94. Han F, Racacho L, Lang AE, Bulman DE, Grimes DA. Refi nement of the DYT15 locus in myoc lonus dystonia. Mov Disord 2007; 22 : 888 \200\2239 2 . 95. Waters CH, Faust PL, Powers J, et al. Neuropathology of lubag (X-linke d dystonia parkinsonism). Mov Disord 1993; 8 : 387 \200\2239 0 . 96. Waters CH, Takahashi H, Wilhelmsen KC, et al. Phenotypic expression of X-linke d dyston ia-parkinsonis m (lubag) in two women. Neurology 1993; 43 : 1555 \200\2238 . 119. Rainier S, Th omas D, Tokarz D, et al. Myofi brillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol 2004; 61 : 1025 \200\2239 . 97. Evidente VG, Advincula J, Esteban R, et al. Phenomenology of \200\230lubag \200\231 or 120. Lee HY, Xu Y, Huang Y, et al. Th e gene for paroxysmal non-kinesigeni c dyskinesia enc odes an enzyme in a stress response pathway. Hum Mol Genet 2004; 13 : 3161 \200\2237 0 . X-linke d dystonia-parkinsonis m. Mov Disord 2002; 17 : 1271 \200\2237 . 98. Evidente VG, Nolte D, Niemann S, et al. Phenotypic and molecular analyzes of X-linke d dystonia-parkinsonis m ( \200\230lubag \200\231) in women. Arch Neurol 2004; 61 : 1956 \200\2239 . 121. Hempelmann A, Kumar S, Muralitharan S, Sander T. Myofi brillogenesis regulator 1 gene (MR- 1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia. Neurosci Let t 2006; 402 : 118 \200\2232 0 . 99. Lee LV, Maranon E, Demaisip C, et al. Th e natural history of sex-linke d recessive dys tonia parkinsonism of Panay, Philippines (XDP). Parkinsonism Relat Disord 2002; 9 : 29 \200 \2233 8 . 122. Spacey SD, Adams PJ, Lam PC, et al. Genetic heterogeneity in paroxys- mal nonkinesigenic dyskinesia. Neurology 2006; 66 : 1588 \200\2239 0 . 100. Lee LV, Rivera C, Teleg RA, et al. Th e unique phenomenology of sex-linke d dystonia p arkinsonism (XDP, DYT3, \200\230lubag \200\231). Int J Neurosci 2011; 121 (Suppl 1): 3 \200\2231 1 . 123. Tomita H, Nagamitsu S, Wakui K, et al. Paroxysmal kinesigenic chore- oathetosis locus maps to chromosome 16p11. 2-q12.1. Am J Hum Genet 1999; 65 : 1688 \200\2239 7 . 101. Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H. Hereditary pro- gressive dystonia wi th marked diurnal fl uctuation. Adv Neurol 1976; 14 : 215 \200\2233 3 . 124. Kikuchi T, Nomura M, Tomita H, et al. Paroxysmal kinesigenic chore- oathetosis (PKC): confi rmation of linkage to 16p11-q2 1, but unsuccess- ful detection of mutations among 157 genes at the PKC-critica l region in seven PKC families. J Hum Genet 2007; 52 : 334 \200 \2234 1 . 102. Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsiv e dystonia. Adv Neurol 1988; 50 : 377 \200\2238 4 . 125. Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China. Eur J Neurol 2011; 18 : 497 \200\22350 3 . 103. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dysto- nia with marked diurnal fl uctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994; 8 : 236 \200\2234 2 . 126. Wang JL, Cao L, Li XH, et al. Identifi cation of PRRT2 as the causa- tive gene of paro xysmal kinesigenic dyskinesias. Brain 2011; 134 : 3493 \200\223501 . 104. Hagenah J, Saunders-Pullman R, Hedrich K, et al. High mutation rate in dopa-responsiv e dystonia: detection with comprehensive GCHI screen- ing. Neurology 2005; 64 : 908 \200 \2231 1 . 127. Valente EM, Spacey SD, Wali GM, et al. A second paroxysmal kinesi- genic choreoathetos is locus (EKD2) mapping on 16q13-q2 2.1 indicates a family of genes which give rise to paro xysmal disorders on human chromosome 16. Brain 2000; 123 : 2040 \200\2235 . 105. Steinberger D, Weber Y, Korinthenberg R, et al. High penetrance and pronounced variati on in expressivity of GCH1 mutations in fi ve fami- lies with dopa-responsiv e dystonia. An n Neurol 1998; 43 : 634 \200\2239 . 106. Furukawa Y, Graf WD, Wong H, Shimadzu M, Kish SJ. Dopa-responsiv e dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) g ene mutations. Neurology 2001; 56 : 260 \200\2233 . 128. Spacey SD, Valente EM, Wali GM, et al. Genetic and clinical heteroge- neity in paroxys mal kinesigenic dyskinesia: evidence for a third EKD gene. Mov Disord 2002; 17 : 717 \200 \2232 5 . 107. Ludecke B, Dworniczak B, Bartholome K. A point mutation in the tyro- sine hydroxylase gene associated with Segawa \200\231s syndrome. Hum Genet 1995; 95 : 123 \200\2235 . 129. Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a cause of paroxysmal exerti on-induce d dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 2008; 1 18 : 2157 \200\2236 8 . 108. Abeling NG, Duran M, Bakker HD, et al. Sepiapterin reductase defi - ciency: an autosom al recessive DOPA-responsiv e dystonia. Mol Genet Metab 2006; 89 : 116 \200\2232 0 . 130. Suls A, Dedeken P, Goffi n K, et al. Paroxysmal exercise-induce d dyski- nesia and epi lepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 2008; 13 1 : 1831 \200\2234 4 . 109. