Update on the Genetics of Dystonia
- 2.7k Downloads
Mainly due to the advent of next-generation sequencing (NGS), the field of genetics of dystonia has rapidly grown in recent years, which led to the discovery of a number of novel dystonia genes and the development of a new classification and nomenclature for inherited dystonias. In addition, new findings from both in vivo and in vitro studies have been published on the role of previously known dystonia genes, extending our understanding of the pathophysiology of dystonia. We here review the current knowledge and recent findings in the known genes for isolated dystonia TOR1A, THAP1, and GNAL as well as for the combined dystonias due to mutations in GCH1, ATP1A3, and SGCE. We present confirmatory evidence for a role of dystonia genes that had not yet been unequivocally established including PRKRA, TUBB4A, ANO3, and TAF1. We finally discuss selected novel genes for dystonia such as KMT2B and VAC14 along with the challenges for gene identification in the NGS era and the translational importance of dystonia genetics in clinical practice.
KeywordsDystonia Classification Nomenclature Novel genes Next-generation sequencing Mutation
Katja Lohmann is supported by the DFG (LO 1555/4-1 and LO 1555/3-2). Christine Klein is a recipient of a career development award from the Hermann and Lilly Schilling Foundation. Further, Katja Lohmann and Christine Klein are supported by the German Ministry of Education and Research (BMBF, DYSTRACT consortium, 01GM1514B) and a Research Unit of the DFG (FOR2488).
Compliance with Ethical Standards
Conflict of Interest
Katja Lohmann declares no conflict of interest.
Christine Klein has received personal fees from Centogene and from the Else Kroener Fresenius Foundation.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Oppenheim H. Ueber eigenenartige Krampfkrankheit des kindlichen und jugendlichen Alters (Dysbasia lordotica progressiva, Dystonia Musculorum Deformans). Neurol Centrabl. 1911;30:1090.Google Scholar
- 2.• C. Klein, S. Fahn, Translation of Oppenheim’s 1911 paper on dystonia, Mov Disord 28 (2013) 851-862. This is a translation and commentary of Oppenheim’s landmark paper coining the term dystonia and most likely describing the first cases of generalized dystonia due to mutations in Tor1A (formerly DYT1) and suspecting a genetic etiology.Google Scholar
- 4.• Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013;28:863–73. This is an important paper that revises the definition and classification of dystonia based on a consensus outcome of an international expert panel. The new classification contains two axes: clinical characteristics and etiology. The latter one replaces the terms “primary” and “dystonia-plus” dystonia with “isolated” and “combined” dystonia, respectively.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.L. Williams, E. McGovern, O. Kimmich, A. Molloy, I. Beiser, J.S. Butler, F. Molloy, P. Logan, D.G. Healy, T. Lynch, R. Walsh, L. Cassidy, P. Moriarty, H. Moore, T. McSwiney, C. Walsh, S. O’Riordan, M. Hutchinson, Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland, Eur J Neurol (2016).Google Scholar
