes that have previously been associated with disease. We review the genetic architecture and phenotype of DYT-THAP1, DYT-GNAL, DYT-ANO3, and DYT-TOR1A by collecting case reports from the literature and performing variant classification using pathogenicity criteria.
Similar content being viewed by others
References
Aguilo F, Zakirova Z, Nolan K et al (2017) THAP1: role in mouse embryonic stem cell survival and differentiation. Stem Cell Reports 9:92–107. https://doi.org/10.1016/j.stemcr.2017.04.032
Ahn JH, Kim AR, Kim NKD et al (2019) The effect of globus pallidus interna deep brain stimulation on a dystonia patient with the GNAL mutation compared to patients with DYT1 and DYT6. JMD 12:120–124. https://doi.org/10.14802/jmd.19006
Antelmi E, Erro R, Pisani A et al (2015) Persistent chorea in DYT6, due to anticholinergic therapy. Parkinsonism Related Disorders 21:1282–1283. https://doi.org/10.1016/j.parkreldis.2015.07.024
Atasu B, Hanagasi H, Bilgic B et al (2018) HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype: HPCA confirmed as a genetic cause of DYT2. Mov Disord 33:1354–1358. https://doi.org/10.1002/mds.27442
Baker M, Strongosky AJ, Sanchez-Contreras MY et al (2014) SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia. Neurogenetics 15:23–30. https://doi.org/10.1007/s10048-013-0378-5
Bessière D, Lacroix C, Campagne S et al (2008) 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. https://doi.org/10.1074/jbc.M707537200
Boyle EA, Li YI, Pritchard JK (2017) An expanded view of complex traits: from polygenic to omnigenic. Cell 169:1177–1186. https://doi.org/10.1016/j.cell.2017.05.038
Bressman SB, de Leon D, Kramer PL et al (1994) Dystonia in Ashkenazi Jews: clinical characterization of a founder mutation. Ann Neurol 36:771–777. https://doi.org/10.1002/ana.410360514
Bressman SB, Sabatti C, Raymond D et al (2000) The DYT1 phenotype and guidelines for diagnostic testing. Neurology 54:1746–1753. https://doi.org/10.1212/WNL.54.9.1746
Camargo CHF, Camargos ST, Cardoso FEC, Teive HAG (2014) DYT6 in Brazil: genetic assessment and clinical characteristics of patients. Tremor Other Hyperkinet Mov 4:226. https://doi.org/10.5334/tohm.193
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 40:9927–9940. https://doi.org/10.1093/nar/gks703
Carecchio M, Panteghini C, Reale C et al (2016) Novel GNAL mutation with intra-familial clinical heterogeneity: expanding the phenotype. Parkinsonism Relat Disord 23:66–71. https://doi.org/10.1016/j.parkreldis.2015.12.012
Charlesworth G, Angelova PR, Bartolomé-Robledo F et al (2015) Mutations in HPCA cause autosomal-recessive primary isolated dystonia. The Am J Human Genet 96:657–665. https://doi.org/10.1016/j.ajhg.2015.02.007
Charlesworth G, Plagnol V, Holmström KM et al (2012) Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. The Am J Human Genet 91:1041–1050. https://doi.org/10.1016/j.ajhg.2012.10.024
Cheng F, Walter M, Wassouf Z et al (2020) Unraveling molecular mechanisms of THAP1 missense mutations in DYT6 dystonia. J Mol Neurosci 70:999–1008. https://doi.org/10.1007/s12031-020-01490-2
Clot F, Grabli D, Burbaud P et al (2011) Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype. Neurogenetics 12:87–89. https://doi.org/10.1007/s10048-010-0264-3
Clouaire T, Roussigne M, Ecochard V et al (2005) The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity. Proc Natl Acad Sci 102:6907–6912. https://doi.org/10.1073/pnas.0406882102
da Silva-Junior FP, dos Santos CO, Silva SMCA et al (2014) Novel THAP1 variants in Brazilian patients with idiopathic isolated dystonia. J Neurol Sci 344:190–192. https://doi.org/10.1016/j.jns.2014.06.012
de Gusmão CM, Fuchs T, Moses A et al (2016) Dystonia-causing mutations as a contribution to the etiology of spasmodic dysphonia. Otolaryngol Head Neck Surg 155:624–628. https://doi.org/10.1177/0194599816648293
Deik AF, O’Riordan S, San Luciano M et al (2012) Spatial discrimination threshold abnormalities are not detected in a pilot study of DYT6 dystonia mutation carriers. Tremor Other Hyperkinet Mov 2:02. https://doi.org/10.5334/tohm.92
