19. Zeman W, Kaelbling R, Pasamanick B. Idiopathic dystonia musculorum deformans. II. Th e formes frustes. Neurology 1960; 10 : 1068 \200\2237 5 . 20. Muller U. Th e monogenic primary dystonias. Brain 2009; 132 : 2005 \200\2232 5 . 21. Ozelius LJ, Hewett JW, Page CE, et al. Th e early-onse t torsion dystonia gene (DYT1) e ncodes an ATP-bindin g protein. Nat Genet 1997; 17 : 40 \200\2238 . 43. Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromoso me 8 in two Mennonite families. Ann Neurol 1997; 42 : 670 \200\2233 . 22. Bressman SB, de Leon D, Brin MF, et al. Idiopathic dystonia among Ashkenazi Jews: evide nce for autosomal dominant inheritance. Ann Neurol 1989; 26 : 612 \200\2232 0 . 44. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are respons ible for DYT6 primary torsion dystonia. Nat Genet 2009; 41 : 286 \200\2238 . 23. Valente EM, Warner TT, Jarman PR, Mathen D, Fletcher NA, Marsden CD, et al. Th e role o f DYT1 in primary torsion dystonia in Europe. Brain 1998; 121 : 2335 \200\2239 . 45. Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saunders-Pullman R. Mutations i n THAP1 (DYT6) in early-onse t dys- tonia: a genetic screening study. Lancet Neurol 2009; 8 : 441 \200\2236 . 24. Fasano A, Nardocci N, Elia AE, Zorzi G, Bentivoglio AR, Albanese A. Non-DYT 1 early-ons e t primary torsion dystonia: comparison with DYT1 phenotype and review of the literature. Mov Disord 2006; 21 : 1411 \200\22318 . 46. Bonetti M, Barzaghi C, Brancati F, et al. Mutation screening of the DYT6/ THAP1 gene in Italy. Mov Disord 2009; 24 : 2424 \200\2237 . CHAPTER 18 Primary Dystonia 199 70. Delmaire C, Vidailhet M, Wassermann D, et al. Diff usion abnormalities in the primary s ensorimotor pathways in writer \200\231s cramp. Arch Neurol 2009; 66 : 502 \200\2238 . 47. Houlden H, Schneider SA, Paudel R, et al. THAP1 mutations (DYT6) are an additional caus e of early-onse t dystonia. Neurology 2010; 74 : 846 \200\2235 0 . 71. Bonilha L, de Vries PM, Vincent DJ, et al. Structural white matter abnormali- ties in p atients with idiopathic dystonia. Mov Disord 2007; 22 : 1110 \200\22316 . 72. Schmidt KE, Linden DE, Goebel R, Zanella FE, Lanfermann H, Zubcov Striatal activation during blepharosp asm revealed by fMRI. 48. Gavarini S, Cayrol C, Fuchs T, et al. Direct interaction between causa- tive genes of D YT1 and DYT6 primary dystonia. Ann Neurol 2010; 68 : 549 \200\2235 3 . AA. Neurology 2003; 60 : 1738 \200\2234 3 . 49. Kaiser FJ, Osmanoric A, Rakovic A, et al. Th e dystonia gene DYT1 is repressed by the t ranscription factor THAP1 (DYT6). Ann Neurol 2010; 68 : 554 \200\2239 . 73. Preibisch C, Berg D, Hofmann E, Solymosi L, Naumann M. Cerebral activation patterns in patients with writer \200\231s cramp: a functional magnetic resonance imaging study. J Neur ol 2001; 248 : 10 \200\22317 . 50. Leube B, Rudnicki D, Ratzlaff T, Kessler KR, Benecke R, Auburger G. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autos omal dominant inheritance and purely focal distribution. Hum Mol Genet 1996; 5 : 1673 \200 \2237 . 74. Oga T, Honda M, Toma K, et al. Abnormal cortical mechanisms of vol- untary muscle relax ation in patients with writer \200\231s cramp: an fMRI study. Brain 2002; 125 : 895 \200 \22390 3 . 51. Bentivoglio AR, Del Grosso N, Albanese A, Cassetta E, Tonali P, Frontali M. Non-DYT 1 d ystonia in a large Italian family. J Neurol Neurosurg Psychiatry 1997; 62 : 357 \200\2236 0 . 75. Peller M, Zeuner KE, Munchau A, et al. Th e basal ganglia are hyperactive during the di scrimination of tactile stimuli in writer \200\231s cramp. Brain 2006; 129 : 2697 \200\2237 0 8 . 52. Valente EM, Bentivoglio AR, Cassetta E, et al. DYT13, a novel primary torsion dystonia locus, maps to chromosome 1p36.13 \200\22336.32 in an Italian family with cranial-cervica l or upper limb onset. Ann Neurol 2001; 49 : 362 \200\2236 . 76. Butterworth S, Francis S, Kelly E, McGlone F, Bowtell R, Sawle GV. Abnormal cortical se nsory activation in dystonia: an fMRI study. Mov Disord 2003; 18 : 673 \200\2238 2 . 53. Bentivoglio AR, Ialongo T, Contarino MF, Valente EM, Albanese A. Phenotypic characteriz ation of DYT13 primary torsion dystonia. Mov Disord 2004; 19 : 200 \200\2236 . 77. Obermann M, Yaldizli O, de Greiff A, et al. Morphometric changes of sen- sorimotor structures in focal dystonia. Mov Disord 2007; 22 : 1117 \200\2232 3 . 78. Dragan ski B, Th un-Hohenstein C, Bogdahn U, Winkler J, May A. \200\230Motor circuit \200\231 gra y matter changes in idiopathic cervical dystonia. Neurology 2003; 61 : 1228 \200\2233 1 . 54. Grimes DA, Han F, Lang AE, George-Hyssop P, Racacho L, Bulman DE. A novel locus for inh erited myoclonus-dystoni a on 18p11. Neurology 2002; 59 : 1183 \200\2236 . 79. Garraux G, Bauer A, Hanakawa T, Wu T, Kansaku K, Hallett M. Changes in brain anatomy in focal hand dystonia. Ann Neurol 2004; 55 : 736 \200\2239 . 