Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector23410.17816/psaic234ReviewsОбзорыUnknownGenetics of hereditary forms of dystoniaГенетика наследственных форм дистонииKrasnovM. Yu.КрасновМаксим Юрьевич
Russian Federation
merritt.kraut@gmail.comTimerbaevaSofiya L.ТимербаеваСофия Л.
Russian Federation
merritt.kraut@gmail.comhttps://orcid.org/0000-0002-2704-6282IllarioshkinSergey N.ИллариошкинСергей Николаевич
Russian Federation

D. Sci. (Med.), Prof., Corr. Member of the Russian Academy of Sciences, Deputy Director, Head, Department for brain research

д.м.н., проф., член-корр. РАН, зам. директора по научной работе, рук. отдела исследований мозга

merritt.kraut@gmail.comResearch Center of NeurologyФГБНУ «Научный центр неврологии»0906201372556202022017Copyright ©; 2013, Krasnov M.Y., Timerbaeva S.L., Illarioshkin S.N.Copyright ©; 2013, Krasnov M.Y., Timerbaeva S.L., Illarioshkin S.N.2013Krasnov M.Y., Timerbaeva S.L., Illarioshkin S.N.Krasnov M.Y., Timerbaeva S.L., Illarioshkin S.N.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/234

Dystonia is one of the most common movement disorders with great medical, social and economic importance. Genetics plays significant role in the development of different, and mainly primary, forms of dystonia. At present the range of hereditary dystonic syndromes comprises more than twenty separate clinicalgenetic variants, which characterizes dystonia as a highly heterogeneous nosologic group calling for differentiated approaches to diagnosis and treatment. Detailed analysis of the literature on hereditary forms of dystonia, including clinical picture, molecular genetic basis, phenotype–genotype correlations, and principles of DNA diagnostics and medical genetic counseling of affected families, is presented.

Дистония – одно из наиболее распространенных двигательных расстройств, имеющих большое медицинское и социально-экономическое значение. Генетика играет значительную роль в развитии различных и в первую очередь первичных форм дистонии. На сегодняшний день спектр наследственных дистонических синдромов включает более двадцати самостоятельных клинико-генетических вариантов, что характеризует дистониюкак чрезвычайно гетерогенную нозологическую группу, требующую дифференцированных подходов к диагностике и лечению. Представлен подробный анализ литературных данных о наследственных формах дистонии, включая клиническую картину, молекулярно-генетические основы развития, корреляции фенотип–генотип, принципы ДНК-диагностики и медико-генетического консультирования отягощенных семей.

dystoniahereditary formsgeneticsphenotypesdiagnosisдистониянаследственные формыгенетикафенотипыдиагнозИллариошкин С.Н., Иванова-Смоленская И.А. Дрожательные гиперкинезы. Руководство для врачей. М.: Атмосфера, 2011.Иллариошкин С.Н., Иванова-Смоленская И.А., Маркова Е.Д. ДНК-диагностика и медико-генетическое консультирование в неврологии. М.: МИА, 2002.Маркова Е.Д., Сломинский П.А., Иллариошкин С.Н. и др. Молекулярно-генетический анализ торсионной дистонии в России. Генетика 2000; 36: 952–958.Тимербаева С.Л. Фокальные и сегментарные формы первичной дистонии: клинические, патофизиологические и молекулярно-генетические аспекты: Дис. … докт. мед. наук. М., 2013.Ahmad F., Davis M.B., Waddy H.M. et al. Evidence for locus heterogeneity in autosomal dominant torsion dystonia. Genomics. 1993; 15: 9–12.Albanese A., Asmus F., Bhatia K.P. et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur. J. Neurol. 2011; 18:5–18.Asmus F., Hjermind L.E., Dupont E. et al. Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype. Brain 2007; 130: 2736–2745.Bennett L.B., Roach E.S., Bowcock A.M. A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16. Neurology 2000; 54: 125–130.Bentivoglio A.R., Ialongo T., Contarino M.F. et al. Phenotypic characterization of DYT13 primary torsion dystonia. Mov. Disord. 2004; 19: 200–206.Bonetti M., Barzaghi C., Brancati F. et al. Mutation screening of the DYT6/THAP1 gene in Italy. Mov. Disord. 