Delamarre A, Chelly J, Guehl D et al (2019) Novel anoctamin-3 missense mutation responsible for early-onset myoclonic dystonia. Parkinsonism Relat Disord 64:346–348. https://doi.org/10.1016/j.parkreldis.2019.04.019
Djarmati A, Schneider SA, Lohmann K et al (2009) Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. The Lancet Neurol 8:447–452. https://doi.org/10.1016/S1474-4422(09)70083-3
Dobričić V, Kresojević N, Westenberger A et al (2014) De novo mutation in the GNAL gene causing seemingly sporadic dystonia in a Serbian patient: de novo GNAL (DYT25) mutation. Mov Disord 29:1190–1193. https://doi.org/10.1002/mds.25876
Dobričić VS, Kresojević ND, Svetel MV et al (2013) Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia. J Neurol 260:1037–1042. https://doi.org/10.1007/s00415-012-6753-6
Domingo A, Erro R, Lohmann K (2016) Novel dystonia genes: clues on disease mechanisms and the complexities of high-throughput sequencing: pathogenic mechanisms in dystonia. Mov Disord 31:471–477. https://doi.org/10.1002/mds.26600
Domingo A, Klein C (2017) Genetics of movement disorders. In: Falup-Pecurariu C, Ferreira J, Martinez-Martin P, Chaudhuri R (eds) Movement disorders curricula. Springer Vienna, Vienna
Dufke C, Hauser A-K, Sturm M et al (2015) Mutations in CIZ1 are not a major cause for dystonia in Germany: letter to the editors. Mov Disord 30:740–743. https://doi.org/10.1002/mds.26198
Dufke C, Sturm M, Schroeder C et al (2014) Screening of mutations in GNAL in sporadic dystonia patients: Ngs approach for GNAL mutation screening. Mov Disord 29:1193–1196. https://doi.org/10.1002/mds.25794
Dulovic-Mahlow M, Gajos A, Baumann H et al (2019) Highly reduced penetrance in a family with a THAP1 nonsense mutation: role of THAP1 expression? Parkinsonism Relat Disord 65:274–276. https://doi.org/10.1016/j.parkreldis.2019.05.036
Erogullari A, Hollstein R, Seibler P et al (2014) THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression. Biochimica et Biophysica Acta (BBA): Gene Regul Mech 1839:1196–1204. https://doi.org/10.1016/j.bbagrm.2014.07.019
Frederick NM, Shah PV, Didonna A et al (2019) Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes. Hum Mol Genet 28:1343–1356. https://doi.org/10.1093/hmg/ddy433
Fuchs T, Gavarini S, Saunders-Pullman R et al (2009) Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 41:286–288. https://doi.org/10.1038/ng.304
Fuchs T, Saunders-Pullman R, Masuho I et al (2013) Mutations in GNAL cause primary torsion dystonia. Nat Genet 45:88–92. https://doi.org/10.1038/ng.2496
Gajos A, Golańska E, Sieruta M et al (2015) High variability of clinical symptoms in a polish family with a novel THAP1 mutation. Int J Neurosci 125:755–759. https://doi.org/10.3109/00207454.2014.981749
Gatto EM, Pardal MMF, Micheli FE (2003) Unusual phenotypic expression of the DYT1 mutation. Parkinsonism Relat Disord 9:277–279. https://doi.org/10.1016/S1353-8020(02)00128-1
Gavarini S, Cayrol C, Fuchs T et al (2010) Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann Neurol 68:549–553. https://doi.org/10.1002/ana.22138
Giri S, Naiya T, Equbal Z et al (2017) Genetic screening of THAP1 in primary dystonia patients of India. Neurosci Lett 637:31–37. https://doi.org/10.1016/j.neulet.2016.11.060
Golanska E, Gajos A, Sieruta M et al (2015) Screening for THAP1 mutations in polish patients with dystonia shows known and novel substitutions. PLoS ONE 10:e0129656. https://doi.org/10.1371/journal.pone.0129656
Gómez-Garre P, Huertas-Fernández I, Cáceres-Redondo MT et al (2014) Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study: replication study of a GWAS in cervical dystonia. Mov Disord 29:1825–1828. https://doi.org/10.1002/mds.26044
Groen JL, Ritz K, Contarino MF et al (2010) DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Mov Disord 25:2420–2427. https://doi.org/10.1002/mds.23285
Groen JL, Ritz K, Warner TT et al (2014) DRD1 rare variants associated with tardive-like dystonia: a pilot pathway sequencing study in dystonia. Parkinsonism Relat Disord 20:782–785. https://doi.org/10.1016/j.parkreldis.2014.04.002