80. Egger K, Mueller J, Schock e M, et al. Voxel based morphometry reveals specifi c gray matter changes in primary dyston ia. Mov Disord 2007; 22 : 1538 \200\2234 2 . 55. Chouery E, Kfoury J, Delague V, et al. A novel locus for autosomal recessive primary to rsion dystonia (DYT17) maps to 20p11.22-q1 3.12. Neurogenetics 2008; 9 : 287 \200\2239 3 . 56. Gimenez-Roldan S, Delgado G, Marin M, Villanueva JA, Mateo D. Hereditary torsion dyston ia in gypsies. Adv Neurol 1988; 50 : 73 \200\2238 1 . 57. Gimenez-Roldan S, Lopez-Fraile IP , Esteban A. Dystonia in Spain: study of a gypsy family and general survey. Adv Neurol 1976 ; 14 : 125 \200\2233 6 . 81. Delmaire C, Vidailhet M, Elbaz A, et al. Structural abnormalities in the cerebellum and sensorimotor circuit in writer \200\231s cramp. Neurology 2007; 69 : 376 \200\2238 0 . 82. Hutchinson M, Nakamura T, Moeller JR, et al. Th e metabolic topography of essential ble pharospasm: a focal dystonia with general implications. Neurology 2000; 55 : 673 \200\2237 . 58. Khan NL, Wood NW, Bhatia KP. Autosomal recessive, DYT2-lik e pri- mary torsion dystonia : a new family. Neurology 2003; 61 : 1801 \200\2233 . 59. Moretti P, Hedera P, Wald J, Fin k J. Autosomal recessive primary general- ized dystonia in two siblings from a consanguineo us family. Mov Disord 2005; 20 : 245 \200\2237 . 83. Asanuma K, Ma Y, Huang C, et al. Th e metabolic pathology of dopa-responsiv e dystonia. Ann Neurol 2005; 57 : 596 \200\22360 0 . 84. Draganski B, Schneider SA, Fiorio M, et al. Genotype \200\223phenotyp e inter- actions in primary dystonias revealed by diff erential changes in brain structure. NeuroImage 2009; 47 : 1141 \200\2237 . 60. Parker N. Hereditary whispering dysphonia. J Neurol Neurosurg Psychiatry 1985; 48 : 218 \200\2232 4 . 61. Ahmad F, Davis MB, Waddy HM, Oley CA, Marsden CD, Harding AE. Evidence for locus hetero geneity in autosomal dominant torsion dysto- nia. Genomics 1993; 15 : 9 \200\2231 2 . 85. Carbon M, Niethammer M, Peng S, et al. Abnormal striatal and thalamic dopamine neurotra nsmission: Genotype-relate d features of dystonia. Neurology 2009; 72 : 2097 \200\22310 3 . 62. Bressman SB, Heiman GA, Nygaard TG, et al. A study of idiopathic tor- sion dystonia in a non-Jewis h family: evidence for genetic heterogeneity. Neurology 1994; 44 : 283 \200 \2237 . 86. Walker RH, Brin MF, Sandu D, Good PF, Shashidharan P. TorsinA immunoreactivity in brain s of patients with DYT1 and non-DYT 1 dys- tonia. Neurology 2002; 58 : 120 \200\2234 . 63. Holmgren G, Ozelius L, Forsgren L, et al. Adult onset idiopathic torsion dystonia is ex cluded from the DYT 1 region (9q34) in a Swedish family. J Neurol Neurosurg Psychiatry 1995 ; 59 : 178 \200\2238 1 . 87. Holton JL, Schneider SA, Ganesharajah T, et al. Neuropathology of pri- mary adult-onse t dystonia. Neurology 2008; 70 : 695 \200\2239 . 88. Rostasy K, Augood SJ, Hewett JW, et al. TorsinA protein and neuropa- thology in early o nset generalized dystonia with GAG deletion. Neurobiol Dis 2003; 12 : 11 \200\2232 4 . 64. Klein C, Pramstaller PP, Castellan CC, Breakefi eld XO, Kramer PL, Ozelius LJ. Clinical and genetic evaluation of a family with a mixed dys- tonia phenotype from South Tyrol. Ann Neurol 1998; 44 : 394 \200\2238 . 89. Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol 65. Albanese A, Bentivoglio AR, Del Grosso N, et al. Phenotype variability of 2009; 8 : 844 \200\2235 6 . dystonia in monozygotic twins. J Neurol 2000; 247 : 148 \200\2235 0 . 90. Albanese A. Terminology for preparations of botulinum toxins. What a 66. Chan J, Brin MF, Fahn S. Idiopathic cervical dystonia: clinical character- diff erence a name makes. JAMA 2011; 305 : 89 \200\22390. istics. Mov Disord 1991; 6 : 119 \200\2232 6 . 91. Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diag- nosis and tre atment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS- E S Task Force. Eur J Neurol 2006; 13 : 433 \200\2234 4 . 67. Quartarone A, Rizzo V, Morgante F. Clinical features of dystonia: a pathophysiological revisitation. Curr Opin Neurol 2008; 21 : 484 \200\2239 0 . 68. Fabbrini G, Pantano P, Tota ro P, et al. Diff usion tensor imaging in patients with primary cervical dystonia and in pa tients with blepharospasm. Eur J Neurol 2008; 15 : 185 \200\2239 . 92. Watts CC, Whurr R, Nye C. Botulinum toxin injections for the treatment of spasmodic dys phonia. Cochrane Database Syst Rev 2004; CD004327 . 93. Balash Y, Giladi N. Effi cacy of ph armacological treatment of dystonia: evidence-base d review including meta-analysi s of the eff ect of botuli- num toxin and other cure options. Eur J Neurol 2004; 11 : 361 \200\2237 0 . 