ABSTRACT
Dystonia is characterized by muscle contractions leading to abnormal postures with involuntary twisting and repetitive movements. Inherited dystonia designated by DYT locus symbols can be separated into three broad phenotypic categories: primary torsion dystonia (PTD), where dystonia is the only clinical sign (except for tremor) (DYT1, 2, 4, 6, 7, 13, 17, and 21); dystonia plus loci, where other phenotypes in addition to dystonia, including parkinsonism or myoclonus, are present (DYT3, 5/14, 11, 12, 15, and 16); and paroxysmal forms of dystonia/dyskinesia (DYT8, 9, 10, 18, 19, and 20). Currently, 19 loci including 10 genes have been identified for inherited dystonias. In this review, the phenotypes associated with these loci and the responsible genes will be discussed.
KEYWORDS
Primary torsion dystonia - dystonia plus - paroxysmal dystonia - dystonia genes
REFERENCES
-
1
Nutt J G, Muenter M D, Aronson A, Kurland L T, Melton III L J.
Epidemiology of focal and generalized dystonia in Rochester, Minnesota.
Mov Disord.
1988;
3
(3)
188-194
-
2
Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group .
A prevalence study of primary dystonia in eight European countries.
J Neurol.
2000;
247
(10)
787-792
-
3
Risch N, de Leon D, Ozelius L et al..
Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.
Nat Genet.
1995;
9
(2)
152-159
-
4
Ozelius L J, Hewett J W, Page C E et al..
The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein.
Nat Genet.
1997;
17
(1)
40-48
-
5
Ozelius L J, Bressman S B.
Genetic and clinical features of primary torsion dystonia.
Neurobiol Dis.
2011;
42
(2)
127-135
-
6
Zirn B, Grundmann K, Huppke P et al..
Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1).
J Neurol Neurosurg Psychiatry.
2008;
79
(12)
1327-1330
-
7
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
(9)
646-650
-
8
Schmidt A, Klein C.
The role of genes in causing dystonia.
Eur J Neurol.
2010;
17
(Suppl 1)
65-70
-
9
Edwards M J, Huang Y Z, Wood N W, Rothwell J C, Bhatia K P.
Different patterns of electrophysiological deficits in manifesting and non-manifesting carriers of the DYT1 gene mutation.
Brain.
2003;
126
(Pt 9)
2074-2080
-
10
Saunders-Pullman R, Shriberg J, Shanker V, Bressman S B.
Penetrance and expression of dystonia genes.
Adv Neurol.
2004;
94
121-125
-
11
Kock N, Naismith T V, Boston H E et al..
Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier.
Hum Mol Genet.
2006;
15
(8)
1355-1364
-
12
Risch N J, Bressman S B, Senthil G, Ozelius L J.
Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia.
Am J Hum Genet.
2007;
80
(6)
1188-1193
-
13
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
-
14
Granata A, Warner T T.
The role of torsinA in dystonia.
Eur J Neurol.
2010;
17
(Suppl 1)
81-87
-
15
Warner T T, Granata A, Schiavo G.
TorsinA and DYT1 dystonia: a synaptopathy?.
Biochem Soc Trans.
2010;
38
(2)
452-456
-
16
Tanabe L M, Kim C E, Alagem N, Dauer W T.
Primary dystonia: molecules and mechanisms.
Nat Rev Neurol.
2009;
5
(11)
598-609
-
17
Bragg D C, Armata I A, Nery F C, Breakefield X O, Sharma N.
Molecular pathways in dystonia.
Neurobiol Dis.
2011;
42
(2)
136-147
-
18
Ozelius L J, Lubarr N, Bressman S B.
Milestones in dystonia.
Mov Disord.
2011;
26
(6)
1106-1126
-
19
Wilcox R A, Winkler S, Lohmann K, Klein C.
Whispering dysphonia in an Australian family (DYT4): A clinical and genetic reappraisal.
Mov Disord.
2011;
In press
-
20
Fuchs T, Gavarini S, Saunders-Pullman R et al..
Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia.
Nat Genet.
2009;
41
(3)
286-288
-
21
Bonetti M, Barzaghi C, Brancati F et al..
Mutation screening of the DYT6/THAP1 gene in Italy.
Mov Disord.
2009;
24
(16)
2424-2427
-
22
Djarmati A, Schneider S A, Lohmann K et al..
Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study.
Lancet Neurol.
2009;
8
(5)
447-452
-
23
Bressman S B, Raymond D, Fuchs T, Heiman G A, Ozelius L J, Saunders-Pullman R.
Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study.
Lancet Neurol.
2009;
8
(5)
441-446
-
24
Paisán-Ruiz C, Ruiz-Martinez J, Ruibal M et al..
Identification of a novel THAP1 mutation at R29 amino-acid residue in sporadic patients with early-onset dystonia.
Mov Disord.
2009;
24
(16)
2428-2429
-
25
Clot F, Grabli D, Burbaud P et al..
Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype.
Neurogenetics.
2011;
12
(1)
87-89
-
26
Groen J L, Ritz K, Contarino M F et al..
DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation.
Mov Disord.
2010;
25
(14)
2420-2427
-
27
Houlden H, Schneider S A, Paudel R et al..
THAP1 mutations (DYT6) are an additional cause of early-onset dystonia.
Neurology.
2010;
74
(10)
846-850
-
28
Söhn A S, Glöckle N, Doetzer A D et al..
Prevalence of THAP1 sequence variants in German patients with primary dystonia.
Mov Disord.
2010;
25
(12)
1982-1986
-
29
Zittel S, Moll C K, Brüggemann N et al..
Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families.
Mov Disord.
2010;
25
(14)
2405-2412
-
30
Xiao J, Zhao Y, Bastian R W et al..
Novel THAP1 sequence variants in primary dystonia.
Neurology.
2010;
74
(3)
229-238
-
31
Groen J L, Yildirim E, Ritz K et al..
THAP1 mutations are infrequent in spasmodic dysphonia.
Mov Disord.
2011;
(Apr)
29
-
32
Blanchard A, Roubertie A, Simonetta-Moreau M et al..
Singular DYT6 phenotypes in association with new THAP1 frameshift mutations.
Mov Disord.
2011;
26
(9)
1775-1777
-
33
Jech R, Bareš M, Křepelová A, Urgošík D, Havránková P, Růžička E.
DYT 6—a novel THAP1 mutation with excellent effect on pallidal DBS.
Mov Disord.
2011;
26
(5)
924-925
-
34
Schneider S A, Ramirez A, Shafiee K et al..
Homozygous THAP1 mutations as cause of early-onset generalized dystonia.
Mov Disord.
2011;
26
(5)
858-861
-
35
Cheng F B, Wan X H, Feng J C, Wang L, Yang Y M, Cui L Y.
Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China.
Eur J Neurol.
2011;
18
(3)
497-503
-
36
De Carvalho Aguiar P, Fuchs T, Borges V et al..
Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion.
Mov Disord.
2010;
25
(16)
2854-2857
-
37
Gavarini S, Cayrol C, Fuchs T et al..
Direct interaction between causative genes of DYT1 and DYT6 primary dystonia.
Ann Neurol.
2010;
68
(4)
549-553
-
38
Clouaire T, Roussigne M, Ecochard V, Mathe C, Amalric F, Girard J P.
The THAP domain of THAP1 is a large C2CH module with zinc-dependent sequence-specific DNA-binding activity.
Proc Natl Acad Sci U S A.
2005;
102
(19)
6907-6912
-
39
Roussigne M, Cayrol C, Clouaire T, Amalric F, Girard J P.
THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies.
Oncogene.
2003;
22
(16)
2432-2442
-
40
Cayrol C, Lacroix C, Mathe C et al..
The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes.
Blood.
2007;
109
(2)
584-594
-
41
Duan W, Zhang Z, Gash D M, Mattson M P.
Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease.
Ann Neurol.
