on (usually one or both arms). Age at onset is divided into young- onset (<20 \200\22330 ye ars) and adult-onset dystonia. Etiology is usually divided into four groups: primary, dysto nia-plus, sec- ondary (or acquired), and heredodegenerative. In the primary group dystonia is the only sign (although most allow tremor to be present as well) and there is no seconda ry cause or neurodegen- eration; in dystonia-plus syndromes, which are similar to primary d ystonia, there is no evidence of a secondary cause or neurode- generation, but signs other than dystonia (e.g. parkinsonism, myoclonus) are present; in secondary dystonia a clear acq uired or exogenous cause is present (e.g. brain injury, drug exposure); and in heredodegene rative dystonia, dystonia is part of a neurodegen- erative syndrome that is oft en inherite d (e.g. Wilson disease). Th e European Federation of Neurological Societies (EFNS) has pro- posed including dystonia-plus syndromes and paroxysmal dysto- nias under the primary dysto nias (Table 17.1). Th e three diff erent ways of classifying dystonia occur in parallel in clinical practice and are essential for diagnosis, prognosis, guiding therapy, and genetic counseling. Psychogenic dystonia is not described in the classifi cation of dystonia. It oc curs as part of a conversion disor- der, tends to be fi xed, and is accompanied by other si gns suggest- ive of a conversion disorder (18 \200\22321). Dystonia is oft en aggravated by voluntary movement. In action dystonia, the dystonic movem ents are elicited only with voluntary movement. When dystonia is evinced only with particul ar actions, it is called task-specifi c dystonia; examples include writer \200\231s cramp a nd the embouchure dystonia of woodwind and brass musicians. Activation of dystonic movement s by actions in remote parts of the body is called overfl ow; examples include leg dystonia while writ- ing or axial dystonia with talking. Factors that tend to exacerbate dystonia i nclude fatigue and emotional stress, whereas the move- ments usually decrease with relaxati on or sleep. Dystonia can oft en improve by tactile or proprioceptive sensory tricks ( gest e antago- niste ). Oft en a patient will be able to improve the abnormal posture to some de gree by touching, or even sometimes thinking about touching, the aff ected body part (2 \200\2236). Despite the \200\230motor \200\231 definition of primary dystonia, there are other, non-mo tor, features in many patients with primary dys- tonia, but these are less studied in secon dary/heredodegenera- tive dystonias (7, 8). Disease-related pain occurs in 30 \200\22370% o f patients, and mild sensory symptoms such as discomfort in the neck, irritation of the eye s or throat before the development of cervical dystonia, blepharospasm, and spasmodic dysph onia, respectively, are common (9, 10). Depressive disorders and a family history of depres sion are more frequent in adult-onset focal dystonia (11 \200\22314) and in manifesting and non-manifesting DYT1 mutation carriers (15). These non-motor symptoms are clinically relev ant, since they may impair quality of life equally to the motor symptoms (10, 16, 17). Genetic classi \201 cation of dystonia Th e DYT loci represent a clinically heterogeneous group of dis- orders including primary dystonia (DYT1, 2, 4, 6, 7, 13, 17, 21), dystonia-pl us (DYT3, 5/14, 11, 12, 15, 16), and paroxysmal dys- tonias (DYT8, 9, 10, 18, 19, 20) (Tabl e 17.2). Th erefore a genetic classifi cation of dystonia is not clinically useful. With re gard to Oxford Textbook of Movement Disorders 178 Table 17.1 Classi \201 cations of dystonia Fahn et al. 1998 (22) 1. Childhood 2. Adolescen ce 3. Adulthood Fahn et al. 2011 (23) 1. Young-onset (<26) 2. Adult-onset (>26) EFNS guidelines 2011 (24) 1. Early-onset (variably de \201 ned as <20 \200\22330 years) 2. Late-onset Age at onset Distribution Focal Segmental Multifocal Generalized hemidystonia Focal Segmental Multifocal Generalized hemidystonia Focal Segmental Multifocal Generalized hemidystonia Etiology Primary (a) Familial (b) Sporadic Primary Primary (a) Primary pure (e.g. DYT1, 6) (a) Primary paroxysmal (e.g. DYT8, 10, 18) Dystonia-plus Dystonia-plus (c) Primary-plus (former dystonia-plus syndromes, e.g. DYT5,11) Secondary Secondary Secondary Heredodegenerative Heredodegenerative Feature of another neurological disease (e.g. dystonic tics, paroxysmal dyskinesias, PD, PSP, etc.) Heredodegenerative Table 17.2 Th e DYT genes, phenotype, and transmission Primary dystonia DYT1 Gene or locus Phenotype Generalized early-limb-onset dystonia Transmissio n AD TOR1A None DYT2 Early-onset generalized dystonia AR DYT4 None Whispering dysphonia AD DYT6 Craniocervical and limb dystonia AD THAP1 18p DYT7 Adult-onset cervical dystonia AD