69. Carbon M, Kingsley PB, Tang C, Bressman S, Eidelberg D. Microstructural white matter ch anges in primary torsion dystonia. Mov Disord 2008 Jan 30; 23 : 234 \200\2239 . Oxford Textbook of Movement Disorders 200 108. Holloway KL, Baron MS, Brown R, Cifu DX, Carne W, Ramakrishnan V. Deep brain stimulati on for dystonia: a meta-analysi s. Neuromodulation 2006; 9 : 253 \200\2236 1 . 94. Bentivoglio AR, Fasano A, Ialongo T, Soleti F, Lo Fermo S, Albanese A. Fift een-yea r e xperience in treating blepharospasm with Botox or Dysport: same toxin, two drugs. Neurotox Res 2009; 15 : 224 \200\2233 1 . 109. 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 . 95. Mejia NI, Vuong KD, Jankovic J. Long-ter m botulinum toxin effi cacy, safety, and immunogenicity. Mov Disord 2005; 20 : 592 \200\2237 . 96. Brin MF, Comella CL, Jankovic J, Lai F, Naumann M. Long-ter m treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Dis ord 2008; 23 : 1353 \200\2236 0 . 110. Krause M, Fogel W, Kloss M, Rasche D, Volkmann J, Tronnier V. Pallidal stimulation for dystonia. Neurosurgery 2004; 55 : 1361 \200\2237 0 . 111. 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 . 97. Albavera-Hernandez C, Rodriguez JM, Idrovo AJ. Safety of botulinum toxin type A among c hildren with spasticity secondary to cerebral palsy: a systematic review of randomized clin ical trials. Clin Rehabil 2009; 23 : 394 \200\22340 7 . 112. 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 . 98. Burke RE, Fahn S. Double-blin d evaluation of trihexyphenidyl in dysto- nia. Adv Neurol 1983; 37 : 189 \200\2239 2 . 113. Egidi M, Franzini A, Marras C, Cavallo M, Mondani M, Lavano A, et al. A survey of Ital ian cases of dystonia treated by deep brain stimulation. J Neurosurg Sci 2007; 51 : 153 \200\2238 . 99. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double blind, prospective trial of hi gh-dosag e trihexyphenidil. Neurology 1986; 36 : 160 \200\2234 . 114. Borggraefe I, Mehrkens JH, Telegravciska M, Berweck S, Botzel K, Heinen F. Bilateral p allidal stimulation in children and adolescents with primary generalized dystonia. Report o f six patients and literature-base d analysis of predictive outcomes variables. Brain Dev 2 010; 32 : 223 \200\2238 . 100. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double- blin d crossover study. Ann Neurol 1982; 11 : 41 \200\2237 . 115. 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 . 101. Jankovic J, Beach J. Long-ter m eff ects of tetrabenazine in hyperkinetic movement disorders. Neurology 1997; 48 : 358 \200\2236 2 . 102. Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dys- tonia. J Clin Neurophysiol 2004; 21 : 18 \200\2233 0 . 116. Krauss JK. Deep brain stimulation for cervical dystonia. J Neurol Neurosurg Psychiatry 2003; 74 : 1598 . 103. Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brai n stimulation in primary gene ralized or segmental dystonia. N Engl J Med 2006; 355 : 1978 \200\2239 0 . 117. Ostrem JL, Marks WJ, Jr, Volz MM, Heath SL, Starr PA. Pallidal deep brain stimulation in patients with cranial-cervica l dystonia (Meige syn- drome). Mov Disord 2007; 22 : 1885 \200\2239 1 . 104. Capelle HH, Krauss JK. Neuromodulation in dystonia: current aspects of deep brain stimulation. Neuromodulation 2009; 12 : 8 \200\2232 1 . 118. Berman BD, Starr PA, Marks WJ, Ostrem JL. Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial \200\223cervica l dystonia. Stereotact Funct Ne urosurg 2009; 87 : 37 \200\2234 4 . 105. Lyons MK, Birch BD, Hillman RA, Boucher OK, Evidente VG. Long-ter m follow-u p of deep brain stimulation for Meige syndrome. Neurosurg Focus 2010; 29 : E5. 119. Pillon B, Ardouin C, Dujardin K, et al. Preservation of cognitive func- tion in dyston ia treated by pallidal stimulation. Neurology 2006; 66 : 1556 \200\2238 . 106. Romito LM, Franzini A, Perani D, et al. Fixed dystonia unresponsive to pallidal stimul ation improved by motor cortex stimulation. Neurology 2007 13; 68 : 875 \200\2236 . 120. National Institute for Health and Clinical Excellence. Selective periph- eral denervat ion of cervical dystonia. Available online at http://guid- ance.nice.org.uk/IPG80 (issued 2 004). 107. National Institute for Health and Clinical Excellence. Deep brain stimulation for trem or and dystonia (excluding Parkinson \200\231s disease). Available online at http: //www ni ce org uk/guidance/IPG188 (issued 2006). 