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al. Mutations in the Na + /K + -AT Pase alpha3 gene ATP1A3 are associated with rapid-onse t dystonia parkinsonism. Neuron 2004 ; 43 : 169 \200\2237 5 . 131. Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I, et al. GLUT1 gene mutations cause sp oradic paroxysmal exercise-induce d dyskinesias. Mov Disord 2009; 24 : 1684 \200\2238 . 110. Lee JY, Gollamudi S, Ozelius LJ, Kim JY, Jeon BS. ATP1A3 mutation in the fi rst Asian case of rapid-onse t dystonia-parkinsonis m. Mov Disord 2007; 22 : 1808 \200\2239 . 132. Roubergue A, Apartis E, Mesnage V, et al. Dystonic tremor caused by mutation of the gl ucose transporter gene GLUT1. J Inherit Metab Dis 2011; 34 : 483 \200\2238 . 111. Brashear A, Dobyns WB, de Carvalho Aguiar P, et al. Th e phenotypic spectrum of rapid- onse t dystonia-parkinsonis m (RDP) and mutations in the ATP1A3 gene. Brain 2007; 130 : 828 \200\2233 5 . 133. Weber YG, Kamm C, Suls A, et al. Paroxysmal choreoathetosis/spastic- ity (DYT9) is caused by a GLUT1 defect. Neurology 2011; 77 : 959 \200\2236 4 . 134. Kojovic M, Kuoppamaki M, Quinn N, Bhatia KP. \200\230Progressive delayed-onse t postanoxic dystonia \200\231 diagnosed with PANK2 mutat ions 26 years aft er onset \200\224a n update. Mov Disord 2010; 25 : 2889 \200\2239 1 . 112. Camargos S, Scholz S, Simon-Sanchez J, et al. DYT16, a novel young-on- se t dystonia-p arkinsonis m disorder: identifi cation of a segregating mutation in the stress-respons e pr otein PRKRA. Lancet Neurol 2008; 7 : 207 \200\2231 5 . 135. Kuoppamaki M, Bhatia KP, Quinn N. Progressive delayed-onse t dystonia aft er cerebral anoxic insult in adults. Mov Disord 2002; 17 : 1345 \200\2239 . 113. 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 : 38 0 \200\2231 . 136. Bhatia KP, Marsden CD. Th e behavioral and motor consequences of focal lesions of the basal ganglia in man. Brain 1994; 117 : 859 \200\2237 6 . 137. Lee JH, Ki CS, Kim DS, Cho J W, Park KP, Kim S. Dopa-responsiv e dys- tonia with a novel initiation codon mutation in th e GCH1 gene misdi- agnosed as cerebral palsy. J Korean Med Sci 2011; 26 : 1244 \200\2236 . 114. Klein C. DYT16: a new twist to familial dystonia. Lancet Neurol 2008; 7 : 192 \200\2233 . 115. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classifi cation. Ann Neurol 1995; 38 : 571 \200\2239 . 138. Slawek J, Friedman A, Bogucki A, Budrewicz S, Banach M. Dopa- responsiv e dystonia (Se gawa variant): clinical analysis of 7 cases with delayed diagnosis. Neurol Neurochir Pol 20 03; 37 (Suppl 5): 117 \200\2232 6 . 116. Fouad GT, Servidei S, Durcan S, Bertini E, Ptacek LJ. A gene for famil- ial paroxysmal dyskinesia (FPD1) maps to chromosome 2q. Am J Hum Genet 1996; 59 : 135 \200\2239 . CHAPTER 17 Dystonia: an overview 189 160. Coubes P, Cif L, El Fertit H, et al. Electrical stimulation of the globus pal- lidus i nternus in patients with primary generalized dystonia: long-ter m results. J Neurosurg 2004 ; 101 : 189 \200\2239 4 . 139. Kiriakakis V, Bhatia KP, Quinn NP, Marsden CD. Th e natural history of tardive dystoni a: a long-ter m follow-u p study of 107 cases. Brain 1998; 121 : 2053 \200\2236 6 . 161. Coubes P, Roubertie A, Vayssiere N, Hemm S, Echenne B. Treatment of DYT1-generalize d dystonia by stimulation of the internal globus pal- lidus. Lancet 2000; 355 : 2220 \200 \2231 . 140. Fiorio M, Gambarin M, Valente EM, et al. Defective temporal process- ing of sensory st imuli in DYT1 mutation carriers: a new endophenotype of dystonia? Brain 2007; 130 : 134 \200\2234 2 . 162. Egidi M, Franzini A, Marras C, et al. A survey of Italian cases of dystonia treated by deep brain stimulation. J Neurosurg Sci 2007; 51 : 153 \200\2238 . 163. Borggraefe I, Boe tzel K, Boehmer J, et al. Return to participation \200\224 signifi cant improvement aft er bilateral pallidal stimulation in rapidly progressive DYT- 1 dystonia. Neuropediatrics 2008 ; 39 : 239 \200\2234 2 . 141. Bara-Jimenez W, Shelton P, Hallett M. Spatial discrimination is abnor- mal in focal hand dystonia. Neurology 2000; 55 : 1869 \200\2237 3 . 142. Sanger TD, Tarsy D, Pascual-Leone A. Abnormalities of spatial and tem- poral sensory d iscrimination in writer \200\231s cramp. Mov Disord 2001; 16 : 94 \200\2239 . 164. Borggraefe I, Mehrkens JH, Telegravciska M, Berweck S, Botzel K, Heinen F. Bilateral p allidal stimulation in children and adoles- cents with primary generalized dystonia \200 \224report of six patients and literature-base d analysis of predictive outcomes variables. Brain Dev 2010; 32 : 223 \200\2238 . 143. Tinazzi M, Fiaschi A, Frasson E, Fiorio M, Cortese F, Aglioti SM. Defi cits of tempora l discrimination in dystonia are independent from the spatial distance between the loci of tactile stimulation. Mov Disord 2002; 17 : 333 \200\2238 . 144. Scontrini A, Conte A, Fabbrini G, et al. Somatosensory temporal dis- crimination teste d in patients receiving botulinum toxin injection for cervical dystonia. Mov Disord 2011; 2 6 : 742 \200\2236 . 