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. Patients with blepharospasm have abnormal contractions of the orbicularis oculi muscles. Mi ld cases are characterized by a simple increase in blink rate and occasional fl urries of b linking; in more severe cases forceful eye closure can interfere with vision, leading to fu nctional blindness. In oromandibular dystonia there is abnormal activity in lower facial, t ongue, jaw, and pharyngeal muscles that can interfere with speaking or swallowing. Brachial dystonia is a form of focal dystonia that can be primarily, or exclusively, present with w riting (writer \200\231s cramp). Th e DYT4 phenotype refers to a large Australian pedigree with twenty aff ected members and autosomal dominant inheritance (60). Penetrance was complete in all the obligate gene carr iers examined; age at onset varied from 13 to 37 years. Many patients presented with \200 \230whispering dysphonia \200\231, while others had cervical dystonia. Most patients eventu ally developed generalized dystonia. Wilson disease co-existed in the same pedigree, but wa s excluded as a cause of dystonia in the aff ected individuals (61). Segmental dystonia can aff ect the upper and lower cranial mus- cles, as in the combination of blepharospasm with oromandibular dystonia, sometimes called Meige \200\231s syndrome. I n craniocervical dystonia, another type of segmental dystonia, the cranial area is involved together with the neck muscles. Unclassi \201 ed phenotypes A number of scattered pedigrees not carrying the DYT1 mutation have been described. In some of these families, DYT6 dystonia has not been excluded. Linka ge studies have not been performed or have not been informative, leaving these pedigrees un mapped. A non-Jewish American family presented with adult-onset DYT1-negative primary dystonia (62) . Th e disease started in the neck in six cases and in a leg in one. All patients developed cervi- cal dystonia, and language impairment (dysarthria or dysphonia) occurred in fi ve. Four patients developed generalization of symp- toms. In a Swedish family transmission was autosomal dominant with a heterogeneous phenotype (63). Th ere was involvement of the face and larynx, and generalization occurred in three of the ten patients. A family from South T yrol had six aff ected individu- als, four of whom developed generalization approximately 5 years aft er onset (64). Th e limbs were involved at onset in all cases except one, who st arted with cervical dystonia. Upper body involvement was observed in three of the four gene ralized cases. An Italian family had six aff ected individuals, one of whom had severe seg- mental dystonia (65). Th e prevalent phenotype was an adult-onset craniocervical dystonia with occasional axial involvement but no generalization. Pathophysiology Dystonia is characterized by an abnormal co-contraction of agonist and anta gonist muscles that is worsened by a selection of task-specifi c movements and is usually r elieved by a selection of sensory tricks. Th e abnormal co-contraction is thought to be cau sed by a dysfunction at the spinal or cortical level or both (67). Reciprocal inhibition is the central nervous system process by which a muscle is inhibited when its antagonist is a ctivated. A decreased reciprocal inhibition at diff erent levels of the central nervous sys tem might contribute to the excessive movement seen in dystonia. Dystonic patients may have faulty processing within the inhibitory interactions between antagonist muscles at the sen - sorimotor cortex level. Neuroimaging studies have recently provided interesting insights to understanding the patho physiological mechanisms of primary pure dystonia. Diff usion magnetic resonance stud- ies found signal abnormalities in various brain areas (including corpus callosum, basal ganglia , pontine, and prefrontal corti- cal areas) in cervical dystonia, writer \200\231s cramp, a nd generalized dystonia, but not in blepharospasm (68 \200\22371). Functional MRI studies c onducted in patients with blepharospasm (72), writer \200\231s cramp (73 \200\22375), or up per limb focal dystonia (76) demonstrated A common phenotype was outlined in a series of forty-three Italian patients with non-DYT1 e arly-onset dystonia (24). Th is was characterized by cervical involvement, frequent non-lim b onset, a relatively benign course, and uncommon generalization. Th is fi nding suggests t hat these non-DYT1 Italian families may share a common genetic defect. Th eir features are similar to the DYT6 Oxford Textbook of Movement Disorders 196 Botulinum toxins