121. Albright AL, Barry MJ, Shaft on DH, Ferson SS. Intrathecal baclofen for generalized dystonia. Dev Med Child Neurol 2001; 43 : 652 \200\2237 . CHAPTER 19 Other Dystonias Julie Phukan and Th omas Warner Introduction Primary forms of dystonia represent around 70% of all cases and are described in the preceding chapter. Th e remainder comprise those cases where dystonia is part of a m ore complex movement disorder or neurological syndrome. Th ese can be divided into four bro ad categories: dystonia-plus syndromes, heredodegenerative disorders, secondary (or symptom atic dystonia), and dystonia that is a feature of another neurological condition. Th e key diff erence from primary dystonia is the presence of other neurological fea- tures in addit ion to dystonia. Many have underlying neurodegen- eration, oft en genetic in origin. synthesis. In vitro studies have shown that patients have reduced GTP cyclohydrolase 1 acti vity, leading to low levels of pterins and monoamines, which explains the dramatic benefi c ial treatment response to levodopa. Most of the missense mutations appear to lie within the core of the protein and impair its tertiary structure and/ or stability (9). Other rare forms of DRD caused by autosomal recessive muta- tions in genes for tyrosine hyd roxylase and sepiapterin reductase have been reported (2, 10, 11). Th ese forms usually hav e additional features such as parkinsonism, cognitive impairment, spastic para- plegia, hyp otonia, myoclonus, seizures, and progressive neurologi- cal deterioration (12). Diagnosis is by recognition of the clinical phenotype and response to levodopa. A phenylala nine loading test and cerebrospinal fl uid (CSF) pterin studies can be useful. Dopamine tra nsporter SPECT or fl uorodopa PET scans are normal in DRD, diff erentiating it from young-o nset Parkinson \200\231s disease presenting with foot dystonia (early use of levodopa is no t usually recommended in these cases). Mutation analysis of GCH1 (DYT5 ) gene is also avail able. Dystonia-plus syndromes In these syndromes, torsion dystonia is associated with another mov ement disorder, typically myoclonus or parkinsonism. Th ere is no evidence of neurodegenera tion and they appear to be caused by neuronal dysfunction. Dopa-responsive dystonia (DRD) Th e classic phenotype of this rare disorder is of early-ons et lower limb dystonia (4 \200\2238 years of age) causing gait disturbance, with diur- nal fl uctuation (worsening of symptoms toward the evening and improvement aft er sleep) and an excellent response to levodopa (1, 2). Parkinsonism can develop later and may be an early feature in adult-onset cases. Additional features include brisk refl exes, spasticity, ankl e clonus, and extensor plantar responses (3). DRD demonstrates a dramatic and sustained response to small doses of levodopa (as low as 50 \200\223200 mg). Benefi t is usually appar- ent within days to weeks, and the motor compli cations of levodopa treatment seen in Parkinson \200\231s disease rarely develop. Because o f the benefi t from levodopa treatment, every patient with early-onset dystonia without an alternative diagnosis should have a trial of levodopa. Myoclonus \200\223dystonia syndrome (MDS) MDS is a rare autosomal dominant condition charac terized by myoclonic jerks and dystonia, aff ecting mainly the neck, trunk, and arms. Preva lence is estimated at two per million in Europe (2). Onset is typically in the fi rst or se cond decade (2, 13) and it usually follows a relatively benign course. Myoclonus tends to d ominate the condition, but dystonia occurs in around two-thirds of patients, typically with cervical dystonia and writer \200\231s cramp. Th e jerks show dramatic improvement with al cohol and benzodiazepines (2, 14), although there is oft en a rebound eff ect. Myoclonus ca n be precipi- tated or aggravated by caff eine, active movement of the involved region, str ess, sudden noise, and tactile stimuli. Depression, anxi- ety, obsessive \200\223compulsive disorder, and panic attacks have been reported in MDS (15). Atypical cases include patients with craniocervical and oro- mandibular dystonia, early hyp otonia with proximal weak ness, spontaneously remitting dystonia, and spasticity mimicking cerebral palsy (4, 5). Associations with anxiety, depression, obsessive \200\223compulsive disorder, and/or sleep disturbances have been reported (6). Most cases are inherited as an autosomal dominant trait with reduced penetrance (30%). Fema les are two to four times more likely to be aff ected than males. Heterozygous mutations in the GCH1 (DYT5 ) gene cause the majority of these cases (5, 7), although deletions have be en described (8). Th e gene encodes GTP cyclohy- drolase 1, an enzyme that catalyzes the fi rst step in the biosynthesis of tetrahydrobiopterin (BH4), an essential co-factor for tyro sine hydroxylase (TH), and the rate-limiting enzyme for dopamine Oxford Textbook of Movement Disorders 202 Inheritance is autosomal dominant with reduced penetrance. Numerous point mutations and sma ll deletions have been identi- fi ed in the epsilon-sarcoglycan gene ( SGCE, DYT11 ) in man y indi- viduals (16 \200\22318). Maternal imprinting of the SGCE gene means that most cases are inherited from mutant paternal alleles (19). Th e sar- coglycans are a family of trans -membrane proteins that are part of the dystrophin-associated glycoprotein in