Abstract
The genetic combined dystonias are a clinically and genetically heterogeneous group of neurologic disorders defined by the overlap of dystonia and other movement disorders such as parkinsonism or myoclonus. The number of genes associated with combined dystonia syndromes has been increasing due to the wider recognition of clinical features and broader use of genetic testing. Nevertheless, these diseases are still rare and represent only a small subgroup among all dystonias. Dopa-responsive dystonia (DYT/PARK-GCH1), rapid-onset dystonia-parkinsonism (DYT/PARK-ATP1A3), X-linked dystonia-parkinsonism (XDP, DYT/PARK-TAF1), and young-onset dystonia-parkinsonism (DYT/PARK-PRKRA) are monogenic combined dystonias accompanied by parkinsonian features. Meanwhile, MYC/DYT-SGCE and MYC/DYT-KCTD17 are characterized by dystonia in combination with myoclonus. In the past, common molecular pathways between these syndromes were the center of interest. Although the encoded proteins rather affect diverse cellular functions, recent neurophysiological evidence suggests similarities in the underlying mechanism in a subset. This review summarizes recent developments in the combined dystonias, focusing on clinico-genetic features and neurophysiologic findings. Disease-modifying therapies remain unavailable to date; an overview of symptomatic therapies for these disorders is also presented.
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Abejero JEE, Jamora RDG, Vesagas TS et al (2019) Long-term outcomes of pallidal deep brain stimulation in X-linked dystonia parkinsonism (XDP): up to 84 months follow-up and review of literature. Parkinsonism Relat Disord 60:81–86. https://doi.org/10.1016/j.parkreldis.2018.09.022
Aneichyk T, Hendriks WT, Yadav R et al (2018) Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly. Cell 172:897-909.e21. https://doi.org/10.1016/j.cell.2018.02.011
Asmus F, Hjermind LE, Dupont E et al (2007) Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype. Brain 130:2736–2745. https://doi.org/10.1093/brain/awm209
Balint B, Guerreiro R, Carmona S et al (2020) KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia. Eur J Neurol. https://doi.org/10.1111/ene.14228
Barbano RL, Hill DF, Snively BM et al (2012) New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. Parkinsonism Relat Disord 18:737–741. https://doi.org/10.1016/j.parkreldis.2012.03.020
Bendi VS, Shou J, Joy S, Torres-Russotto D (2018) Motor fluctuations and levodopa-induced dyskinesias in dopa-responsive dystonia. Park Relat Disord 50:126–127. https://doi.org/10.1016/j.parkreldis.2018.02.011
Besa Lehmann V, Rosenbaum M, Bulman DE et al (2020) A case report of myoclonus-dystonia with isolated myoclonus phenotype and novel mutation successfully treated with deep brain stimulation. Neurol Ther 9:187–191. https://doi.org/10.1007/s40120-020-00186-4
Beste C, Mückschel M, Rosales R et al (2017) Striosomal dysfunction affects behavioral adaptation but not impulsivity-evidence from X-linked dystonia-parkinsonism: executive function in XDP. Mov Disord 32:576–584. https://doi.org/10.1002/mds.26895
Beste C, Mückschel M, Rosales R et al (2018) The basal ganglia striosomes affect the modulation of conflicts by subliminal information—evidence from X-linked dystonia Parkinsonism. Cereb Cortex 28:2243–2252. https://doi.org/10.1093/cercor/bhx125
Beukers RJ, Foncke EM, van der Meer JN et al (2011) Functional magnetic resonance imaging evidence of incomplete maternal imprinting in myoclonus-dystonia. Arch Neurol 68:802–805. https://doi.org/10.1001/archneurol.2011.23
Blauwendraat C, Heilbron K, Vallerga CL et al (2019) Parkinson’s disease age at onset genome-wide association study: defining heritability, genetic loci, and alpha-synuclein mechanisms. Mov Disord 34:866–875. https://doi.org/10.1002/mds.27659