Botulinum neurotoxins (BoNTs) inhibit the vesicular release of acetylcholi ne at the neuromuscular junction, resulting in a tran- sient localized impairment of neurot ransmission. Diff erent forms of type A and one type B BoNT are available for clinical use (90) (Table 18.3). that several deep structures and cortical areas may be acti- vated, depending on the diff e rent modalities of examination. Voxel-based morphometry showed an increase in gray mat- ter density or volume in various areas, including the cerebel- lum, basal ganglia, and primary somatosensory cortex, which might represent plastic changes secondary to overuse (77 \200 \22381). PET studies have provided information about areas of abnor- mal metabolism in diff erent types of dystonia and in diff erent conditions (e.g. during active involuntary movem ent or during sleep), providing insight into the role of cerebellar and subcorti- cal struc tures compared with cortical areas (82, 83). In properly adjusted doses, BoNTs are an eff ective and safe treatment for cranial and cerv ical dystonia (91). According to one systematic review, no conclusions can be drawn on the effi - cacy of BoNT for diff erent types of spasmodic dysphonia (92), although uncontrolled studies have found this treatment effi ca- cious. BoNT/A is also effi cacious for the trea tment of writing dystonia (93). Several studies have analyzed genetically classifi ed dystonias to investigate functional a nd morphological changes. Non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carr iers have signifi cantly larger basal ganglia than symptomatic DYT1 mutation carriers, with a negative correlation between severity of dystonia and basal ganglia size in DYT1 patient s (84). In DYT6 and DYT1 dystonia patients, D2 receptor availability is reduced in the caud ate and putamen and [ 11 C]raclopride binding is also reduced in the ventrolateral thalamus (85). Th ese changes were more pro- nounced in DYT6 than in DYT1 carriers, without any dif f erence between manifesting and non-manifesting carriers. Several stud- ies have failed to detect neuropathological changes in DYT1 dys- tonia. In particular, immunohistochemistry o f the basal ganglia has not revealed morphological abnormalities (86). More recently, howev er, brainstem abnormalities were observed in four typical DYT1 patients who had perinuclear inclusion bodies in the mid- brain reticular formation and periaqueductal gray matter. Th ese inclusions stained positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. Similar fi ndings were not reported in genetically unclassifi ed adult-onset pri mary pure dystonia patients (87). Th ese fi ndings suggest that the underlying molecular pa thological mechanisms might diff er in diff erent dystonia types. In another study, nigral dopaminergic neurons were found to be larger in the substantia nigra of dystonia patients c ompared with healthy controls, with no diff erence between DYT1 and non-DYT1 cases (88). BoNT injections can be performed directly or by EMG- or ultrasound-guided targeting, and th ere is no consensus on which is the most appropriate practice. In recent years, the results of long-term studies of the effi cacy and safety of BoNT/A have become available, new form ulations of BoNT/A have been marketed, and new studies of BoNT/B have been performed. Th e effi cacy and safety profi le of BoNT treatments have been evaluated in long-term obse rvational studies. BoNT/A is eff ective and safe in treating blepharospasm, with long-lasti ng effi cacy for up to 15 years (94). In patients with diff erent dystonia types fol- lowed for over 12 years there was no decline of effi cacy and the main side eff ects were muscle weakness in or around the injected region (95). OnabotulinumtoxinA immunogenicity was foun d to be low aft er long-term use (96). A meta-analysis found that adverse events are more f requent among children with cerebral palsy than in individuals with other conditions (97). BoNTs are safe when repeated treatments are performed over many years, but doctors and pati ents should be aware that high cumulative doses may be dangerous, particularly in children. Systemic treatments Little evidence-based information is available for other medical treatm ents for primary dystonia. Anticholinergic drugs at high dosage are reported to be eff ective in the treatment of chil dhood-onset primary or secondary general- ized dystonias (98, 99). Th is therapy is general ly well tolerated when the dose is started low and increased slowly. Trihexyphenidyl should be titrated up to a dosage of 30 \200\22340 mg/day, but some