cardiac and skeletal mus- cle. SGCE is expressed in a wide variety of tissues, but incorpora- tion of e xon 11b leads to a brain-specifi c SGCE splice variant, found mainly in midbrain monoaminer gic neurons, cerebellar Purkinje cells, hippocampus, and cortex (20). Mutant SGCE appears t o be abnormally traffi cked and is retained intracellularly (instead of at its normal locat ion at the neuronal plasma membrane) where it is degraded by the proteasome (21). Th e DYT1 gene product, torsinA, binds SGCE, promotes its degradation, and contributes to its qual- ity control; mice carrying mutations in both TorsinA and SGCE show earlier onset of motor d efi cit (22). syndrome. DYT16 dystonia \200\223parkinsonism is an autosomal reces- sive condition reporte d in two consanguineous Brazilian families and one sporadic case (29). Progressive early-on set generalized dystonia occurs with axial, oromandibular, and laryngeal involve- ment in a ddition to parkinsonian features. Homozygous mis- sense mutations within the stress respons e gene protein kinase interferon-inducible double-stranded RNA-dependent activator ( PRKRA ) were identifi ed in aff ected individuals. A heterozygous frameshift mutation leading to protein truncation was also identi- fi ed in a sporadic German case with early-onset dyston ia (30). Th e PRKRA gene binds double-stranded RNA and is involved in the cellular stress r esponse, although the mechanism that results in dystonia \200\223parkinsonism is unknown. Th e dopamine transporter defi ciency syndrome is an autosomal recessive condition which ma nifests in infancy with severe dystonia \200\223 parkinsonism, an eye movement disorder, an d pyramidal tract fea- tures (31). Th e ratio of homovanillic acid to 5-hydroxyindoleacetic acid in the CSF was raised. Loss of function mutations were identi- fi ed in the gene enco ding the dopamine transporter (SLC6A3). Diagnosis is clinical, but can be confi rmed by mutation analy- sis of the SGCE gene. Treat ment is problematic. In patients with response to alcohol, GABAergic drugs such as clonazep am and gamma-hydroxybutyrate have marked, but transient, eff ects and addiction can be a pr oblem. Cervical dystonia and writer \200\231s cramp may respond to botulinum toxin injectio ns. Response to high-dose levodopa has been reported in two patients with SGCE deletions, w ith improvement even in myoclonus (23). In severe cases bilat- eral deep brain stimulation (DBS) of the globus pallidus internus (GPi) has conferred lasting improvement in both dysto nia and myoclonus. Heredodegenerative disorders with dystonia Dystonia can be part of a more widespread geneti c neurological disorder where there is underlying neurodegeneration; these are referred to as heredodegenerative causes. Selected conditions are described below and others are summar ized in Table 19.1. X-linked dystonia \200\223parkinsonism (XDP, DYT3) Th is progressive X-linked neurodegenera tive dystonia is pre- dominantly found in Philippino males (32). Onset of symptoms is betwe en 12 and 64 years, and either dystonia or parkinsonism may be the presenting clinical feat ure (32). Ninety per cent of cases present with focal dystonia aff ecting almost any body p art which progresses over years, oft en becoming generalized. Parkinsonism develops in more than 50% of all cases oft en within 2 years of dysto- nia onset, and freezing may be a pro minent feature (32, 33). Other features include myoclonus, chorea, focal tremor, myorhythmi a, and chorea-ballism (33). Duration of illness is around 16 years, with death at a mean ag e of 55 years. Female heterozygotes can manifest mild dystonia or chorea. Rapid-onset dystonia \200\223parkinsonism (RDP) RDP is a rare, autosomal dominant movement disorder with reduced penetrance. Typically, there is abrupt onset of dystonia and parkin- sonism, developing over a period of hours to weeks followed by little progression (2, 24, 2 5). Onset is associated with specifi c physi- cal triggers such as fever, strenuous exercis e, childbirth, excessive alcohol consumption, or psychological stress. RDP usually presents in adolescence or young adulthood. Common symptoms are pos- tural instability, bradykinesi a, and limb and cranial dystonia with a rostrocaudal gradient of involvement. Th e limited pathology stud- ied to date has found no evidence of neurodegeneration, suggesting a functi onal mechanism. Some patients have reduced levels of CSF homovanillic acid, implying involv ement of the dopaminergic sys- tem, but there is a poor response to dopaminergic medication s. PET scans have revealed decreased striatal glucose metabolism, but no evidence for loss of nigrostriatal dopaminergic projections (34). Neuropathological analysis demonstrates a mult ifocal mosaic pattern of astrocytosis in the caudate and lateral putamen, with