- 11.• M. Zech, S. Boesch, A. Jochim, S. Weber, T. Meindl, B. Schormair, T. Wieland, C. Lunetta, V. Sansone, M. Messner, J. Mueller, A. Ceballos-Baumann, T.M. Strom, R. Colombo, W. Poewe, B. Haslinger, J. Winkelmann, Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up, Mov Disord (2016). This is a relevant paper in two respects: first, it uses exome sequencing to detect the cause of dystonia in a small group of patients underlining the heterogeneity of dystonia. Second, it described the first de novo mutation in ANO3 providing increasing evidence for a pathogenic role of mutations in this gene.Google Scholar
- 12.•• Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, et al. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord. 2016;31:436–57. This paper is of major importance since it suggests a new nomenclature system for genetic movement disorders based on extensive considerations and discussions among an expert panel and members of the Movement Disorder Society.CrossRefPubMedGoogle Scholar
- 28.• Brüggemann N, Kühn A, Schneider SA, Kamm C, Wolters A, Krause P, et al. Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia. Neurology. 2015;84:895–903. This paper provides a translational aspect on the partially differential clinical outcome after deep brain stimulation in carriers of mutations in different dystonia genes.Google Scholar
- 30.B.A. Sosa, F.E. Demircioglu, J.Z. Chen, J. Ingram, H.L. Ploegh, T.U. Schwartz, How lamina-associated polypeptide 1 (LAP1) activates Torsin, Elife 3 (2014) e03239.Google Scholar
- 32.F.E. Demircioglu, B.A. Sosa, J. Ingram, H.L. Ploegh, T.U. Schwartz, Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia, Elife 5 (2016).Google Scholar
- 33.•• Grillet M, Dominguez Gonzalez B, Sicart A, Pottler M, Cascalho A, Billion K, et al. Torsins are essential regulators of cellular lipid metabolism. Dev Cell. 2016;38:235–47. This is a very important study that links Torsin mutations to dysregulated cellular lipid metabolism and thus suggests a novel disease mechanism in dystonia.Google Scholar
- 34.• V.G. Shakkottai, A. Batla, K. Bhatia, W.T. Dauer, C. Dresel, M. Niethammer, D. Eidelberg, R.S. Raike, Y. Smith, H.A. Jinnah, E.J. Hess, S. Meunier, M. Hallett, R. Fremont, K. Khodakhah, M.S. LeDoux, T. Popa, C. Gallea, S. Lehericy, A.C. Bostan, P.L. Strick, Current opinions and areas of consensus on the role of the cerebellum in dystonia, Cerebellum (2016). This is an important review summarizing and discussing data on the neuroanatomical site of origin of dystonia. It illustrates that the cerebellum plays a role in the pathophysiology of dystonia, but it is probably neither the primary nor sole relevant neuroanatomical structure.Google Scholar
- 35.E. Premi, M. Diano, S. Gazzina, F. Cauda, V. Gualeni, M. Tinazzi, M. Fiorio, P. Liberini, C. Lazzarini, S. Archetti, G. Biasotto, M. Turla, V. Bertasi, M. Cotelli, R. Gasparotti, A. Padovani, B. Borroni, Functional connectivity networks in asymptomatic and symptomatic DYT1 carriers, Mov Disord (2016).Google Scholar
- 47.• Masuho I, Fang M, Geng C, Zhang J, Jiang H, Ozgul RK, et al. Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol Genet. 2016;2:e78. This is an interesting case report on a family with homozygous mutations in an actually dominantly inherited disorder. The data are not only descriptive on the phenotypic level but are accompanied by detailed functional analysis of the mutation underlining the importance of functional studies.Google Scholar
- 50.• Chen DH, Meneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES, et al. ADCY5-related dyskinesia: broader spectrum and genotype-phenotype correlations. Neurology. 2015;85:2026–35. This study reports many cases of ADCY5-related dyskinesia with a wide range of hyperkinetic abnormal movements.Google Scholar