1999;
46
(4)
587-597
-
42
Kaiser F J, Osmanoric A, Rakovic A et al..
The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6).
Ann Neurol.
2010;
68
(4)
554-559
-
43
Valente E M, Bentivoglio A R, Cassetta E et al..
DYT13, a novel primary torsion dystonia locus, maps to chromosome 1p36.13–36.32 in an Italian family with cranial-cervical or upper limb onset.
Ann Neurol.
2001;
49
(3)
362-366
-
44
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
-
45
Defazio G, Berardelli A, Hallett M.
Do primary adult-onset focal dystonias share aetiological factors?.
Brain.
2007;
130
(Pt 5)
1183-1193
-
46
Waddy H M, Fletcher N A, Harding A E, Marsden C D.
A genetic study of idiopathic focal dystonias.
Ann Neurol.
1991;
29
(3)
320-324
-
47
Leube B, Rudnicki D, Ratzlaff T, Kessler K R, Benecke R, Auburger G.
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
(10)
1673-1677
-
48
Norgren N, Mattson E, Forsgren L, Holmberg M.
A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3
Neurogenetics.
2011;
12
(2)
137-143
-
49
Jarman P R, del Grosso N, Valente E M et al..
Primary torsion dystonia: the search for genes is not over.
J Neurol Neurosurg Psychiatry.
1999;
67
(3)
395-397
-
50
Müller U.
The monogenic primary dystonias.
Brain.
2009;
132
(Pt 8)
2005-2025
-
51
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
-
52
Waters C H, Faust P L, Powers J et al..
Neuropathology of lubag (x-linked dystonia parkinsonism).
Mov Disord.
1993;
8
(3)
387-390
-
53
Evidente V G, Advincula J, Esteban R et al..
Phenomenology of “Lubag” or X-linked dystonia-parkinsonism.
Mov Disord.
2002;
17
(6)
1271-1277
-
54
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
(1)
7-17
-
55
Makino S, Kaji R, Ando S et al..
Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism.
Am J Hum Genet.
2007;
80
(3)
393-406
-
56
Segawa M.
Dopa-responsive dystonia.
Handb Clin Neurol.
2011;
100
539-557
-
57
Arrabal L, Teresa L, Sánchez-Alcudia R et al..
Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant.
Neurogenetics.
2011;
12
(3)
183-191
-
58
Grötzsch H, Pizzolato G P, Ghika J et al..
Neuropathology of a case of dopa-responsive dystonia associated with a new genetic locus, DYT14.
Neurology.
2002;
58
(12)
1839-1842
-
59
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
-
60
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
(Pt 3)
828-835
-
61
Blanco-Arias P, Einholm A P, Mamsa H et al..
A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia-parkinsonism.
Hum Mol Genet.
2009;
18
(13)
2370-2377
-
62
Einholm A P, Toustrup-Jensen M S, Holm R, Andersen J P, Vilsen B.
The rapid-onset dystonia parkinsonism mutation D923N of the Na+, K+-ATPase alpha3 isoform disrupts Na+ interaction at the third Na+ site.
J Biol Chem.
2010;
285
(34)
26245-26254
-
63
Rodacker V, Toustrup-Jensen M, Vilsen B.
Mutations Phe785Leu and Thr618Met in Na+,K+-ATPase, associated with familial rapid-onset dystonia parkinsonism, interfere with Na+ interaction by distinct mechanisms.
J Biol Chem.
2006;
281
(27)
18539-18548
-
64
Kabakci K, Isbruch K, Schilling K et al..
Genetic heterogeneity in rapid onset dystonia-parkinsonism: description of a new family.
J Neurol Neurosurg Psychiatry.
2005;
76
(6)
860-862
-
65
Camargos S, Scholz S, Simón-Sánchez 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
-
66
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
-
67
Nardocci N.
Myoclonus-dystonia syndrome.
Handb Clin Neurol.
2011;
100
563-575
-
68
Kyllerman M, Forsgren L, Sanner G, Holmgren G, Wahlström J, Drugge U.