rel- atively selective degeneration of the striosome compartment (35). A founder mutation about 1000 \200\2232000 years ago is thought to explain the geographical clustering in the Philippines . Th e disease locus, DYT3, has been mapped to Xq13.1. Th e condition is caused by loss of function mutations in the alpha-3 subunit of the Na + / K + -ATPase pump ( ATP1A3 gene) (26), which is crucial for maintaining the electrochemical gradient across the cell membrane (27). In a mouse model using striatal and cerebellar injections of oua- bain (an inhibitor of the Na + /K + -ATPase pump) a phenotype simi- lar to RDP was produced, with dystonia resulting from cerebellar injection and parkinsonism resulting from basal ganglia injection (28). Th ese mild symptoms rapidly transformed into persistent dys- tonia and rigidity aft er stres s, simulating the clinical features of this condition. An SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu comp osite) retro-transposon inser- tion has been identifi ed in an intron of TAF1, a major tran scrip- tion factor (36). Th is retro-transposon insertion appears to reduce neuron-specifi c expression of TAF1 in the caudate nucleus, possibly through DNA methylation changes. In t urn, this impairs transcrip- tion of a number of neuronal genes related to cell division an d pro- liferation, including the dopamine D2 receptor gene. Th e resulting imbalance in act ivity of striosomal and matrix-based pathways (the latter are relatively spared until the p arkinsonian phase of the illness) is postulated to give rise to abnormal movement. Th e pre ferential Treatment is generally supportive. Levodopa is not eff ective and response to GPi DBS has been poor. Recently, two other dystonia \200\223parkinsonism syndromes have been described: DYT16 dyst onia and dopamine transporter defi ciency CHAPTER 19 Other Dystonias 203 Table 19.1 Other neurodegenerative syndromes that can cause dystonia Inheritance/gene Disor der Autosomal recessive Ataxia telangiectasia ATM gene Onset 2 \200\2234 years Clinical features Cerebellar ataxia, oculomotor apraxia, choreoathetosis, grimacing, dysart hria, telangiectases Variable immunode \201 ciency Predisposition to malignancies Dystonia (late feature) Usually wheelchair bound by 10 years Death in the second decade Investigations/pathology Increased serum alpha-fetoprotein Decreased serum levels IgA, IgE, IgG Pathology: cerebellar Purkinje cell loss; spinal cord degeneration; posterior and late ral columns and anterior horn cells Hereditary chorea-acanthocytosis (neuroacanthocytosis) Autosomal recessive Chorein gene Th ird to fourth decade Chorea (especially of mouth, tongue, lip- and tongue-biting), tics, dystonia, parkinsonism, behavioral disinhibition, cognitive decline Peripheral neuropathy Acanthocytosis on EM Raised creatine kinase in blood EMG Pathology: basal ganglia neuronal loss Rett syndrome Sporadic or X-linked dominant Most commonly MECP gene After 1 year in girls (fatal neonatal encephalopathy in boys) \200\230Acquired microcephaly \200\231 Severe regression of language and motor skills Auti stic behavior Stereotypies of the hands Prolonged QT interval Spasticity, dystonia, seizure s, muscle wasting and scoliosis Pathology: decreased brain size especially frontal lobe and later cerebellar atrophy Infantile bilateral striatal necrosis and familial striatal necrosis Sporadic, but some inherited in an autosomal recessive or maternal pattern Chorea, dystonia, rigidity, ballism, stereotyped cry, grimace, hyperextension of the neck i n response to stimuli Spongy degeneration of caudate and putamen Neuronal intranuclear inclusion disease Typically occurs sporadically but inherited forms described Childhood onset Adult onset less common Ataxia, spasticity, parkinsonism, autonomic dysfunction and cognitive de \201 cits, dyston ia, chorea, motor neuropathy Intranuclear inclusions composed of eosinophilic ubiquinated material in the central, perip heral, and autonomic nervous systems Ataxia with vitamin E de \201 ciency Autosomal recessive Mutations in the gene encoding alpha-tocopherol transfer protein Onset before 20 years Similar to Friedreich \200\231s ataxia Ataxia, dystonia (more frequent than Friedreich \200 \231s), dysarthria, loss of vibration sense and deep tendon re \202 exes Head titubation X anthelasma, tendon xanthomas, retinitis pigmentosa, deafness, sphincter involvement Laboratory \201 ndings: very low vitamin E levels; cholesterol and triglyceride levels ma y be high Vitamin E supplementation may retard progression of the disease loss of striosomal medium spiny striatal projection neurons (MSNs) is consistent with the e xpression of the neuron-specifi c isoform of TAF1 that in the rat is enriched in striosomal MSNs (37). neuroaxonal dystrophy, and neuroferritinopathy. Idiopathic