165. Isaias IU, Alterman RL, Tagliati M. Deep brain stimulation for pri- mary generalized d ystonia: long-ter m outcomes. Arch Neurol 2009; 66 : 465 \200\2237 0 . 145. Bradley D, Whelan R, Kimmich O, et al. Temporal discrimination thresholds in adult-ons e t primary torsion dystonia: an analysis by task type and by dystonia phenotype. J Neurol 2012; 259 : 77 \200\22382 . 166. Isaias IU, Alterman RL, Tagliati M. Outcome predictors of pallidal stim- ulation in pa tients with primary dystonia: the role of disease duration. Brain 2008; 131 : 1895 \200\223 90 2 . 146. Bradley D, Whelan R, Walsh R, et al. Comparing endophenotypes in adult-onse t primary torsion dystonia. Mov Disord 2010; 25 : 84 \200\2239 0 . 147. Bradley D, Whelan R, Walsh R, et al. Temporal discrimination thresh- old: VBM evidence for an endophenotype in adult ons et primary tor- sion dystonia. Brain 2009; 132 : 2327 \200\2233 5 . 167. Loher TJ, Capelle HH, Kaelin-Lang A, et al. Deep brain stimulation for dystonia: outco me at long-ter m follow-u p. J Neurol 2008; 255 : 881 \200\2234 . 168. Benecke R, Jost WH, Kanovsky P, Ruzicka E, Comes G, Grafe S. A new botulinum toxin typ e A free of complexing proteins for treatment of cervical dystonia. Neurology 2005; 64 : 19 49 \200\2235 1 . 148. Frima N, Nasir J, Grunewald RA. Abnormal vibration-induce d illusion of movement in id iopathic focal dystonia: an endophenotypic marker? Mov Disord 2008; 23 : 373 \200\2237 . 169. Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A a nd B for the treatment of cervical dystonia. Neurology 2005; 65 : 1423 \200\2239 . 149. Frima N, Rome SM, Grunewald RA. Th e eff ect of fatigue on abnormal vibration induced illusion of movement in idiopathic focal dystonia. J Neurol Neurosurg Psychiatry 2003; 74 : 1154 \200\2236 . 170. Krauss JK, Pohle T, Weber S, Ozdoba C, Burgunder JM. Bilateral stim- ulation of globus pallidus internus for treatment of cervical dystonia. Lancet 1999; 354 : 837 \200\2238 . 150. Grunewald RA, Yoneda Y, Shipman JM, Sagar HJ. Idiopathic focal dys- tonia: a disorder of muscle spindle aff erent processing? Brain 1997; 120 : 2179 \200\2238 5 . 171. Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dys- tonia. J Clin Neurophysiol 2004; 21 : 18 \200\2233 0 . 151. Rome S, Grunewald RA. Abnormal perception of vibration-induce d illusion of movement i n dystonia. Neurology 1999; 53 : 1794 \200\22380 0 . 152. Fiorio M, Tinazzi M, Aglioti SM. Selective impairment of hand mental 172. Eltahawy HA, Saint-Cyr J, Poon YY, Moro E, Lang AE, Lozano AM. Pallidal deep brain sti mulation in cervical dystonia: clinical outcome in four cases. Can J Neurol Sci 2004; 31 : 328 \200\2233 2 . rotation in patients with focal hand dystonia. Brain 2006; 129 : 47 \200\2235 4 . 173. Bhatia KP. Familial (idiopathic) paroxysmal dyskinesias: an update. 153. Hallett M. Neurophysiology of dystonia: the role of inhibition. Neurobiol Semin Neurol 2001; 21 : 69 \200\2237 4 . Dis 2011; 42 : 177 \200\2238 4 . 174. Bhatia KP. Th e paroxysmal dyskinesias. J Neurol 1999; 246 : 149 \200\2235 5 . 175. Kl epper J. Glucose transporter defi ciency syndrome (GLUT1DS) and 154. Edwards MJ, Huang YZ, Wood NW, Rothwell JC, Bhatia KP. Diff erent patterns of electrop hysiological defi cits in manifesting and non-manifestin g carriers of the DYT1 gene mutati on. Brain 2003; 126 : 2074 \200\2238 0 . the ketogenic diet. Epilepsia 2008; 49 (Suppl 8): 46 \200\2239 . 176. Damier P, Th obois S, Witjas T, et al. Bilateral deep brain stimulation of the globus pallidus to treat tardive dyskinesia. Arch Gen Psychiatry 2007; 64 : 170 \200\2236 . 155. Quartarone A, Bagnato S, Rizzo V, et al. Abnormal associative plas- ticity of the huma n motor cortex in writer \200\231s cramp. Brain 2003; 126 : 2586 \200\2239 6 . 177. Vidailhet M, Yelnik J, Lagrange C, et al. Bilateral pallidal deep brain stimulation fo r the treatment of patients with dystonia \200\223choreoatheto- si s cerebral palsy: a pros pective pilot study. Lancet Neurol 2009; 8 : 709 \200\2231 7 . 156. Quartarone A, Morgante F, Sant \200\231angelo A, et al. Abnormal plasticity of sensori motor circuits extends beyond the aff ected body part in focal dystonia. J Neurol Neurosurg Psychiatry 2008; 79 : 985 \200\2239 0 . 178. Ruiz PJ, Ayerbe J, Bader B, et al. Deep brain stimulation in chorea acan- 157. Quartarone A, Pisani A. Abnormal plasticity in dystonia: disruption of thocytosis. Mov Disord 2009; 24 : 1546 \200\2237 . synaptic homeostasis. Neurobiol Dis 2011; 42 : 162 \200\2237 0 . 179. Grandas F, Fernandez-Carballal C, Guzman-de-Villoria J, Ampuero I. Treatment of a dyst onic storm with pallidal stimulation in a patient with PANK2 mutation. Mov Disord 2011; 26 : 921 \200\2232 . 158. Edwards MJ, Huang YZ, Mir P, Rothwell JC, Bhatia KP. Abnormalities in motor cortical p lasticity diff erentiate manifesting and nonmanifest- ing DYT1 carriers. Mov Disord 2006; 2 1 : 2181 \200\2236 . 