2009; 24: 2424–2427.Bonnet C., Gregoire M.J., Vibert M. et al. Cryptic 7q21 and 9p23 deletions in a patient with apparently balanced de novo reciprocal translocation t(7;9) (q21;p23) associated with a dystonia-plus syndrome: paternal deletion of the epsilon-sarcoglycan (SGCE) gene. J. Hum. Genet. 2008; 53: 876–885.Blanchard A., Ea V., Roubertie A. et al. DYT6 dystonia: review of the literature and creation of the UMD locus-specific database (LSDB) for mutations in the THAP1 gene. Hum. Mut. 2011; 32: 1213–1224.Bragg D.C., Armata I.A., Nery F.C. et al. Molecular pathways in dystonia. Neurobiol. Dis. 2011; 42: 136–147.Brashear A., Dobyns W.B., de Carvalho Aguiar P. et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 2007; 130: 828–835.Breakefield X.O., Blood A.J., Li Y. et al. The pathophysiological basis of dystonias. Nat. Rev. Neurosci. 2008; 9: 222–234.Bressman S.B. Genetics of dystonia: an overview. Parkinsonism and Related Disorders 2007; 13: 347–355.Butler A.G., Duffey P.O., Hawthorne M.R. et al. The socioeconomic implications of dystonia. Adv. Neurol. 1998; 78: 349–358.Calakos N., Patel V.D., Gottron M. et al. Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia. J. Med. Genet. 2010; 47: 646–650.Camargos S., Scholz S., Simon-Sanchez J. et al. DYT16, a novel youngonset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 2008; 7: 207–215.Charlesworth G., Plagnol V., Holmstrom K.M. et al. Mutation in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am. J. Hum. Genet. 2012; 91: 1041–1050.61Chouery E., Kfoury J., Delague V. et al. A novel locus for autosomal recessive primary torsion dystonia (DYT17) maps to 20p11.22-q13.12. Neurogenetics. 2008; 9: 287–293.Clot F., Grabli D., Cazeneuve C. et al. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with dopa-responsive dystonia. Brain 2009; 132: 1753–1763.Corvol J.C., Studler J.M., Schonn J.S. et al. Gαolfis necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. J. Neurochem. 2001; 76: 1585–1588.DeBerardinis R.J., Conforto D., Russell K. et al. Myoclonus in a patient with a deletion of the epsilon-sarcoglycan locus on chromosome 7q21. Am. J. Med. Genet. 2003; 121: 31–36.DeCarvalho Aguiar P., Sweadner K.J., Penniston J.T. et al. Mutations in the Na/K-ATPase alpha3 gene ATP1A3 are associated with rapidonset dystonia parkinsonism. Neuron 2004; 43: 169–175.Defazio G., Berardelli A., Hallett M. Do primary adultonset focal dystonias share aetiological factors? Brain 2007; 130: 1183–1193.Demirkiran M., Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann. Neurol. 1995; 38: 571–579.Djarmati A., Schneider S.A., Lohmann K. et al. Mutations in THAP1 (DYT6) and generalized dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol. 2009; 8: 416-418.Evidente V.G., Advincula J., Esteban R. et al. Phenomenology of ‘‘lubag’’ or X-linked dystonia-parkinsonism. Mov. Disord. 2002; 17: 1271–1277.Fuchs T., Saunders-Pullman R., Masuho I. et al. Mutations in GNAL cause primary torsion dystonia. Nat. Genet. 2013; 45: 88-92.Furukawa Y., Kish S.J., Lang A.E. Scoliosis in a dopa-responsive dystonia family with a mutation of the GTP cyclohydrolase I gene. Neurology 2000; 54: 2187.Ghezzi D., Viscomi C., Ferlini A. et al. Paroxysmal non-kinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence. Hum. Mol. Genet. 2009; 18: 1058–1064.Gimenez-Roldan S., Delgado G., Marin M. et al. Hereditary torsion dystonia in gypsies. Adv. Neurol. 1988; 50: 73–81.Goto S., Lee L.V., Munoz E.L. et al. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann. Neurol. 2005; 58: 7–17.Granata A., Warner T.T. The role of torsinA in dystonia. Eur. J. Neurol. 2010; 17 (Suppl.1): 81–87.Grimes D.A., Han F., Lang A.E. et al. A novel locus for inherited myoclonus-dystonia on 18p11. Neurology 2002; 59: 1183–1186.Groen J.L., Ritz K., Contarino M.F. et al. 2010. DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Mov. Disord. 