basal ganglia calcifi cation (Fa hr \200\231s disease) is also discussed. Wilson disease Wilson disease is a rare autosomal recessive disorder of copper transportati on caused by mutation of the ATP7B gene which encodes a copper transporter. Clinical manife stations result from copper accumulation in the brain and liver and may present in child- h ood or adulthood, typically presenting with hepatic (40%), neu- rological (40%), or psychia tric (20%) symptoms. Prevalence is estimated at 1 in 30 000 in most populations, with highe r preva- lence in Japan and China. Wilson disease is covered in detail in Chapter 23, and t his section will only consider the association with dystonia. Treatment of XDP with oral medication is disappointing, with variable benefi t from levodop a. However, bilateral GPi DBS has been used successfully to treat the condition (38). Metabolic disorders Metal and mineral metabolism A number of genetic disorders are characte rized by deposition of metal in the brain, predominantly copper and iron. Th e basal gangli a appear particularly susceptible to metal deposition and hence these conditions have mixed movement disorders, with predominant dystonia and parkinsonism. Th e key conditions are Wi lson disease for copper, and neurodegeneration with brain iron accumulation (NBIA) for iron , which can be subdivided into specifi c genetic condi- tions: pantothenate kinase-associat ed neurodegeneration, infantile Th ree basic neurological presentations have been identifi ed: parkinsonism, generalized dy stonia, and a tremor-predominant form. Dystonia is common, and has been reported in up to Oxford Textbook of Movement Disorders 204 65% of patients. It oft en aff ects cranial structures, with promi- nent dysarthria, dyspha gia, drooling, risus sardonicus (a fi xed pseudo-smile), and abnormal posturing (39). With time the dystonia becomes more extensive, oft en becoming segmental or generalized. and ferritin in the brain due to a mutation in the ferritin light chain gene ( FTL1 ) (45). Fewer than 100 cases have been described. Patients present with chorea or dystonia with asymmetric limb involvement and sometimes evi dence of parkinsonism and ataxia (46). With time, orofacial dystonia develops, aff ecting s peech, and dysphagia can be a signifi cant problem. Eye movements are pre- served. A progre ssive frontal and subcortical cognitive decline has been described. Neurodegeneration with brain iron accumulation type 1 (NBIA-1) Th is term encompasses a num ber of disorders of iron accumulation in the brain, including those previously labeled Hall ervoden \200\223Spatz disease. Th e most common form is pantothenate kinase-associated neur odegeneration (PKAN) which accounts for approximately 50% of cases. Other disorders of iron accumulation include neuroferriti- nopathy and infantile neuroaxonal dystrophy. Serum ferritin is low, typically \211 20 g/dl (46), in the presence of normal serum ir on, transferrin, and hemoglobin levels. MRI in all patients demonstrates excess brain iron accumulation on T2* MRI in the putamen and globus pallidus, oft en with cystic changes. Mol ecular genetic testing for FTL is available. Neuropathology reveals iron and ferritin deposition both within neurons and extracellularly in the basal ganglia, forebrain, and cerebellum with accompanying neuronal loss. In mice e xpressing a mutant human form of the FTL gene, there was increased cyto- plasmic FTL, ferri tin heavy chain polypeptides, and iron (47). It was suggested that the pathogenesis in neur oferritinopathy resulted from a combination of reduction in iron-storage function and enhan ced toxicity associated with iron-induced ferritin aggregates in the brain. PKAN is a rare autosomal recessive disorder of co-enzyme A (CoA) metabolism. Estimated prev alence is 1 \200\2233 per million, sug- gesting a carrier frequency of 1 in 275 \200\223300 . Th e majority have mutations in the pantothenate kinase 2 gene. Onset is usually in the fi rst decade, but adult-onset cases have been described (40). Th e course of the disease is progressive over 10 \200\22312 years, although survival can be lo nger. PKAN can be famil- ial or sporadic. It is characterized clinically by prominent dysto nia (in up to 87%), parkinsonism, cognitive impairment, pseudobulbar features, spasticity, and cerebellar ataxia (40, 41). Limb dystonia can lead to children being considered to be c lumsy before other symp- toms emerge (41). Cranial dystonia can lead to recurrent trauma of the tongue, even leading to dental extraction. Axial dystonia occurs later in the course o f illness. Pigmentary retinopathy occurs in around two-thirds of cases, with night blindnes s and progressive peripheral visual fi eld loss. Intellectual involvement is variable, as a re seizures. Treatment is symptomatic and