Blood AJ, Waugh JL, Münte TF et al (2018) Increased insula-putamen connectivity in X-linked dystonia-parkinsonism. NeuroImage Clin 17:835–846. https://doi.org/10.1016/j.nicl.2017.10.025
Bragg DC, Mangkalaphiban K, Vaine CA et al (2017) Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. Proc Natl Acad Sci 114:E11020–E11028. https://doi.org/10.1073/pnas.1712526114
Brashear A, Dobyns WB, de Carvalho AP et al (2007) The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 130:828–835. https://doi.org/10.1093/brain/awl340
Brashear A, Mink JW, Hill DF et al (2012) ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia: case report. Dev Med Child Neurol 54:1065–1067. https://doi.org/10.1111/j.1469-8749.2012.04421.x
Brashear A, Sweadner KJ, Cook JF et al (2018) ATP1A3-Related Neurologic Disorders (2008). [Updated 2018 Feb 22]. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews. University of Washington, Seattle, Seattle (WA), 1993–2020. https://www.ncbi.nlm.nih.gov/books/NBK1115/
Brücke C, Horn A, Huppke P et al (2015) Failure of pallidal deep brain stimulation in a case of rapid-onset dystonia Parkinsonism (DYT12). Mov Disord Clin Pract 2:76–78. https://doi.org/10.1002/mdc3.12124
Bruggemann N, Stiller S, Tadic V et al (2014) Non-motor phenotype of dopa-responsive dystonia and quality of life assessment. Park Relat Disord 20:428–431. https://doi.org/10.1016/j.parkreldis.2013.12.014
Brüggemann N, Heldmann M, Klein C et al (2016) Neuroanatomical changes extend beyond striatal atrophy in X-linked dystonia parkinsonism. Parkinsonism Relat Disord 31:91–97. https://doi.org/10.1016/j.parkreldis.2016.07.012
Brüggemann N, Domingo A, Rasche D et al (2019) Association of pallidal neurostimulation and outcome predictors with X-linked dystonia Parkinsonism. JAMA Neurol 76:211. https://doi.org/10.1001/jamaneurol.2018.3777
Calderon DP, Fremont R, Kraenzlin F, Khodakhah K (2011) The neural substrates of rapid-onset dystonia-Parkinsonism. Nat Neurosci 14:357–365. https://doi.org/10.1038/nn.2753
Camargos S, Scholz S, Simón-Sánchez J et al (2008) DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol 7:207–215. https://doi.org/10.1016/S1474-4422(08)70022-X
Camargos S, Lees AJ, Singleton A, Cardoso F (2012) DYT16: the original cases: figure 1. J Neurol Neurosurg Psychiatry 83:1012–1014. https://doi.org/10.1136/jnnp-2012-302841
Carbon M, Raymond D, Ozelius L et al (2013) Metabolic changes in DYT11 myoclonus-dystonia. Neurology 80:385–391. https://doi.org/10.1212/WNL.0b013e31827f0798
Cheng H, Capponi S, Wakeling E et al (2020) Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity. Hum Mutat 41:449–464. https://doi.org/10.1002/humu.23936
Cook JF, Hill DF, Snively BM et al (2014) Cognitive impairment in rapid-onset dystonia-parkinsonism: cognitive Impairment in RDP. Mov Disord 29:344–350. https://doi.org/10.1002/mds.25790
Dard R, Mignot C, Durr A et al (2015) Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation. Dev Med Child Neurol 57:1183–1186. https://doi.org/10.1111/dmcn.12927
de Carvalho AP, Sweadner KJ, Penniston JT et al (2004) Mutations in the Na+/K+-ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia Parkinsonism. Neuron 43:169–175. https://doi.org/10.1016/j.neuron.2004.06.028
de Carvalho AP, Borges V, Ferraz HB, Ozelius LJ (2015) Novel compound heterozygous mutations in PRKRA cause pure dystonia. Mov Disord 30:877–878. https://doi.org/10.1002/mds.26175
De Roxas RC, Jamora RDG (2019) Cost-analysis of the different treatment modalities in X-linked dystonia-Parkinsonism. Front Neurol 10:500. https://doi.org/10.3389/fneur.2019.00500
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
Demos MK, van Karnebeek CD, Ross CJ et al (2014) A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 9:15. https://doi.org/10.1186/1750-1172-9-15
Domingo A, Lee LV, Brüggemann N et al (2014) Woman with X-linked recessive dystonia-parkinsonism: clue to the epidemiology of Parkinsonism in Filipino women? JAMA Neurol 71:1177. https://doi.org/10.1001/jamaneurol.2014.56