25: 2420–2427.Hack A.A., Groh M.E., McNally E.M. Sarcoglycans in muscular dystrophy. Microsc. Res. Tech. 2000; 48: 167–180.Herzfeld T., Nolte D., Muller U. Structural and functional analysis of the human TAF1/DYT3 multiple transcript system. Mamm. Genome 2007; 18: 787–795.Ichinose H., Ohye T., Takahashi E. et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat. Genet. 1994; 8: 236–242.Illarioshkin S.N., Markova E.D., Slominsky P.A. et al. Analysis of the GTP cyclohydrolase I gene in Russian families with dopa-responsive dystonia. Arch. Neurol. 1998; 55: 789–792.Jamora R.D.G., Tan E.K., Liu C.P. et al. DYT1 mutations amongst adult primary dystonia patients in Singapore with review of literature comparing East and West. J. Neurol. Sci. 2006; 247: 35–37.Jech R., Bares M., Krepelova A. et al. DYT 6 – a novel THAP1 mutation with excellent effect on pallidal DBS. Mov. Disord. 2011; 26: 924–925.Khan N.L., Wood N.W., Bhatia K.P. Autosomal recessive, DYT2- like primary torsion dystonia: a new family. Neurology 2003; 61: 1801–1803.Kinugawa K., Vidailhet M., Clot F. et al. Myoclonus-dystonia: an update. Mov. Disord. 2009; 24: 479–489.Klein C., Brin M.F., De Leon D. et al. De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia. Hum. Mol. Genet. 1998; 7: 1133–1136.Kong C.K., Ko C.H., Tong S.F. et al. Atypical presentation of doparesponsive dystonia: generalized hypotonia and proximal weakness. Neurology 2001; 57: 1121–1124.Kuyper D.J. et al. Nonmotor manifestations of dystonia: A systematic review. Mov. Disord. 2011; 26: 1206–1217.Lee H.Y., Xu Y., Huang Y. et al. The gene for paroxysmal nonkinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum. Mol. Genet. 2004; 13: 3161–3170.Lee L.V., Pascasio F.M., Fuentes F.D. et al. Torsion dystonia in Panay, Philippines. Adv. Neurol. 1976; 14: 137–151.Lee L.V., Rivera C., Teleg R.A. et al. The unique phenomenology of sex-linked dystonia parkinsonism (XDP, DYT3, ‘‘lubag’’). Int. J. Neurosci. 2011; 121 (Suppl 1): 3–11.Leube B., Rudnicki D., Ratzlaff T. et al. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distribution. Hum. Mol. Genet. 1996; 5: 1673–1677.Lohmann K., Wilcox R.A., Winkler S. et al. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann. Neurol. doi:10.1002/ana.23829. [Epub ahead of print].Marechal L., Raux G., Dumanchin C. et al. Severe myoclonus-dystonia syndrome associated with a novel epsilon-sarcoglycan gene truncating mutation. Am. J. Med. Genet. Neuropsychiatr. Genet. 2003; 119: 114–117.Margari L., Perniola T., Illiceto G. et al. Familial paroxysmal exercise-induced dyskinesia and benign epilepsy: a clinical and neurophysiological study of an uncommon disorder. Neurol. Sci. 2000; 21: 165–172.Misbahuddin A., Placzek M., Lennox G. et al. Myoclonus-dystonia syndrome with severe depression is caused by an exon-skipping mutation in the epsilon-sarcoglycan gene. Mov. Disord. 2007; 22: 1173–1175.Moretti P., Hedera P., Wald J. et al. Autosomal recessive primary generalized dystonia in two siblings from a consanguineous family. Mov. Disord. 2005; 20: 245–247.Muller U. The monogenic primary dystonias. Brain 2009; 132: 2005-2025.Munchau A., Valente E.M., Shahidi G.A. et al. A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study. J. Neurol. Neurosurg. Psychiatry. 2000; 68: 609–614.Naiya T., Biswas A., Neogi R. et al. Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta. Neurol. Scand. 2006: 114: 210–215.Norgren N., Mattson E., Forsgren L. et al. A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3. Neurogenetics 2011; 12: 137–143.Nygaard T.G., Raymond D., Chen C. et al. Localization of a gene for myoclonus-dystonia to chromosome 7q21-q31. Ann. Neurol. 1999; 46: 794–798.Nygaard T.G., Takahashi H., Heiman G.A. et al. Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia. Ann. Neurol. 1992; 32: 603–608.Nygaard T.G., Waran S.P., Levine R.A. et al. Dopa-responsive dystonia simulating cerebral palsy. Pediatr. Neurol. 