Hammer M, Abravanel A, Peckham E et al (2019) Blepharospasm: a genetic screening study in 132 patients. Parkinsonism Relat Disord 64:315–318. https://doi.org/10.1016/j.parkreldis.2019.04.003
Hollstein R, Reiz B, Kötter L et al (2017) Dystonia-causing mutations in the transcription factor THAP1 disrupt HCFC1 cofactor recruitment and alter gene expression. Hum Mol Genet 26:2975–2983. https://doi.org/10.1093/hmg/ddx187
Houlden H, Schneider SA, Paudel R et al (2010) THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 74:846–850. https://doi.org/10.1212/WNL.0b013e3181d5276d
Inzelberg R, Hassin-Baer S, Jankovic J (2014) Genetic movement disorders in patients of Jewish ancestry. JAMA Neurol 71:1567. https://doi.org/10.1001/jamaneurol.2014.1364
Iqbal Z, Koht J, Pihlstrøm L et al (2019) Missense mutations in DYT-TOR1A dystonia. Neurol Genet 5:e343. https://doi.org/10.1212/NXG.0000000000000343
Karczewski KJ, Francioli LC, for the Genome Aggregation Database Consortium et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7
Kumar KR, Davis RL, Tchan MC et al (2019) Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat Disord 69:111–118. https://doi.org/10.1016/j.parkreldis.2019.11.004
Kumar KR, Lohmann K, Klein C (2012) Genetics of Parkinson disease and other movement disorders. Curr Opin Neurol 25:466–474. https://doi.org/10.1097/WCO.0b013e3283547627
Kumar KR, Lohmann K, Masuho I et al (2014) Mutations in GNAL: a novel cause of craniocervical dystonia. JAMA Neurol 71:490. https://doi.org/10.1001/jamaneurol.2013.4677
Kuo M-C, Lin H-I, Lin C-H (2019) Craniocervical dystonia with levodopa-responsive parkinsonism co-segregating with a pathogenic ANO3 mutation in a Taiwanese family. Parkinsonism Relat Disord 62:236–238. https://doi.org/10.1016/j.parkreldis.2019.01.020
LeDoux MS, Vemula SR, Xiao J et al (2016) Clinical and genetic features of cervical dystonia in a large multicenter cohort. Neurol Genet 2:e69. https://doi.org/10.1212/NXG.0000000000000069
LeDoux MS, Xiao J, Rudzińska M et al (2012) Genotype–phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism Relat Disord 18:414–425. https://doi.org/10.1016/j.parkreldis.2012.02.001
Lee W-W, Ahn T-B, Chung SJ, Jeon BS (2012) Phenotypic differences in DYT1 between ethnic groups. Curr Neurol Neurosci Rep 12:341–347. https://doi.org/10.1007/s11910-012-0285-4
Lohmann K, Schmidt A, Schillert A et al (2014) Genome-wide association study in musician’s dystonia: a risk variant at the arylsulfatase G locus?: genetic risk factor in musician’s dystonia. Mov Disord 29:921–927. https://doi.org/10.1002/mds.25791
Lohmann K, Uflacker N, Erogullari A et al (2012) Identification and functional analysis of novel THAP1 mutations. Eur J Hum Genet 20:171–175. https://doi.org/10.1038/ejhg.2011.159
Ma L, Chen R, Wang L et al (2013) No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families. Mov Disord 28:1899–1901. https://doi.org/10.1002/mds.25542
Ma L-Y, Wang L, Yang Y-M et al (2015) Mutations in ANO3 and GNAL gene in thirty-three isolated dystonia families. Mov Disord 30:743–744. https://doi.org/10.1002/mds.26190
Ma L-Y, Wang L, Yang Y-M, Wan X-H (2015) Mutations in GNAL gene in 214 cases with isolated dystonia. Parkinsonism Relat Disord 21:1367–1368. https://doi.org/10.1016/j.parkreldis.2015.08.026
Masuho I, Chavali S, Muntean BS et al (2018) Molecular deconvolution platform to establish disease mechanisms by surveying GPCR signaling. Cell Reports 24:557-568.e5. https://doi.org/10.1016/j.celrep.2018.06.080
Masuho I, Fang M, Geng C et al (2016) Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol Genet 2:e78. https://doi.org/10.1212/NXG.0000000000000078
Miltgen M, Blanchard A, Mathieu H et al (2016) Novel heterozygous mutation in ANO3 responsible for craniocervical dystonia. Mov Disord 31:1251–1252. https://doi.org/10.1002/mds.26717