- 51.V. Tadic, M. Kasten, N. Bruggemann, S. Stiller, J. Hagenah, C. Klein, Dopa-responsive dystonia revisited: diagnostic delay, residual signs, and nonmotor signs, Arch Neurol (2012) 1-5.Google Scholar
- 59.• Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol. 2015;52:56–64. This important article illustrates the broad phenotypic spectrum of mutations in a single gene, i.e., ATP1A3.Google Scholar
- 61.M. Hully, J. Ropars, L. Hubert, N. Boddaert, M. Rio, M. Bernardelli, I. Desguerre, V. Cormier-Daire, A. Munnich, P. de Lonlay, L. Reilly, C. Besmond, N. Bahi-Buisson, Mosaicism in ATP1A3-related disorders: not just a theoretical risk, Neurogenetics (2016).Google Scholar
- 67.• Boulay AC, Saubamea B, Cisternino S, Mignon V, Mazeraud A, Jourdren L, et al. The sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels. Front Cell Neurosci. 2015;9:9. This functional study highlights a potential disease mechanism of mutations in the SGCE gene by linking the sarcoglycan complex to the cerebrovascular system.Google Scholar
- 68.•• A. Keller, A. Westenberger, M.J. Sobrido, M. Garcia-Murias, A. Domingo, R.L. Sears, R.R. Lemos, A. Ordonez-Ugalde, G. Nicolas, J.E. da Cunha, E.J. Rushing, M. Hugelshofer, M.C. Wurnig, A. Kaech, R. Reimann, K. Lohmann, V. Dobricic, A. Carracedo, I. Petrovic, J.M. Miyasaki, I. Abakumova, M.A. Mae, E. Raschperger, M. Zatz, K. Zschiedrich, J. Klepper, E. Spiteri, J.M. Prieto, I. Navas, M. Preuss, C. Dering, M. Jankovic, M. Paucar, P. Svenningsson, K. Saliminejad, H.R. Khorshid, I. Novakovic, A. Aguzzi, A. Boss, I. Le Ber, G. Defer, D. Hannequin, V.S. Kostic, D. Campion, D.H. Geschwind, G. Coppola, C. Betsholtz, C. Klein, J.R. Oliveira, Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice, Nat Genet (2013). This comprehensive study elucidated a frequent cause of primary familial brain calcification by identification of mutations in the PDGFB gene. It not only reported the cause of the disease in several multiplex families but also demonstrated corresponding brain calcifications in mouse models at different ages and linked this complex form of dystonia to dysfunction of the blood brain barrier.Google Scholar
- 77.• Quadri M, Olgiati S, Sensi M, Gualandi F, Groppo E, Rispoli V, et al. PRKRA mutation causing early-onset generalized dystonia-parkinsonism (DYT16) in an Italian family. Mov Disord. 2016;31:765–7. This interesting paper confirms biallelic mutations in the PRKRA gene as a cause of dystonia-parkinsonism and demonstrates a founder effect.Google Scholar
- 81.Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. 2015;17:405–24.CrossRefPubMedPubMedCentralGoogle Scholar
- 85.•• J.A. O’Rawe, Y. Wu, M.J. Dorfel, A.F. Rope, P.Y. Au, J.S. Parboosingh, S. Moon, M. Kousi, K. Kosma, C.S. Smith, M. Tzetis, J.L. Schuette, R.B. Hufnagel, C.E. Prada, F. Martinez, C. Orellana, J. Crain, A. Caro-Llopis, S. Oltra, S. Monfort, L.T. Jimenez-Barron, J. Swensen, S. Ellingwood, R. Smith, H. Fang, S. Ospina, S. Stegmann, N. Den Hollander, D. Mittelman, G. Highnam, R. Robison, E. Yang, L. Faivre, A. Roubertie, J.B. Riviere, K.G. Monaghan, K. Wang, E.E. Davis, N. Katsanis, V.M. Kalscheuer, E.H. Wang, K. Metcalfe, T. Kleefstra, A.M. Innes, S. Kitsiou-Tzeli, M. Rosello, C.E. Keegan, G.J. Lyon, TAF1 variants are associated with dysmorphic features, intellectual disability, and neurological manifestations, Am J Hum Genet 97 (2015) 922-932. This manuscript describes bona fide mutations in the TAF1 gene, the gene that is also dysregulated in X-linked dystonia-parkinsonism (XDP) due to several disease-specific changes.Google Scholar
