Website Edition: February/March 2009

The twists and turns of dystonia genes and loci: an update

By Christine Klein, MD
Professor, Department of Clinical and Molecular Neurogenetics
Department of Neurology, University of Lübeck
Lübeck, Germany

The growing list of 'DYTs' represents an assortment of clinically and genetically heterogeneous forms of dystonia characterized by the key features of involuntary twisting and repetitive movements resulting in abnormal postures (Table). In other familial movement disorders such as monogenic parkinsonism or autosomal dominant ataxia, it is difficult, if not impossible, to distinguish different 'PARKs' or 'SCAs' on clinical grounds. In the dystonias, however, knowledge of important clinical 'red flags' may lead to the correct diagnosis of a specific genetic form even prior to molecular testing: diurnal variation of symptoms and response to levodopa in dopa-responsive dystonia (DRD; DYT5), a combination of dystonia with myoclonus, ameliorated by alcohol intake in myoclonus-dystonia (DYT11) or abrupt onset of severe dystonia and parkinsonism in rapid-onset dystonia-parkinsonism (RDP; DYT12), just to name a few.

New genes and loci

The year 2008 has seen a particularly large number of changes to the list of DYTs including the i) detection of a novel dystonia gene (DYT16); ii) association of a dystonia/dyskinesia phenotype with a gene previously linked to GLUT1 deficiency syndrome (DYT18); iii) identification of a new dystonia gene locus (DYT17); iv) designation of paroxysmal kinesigenic and nonkinesigenic dyskinesia as DYT19 and DYT20, respectively; and v), re-definition of a putatively new form (DYT14) of dopa-responsive dystonia (DRD) as the previously known form of DRD, i.e. DYT5. In the following, a short summary of these new discoveries will be given:

  1. DYT16 dystonia is a recessively inherited form of early-onset generalized dystonia that is associated with a homozygous missense mutation in the PRKRA gene(1). Affected members from three Brazilian families shared the same P222L mutation, inherited from a common founder. This mutation is associated with prominent bulbar involvement with dysphonia, dysarthria, and even dysphagia, reminiscent of DYT6 dystonia or the acute phase of RDP (DYT12). As mentioned by the authors, parkinsonism is a less prominent feature(2). Shortly after the initial report, a patient with early-onset generalized dystonia was described to carry a heterozygous frameshift mutation in PRKRA(3). Currently, little is known about the function of the PRKRA protein, short for protein kinase, interferon-inducible double-stranded RNA-dependent activator. PRKRA binds double-stranded RNA and can also be activated by cellular protein activators.
  2. The SLC2A1 gene, previously linked to GLUT1 deficiency syndrome, was identified to cause also paroxysmal exertion-induced dyskinesia(4,5) and was designated as DYT18. Of note, the clinical picture associated with paroxysmal choreoathetosis with episodic ataxia and spasticity (DYT9) resembles that of DYT18 and has been linked to an overlapping region on chromosome 1p(6). It remains to be seen whether DYT18 and DYT9 are the same condition.
  3. A new dystonia gene locus (DYT17) has been mapped to chromosome 20 in a consanguineous Lebanese family with three sisters suffering from recessively inherited primary focal torsion dystonia with onset in adolescence. Prominent features include dystonia and dysarthria, along with segmental or generalized dystonia(7). iv) A second form of paroxysmal kinesigenic and of nonkinesigenic dyskinesia was designated as DYT19(8) and DYT20(9) respectively.
  4. A putatively new form (DYT14) of DRD was found to be identical with classic DRD (DYT5). Misclassification of one patient from the putative DYT14 family had led to false locus assignment to an area outside of the GCH1 gene. After exclusion of this patient, linkage became compatible with DYT5, and a deletion of the GCH1 gene was found as the disease cause(10).
Advances in the understanding of known genes

The pathophysiological basis of dystonias with an emphasis on known monogenic forms has been summarized in an excellent review article(11). For example, recent studies have further implicated the DYT1-encoded protein, TorsinA, in a disease mechanism involving mislocalization to the nuclear envelope(12,13). Previous findings of a protective effect of an intragenic polymorphism, D216H, in carriers of the DYT1 mutation(14) could be confirmed in a large European sample of mutation carriers(15). Very recently, the mitochondrial targeting sequence of the MR-1 gene was demonstrated to confer a deleterious action leading to paroxysmal non-kinesigenic dyskinesia (DYT8)(16).

Future perspectives

One may expect that new dystonia gene loci will be added, while others will be 'merged' or even 'disappear'. It is difficult even for the dystonia specialist to keep up with these rapid changes in locus assignment, and there is an urgent need for a more rigorous and consistent classification scheme for monogenic forms of dystonia. The identification of new dystonia genes will improve our understanding of the rare monogenic forms and of dystonia in general. Although genetics are likely to play an important role also in focal and segmental dystonia, no such factor has yet been identified. Genome-wide association studies will be a critical future aim in dystonia research. Due to the relative rarity even of focal forms of the disease, large-scale international collaborations will be necessary to achieve this important goal.