Mok KY, Schneider SA, Trabzuni D et al (2014) Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel: GWAS in Cervical Dystonia: NALCN Association. Mov Disord 29:245–251. https://doi.org/10.1002/mds.25732
Mu W, Tochen L, Bertsch C et al (2019) Intracranial calcifications and dystonia associated with a novel deletion of chromosome 8p11.2 encompassing SLC20A2 and THAP1. BMJ Case Rep 12:e228782
Naslavsky MS, Yamamoto GL, de Almeida TF et al (2017) Exomic variants of an elderly cohort of Brazilians in the ABraOM database: NASLAVSKY et al. Hum Mutat 38:751–763. https://doi.org/10.1002/humu.23220
Newman JRB, Sutherland GT, Boyle RS et al (2012) Common polymorphisms in dystonia-linked genes and susceptibility to the sporadic primary dystonias. Parkinsonism Relat Disord 18:351–357. https://doi.org/10.1016/j.parkreldis.2011.11.024
Ohlei O, Dobricic V, Lohmann K et al (2018) Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia. Parkinsonism Relat Disord 57:50–57. https://doi.org/10.1016/j.parkreldis.2018.07.018
Olschewski L, Jesús S, Kim H-J et al (2019) Role of ANO3 mutations in dystonia: a large-scale mutational screening study. Parkinsonism Relat Disord 62:196–200. https://doi.org/10.1016/j.parkreldis.2018.12.030
Opal P, Tintner R, Jankovic J et al (2002) Intrafamilial phenotypic variability of the DYT1 dystonia: From asymptomatic TOR1A gene carrier status to dystonic storm. Mov Disord 17:339–345. https://doi.org/10.1002/mds.10096
Osmanovic A, Dendorfer A, Erogullari A et al (2011) Truncating mutations in THAP1 define the nuclear localization signal: letters to the editor. Mov Disord 26:1565–1567. https://doi.org/10.1002/mds.23611
Ozelius LJ, Hewett JW, Page CE et al (1997) The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 17:40–48. https://doi.org/10.1038/ng0997-40
Paisán-Ruiz C, Ruiz-Martinez J, Ruibal M et al (2009) Identification of a novel THAP1 mutation at R29 amino-acid residue in sporadic patients with early-onset dystonia: letters to the editor. Mov Disord 24:2428–2429. https://doi.org/10.1002/mds.22849
Panda PK, Sharawat IK (2020) COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: report of a new case and review of published literature. Brain Develop 42:329–335. https://doi.org/10.1016/j.braindev.2020.01.004
Pandey S, Sankhla CS, Ramprasad VL, Geetha TS (2019) Novel GNAL mutation in an Indian patient with generalized dystonia and response to deep brain stimulation. Parkinsonism Relat Disord 62:246–247. https://doi.org/10.1016/j.parkreldis.2019.01.011
Paudel R, Li A, Hardy J et al (2016) DYT6 Dystonia: a neuropathological study. Neurodegener Dis 16:273–278. https://doi.org/10.1159/000440863
Powis Z, Towne MC, Hagman KDF et al (2020) Clinical diagnostic exome sequencing in dystonia: genetic testing challenges for complex conditions. Clin Genet 97:305–311. https://doi.org/10.1111/cge.13657
Putzel GG, Battistella G, Rumbach AF et al (2018) Polygenic risk of spasmodic dysphonia is associated with vulnerable sensorimotor connectivity. Cereb Cortex 28:158–166. https://doi.org/10.1093/cercor/bhw363
Rentzsch P, Witten D, Cooper GM et al (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47:D886–D894. https://doi.org/10.1093/nar/gky1016
Richards S, Aziz N, et al on behalf of the ACMG Laboratory Quality Assurance Committee, Richards S, Aziz N 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 17:405–423
Risch NJ, Bressman SB, Senthil G, Ozelius LJ (2007) Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. The Am J Human Genet 80:1188–1193. https://doi.org/10.1086/518427
Schneider SA, Ramirez A, Shafiee K et al (2011) Homozygous THAP1 mutations as cause of early-onset generalized dystonia. Mov Disord 26:858–861. https://doi.org/10.1002/mds.23561
Sengel C, Gavarini S, Sharma N et al (2011) Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain: dimerization of THAP1. J Neurochem 118:1087–1100. https://doi.org/10.1111/j.1471-4159.2011.07386.x
Siokas V, Aloizou A-M, Tsouris Z et al (2019) Risk factor genes in patients with dystonia: a comprehensive review. Tremor Other Hyperkinet Mov 8:559. https://doi.org/10.5334/tohm.437