Domingo A, Westenberger A, Lee LV et al (2015) New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3). Eur J Hum Genet 23:1334–1340. https://doi.org/10.1038/ejhg.2014.292
Domingo A, Amar D, Grütz K et al (2016) Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism. Cell Mol Life Sci 73:3205–3215. https://doi.org/10.1007/s00018-016-2159-4
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
dos Santos CO, da Silva-Júnior FP, Puga RD et al (2018) The prevalence of PRKRA mutations in idiopathic dystonia. Parkinsonism Relat Disord 48:93–96. https://doi.org/10.1016/j.parkreldis.2017.12.015
Esapa CT, Waite A, Locke M et al (2007) SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA. Hum Mol Genet 16:327–342. https://doi.org/10.1093/hmg/ddl472
Evidente VGH, Advincula J, Esteban R et al (2002) Phenomenology of ?Lubag? or X-linked dystonia-parkinsonism. Mov Disord 17:1271–1277. https://doi.org/10.1002/mds.10271
Fernandez HH, Rosales RL (2011) Uncovering the mystery from the Philippine island of Panay. Int J Neurosci 121:1–2. https://doi.org/10.3109/00207454.2010.526727
Frucht SJ, Bordelon Y, Houghton WH, Reardan D (2005) A pilot tolerability and efficacy trial of sodium oxybate in ethanol-responsive movement disorders. Mov Disord 20:1330–1337. https://doi.org/10.1002/mds.20605
Furukawa Y, Shimadzu M, Rajput AH et al (1996) GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia. Ann Neurol 39:609–617. https://doi.org/10.1002/ana.410390510
Furukawa Y, Lang AE, Trugman JM et al (1998) Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology 50:1015–1020. https://doi.org/10.1212/wnl.50.4.1015
Furukawa Y, Nygaard TG, Gutlich M et al (1999) Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia. Neurology 53:1032–1041
Furukawa Y, Guttman M, Sparagana SP et al (2000) Dopa-responsive dystonia due to a large deletion in the GTP cyclohydrolase I gene. Ann Neurol 47:517–520
Fusilli C, Migliore S, Mazza T et al (2018) Biological and clinical manifestations of juvenile Huntington’s disease: a retrospective analysis. Lancet Neurol 17:986–993. https://doi.org/10.1016/S1474-4422(18)30294-1
Goto S, Lee LV, Munoz EL et al (2005) Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann Neurol 58:7–17. https://doi.org/10.1002/ana.20513
Goto S, Kawarai T, Morigaki R et al (2013) Defects in the striatal neuropeptide Y system in X-linked dystonia-parkinsonism. Brain 136:1555–1567. https://doi.org/10.1093/brain/awt084
Graziola F, Stregapede F, Travaglini L et al (2019) A novel KCTD17 mutation is associated with childhood early-onset hyperkinetic movement disorder. Park Relat Disord 61:4–6. https://doi.org/10.1016/j.parkreldis.2018.12.001
Grimes DA, Barclay CL, Duff J et al (2002) Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture? J Neurol Neurosurg Psychiatry 72:801–804
Groen JL, Andrade A, Ritz K et al (2015) CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. Hum Mol Genet 24:987–993. https://doi.org/10.1093/hmg/ddu513
Groen JL, Ritz K, Jalalzadeh H et al (2015) RELN rare variants in myoclonus-dystonia. Mov Disord 30:415–419. https://doi.org/10.1002/mds.26070
Grünewald A, Djarmati A, Lohmann-Hedrich K et al (2008) Myoclonus-dystonia: significance of large SGCE deletions. Hum Mutat 29:331–332. https://doi.org/10.1002/humu.9521
Grütz K, Seibler P, Weissbach A et al (2017) Faithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia. Sci Rep 7:41156. https://doi.org/10.1038/srep41156
Habibi SAH, Albanese A, Elia AE et al (2019) Amyotrophic onset in GCH1 dopa-responsive dystonia. Iran J Neurol 18:181–183
Hainque E, Vidailhet M, Cozic N et al (2016) A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia. Neurology 86:1729–1735. https://doi.org/10.1212/WNL.0000000000002631
Hanajima R, Nomura Y, Segawa M, Ugawa Y (2007) Intracortical inhibition of the motor cortex in Segawa disease (DYT5). Neurology 68:1039–1044. https://doi.org/10.1212/01.wnl.0000257816.92101.54