Table: Monogenic forms of dystonia with a DYT designation

Designation Dystonia type Inheritance Gene locus Gene OMIM number
DYT1 Early-onset generalized torsion dystonia (TD) Autosomal dominant 9q GAG deletion in DYT1 128100
DYT2 Autosomal recessive TD Autosomal recessive Unknown Unknown 224500
DYT3 X-linked dystonia parkinsonism; "lubag" X-chromosomal recessive Xq TAF1/DY T3 314250
DYT4 "Non-DYT1" TD; whispering dysphonia Autosomal dominant Unknown Unknown 128101
DYT5a/DYT14

DYT5b
Dopa-responsive dystonia; Segawa syndrome Autosomal dominant

Autosomal recessive
14q

11p
GTP-cyclohydrolase

Tyrosine hydroxylase
128230
DYT6 Adolescent-onset TD of mixed type Autosomal dominant 8p Unknown 602629
DYT7 Adult-onset focal TD Autosomal dominant 18p Unknown 602124
DYT8 Paroxysmal nonkinesigenic dyskinesia Autosomal dominant 2q Myofibrillo-genesis regulator 1 118800
DYT9 Paroxysmal choreoathetosis with episodic ataxia and spasticity Autosomal dominant 1p Unknown 601042
DYT10 Paroxysmal kinesigenic choreoathetosis Autosomal dominant 16p-q Unknown 128200
DYT11 Myoclonus-dystonia Autosomal dominant 7q epsilon-sarcoglycan 159900
DYT12 Rapid-onset dystonia-parkinsonism Autosomal dominant 19q Na/K ATPase alpha 3 128235
DYT13 Multifocal/segmental dystonia Autosomal dominant 1p unknown 607671
DYT14/DYT5a Dopa-responsive dystonia Autosomal dominant 14q GTP-cyclohydrolase 607195
DYT15 Myoclonus-dystonia Autosomal dominant 18p unknown 607488
DYT16 Young-onset dystonia-parkinsonism Autosomal recessive 2p PRKRA 603424
DYT17 Autosomal recessive primary torsion dystonia Autosomal recessive 20pq unknown 612406
DYT18 Paroxysmal exertion-induced dyskinesia 2 Autosomal dominant 1p SLC2A1 612126
DYT19 Episodic kinesigenic dyskinesia 2 Autosomal dominant 16q unknown 611031
DYT20 Paroxysmal nonkinesigenic dyskinesia 2 Autosomal dominant 2q unknown 607488

Adapted from www.ncbi.nlm.nih.gov/omim/. New designations/loci/genes from 2008 are highlighted.

Acknowledgments

CK is supported by a Lichtenberg Grant from the Volkswagen Foundation and a Career Development Award from the Hermann and Lilly Schilling Foundation.

References
  1. Camargos S, Scholz S, Simon-Sanchez J, et al. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol 2008;7(3):207-215.
  2. Klein C. DYT16: a new twist to familial dystonia. Lancet Neurol 2008;7(3):192-193.
  3. Seibler P, Djarmati A, Langpap B, et al. A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalised dystonia in a German patient. Lancet Neurol 2008;7(5):380-381.
  4. Weber YG, Storch A, Wuttke TV, 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(6):2157-2168.
  5. 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(Pt 7):1831-1844.
  6. Auburger G, Ratzlaff T, Lunkes A, et al. A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197. Genomics 1996;31(1):90-94.
  7. Chouery 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(4):287-293.
  8. Valente EM, Spacey SD, Wali GM, et al. A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16. Brain 2000;123 ( Pt 10):2040-2045.
  9. Spacey SD, Adams PJ, Lam PC, et al. Genetic heterogeneity in paroxysmal nonkinesigenic dyskinesia. Neurology 2006;66(10):1588-1590.
  10. Wider C, Melquist S, Hauf M, et al. Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5. Neurology 2008;70(16 Pt 2):1377-1383.
  11. Breakefield XO, Blood AJ, Li Y, Hallett M, Hanson PI, Standaert DG. The pathophysiological basis of dystonias. Nat Rev Neurosci 2008;9(3):222-234.
  12. Nery FC, Zeng J, Niland BP, et al. TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton. J Cell Sci 2008;121(Pt 20):3476-3486.
  13. Giles LM, Chen J, Li L, Chin LS. Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope. Hum Mol Genet 2008;17(17):2712-2722.
  14. Risch NJ, Bressman SB, Senthil G, Ozelius LJ. Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia. Am J Hum Genet 2007;80(6):1188-1193.
  15. Kamm C, Fischer H, Garavaglia B, et al. Susceptibility to DYT1 dystonia in European patients is modified by the D216H polymorphism. Neurology 2008;70(23):2261-2262.
  16. 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.

Christine KleinAbout Dr. Klein:
Dr. Christine Klein is a native of Hamburg, Germany. She attended the Medical Schools of Hamburg, Heidelberg, and Luebeck, Germany, and took her final year studies in England, including one trimester at The National Hospital for Neurology and Neurosurgery, Queen Square, London. She moved to Boston from 1997-1999 for a fellowship in Molecular Neurogenetics under the mentorship of Dr. X. O. Breakefield. Dr. Klein completed her neurology training at Luebeck University with Dr. D. Koempf in 2004, followed by a research and clinical fellowship in movement disorders with Dr. A. E. Lang in Toronto, Canada. She was appointed a Lichtenberg Professor of Clinical and Molecular Neurogenetics at the Department of Neurology of Luebeck University in 2005, where her research has focused on the clinical and molecular genetics of movement disorders. Dr. Klein is a past member of the Editorial Board of the Movement Disorders Journal and a present member of the Editorial Board of Neurology. She has published close to 200 scientific papers and is the recipient of the Heinrich Pette Award of the German Neurological Association (2007) and of the Derek Denny-Brown Award of the American Neurological Association (2008). In February 2009, Dr. Klein becomes head of the new Schilling Department of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Germany.