180. Tassorelli C, Mancini F, Balloni L, et al. Botulinum toxin and neuromo- tor rehabilita tion: an integrated approach to idiopathic cervical dysto- nia. Mov Disord 2006; 21 : 2240 \200\223 3 . 159. Augood SJ, Hollingsworth Z, Albers DS, et al. Dopamine transmis- sion in DYT1 dystonia : a biochemical and autoradiographical study. Neurology 2002; 59 : 445 \200\2238 . This page intentionally left blank CHAPTER 18 Primary Dystonia Antonio A. Elia and Alberto Albanese De \201 nition and classi \201 cation Th e term dystonia was introduced to describe patie nts with severe generalized abnormal movements and postures, who were believed to have an a lteration of muscle tone (hence the word \200\230dystonia \200\231) (1). Th e phenomenolog ical description coincided with the generalized phenotype for many decades. In June 1975, a n international con- ference chaired by Stanley Fahn in New York recognized the clin- ical features of focal forms of dystonia (2). Later, David Marsden proposed gathering together u nder the heading of dystonia noso- logic entities that were previously considered independe nt forms (e.g. blepharospasm, torticollis, \200\230spastic \200\231 dysphonia, writer \200 \231s cramp) (3 \200\2235). Finally, in 1984, an ad hoc committee of the Dystonia Medical R esearch Foundation documented the occurrence in all forms of dystonia \200\230of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal pos tures \200\231 (6). Later, the basic clinical features (dystonic movements and pos- tures) and additional clinical features (activation/deactivation) of dystonia were described (7, 8 ). an ad hoc committee which convened in Grottaferrata, Rome, in May 2011 (consensus not yet p ublished). Phenomenology of primary dystonia Dystonia can occur at rest, during voluntary movement, or in par- oxysmal form, following a specifi c trigger. Th ese features must be appreciated b y expert clinical examination and are best observed in primary dystonia forms. Th e clinica l picture becomes more com- plex when dystonia features are combined or intermixed with oth er movement disorders in dystonia-plus syndromes. Cardinal features Following Marsden \200\231s seminal observation (12), it is commonly acce pted that dystonia encompasses a combination of movements and postures to generate sustaine d muscle contractions, repetitive twisting movements, and abnormal postures (torsion dyston ia). Dystonic postures can precede the occurrence of dystonic move- ments, and in rare case s can persist without appearance of the lat- ter (fi xed dystonia) (7). Dystonic movements have specifi c features that can be recognized by clinical examination: speed of contrac- t ions may be slow or rapid, but at the peak of movement it is sus- tained; movements almost always have a consistent directional or posture-assuming character. Dystonic movements and postures are commonly aggravated during voluntary motion, and in milder forms they may only occur during some specifi c voluntary actions (task-specifi c dystonia). Classifi cation of dystonia syndromes has changed over time. Fahn and Eldridge (2) fi rst d istinguished primary dystonia (with or without hereditary pattern), secondary dystonia (wit h other hereditary neurological syndromes or due to known environ- mental cause), and psych ological forms of dystonia. Later, Fahn, Marsden, and Calne proposed a classifi cation of d ystonia based on three axes, describing for each patient the age at disease onset (early vs adult), distribution of involved body sites (from focal to generalized), and etiology (dif f erentiating idiopathic dystonia syndromes, sporadic or familial, from symptomatic ones) ( 6, 9). Th e fi rst two axes have remained unchanged over years, whereas the aetiological cl assifi cation has been expanded to include four subgroups of dystonia syndromes: primary, d ystonia-plus (i.e. dystonia with parkinsonism or myoclonic jerks), secondary, and heredodeg enerative (10). Dystonic movements may be regular, appearing as tremor (dystonic tremor (13)). When they ar e fast and jerky, they may resemble myoclonus. Dystonic tremor may precede clear abnor- mal posturing, and its occurrence in isolation may lead to the diagnosis of dystonia being mis sed (7). A tremor similar to essential tremor may occur in dystonia and can be mistaken for non-dystonic tremor, particularly when isolated (14). Th e diagno- sis of dystonia can be missed or delayed in a number of patients with task- and position-specifi c tremors, partic ularly primary writing tremor, occupational tremors, or isolated voice tremor, as typical f eatures of dystonia may not develop until many years aft er onset. Head or voice tremors ob served in tremulous forms of cervical dystonia can be very hard to distinguish