Hanssen H, Heldmann M, Prasuhn J et al (2018) Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism. Brain 141:2995–3008. https://doi.org/10.1093/brain/awy222
Hanssen H, Prasuhn J, Heldmann M et al (2019) Imaging gradual neurodegeneration in a basal ganglia model disease. Ann Neurol 86:517–526. https://doi.org/10.1002/ana.25566
Heinzen EL, Swoboda KJ, Hitomi Y et al (2012) De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet 44:1030–1034. https://doi.org/10.1038/ng.2358
Hess CW, Raymond D, Aguiar Pde C et al (2007) Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers. Neurology 68:522–524. https://doi.org/10.1212/01.wnl.0000253188.76092.06
Holm R, Toustrup-Jensen MS, Einholm AP et al (2016) Neurological disease mutations of α3 Na+, K+-ATPase: structural and functional perspectives and rescue of compromised function. Biochim Biophys Acta BBA Bioenerg 1857:1807–1828. https://doi.org/10.1016/j.bbabio.2016.08.009
Huang YZ, Trender-Gerhard I, Edwards MJ et al (2006) Motor system inhibition in dopa-responsive dystonia and its modulation by treatment. Neurology 66:1088–1090. https://doi.org/10.1212/01.wnl.0000214304.03105.f4
Ichinose H, Ohye T, Takahashi E et al (1994) Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 8:236–242. https://doi.org/10.1038/ng1194-236
Ichinose H, Ohye T, Matsuda Y et al (1995) Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency. J Biol Chem 270:10062–10071. https://doi.org/10.1074/jbc.270.17.10062
Ilic TV, Meintzschel F, Cleff U et al (2002) Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol 545:153–167
Ishii A, Saito Y, Mitsui J et al (2013) Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients. PLoS ONE 8:e56120. https://doi.org/10.1371/journal.pone.0056120
Ito N, Hendriks WT, Dhakal J et al (2016) Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells. Dis Model Mech 9:451–462. https://doi.org/10.1242/dmm.022590
Jankovic J (2006) Treatment of dystonia. Lancet Neurol 5:864–872. https://doi.org/10.1016/S1474-4422(06)70574-9
Klockgether T, Mariotti C, Paulson HL (2019) Spinocerebellar ataxia. Nat Rev Dis Primer 5:24. https://doi.org/10.1038/s41572-019-0074-3
Lazarov E, Hillebrand M, Schröder S et al (2020) Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity. Neurobiol Dis 143:105012. https://doi.org/10.1016/j.nbd.2020.105012
Lee H, Deignan JL, Dorrani N et al (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312:1880–1887. https://doi.org/10.1001/jama.2014.14604
Lopez-Laso E, Beyer K, Opladen T et al (2012) Dyskinesias as a limiting factor in the treatment of Segawa disease. Pediatr Neurol 46:404–406. https://doi.org/10.1016/j.pediatrneurol.2012.03.003
Luciano MS, Ozelius L, Sims K et al (2009) Responsiveness to levodopa in epsilon-sarcoglycan deletions. Mov Disord 24:425–428. https://doi.org/10.1002/mds.22375
Makino S, Kaji R, Ando S et al (2007) Reduced neuron-specific expression of the TAF1 gene is associated with X-Linked Dystonia-Parkinsonism. Am J Hum Genet 80:393–406. https://doi.org/10.1086/512129
Malek N, Fletcher N, Newman E (2015) Diagnosing dopamine-responsive dystonias. Pr Neurol 15:340–345. https://doi.org/10.1136/practneurol-2015-001101
Marce-Grau A, Correa M, Vanegas MI et al (2019) Childhood onset progressive myoclonic dystonia due to a de novo KCTD17 splicing mutation. Park Relat Disord 61:7–9. https://doi.org/10.1016/j.parkreldis.2019.01.004
Marzin P, Mignot C, Dorison N et al (2018) Early-onset encephalopathy with paroxysmal movement disorders and epileptic seizures without hemiplegic attacks: about three children with novel ATP1A3 mutations. Brain Dev 40:768–774. https://doi.org/10.1016/j.braindev.2018.05.008
Mencacci NE, Isaias IU, Reich MM et al (2014) Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers. Brain 137:2480–2492. https://doi.org/10.1093/brain/awu179