Siokas V, Dardiotis E, Tsironi EE et al (2017) The Role of TOR1A polymorphisms in dystonia: a systematic review and meta-analysis. PLoS ONE 12:e0169934. https://doi.org/10.1371/journal.pone.0169934
Söhn AS, Glöckle N, Doetzer AD et al (2010) Prevalence of THAP1 sequence variants in German patients with primary dystonia: THAP1 sequence variants in primary dystonia. Mov Disord 25:1982–1986. https://doi.org/10.1002/mds.23207
Starita LM, Ahituv N, Dunham MJ et al (2017) Variant interpretation: functional assays to the rescue. The Am J Human Genet 101:315–325. https://doi.org/10.1016/j.ajhg.2017.07.014
Steeves TD, Day L, Dykeman J et al (2012) The prevalence of primary dystonia: a systematic review and meta-analysis: prevalence of dystonia. Mov Disord 27:1789–1796. https://doi.org/10.1002/mds.25244
Tian J, Vemula SR, Xiao J et al (2018) Whole-exome sequencing for variant discovery in blepharospasm. Mol Genet Genomic Med 6:601–626. https://doi.org/10.1002/mgg3.411
Tunc S, Denecke J, Olschewski L et al (2019) A recurrent de-novo ANO3 mutation causes early-onset generalized dystonia. J Neurol Sci 396:199–201. https://doi.org/10.1016/j.jns.2018.11.024
Vemula SR, Puschmann A, Xiao J et al (2013) Role of Gα(olf) in familial and sporadic adult-onset primary dystonia. Hum Mol Genet 22:2510–2519. https://doi.org/10.1093/hmg/ddt102
Whiffin N, Minikel E, Walsh R et al (2017) Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med 19:1151–1158. https://doi.org/10.1038/gim.2017.26
Winter P, Kamm C, Biskup S et al (2012) DYT7 gene locus for cervical dystonia on chromosome 18p is questionable: 18p location of DYT7 questionable. Mov Disord 27:1820–1822. https://doi.org/10.1002/mds.25219
Xiao J, Uitti RJ, Zhao Y et al (2012) Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann Neurol 71:458–469. https://doi.org/10.1002/ana.23547
Xiao J, Zhao Y, Bastian RW et al (2010) Novel THAP1 sequence variants in primary dystonia. Neurology 74:229–238. https://doi.org/10.1212/WNL.0b013e3181ca00ca
Xiromerisiou G, Houlden H, Scarmeas N et al (2012) THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. Mov Disord 27:1290–1294. https://doi.org/10.1002/mds.25146
Yellajoshyula D, Liang C-C, Pappas SS et al (2017) The DYT6 dystonia protein THAP1 regulates myelination within the oligodendrocyte lineage. Dev Cell 42:52-67.e4. https://doi.org/10.1016/j.devcel.2017.06.009
Yoo D, Kim H-J, Lee JS et al (2018) Early-onset generalized dystonia starting in the lower extremities in a patient with a novel ANO3 variant. Parkinsonism Relat Disord 50:124–125. https://doi.org/10.1016/j.parkreldis.2018.02.012
Zakirova Z, Fanutza T, Bonet J et al (2018) Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. PLoS Genet 14:e1007169. https://doi.org/10.1371/journal.pgen.1007169
Zech M, Boesch S, Jochim A et al (2017) Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up: diagnostic exome sequencing in dystonia. Mov Disord 32:549–559. https://doi.org/10.1002/mds.26808
Zech M, Boesch S, Sycha T et al (2015) TOR1A, THAP1, and GNAL mutational screening in Austrian patients with primary isolated dystonia: letter to the editors. Mov Disord 30:1853–1854. https://doi.org/10.1002/mds.26458
Zech M, Gross N, Jochim A et al (2014) Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls: novel ANO3 and GNAL variants in dystonia. Mov Disord 29:143–147. https://doi.org/10.1002/mds.25715
Zech M, Lam DD, Francescatto L et al (2015) Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. The Am J Human Genet 96:883–893. https://doi.org/10.1016/j.ajhg.2015.04.010
Zirn B, Grundmann K, Huppke P et al (2008) Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1). J Neurol Neurosurg Psychiatry 79:1327–1330. https://doi.org/10.1136/jnnp.2008.148270
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Domingo, A., Yadav, R. & Ozelius, L.J. Isolated dystonia: clinical and genetic updates. J Neural Transm 128, 405–416 (2021). https://doi.org/10.1007/s00702-020-02268-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-020-02268-x