1994; 11: 236–240.Ozelius L.J., Bressman S.B. THAP1: role in focal dystonia? Neurology 2010; 74: 192-193.Ozelius L.J., Lubarr N., Bressman S.B. Milestones in dystonia. Mov. Disord. 2011; 26: 1106–1126.Parker N. Hereditary whispering dysphonia. J. Neurol. Neurosurg. Psychiatry. 1985; 48: 218–224.Paudel R., Hardy J., Revesz T. et al. Review: Genetics and neuropathology of primary pure dystonia. Neuropathol. Appl. Neurobiol.2012; 38: 520Petrucci S., Valente E.M. Genetic issues in the diagnosis of dystonias. Frontiers in Neurology. doi:10.3389/fneur.2013.00034. [Epub ahead of print].Rainier S., Thomas D., Tokarz D. et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch. Neurol. 2004; 61: 1025–1029.Roubergue A., Apartis E., Mesnage V. et al. Dystonic tremor caused by mutation of the glucose transporter gene GLUT1. J. Inherit. Metab. Dis. 2011; 34: 483–488.Schneider S.A., Paisan-Ruiz C., Garcia-Gorostiaga I. et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov. Disord. 2009; 24: 1684–1688.Seibler P., Djarmati A., Langpap B. et al. A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalized dystonia in a German patient. Lancet Neurol. 2008; 7: 380–381.Spacey S.D., Adams P.J., Lam P.C. et al. Genetic heterogeneity in paroxysmal nonkinesigenic dyskinesia. Neurology 2006; 66: 1588–1590.Spacey S.D., Valente E.M., Wali G.M. et al. Genetic and clinical heterogeneity in paroxysmal kinesigenic dyskinesia: Evidence for a third EKD gene. Mov. Disord. 2002; 17: 717–725.Steeves T.D., Day L., Dykeman J. et al. The prevalence of primary dystonia: A systematic review and meta-analysis. Mov. Disord. 2012; 27: 1789–1796.Steinberger D., Blau N., Goriuonov D. et al. Heterozygous mutation in 50-untranslated region of sepiapterinreductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 2004; 5: 187–190.Steinberger D., Topka H., Fischer D. et al. GCH1 mutation in a patient with adult-onset oromandibular dystonia. Neurology 1999; 52: 877–879.Suls A., Dedeken P., Goffin K. et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 2008; 131: 1831–1844.Svetel M., Ozelius L.J., Buckley A. et al. Rapid-onset dystoniaparkinsonism: case report. J. Neurol. 2010; 257: 472–474.Trender-Gerhard I., Sweeney M.G., Schwingenschuh P. et al. Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. J. Neurol. Neurosurg. Psychiatry 2009; 80: 839–845.Valente E.M., Bentivoglio A.R., Cassetta E. et al. Identification of a novel primary torsion dystonia locus (DYT13) on chromosome 1p36 in an Italian family with cranial-cervical or upper limb onset. Neurol. Sci.2001; 22: 95–96.Van Hove J.L., Steyaert J., Matthijs G. et al. Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency. J. Neurol Neurosurg. Psychiatry 2006; 77: 18–23.Verbeek M.M., Steenbergen-Spanjers G.C., Willemsen M.A. et al. Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. Ann. Neurol. 2007; 62: 422–426.Waters C.H., Faust P.L., Powers J. et al. Neuropathology of lubag (X-linked dystonia parkinsonism). Mov. Disord. 1993; 8: 387–390.Weber Y.G., Storch A., Wuttke T.V. et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J. Clin. Invest. 2008; 118: 2157–2168.Winter P., Kamm C., Biskup S. et al. DYT7 gene locus for cervical dystonia on chromosome 18p is questionable. Mov. Disord. 2012; 27:1819–1821.Xiao J., Uitti R.J., Zhao Y. et al.Mutations in СIZ1 cause adult onset primary cervical dystonia. Ann. Neurol. 2012; 71: 458–469.Xiromerisiou G., Houlden H., Scarmeas N. et al. THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. Mov. Disord. 2012; 27: 1290-1294.Zirn B., Grundmann K., Huppke P. et al. Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1). J. Neurol. Neurosurg. Psychiatry 2008; 79: 1327–1330.Zittel S., Moll C.K., Bruggemann N. et al. 2010. Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families. Mov. Disord. 25: 2405–2412.http://www.nice.org.uk/guidance/IPG188. National Institute for Health and Clinical Excellence. Deep brain stimulation for tremor and dystonia (excluding Parkinson’s disease).http://www.bh4.org