patients might require up to 60 100 mg/day, although dose-related side eff ects (e. g. drowsiness, memory diffi culty, a nd urinary retention) might limit its usefulness, especially in adults. An emerging line of evidence indicates that dystonia could be a disorder of neuroplasticity . In some susceptible individuals, the mechanisms of neuroplasticity during the acquisition of new motor skills are subtly abnormal. In the presence of such a genetic predisposition, environmental factors, such as repetitive training or peripheral nervous system, injury ma y trigger an abnormal maladaptive plasticity, which can lead to overt dystonia. Treatment Th ere is no aetiological or neuroprotective treatment for pri- mary pure dystoni a syndromes. Aetiological therapies are avail- able for some dystonia-plus syndromes of met abolic origin, such as levodopa-responsive dystonia, or non-primary forms, such as Wilson d isease. Symptomatic treatments aim to relieve invol- untary movements, correct abnormal pos tures, prevent contrac- tures, reduce pain and embarrassment, and improve function (89). Bo tulinum toxin is the fi rst-line treatment for most types of focal dystonia. Neurosurgical treatments have an increasing role in the symptomatic treatment plan. Evidence-based treatm ent guide- lines have recently been published by the European Federation of Neurological Sc iences (11). Non-controlled trials are available for the eff ects of antidopamin- ergic drugs. Tetrabena zine was eff ective in one small double-blind randomized crossover study (100). Th e positi ve eff ect of this treat- ment was confi rmed in a large series of patients with diff erent types of movement disorders, including dystonia, followed up retrospec- tively for a mean duration of 6.6 years (101). Deep brain stimulation (DBS) Long-term electrical stimulation of the globus palliduus inter nus (GPi) is now established as an eff ective treatment for primary gen- eralized or segmen tal dystonia (102, 103). A randomized \200\230sham stimulation-controlled \200\231 6-month trial has shown that bilateral high-frequency stimulation of the GPi is effi cacious in re ducing CHAPTER 18 Primary Dystonia 197 Table 18.3 Main muscles involved and typical BoNT doses in more common focal dystonias Ona-BoNT/A Orbicularis oculi: 1.25 \200\2232.5U for each site (4 sites) Abo-BoNT/A Orbicularis oculi: 5 \200\22310U for each site (4 sites) Inco-BoNT/A Orbicularis oculi 1.25 \200\2232.5U for each site (4 sites) Rima-BoNT/B Orbicularis oculi: 50 \200\223100U for each site (4 sites) Blepharospasm Oromandibular dystonia Perioral muscles: 2.5 \200\2235U for each site (4 \200\2235 sites) Masseter: 15 \200\22360U for each side (1 \200\2232 sites) Perioral muscles: 10 \200\22320U for each site (2 \200\2233 sites) Masseter: 60 \200\223240 U for each side (1 \200\2232 sites) Perioral muscles: 2.5 \200\2235U for each site (4 \200\2235 sites) Masseter: 15 \200\22360U for each side (1 \200\2232 sites) Perioral muscles: 100 \200\223200U for each site (4 \200\2235 sites) Masseter: 600 \200\223 2400U for each side (1 \200\2232 sites) Torticollis Contralateral sternocleidomastoid: 25 \200\22350U for each site (2 sites) Omolateral nuchal muscles: 25 \200\22350U for each site (2 sites) Contralateral sternocleidomastoid: 100 \200\223200U for each site (2 sites) Omolateral nuch al muscles: 100 \200\223200U for each site (2 sites) Contralateral sternocleidomastoid: 25 \200\22350U for each site (2 sites) Omolateral nuchal muscles: 25 \200\22350U for each site (2 sites) Contralateral sternocleidomastoid: 1000 \200\2232000U for each site (2 sites) Omolateral nu chal muscles: 1000 \200\2232000U for each site (2 sites) Laterocollis Omolateral splenius capitis: 12.5 \200\22337.5U for each site (2 \200\2233 sites) Omolatera l sternocleidomastoid: 6.25 \200\22312.5U for each site (2 sites) Omolateral splenius capitis: 50 \200\223150U for each site (2 \200\2233 sites) Omolateral s ternocleidomastoid: 25 \200\22350U for each site (2 sites). Omolateral splenius capitis: 12.5 \200\22337.5U for each site (2 \200\2233 sites) Omolatera l sternocleidomastoid: 6.25 \200\22312.5U for each site (2 sites) Omolateral splenius capitis: 500 \200\2231500U for each site (2 \200\2233 sites) Omolateral sternocleidomastoid: 250 \200\223500U for each site (2 sites) Retrocollis Bilateral splenius capitis: 18.75 \200\22350U for each side Bilateral splenius capitis: 75 \200\223200U for each side Bilateral splenius capitis: 18.75 \200\22350U for each side Bilateral splenius capitis: 750 \200\2232000U for each side Anterocollis Bilateral scalenus anterior: 