from essenti al tremor. In some cases, only family history orientates in favor of the correct diagnosis, particularly if family members are ascer- tained to have dystonia. Th e recently published European dystonia guidelines (11) refi ne the aetiological axis dis tinguishing primary (or idiopathic) syndromes, heredodegenerative (where dystonia is a feat ure of a genetic disorder characterized by neurodegeneration) and second- ary (or symptomat ic) syndromes (Table 18.1). Based on the pheno- type, primary dystonias are further subdivi ded into primary pure (with dystonia only), primary-plus (with other associated move- ment disorders), and primary paroxysmal (characterized by inter- mittent symptoms). Th is classi fi cation has recently been revised by Oxford Textbook of Movement Disorders 192 Table 18.1 Aetiological classi \201 cation of dystonia (11) \227\206 Primary pure dystoni a Dystonia is the only clinical sign (apart from tremor) and there is no identi \201 able exogenous cause or other inherited or degenerative disease. Examples are DYT1 and DYT6 dystonias. \227\206 Primary dystonia-plus Dystonia is a prominent sign, but is associated with anothe r movement disorder (e.g. myoclonus or parkinsonism). Th ere is no evidence of neurodegeneration. Examples are levodopa-responsive dystonia (DYT5) and myoclonus \200\223d ystonia (DYT11). \227\206 Primary paroxysmal Dystonia occurs in brief episodes with normality in between. T h ese disorders are classi \201 ed as idiopathic (often familial, although sporadic cases also occur) and symptomatic due to a variety of causes. Th ree main forms are known dependi ng on the triggering factor. In paroxysmal kinesigenic dyskinesia (PKD, DYT9) attacks are i nduced by sudden movement; in paroxysmal exercise-induced dystonia (PED) attacks are induce d by exercise such as walking or swimming; and in the non-kinesigenic form (PNKD, DYT8) att acks are induced by alcohol, co \200 ee, tea, etc. A complicated familial form with PNKD a nd spasticity (DYT10) has also been described. \227\206 Heredodegenerative Dystonia is a feature, among other neurological signs, of a he redodegenerative disorder. An example is Wilson disease. \227\206 Secondary Dystonia is a symptom of an identi \201 ed neurological condition, such as a focal brain lesion, or expo sure to drugs or chemicals. Examples are dystonia due to a brain tumor, OFF-period dystonia in Parkinson \200\231s disease. Associated features Dystonia has some unique activation/deactivation features that can be r ecognized if appropriately looked for and serve as a basis for the diagnosis: geste antagon iste (or sensory tricks), mirroring, and overfl ow. Criteria for identifying these features , when present, have recently been published (8). diagnosis is clearly evidenced by physical examination. Otherwise, at least two associated features must be observed to reach a clinical diagnosis. EMG observation of features associ ated with dystonia is helpful when physical observation is insuffi cient (Fig. 18.1). Epidemiology Th e prevalence of primary dystonia is diffi cult to ascertain, ranging from 2 to 50 cases per million for early-onset primary dystonia, and from 30 to 7320 cases per mi llion for late-onset dystonia. On the basis of the best available prevalence studies, prima ry dystonia may account for 11.1 per 100 000 early-onset cases in Ashkenazi Jews from the N ew York area, 60 per 100 000 late-onset cases in Northern England, and 300 per 100 000 late -onset cases in the Italian population aged over 50 (18). Geste antagoniste has been described in patients with diff erent forms of focal dystonia, w ho reduce or even abolish dystonic pos- tures while making some specifi c voluntary movemen ts. For exam- ple, cranial dystonia patients can apply pressure to the eyebrows or touch th e skin beside the eyes to relief blepharospasm; cervical dys- tonia patients can place a ha nd on the side of the face, the chin, or the back of the head, or touch these areas with on e or more fi ngers, to reduce neck contractions; writer \200\231s cramp patients can touch the aff ected arm with the opposite hand. In contrast with the cardinal signs of dystonia, the geste is never forceful, but is natural and ele- gant (8). Th e mechanism of action of the geste is debated; its action is not associated with mechanical correction by counter-pr essure (15). A geste does not improve non-dystonic essential head tremor, it is uncommon in early post-traumatic dystonia, and it has atypical phenomenology in patients with psychoge nic dystonia (8). Geste effi cacy may diminish as the disease progresses. For a number of reasons, the true prevalence of dystonia is prob- ably underestimated. Pati ents with mild phenotypes (so-called formes frustes (19)) may not seek medical advice; thos e in whom the clinical diagnosis is missed require expert