Mencacci NE, R’Bibo L, Bandres-Ciga S et al (2015) The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort. Hum Mol Genet 24:5326–5329. https://doi.org/10.1093/hmg/ddv255
Mencacci NE, Rubio-Agusti I, Zdebik A et al (2015) A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am J Hum Genet 96:938–947. https://doi.org/10.1016/j.ajhg.2015.04.008
Nardocci N (2011) Myoclonus-dystonia syndrome. Handb Clin Neurol 100:563–575. https://doi.org/10.1016/B978-0-444-52014-2.00041-0
Nardocci N, Zorzi G, Barzaghi C et al (2008) Myoclonus-dystonia syndrome: clinical presentation, disease course, and genetic features in 11 families. Mov Disord 23:28–34. https://doi.org/10.1002/mds.21715
Nishiyama A, Endo T, Takeda S, Imamura M (2004) Identification and characterization of epsilon-sarcoglycans in the central nervous system. Brain Res Mol Brain Res 125:1–12. https://doi.org/10.1016/j.molbrainres.2004.01.012
Nolte D, Niemann S, Muller U (2003) Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism. Proc Natl Acad Sci 100:10347–10352. https://doi.org/10.1073/pnas.1831949100
Nygaard TG, Takahashi H, Heiman GA et al (1992) Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. Ann Neurol 32:603–608. https://doi.org/10.1002/ana.410320502
O’Rawe JA, Wu Y, Dörfel MJ et al (2015) TAF1 variants are associated with dysmorphic features, intellectual disability, and neurological manifestations. Am J Hum Genet 97:922–932. https://doi.org/10.1016/j.ajhg.2015.11.005
O’Sullivan JD, Costa DC, Gacinovic S, Lees AJ (2001) SPECT imaging of the dopamine transporter in juvenile-onset dystonia. Neurology 56:266–267
Oblak AL, Hagen MC, Sweadner KJ et al (2014) Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings. Acta Neuropathol (Berl) 128:81–98. https://doi.org/10.1007/s00401-014-1279-x
Opladen T, Hoffmann GF, Blau N (2012) An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 35:963–973. https://doi.org/10.1007/s10545-012-9506-x
Paciorkowski AR, McDaniel SS, Jansen LA et al (2015) Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 56:422–430. https://doi.org/10.1111/epi.12914
Panagiotakaki E, De Grandis E, Stagnaro M et al (2015) Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients. Orphanet J Rare Dis 10:123. https://doi.org/10.1186/s13023-015-0335-5
Pasco PMD, Ison CV, Muňoz EL et al (2011) Understanding XDP through imaging, pathology, and genetics. Int J Neurosci 121:12–17. https://doi.org/10.3109/00207454.2010.526729
Pauly MG, López MR, Westenberger A et al (2020) Expanding data collection for the MDSGene database: X-linked dystonia-parkinsonism as use case example. Mov Disord. https://doi.org/10.1002/mds.28289 ((Epub ahead of print))
Peall KJ, Waite AJ, Blake DJ et al (2011) Psychiatric disorders, myoclonus dystonia, and the epsilon-sarcoglycan gene: a systematic review. Mov Disord 26:1939–1942. https://doi.org/10.1002/mds.23791
Pittock SJ, Joyce C, O’Keane V et al (2000) Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred. Neurology 55:991–995. https://doi.org/10.1212/WNL.55.7.991
Quadri M, Olgiati S, Sensi M et al (2016) PRKRA mutation causing early-onset generalized dystonia-parkinsonism (DYT16) in an Italian family: new family with PRKRA P222L mutation. Mov Disord 31:765–767. https://doi.org/10.1002/mds.26583
Rajput AH, Gibb WR, Zhong XH et al (1994) Dopa-responsive dystonia: pathological and biochemical observations in a case. Ann Neurol 35:396–402. https://doi.org/10.1002/ana.410350405
Rakovic A, Domingo A, Grütz K et al (2018) Genome editing in induced pluripotent stem cells rescues TAF1 levels in X-linked dystonia-parkinsonism: removal of the SVA rescues TAF1 expression. Mov Disord 33:1108–1118. https://doi.org/10.1002/mds.27441
Raymond D, Saunders-Pullman R, Ozelius L (2020) SGCE Myoclonus-Dystonia (2003). [Updated 2020 Jun 4]. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews®. University of Washington, Seattle, Seattle (WA), 1993–2020. https://www.ncbi.nlm.nih.gov/books/NBK1414/