40 \200\22360U for each side Bilateral scalenus anterior: 160 \200\223240U for each side Bilateral scalenus anterior: 40 \200\22360U for each side Bilateral scalenus anterior: 1600 \200\2232400U for each side Laryngeal dystonia (adductor type) Vocal cord (thyroarytenoid muscle): 1.25 \200\2232.5U for each side (5 \200\22310U if unila teral) Lateral cricoarytenoid: 2.5 \200\2235U for each side Vocal cord (thyroarytenoid muscle): 5U for each side (20 if unilateral) Lateral cricoaryten oid: 10 \200\22320U for each side Vocal cord (thyroarytenoid muscle): 1.25 \200\2232.5U for each side (5 \200\22310U if unila teral) Lateral cricoarytenoid: 2.5 \200\2235U for each side Vocal cord (thyroarytenoid muscle): 50 \200\223100U for each side (200 \200\223500U if unil ateral) Lateral cricoarytenoid: 100 \200\223200 for each side motor impairment and disability in patients with primary general- ized or cervical dystonia (103). features, with improvement in the latter oft en developed by weeks or months (109 \200\2231 11). Overall, the most benefi cial results with pal- lidal DBS were reported in children wi th primary generalized dys- tonia, particularly in DYT1 dystonia, which improves by 40 \200 \22390% (112 \200\223114). Long-term effi cacy was reported to be sustained aft er more tha n 5 years of follow-up (115). In patients with cervical dys- tonia, GPi DBS has so far been used mainly in those who were not thought to be ideal candidates for peripheral denervatio n, includ- ing patients with head tremor and myoclonus or marked phasic movements (116). Surgery is indicated aft er medications or BoNT have failed to provide adequate improvement . Th ere is limited experience for targets other than the GPi (104), such as the thalamus, the sub- thalamic nucleus (105), and the cerebral cortex (106). Chronic stimulation in dyst onia uses higher pulse-widths and voltages than in Parkinson \200\231s disease, resulting i n earlier battery depletion; replacement may sometimes be needed every 2 years or less. GPi DBS is generally less eff ective in secondary dystonia. Th is pro- cedure requires a speci alized expertise and a multidisciplinary team, and may be limited by the occurrence of side eff ects. Other indications are still being explored, such as status dystonicus, task-spec ifi c dystonias, camptocormia, secondary hemidystonia, pantothenate-kinase-associated neuro degeneration, Lesch \200\223Nyhan disease, and cerebral-palsy-related dystonia \200\223chor eoathetosis. Safety aspects which have to be considered include surgery- related complications, stimulat ion-induced side eff ects, and hardware-related problems. Chronic high-voltage GPi DBS may induce a parkinsonian gait or bradykinesia in limbs unaff ected by dystonia (117, 118). Bil ateral pallidal stimulation does not impair cognitive performance (119). According to a National Institute for Health and Clinical Excellence (NICE) guideline (107) , GPi DBS provides marked benefi t with improvement of dystonia motor scores (34 \200\22388 %) and disability scores (40 \200\22350%). A meta-analysis using a regression anal- ysis, p ublished in 2006, revealed that longer duration of dystonia correlated negatively with surg ical outcome (108). Improvement of dystonia aft er DBS commonly follows a specifi c pattern , with phasic (clonic or tremulous) elements improving earlier than tonic Other neurosurgical procedures According to the NICE guidelines (120), selective peripheral den- ervation in cervical dystonia requires specialized expertise, but is safe, with infre quent and minimal side eff ects, and is indicated exclusively in cervical dystonia. Accordi ng to EFNS guidelines there is insuffi cient evidence to use this treatment in primary dys- tonia, although this procedure may be indicated in patients aff ected Oxford Textbook of Movement Disorders 198 by secondary dystonia combined with spasticity (91). Intrathecal baclofen has been used in patients with severe generalized dysto- nia. Since this treatment is complicated by medicat ion-related side eff ects, it is currently indicated only in patients where secondary dysto nia is combined with spasticity (121). 25. Opal P, Tintner R, Jankovic J, et al. Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm. Mov Disord 2002; 1 7 : 339 \200\2234 5 . 26. Bentivoglio AR, Loi M, Valente EM, Ialongo T, Tonali P, Albanese A. Phenotypic variabil ity of DYT1-PT D: does the clinical spectrum include psychogenic dystonia? Mov Disord 2002; 17 : 1058 \200\2236 3 . 27. Gambarin M, Valente EM, Liberini P, et al. 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