evaluation to resolve diagnostic uncertainty. Conditions that are more common or bet- ter known than dystonia oft en include other movement disorders, such as Parkinson \200\231s disease, essential tremor, myoclonus , tics, and psychogenic forms (14). Overfl ow and mirroring are two related clinical phenomena that reveal or enhance dystonia and prove particularly helpful in cases with mild or inconstant phenomenology. Overfl ow is an uninten- tional contraction of muscles not primarily involved by dystonia, usually loca ted in neighboring body sites, which are activated at the peak of dystonic movements (16). For example, a patient with cervical dystonia may have involvement of the unaff ected upper limb by occasional spread of dystonia activity. Mirror dystonia occurs on the aff ected bo dy side when a specifi c task is performed by the homologous opposite unaff ected body part . Usually specifi c tasks elicit mirror dystonia; they must be identifi ed in order to appr eciate this feature. For example, patients with writer \200\231s cramp may present mirror d ystonia of the dominant hand while writing with the non-dominant unaff ected hand (17). Ove rfl ow and mir- roring are considered a clinical expression of lack of inhibition occurring in dystonia (8). Etiology A genetic predisposition and environmental factors both play a sig- nifi cant role in the etiology of primary dystonia. Genetic defects are known for only a minority of case s presenting with a pure dys- tonia phenotype (20). In contrast, dystonia-plus syndromes ar e better classifi ed genetically (Table 18.2). We describe here only the primary pure dysto nia syndromes. Dystonia-plus and paroxysmal dystonias are dealed with in Chapters 19 and 26 . DYT1 dystonia A common cause of generalized primary pure dystonia is the GAG deletion in th e DYT1 gene encoding the protein TorsinA (21). Th e disease was originally described among Ashkenazi Jews as hav- ing a relatively homogeneous phenotype characterized by early limb- onset generalized dystonia (22). It was later reported that, par- ticularly in Caucasian pa tients (23), the DYT1 phenotype is broader than originally thought. Th e \200\230classical \200\231 DYT1 phenotype is charac- terized by early onset in a limb, and generalization wi thout spread to the craniocervical region (23). In a series of patients with early-onset Diagnostic algorithm A diagnostic algorithm for identifying the features of primary dys- to nia has recently been proposed (8). According to this schema, when all the cardinal feature s of dystonia are observed, the clinical CHAPTER 18 Primary Dystonia 193 Hallmark signs: dystonic postures and movements Activation/deactivation features: gestes (tricks), mirroring, over \202ow Both signs have complete phenomenology NO YES At least two signs are present EMG mapping NO YES Features of dystonia are present Fig. 18.1 Flowchart for the diagnosis of mobile (torsion) dystonia. Th is stepped approach allows a clinical diagnostic level to be reached based on objective clinical criteria. (Rep roduced with permission from Albanese A, Lalli S. Is this dystonia? Mov Disord 2009; 24: 17 25 \200\22331) YES Diagnostic criteria for mobile (torsion) dystonia are met primary dystonia, it has been confi rmed that dystonia never starts in the craniocervical r egion in DYT1 carriers, although craniocer- vical sites can be involved at later stages (24 ). It is remarkable that DYT1 patients who develop severe generalized involvement can carry out their daily activities with signifi cant adaptation in many cases. Extreme cases have also been observed, ranging from asymp- tomatic status to craniocervical involvement or eve n status dystoni- cus (25 \200\22328). but its pathogenicity has not been ascertained (39). TorsinA is a heat-shock and ATP-bindin g protein and a member of the AAA+ superfamily. Th e normal protein is widely distributed i n many species and is located in the endoplasmic reticulum (40, 41). Immunohistochemical st udies have revealed that TorsinA is a con- stituent of Lewy bodies (42). DYT6 dystonia Th e DYT6 locus was originally mapped in two Mennonite families with primary pure dystonia and autosomal dominant transmis- sion (43). Mutations in the THAP1 (Th anatos -associated-domain containing apoptosis-associated protein 1) gene have been found to be re sponsible for DYT6 dystonia with an estimated penetrance of approximately 60% (44). In an A merican series, THAP1 hetero- zygous mutations were identifi ed in nine out of thirty-six ( 25%) DYT1-negative families with early-onset non-focal primary dysto- nia (45). European se ries have reported a lower mutation frequency with an overall prevalence of 1 \200\2232.5% in primary dystonia cohorts from all over Europe (46, 47). Th e spectrum of THAP1 mutations includes missense, nonsense, and frame-shift mutations of all three