Alcohol-responsive myoclonic dystonia in a large family: dominant inheritance and phenotypic variation.
Mov Disord.
1990;
5
(4)
270-279
-
69
Peall K J, Waite A J, Blake D J, Owen M J, Morris H R.
Psychiatric disorders, myoclonus dystonia, and the epsilon-sarcoglycan gene: A systematic review.
Mov Disord.
2011;
(Jun)
28
-
70
Kinugawa K, Vidailhet M, Clot F, Apartis E, Grabli D, Roze E.
Myoclonus-dystonia: an update.
Mov Disord.
2009;
24
(4)
479-489
-
71
Asmus F, Hjermind L E, Dupont E et al..
Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype.
Brain.
2007;
130
(Pt 10)
2736-2745
-
72
Bonnet C, Grégoire M J, Vibert M, Raffo E, Leheup B, Jonveaux P.
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
(10)
876-885
-
73
Guettard E, Portnoi M F, Lohmann-Hedrich K et al..
Myoclonus-dystonia due to maternal uniparental disomy.
Arch Neurol.
2008;
65
(10)
1380-1385
-
74
Zimprich A, Grabowski M, Asmus F et al..
Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.
Nat Genet.
2001;
29
(1)
66-69
-
75
Beukers R J, Foncke E M, van der Meer J N, Veltman D J, Tijssen M A.
Functional magnetic resonance imaging evidence of incomplete maternal imprinting in myoclonus-dystonia.
Arch Neurol.
2011;
68
(6)
802-805
-
76
Hack A A, Groh M E, McNally E M.
Sarcoglycans in muscular dystrophy.
Microsc Res Tech.
2000;
48
(3-4)
167-180
-
77
Han F, Racacho L, Lang A E, Bulman D E, Grimes D A.
Refinement of the DYT15 locus in myoclonus dystonia.
Mov Disord.
2007;
22
(6)
888-892
-
78
Grimes D A, Han F, Lang A E, St George-Hyssop P, Racacho L, Bulman D E.
A novel locus for inherited myoclonus-dystonia on 18p11.
Neurology.
2002;
59
(8)
1183-1186
-
79
Bruno M K, Lee H Y, Auburger G W et al..
Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia.
Neurology.
2007;
68
(21)
1782-1789
-
80
Rainier S, Thomas D, Tokarz D et al..
Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis.
Arch Neurol.
2004;
61
(7)
1025-1029
-
81
Lee H Y, Xu Y, Huang Y et al..
The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway.
Hum Mol Genet.
2004;
13
(24)
3161-3170
-
82
van Rootselaar A F, Schade van Westrum S, Velis D N, Tijssen M A.
The paroxysmal dyskinesias.
Pract Neurol.
2009;
9
(2)
102-109
-
83
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
(6)
1058-1064
-
84
Spacey S D, Adams P J, Lam P C et al..
Genetic heterogeneity in paroxysmal nonkinesigenic dyskinesia.
Neurology.
2006;
66
(10)
1588-1590
-
85
Mehta S H, Morgan J C, Sethi K D.
Paroxysmal dyskinesias.
Curr Treat Options Neurol.
2009;
11
(3)
170-178
-
86
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
-
87
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
(6)
2157-2168
-
88
Schneider S A, Paisan-Ruiz C, Garcia-Gorostiaga I et al..
GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias.
Mov Disord.
2009;
24
(11)
1684-1688
-
89
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
(2)
483-488
-
90
Weber Y G, Kamm C, Suls A et al..
Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.
Neurology.
2011;
77
(10)
959-964
-
91
Ku C S, Naidoo N, Pawitan Y.
Revisiting Mendelian disorders through exome sequencing.
Hum Genet.
2011;
129
(4)
351-370
Laurie J. OzeliusPh.D.
Associate Professor, Department of Genetics and Genomic Sciences and Neurology, Mount Sinai School of Medicine
One Gustave L. Levy Place, Box 1498, New York, NY 10029
eMail: laurie.ozelius@mssm.edu