supportive, and no drugs have been shown to alter the course o f neuroferritinopathy. Th e role of iron chelation and venesection is under review. Infantile and atypical neuroaxonal dystrophy (INAD) INAD is an autosomal recessive conditio n that presents between the ages of 6 months and 3 years with truncal hypotonia, progres- s ive psychomotor delay, cerebellar ataxia, pyramidal signs, strabis- mus, nystagmus, and opt ic atrophy. Tetraparesis and progressive cognitive decline and seizure follow, with death t ypically in the fi rst decade (48). MRI demonstrates hypointensity of the globus pal- lidus (indicating iron accumulation) in addition to cerebellar atro- phy. Th e signal abnormalit y diff ers from the \200\230eye of the tiger \200\231 sign of PKAN as there is no central hyperintensity (49). loss, glio- sis, axonal spheroids, and iron deposition in the globus pal- lidus, red nucleu s, and substantia nigra. Th e HARP syndrome (hypo-prebetalipoproteinaemia, acanthocytosis, retinitis pigmen- tosa) is part of the PKAN spectrum. Neuropathological features include neuronal Th e diagnosis is suggested by MRI fi ndings of bilateral hyper- intense signal changes in the anteromedial globus pallidus with surrounding hypointensity in the globus pallidus and substantia nigra pars reticulata on T 2 -weighted images. Th is \200\230eye-of-the-tiger \200\231 sign is highly specifi c to PKAN. Most patients have mutations in the PANK2 gene ( 40, 41) and molecular analysis can confi rm the diagnosis. Atypical forms present later (2 \200\2237 years) with a picture of static encephalopathy an d later deterioration from 7 to 12 years, with progressive dystonia, ataxia, dysarthria, an d neurobehavioural dis- turbance (41). Again, MRI demonstrates iron accumulation in the med ial and lateral portions of the pallidum, and there may be EEG abnormalities. Both infantile and later forms of neuroaxonal dystrophy are caused by mutations in the PLA2 G6 gene, which encodes iPLA 2 -VIa, a calcium-independent phospholipase, which may disrupt mem- brane homeostasis (41, 48, 49). Treatment is symptomatic. Dystonia may occasionally benefi t from baclofen, trihexyphenidyl , or botulinum toxin. Bilateral pal- lidal stimulation and thalamotomy have also been used for intrac- table generalized dystonia in PKAN with evidence of sustained benefi t (42, 43) . A recent phase II trial of the oral iron-chelating drug deferiprone in ten patients with PKAN, demonstrated reduced pallidal iron content at 6 months as assessed by MRI T2* relaxom etry (44). However, there was no clinical change in dystonia or quality of life over the sa me period. It is possible that longer-term therapy, or earlier intervention, may aff ect ne urologi- cal progress. Two cases of Pakistani and Indian descent with dystonia \200\223 parkinsonism have also bee n found to have mutations in PLA2G6 (homozygous missense mutations) with an onset at 10 \200\22326 years of subacute dystonia \200\223parkinsonism, pyramidal signs, eye movement a bnormalities, and cognitive/psychiatric features (50). Cerebellar features which are presen t in typical INAD were absent in these cases. Also in contrast with INAD, iron was absent i n the basal gan- glia. Th ree individuals had good response to levodopa. Neuroferritinopathy Neuroferritinopathy is an adult-onset (mean age 40) autosomal dominant disorder which results in abnormal aggregates of iron Idiopathic basal ganglia calci \201 cation Idiopathic basal ganglia calcifi cation (Fahr \200\231s disease) is an auto- somal dominant neurodegenerative disease with basal ganglia CHAPTER 19 Other Dystonias 205 calcifi cation that typically presents between 30 and 50 years of age with chorea, dystonia , parkinsonism, ataxia, seizures, cognitive impairment, and neuropsychiatric disorder (51, 52). Pyramidal and cerebellar signs may also feature. It is slowly progressive. Over thirty aff ected families have been reported (53). sphingolipidoses the pathway of degradation of sphingolipids is dis- rupted, either by spec ifi c enzyme defi ciency or by lack of activator protein. Th is results in sphingolipid acc umulation in one or more organs, particularly the brain. Th e inheritance is autosomal rece s- sive in all these conditions except Fabry \200\231s disease and Pelizaeus \200\223 Merzb acher disease, which are X-linked. Calcifi cation of the globus pallidus, putamen, caudate, thalamus, and dentate nucleus is e vident on neuroimaging. Histopathology demonstrates perivascular iron deposits in the basal ganglia and dentate nucleus. A locus, IBGC1, has been identifi ed on chromo- some 14q (54) but the responsible gene has not been identifi ed. Treatment is symptomatic. Niemann \200\223Pick disease type C is described in detail below. Th e other lysosomal storage disorders are outlined in Table 19.2.