exons. Owing to phenotypic heterogeneity, it is not possible to iden- tify DYT1 patients based onl y on their clinical presentation. Five other phenotypes have been described in addition to the classic limb- onset presentation (24, 29): generalized dystonia with crani- ocervical i nvolvement, more frequent in Europe than in North America (30), generalized myoclonus \200 \223dystonia, with a phenotype more severe than observed in DYT11 myoclonus \200\223dystoni a (31), focal dystonia with slow progression and occasional later spread even several years aft er onset (32, 33); late-onset DYT1 forms (25), and rarer cases of DYT1 dystonia with n on-limb presentation which may have cervical, laryngeal, or trunk onset (34, 35). Gene penetrance is believed to be around 30% (21, 27), mean- ing that the proportion of asy mptomatic mutation carriers is higher than that of manifesting patients. Th is has prompted the search for potential endophenotypes to help identify manifesting as well as non-manife sting DYT1 carriers. Two potential endophenotypes have emerged: reduction of striatal D2 re ceptor binding shown by PET studies (36), and higher tactile and visuotactile temporal dis- crimination thresholds or temporal order judgements (37). Th ese fi ndings need to be conf i rmed and have not been integrated into a coherent diagnostic protocol. Th e THAP1 phenotype typically presents with early-onset dys- tonia (age range, 9 \200\2234 9 years) and frequent involvement of the craniocervical area. Th e motor features oft en ap pear in adolescence and may progress rapidly. Speech is commonly aff ected because of oroma ndibular or laryngeal involvement (or both). Interestingly, THAP1 mutations have been recen tly found in cases with much later onset (fi ft h or sixth decade) and focal or segmental p henom- enology involving the cervical or laryngeal areas (46, 47). Th is sug- gests that th e gene may also play a pathogenic role in late-onset, focal, or segmental PD. Th e DYT1 gene is named TOR1A (21). Th e disease is caused by a unique mutation that delete s one of a pair of GAG triplets from the carboxyl terminal in TorsinA. Th is unique DYT1 ha plo- type, originally found in Ashkenazi Jews, has also been observed in non-Jewish patient s (38) and represents the only pathogenic disease mutation identifi ed in TOR1A . An 18 bp deletion has also been found in families with primary dystonia and myoclonus, THAP1 is a member of the family of sequence-specifi c DNA-binding factors. Its function is still poorly understood; recent studies provided evidence that THAP1 and TOR1A are intercon - nected in a common pathway (48), because wild-type THAP1 represses the expression of TOR1 A (49). Oxford Textbook of Movement Disorders 194 Table 18.2 DYT genotypes associated with dystonias* Disease (OMIM) Map position Gene Transmission Phenotype Pure dystonia DYT1 (128100) 9q34 TOR1A AD Generalized early-limb-onset dystonia DYT2 (224500) AR Early-onset generalized dystonia with prominent craniocervical involvement DYT4 (128101) AD Whispering dysphonia DYT6 (602629) 8p11. 21 THAP1 AD Mixed-type dystonia, early-onset generalized with craniocervical involvement DYT7 (602124) 18p AD Mixed-type dystonia DYT13 (607671) 1p36. 13 \200\22336. 32 AD Mixed-type dystonia DYT17 (612406) 20p11.2-q13.12 AR Segmental or generalized dystonia with severe dysphonia DTY21 (not assigned) 2q14.3-q21.3 AD Mixed-type dystonia, late-onset multifocal with craniocervical involvement Dystonia-plus DYT5/DYT14 (128230) 14q22 GCH1 TH SPR SGCE ATP1A3 AD Dopa-responsive dystonia 11p15.5 AR Dopa-responsive dystonia 2p13.2 AR Dopa-responsive dystonia DYT11 (159900) 11q23. 1, 7q21 AD Myoclonus \200\223dystonia DYT12 (128235) 19q12-q13. 2 AD Rapid-onset dystonia \200\223parkinsonism DYT15 (607488) 18p11 AD Myoclonus \200\223dystonia DYT16 (612067) 2q31. 3 PRKRA AR Dystonia \200\223parkinsonism Paroxysmal dystonia DYT8 (118800) 2q35 MR1 SLC2A1 AD Paroxysmal non-kinesigenic dyskinesia DYT9/DYT18 (612126) 1p35-p31. 3 AD Paroxysmal exercise-induced dyskinesia DYT10 (128200) 16p11. 2-q12. 1 AD Episodic kinesigenic dyskinesia DYT19 (611031) 16q13-q22. 1 AD Episodic kinesigenic dyskinesia DYT20 (611147) 2q31 AD Paroxysmal exercise-induced dyskinesia Heredodegenerative DYT3 (314250) Xq13 TAF1 X-linked Dystonia \200\223parkinsonism Th e gene name is indicated when known; otherwise, the locus is reported. AD, autosomal dominant; AR, autosomal recessive; ATP1A3, ATPase, Na + /K + transporting; GC H1, guanosine triphosphate cyclohydrolase 1; MR1 , myo \201 brillogenesis regulator 1; PRK RA , double-stranded RNA-activated protein kinase; SGCE , -sarcoglycan; SLC2A1 , solute carrier family 2 (facilitated glucose transporter), member 1; SPR , sepiapterin reductase; TAF1 , TATA boxing-binding protein associated factor; TH , tyrosine hydroxylase; THAP1 , th anatos-associated protein; TOR1A , torsin A gene. THAP1 -associated DYT6 dystonia should be considered in patients with early-onset DYT1-nega tive generalized or segmental dystonia, particularly if cranial involvement is prominent. A s a rule, age at onset is higher than in DYT1 dystonia, and the topographic distribution di ff ers between the two forms. Th e exact prevalence of DYT6 dystonia is still undetermined. or the cervical region (53). Disability was mild even in generalized cases. A peculiar feat ure of the DYT13 phenotype is prominent cervical or upper limb involvement, similarly to th e DYT6 phe- notype, although the DYT13 family has tested negative for DYT6 mutations. Th e DYT15 locus was mapped in a large Canadian kindred, whose thirteen aff ected members h ad alcohol-responsive myo- clonic dystonia involving the upper limbs, hands, and axial mus- cles (54). Mapped loci Th e DYT7 locus, mapping to the short arm of chromosome 18, was identifi ed in a large German family with an autosomal dominant focal pure dystonia phenotype (50). Th e m ean age of disease onset was 40 years with a prevalent phenotype characterized by focal cer - vical dystonia. In some patients a segmental distribution has been reported, where cervic al dystonia is associated with Meige \200\231s syn- drome or writer \200\231s cramp. No pat ient had generalized dystonia. Th e DYT17 dystonia locus was mapped in a single consanguin- eous Lebanese family with thre e sisters suff ering from recessively inherited primary pure dystonia and onset in adolesce nce (55). Th e site of onset was cervical, with progression to segmental distribu- tion in two of the sisters and generalization in one. Prominent fea- tures were dystonia and dysart hria, unresponsive to levodopa. Th e DYT21 locus was recently mapped on chromosome 2 in a family from northern Sweden with sixteen members aff ected by late-onset pure torsion dystonia. Th e disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. Age at onset ra nges between 13 and 50 years, and the Th e DYT13 locus was mapped in a large Italian family with prominent craniocervical and upp er limb involvement and a pure dystonia phenotype (51, 52). In the majority of cases onset was in infancy or adolescence. Of the eleven defi nitely aff ected individu- als, two had g eneralized dystonia with early onset in the upper limb CHAPTER 18 Primary Dystonia 195 prevalent phenotype is a multifocal dystonia with prominent craniocervical involvement. genotype, although DYT6 gene mutations were excluded in these subjects. Focal dystonia with onset in adulthood may be the only clinical sign in many patients, who usually have no or mild progression to a segmental pure dystonia. Th e most frequent forms of dystonia with typical sporadic occurrence that remain genetically unclassifi ed are blep harospasm, spasmodic dysphonia, cervical dystonia, Meige \200\231s syndrome, and occupation al upper limb dystonia. Classi \201 ed phenotypes DYT2 is a recessive pure dystonia phenotype originally described in three consanguineous pedigrees of Spanish gypsies. Th e disease was named \200\230auto somal recessive dystonia in gypsies \200\231 and listed as DYT2 (56, 57). In two of the fam ilies the presentation was simi- lar to that of DYT1 dystonia, consisting of early limb ons et and progression to generalization; in a third family dystonia presented with prominent o romandibular and cervical involvement (57). A Sephardic Jewish Iranian family with a simila r phenotype and auto- somal recessive inheritance was later described (58). Th ree siblings in this family had primary dystonia with limb onset in childhood, and slow progression to generalization with predominant cranio- cervical involvement. Two patients presented with f oot dystonia and gait abnormalities as early features, and all had cervical involve- ment, facial grimacing, blepharospasm, and upper and lower limb dystonia. Two patients also had d ystonic dysphagia. A third family with childhood-onset generalized dystonia and autosomal r eces- sive inheritance also shared the broad DYT2 phenotype (59). Cervical dystonia is the most common of these forms. Diff erent abnormal head positions can be observed, including horizontal head rotation (torticollis), head tilting (laterocollis) , head fl exion (antecollis), and head extension (retrocollis). Th ese postures can be vari ably combined depending on the neck muscles involved. Repetitive head jerks can resemble he ad tremor, but can be dif- ferentiated when a directional preponderance and sustainment at peak of movement are observed. Pain occurs in 75% of patients with cervical dystonia (66). Cranial dystonias are less prevalent than cervical forms. Spasmodic dysphonia aff ects the vocal folds; abnormal adduction, which causes a strained strangled voice, is more common th an abduction, in which the voice sounds whisper- ing and breathy.