Rittiner JE, Caffall ZF, Hernández-Martinez R et al (2016) Functional genomic analyses of mendelian and sporadic disease identify impaired eIF2α signaling as a generalizable mechanism for dystonia. Neuron 92:1238–1251. https://doi.org/10.1016/j.neuron.2016.11.012
Ritz K, van Schaik BD, Jakobs ME et al (2011) SGCE isoform characterization and expression in human brain: implications for myoclonus-dystonia pathogenesis? Eur J Hum Genet 19:438–444. https://doi.org/10.1038/ejhg.2010.206
Rosewich H, Thiele H, Ohlenbusch A et al (2012) 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. https://doi.org/10.1016/S1474-4422(12)70182-5
Rosewich H, Baethmann M, Ohlenbusch A et al (2014) A novel ATP1A3 mutation with unique clinical presentation. J Neurol Sci 341:133–135. https://doi.org/10.1016/j.jns.2014.03.034
Rosewich H, Ohlenbusch A, Huppke P et al (2014) The expanding clinical and genetic spectrum of ATP1A3-related disorders. Neurology 82:945–955. https://doi.org/10.1212/WNL.0000000000000212
Rosewich H, Sweney MT, DeBrosse S et al (2017) Research conference summary from the 2014 international task force on ATP1A3 -related disorders. Neurol Genet 3:e139. https://doi.org/10.1212/NXG.0000000000000139
Rudakou U, Ouled Amar Bencheikh B, Ruskey JA et al (2019) Common and rare GCH1 variants are associated with Parkinson’s disease. Neurobiol Aging 73(231):e1-231. https://doi.org/10.1016/j.neurobiolaging.2018.09.008 ((e6))
Rughani AI, Lozano AM (2013) Surgical treatment of myoclonus dystonia syndrome. Mov Disord 28:282–287. https://doi.org/10.1002/mds.25326
Sabouraud P, Riquet A, Spitz M-A et al (2019) Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3. Eur J Paediatr Neurol 23:448–455. https://doi.org/10.1016/j.ejpn.2019.02.004
Sasaki M, Ishii A, Saito Y et al (2014) Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology 82:482–490. https://doi.org/10.1212/WNL.0000000000000102
Segawa M (2011) Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev 33:195–201. https://doi.org/10.1016/j.braindev.2010.10.015
Segawa M, Nomura Y, Hayashi M (2013) Dopa-responsive dystonia is caused by particular impairment of nigrostriatal dopamine neurons different from those involved in Parkinson disease: evidence observed in studies on Segawa disease. Neuropediatrics 44:61–66. https://doi.org/10.1055/s-0033-1337337
Shin JH, Lee WW, Lee JY et al (2020) GCH-1 genetic variant may cause Parkinsonism by unmasking the subclinical nigral pathology. J Neurol 267:1952–1959. https://doi.org/10.1007/s00415-020-09788-2
Song PC, Le H, Acuna P et al (2020) Voice and swallowing dysfunction in X-linked dystonia parkinsonism. The Laryngoscope 130:171–177. https://doi.org/10.1002/lary.27897
Steinberger D, Weber Y, Korinthenberg R et al (1998) High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann Neurol 43:634–639. https://doi.org/10.1002/ana.410430512
Steinberger D, Trubenbach J, Zirn B et al (2007) Utility of MLPA in deletion analysis of GCH1 in dopa-responsive dystonia. Neurogenetics 8:51–55. https://doi.org/10.1007/s10048-006-0069-6
Stephen CD, Go CL, Acuna P, Sharma N (2020) Phasic knee bending dystonic and Parkinsonian gait: a characteristic finding in X-linked dystonia Parkinsonism. Mov Disord Clin Pract 7:448–452. https://doi.org/10.1002/mdc3.12929
Sweadner KJ, Toro C, Whitlow CT et al (2016) ATP1A3 mutation in adult rapid-onset ataxia. PLoS ONE 11:e0151429. https://doi.org/10.1371/journal.pone.0151429
Tadic V, Kasten M, Bruggemann N et al (2012) Dopa-responsive dystonia revisited: diagnostic delay, residual signs, and nonmotor signs. Arch Neurol. https://doi.org/10.1001/archneurol.2012.574
Tarrano C, Wattiez N, Delorme C et al (2020) Visual sensory processing is altered in myoclonus dystonia. Mov Disord 35:151–160. https://doi.org/10.1002/mds.27857
Timmers ER, Smit M, Kuiper A et al (2019) Myoclonus-dystonia: distinctive motor and non-motor phenotype from other dystonia syndromes. Park Relat Disord 69:85–90. https://doi.org/10.1016/j.parkreldis.2019.10.015