- 89.F.C. Chang, A. Westenberger, R.C. Dale, M. Smith, H.S. Pall, B. Perez-Duenas, P. Grattan-Smith, R.A. Ouvrier, N. Mahant, B.C. Hanna, M. Hunter, J.A. Lawson, C. Max, R. Sachdev, E. Meyer, D. Crimmins, D. Pryor, J.G. Morris, A. Munchau, D. Grozeva, K.J. Carss, L. Raymond, M.A. Kurian, C. Klein, V.S. Fung, Phenotypic insights into ADCY5-associated disease, Mov Disord (2016).Google Scholar
- 90.•• S. Petrovski, S. Kury, C.T. Myers, K. Anyane-Yeboa, B. Cogne, M. Bialer, F. Xia, P. Hemati, J. Riviello, M. Mehaffey, T. Besnard, E. Becraft, A. Wadley, A.R. Politi, S. Colombo, X. Zhu, Z. Ren, I. Andrews, T. Dudding-Byth, A.L. Schneider, G. Wallace, A.B. Rosen, S. Schelley, G.M. Enns, P. Corre, J. Dalton, S. Mercier, X. Latypova, S. Schmitt, E. Guzman, C. Moore, L. Bier, E.L. Heinzen, P. Karachunski, N. Shur, T. Grebe, A. Basinger, J.M. Nguyen, S. Bezieau, K. Wierenga, J.A. Bernstein, I.E. Scheffer, J.A. Rosenfeld, H.C. Mefford, B. Isidor, D.B. Goldstein, Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures, Am J Hum Genet 98 (2016) 1001-1010. This nicely performed screening study elucidated mutations in the GNB1 gene as a rare but recurrent cause of a complex form of dystonia and highlights G protein-mediated signaling as one disease mechanism in dystonia and neurodevelopmental disability.Google Scholar
- 92.L.A. Menke, M. Engelen, M. Alders, V.J. Odekerken, F. Baas, J.M. Cobben, Recurrent GNAO1 mutations associated with developmental delay and a movement disorder, J Child Neurol (2016).Google Scholar
- 95.S. Edvardson, G. Tian, H. Cullen, H. Vanyai, L. Ngo, S. Bhat, A. Aran, M. Daana, N. Da’amseh, B. Abu-Libdeh, N.J. Cowan, J. Heng, O. Elpeleg, Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway, Hum Mol Genet (2016).Google Scholar
- 96.•• Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet. 2016;99:1377–87. This paper represents one of the two studies elucidating KMT2B mutations as a relatively common cause of early-onset dystonia.CrossRefPubMedGoogle Scholar
- 97.•• E. Meyer, K.J. Carss, J. Rankin, J.M. Nichols, D. Grozeva, A.P. Joseph, N.E. Mencacci, A. Papandreou, J. Ng, S. Barral, A. Ngoh, H. Ben-Pazi, M.A. Willemsen, D. Arkadir, A. Barnicoat, H. Bergman, S. Bhate, A. Boys, N. Darin, N. Foulds, N. Gutowski, A. Hills, H. Houlden, J.A. Hurst, Z. Israel, M. Kaminska, P. Limousin, D. Lumsden, S. McKee, S. Misra, S.S. Mohammed, V. Nakou, J. Nicolai, M. Nilsson, H. Pall, K.J. Peall, G.B. Peters, P. Prabhakar, M.S. Reuter, P. Rump, R. Segel, M. Sinnema, M. Smith, P. Turnpenny, S.M. White, D. Wieczorek, S. Wiethoff, B.T. Wilson, G. Winter, C. Wragg, S. Pope, S.J. Heales, D. Morrogh, A. Pittman, L.J. Carr, B. Perez-Duenas, J.P. Lin, A. Reis, W.A. Gahl, C. Toro, K.P. Bhatia, N.W. Wood, E.J. Kamsteeg, W.K. Chong, P. Gissen, M. Topf, R.C. Dale, J.R. Chubb, F.L. Raymond, M.A. Kurian, Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia, Nat Genet (2016). This paper represents one of the two studies elucidating KMT2B mutations as a relatively common cause of early-onset dystonia.Google Scholar
- 98.K. Lohmann, C. Klein, Next generation sequencing and the future of genetic diagnosis, Neurotherapeutics (2014).Google Scholar