Torres JAKL, Rosales RL (2017) Nonmotor symptoms in dystonia. Int Rev Neurobiol 134:1335–1371. https://doi.org/10.1016/bs.irn.2017.05.003
Trender-Gerhard I, Sweeney MG, Schwingenschuh P et al (2009) Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry 80:839–845. https://doi.org/10.1136/jnnp.2008.155861
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
van der Meer JN, Beukers RJ, van der Salm SM et al (2012) White matter abnormalities in gene-positive myoclonus-dystonia. Mov Disord 27:1666–1672. https://doi.org/10.1002/mds.25128
Vaughn LS, Bragg DC, Sharma N et al (2015) Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT. J Biol Chem 290:22543–22557. https://doi.org/10.1074/jbc.M115.669408
Viollet L, Glusman G, Murphy KJ et al (2015) Alternating hemiplegia of childhood: retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry. PLoS ONE 10:e0127045. https://doi.org/10.1371/journal.pone.0127045
Wang X, Yu X (2020) Deep brain stimulation for myoclonus dystonia syndrome: a meta-analysis with individual patient data. Neurosurg Rev. https://doi.org/10.1007/s10143-019-01233-x
Wassenberg T, Schouten MI, Helmich RC et al (2020) Autosomal dominant GCH1 mutations causing spastic paraplegia at disease onset. Park Relat Disord 74:12–15. https://doi.org/10.1016/j.parkreldis.2020.03.019
Weissbach A, Klein C (2014) Hereditary dystonia and Parkinsonism: two sides of the same coin? Brain 137:2402–2404. https://doi.org/10.1093/brain/awu181
Weissbach A, Kasten M, Grünewald A et al (2013) Prominent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus-dystonia. Park Relat Disord 19:422–425. https://doi.org/10.1016/j.parkreldis.2012.12.004
Weissbach A, Baumer T, Bruggemann N et al (2015) Premotor-motor excitability is altered in dopa-responsive dystonia. Mov Disord. https://doi.org/10.1002/mds.26365
Weissbach A, Bäumer T, Rosales R et al (2015) Neurophysiological fingerprints of X-linked dystonia-parkinsonism: a model basal ganglia disease: letter to the Editors. Mov Disord 30:873–875. https://doi.org/10.1002/mds.26224
Weissbach A, Werner E, Bally JF et al (2017) Alcohol improves cerebellar learning deficit in myoclonus-dystonia: a clinical and electrophysiological investigation. Ann Neurol 82:543–553. https://doi.org/10.1002/ana.25035
Westenberger A, Rosales RL, Heinitz S et al (2013) X-linked Dystonia-Parkinsonism manifesting in a female patient due to atypical turner syndrome: genetics of XDP in an Affected Woman. Mov Disord 28:675–678. https://doi.org/10.1002/mds.25369
Westenberger A, Reyes CJ, Saranza G et al (2019) A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism. Ann Neurol 85:812–822. https://doi.org/10.1002/ana.25488
Xiao J, Vemula SR, Xue Y et al (2017) Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome. Neurobiol Dis 98:52–65. https://doi.org/10.1016/j.nbd.2016.11.003
Yoo D, Kim HJ, Lee JS et al (2018) Early-onset generalized dystonia starting in the lower extremities in a patient with a novel ANO3 variant. Park Relat Disord. https://doi.org/10.1016/j.parkreldis.2018.02.012
Yoshino H, Nishioka K, Li Y et al (2018) GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease. J Neurol 265:1860–1870. https://doi.org/10.1007/s00415-018-8930-8
Zech M, Castrop F, Schormair B et al (2014) DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family: confirmation of DYT16 Dystonia. Mov Disord 29:1504–1510. https://doi.org/10.1002/mds.25981
Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996) The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 109:127–135
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Weissbach, A., Saranza, G. & Domingo, A. Combined dystonias: clinical and genetic updates. J Neural Transm 128, 417–429 (2021). https://doi.org/10.1007/s00702-020-02269-w
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DOI: https://doi.org/10.1007/s00702-020-02269-w