DYT13 1p36.13 \200\22336.32 Craniocervical, laryngeal, and limb dystonia AD DYT17 20p11.2-q13.12 Segmental or generalized dystonia, severe dysphonia AR DYT21 2q14.3-q21.3 Adult-onset generalized or multifocal dystonia, starting with blepharospasm AD Dystonia-plu s syndromes DYT3 Dystonia \200\223parkinsonism (neurodegeneration) XR TAF1 DYT5a Dopa-responsive dystonia AD GTPCH1 DYT5b Dopa-responsive dystonia AR TH DYT11 Myoclonus \200\223dystonia AD SGCE DYT12 Rapid-onset dystonia \200\223parkinsonism AD ATP1A3 18p11 DYT15 Myoclonus \200\223dystonia AD DYT16 Early-onset dystonia \200\223parkinsonism AR PRKRA Paroxysmal dystonias DYT8 Paroxysmal non-kinesigenic dyskinesia AD MR1 DYT9/DYT18 Paroxysmal exercise-induced dystonia with wide phenotypical spectrum (e.g. spasticity, atax ia, seizures) AD SLC2A1 (GLUT1) DYT10 Paroxysmal kinesigenic dyskinesia AD PRRT2 16q DYT19 Paroxysmal kinesigenic dyskinesia 2 AD DYT20 2q Paroxysmal non-kinesigenic dyskinesia 2 AD disorder usually plateaus 5 \200\22310 years aft er onset. Prevalence reports of primary dy stonia vary widely from 3 to over 7000 per million depending on dystonia subtype (e.g. foca l vs generalized), ethnicity, and ascertainment methodology; most point to an estimated cru de prevalence of about 300 \200\223500 per million with focal dystonias being about seven t o ten times more common than generalized dystonia (27 \200\22329). However, the prevalence of primary dystonia is thought to be underestimated (29). genetic causes of heredodegenerative dystonias, many genes have been identifi ed (Table 17. 3). Primary dystonia Th e phenotypic spectrum of primary dystonia is wide, ranging from young-o nset generalized to adult-onset focal dystonia (25, 26). As per the defi nition, there are no additional signs and the CHAPTER 17 Dystonia: an overview 179 Young-onset primary dystonia Age at onset is usually in childhood or adolescence. Limb onse t is typical, with spread of symptoms over some years which then pla- teaus, oft en resulti ng in generalized dystonia. However, some patients may only develop focal or segmental dyst onia. Young-onset primary dystonia does not usually involve cranial or bulbar structures. DYT17 is autosomal recessive and was mapped to chromosome 20 in a consanguineous Lebanese f amily with cervical dystonia and progression to segmental dystonia in two siblings and gene ralized dystonia in a third sibling who also featured severe dysphonia and dysarthria (55). Adult-onset primary dystonia (APD) Th e onset of APD is in adulthood, and the muscles aff e cted depend on the age at onset. Focal dystonia is more common, but can become segmental, w ith spread of symptoms over some years, especially with blepharospasm (56, 57). Lower limb APD is very unusual for primary dystonia and is usually due to secondary/heredodegenera- ti ve causes. DYT1 dystonia (Oppenheim dystonia, dystonia musculorum deformans), a major cause of young-o nset primary dystonia, is an autosomal dominant condition with reduced penetrance (30%). It is caused by a heterozygous GAG deletion mutation of the TOR1A (TorsinA) gene located on t he long arm of chromosome 9. TOR1A codes for torsinA, an AAA+ superfamily of molecular chap erones (30). Th e GAG deletion in TOR1A accounts for about 80% of young-onset primary dysto nia in the Ashkenazi Jewish population because of the founder mutation, but less than 50% i n the non-Jewish population (31 \200\22335). Two missense mutations in the TOR1A gene have been described, each in a single case (36). A third missense variant, D216H, is protective against pen- etrance of the GAG deletion when inherited in trans (37, 38). Th e typical cli nical phenotype associated with DYT1 dystonia is characterized by young onset (mean age 13 years), starting in a limb (arm or leg is aff ected fi rst in 90% of cases) and progressing to generalized/multifocal (65%) involvement; spread to cranial structures is less common ( 15 \200\22320%) (31, 35). However, there is a wide phenotypic and intrafamilial variability , from severe dys- tonic storm to mild writer \200\231s cramp, as well as various atypical phenotypes (39, 40). Clinical phenotypes Among adult-onset cranial and cervical dystonias, cervical dysto- nia i s the most common. Typical age at onset is around 40 years (56, 58), and women are more oft en aff ected than men. It may start with gradual onset of discomfort or pain in the neck, followed by involuntary pulling of the head in a particular direction because of contractio n of certain neck and shoulder muscles. Various combi- nations of neck muscles may be invol ved to produce abnormal head positions, including horizontal turning (torticollis), tilting (latero- collis), fl exion (anterocollis), or extension (retrocollis). Jerky tremor, which worsens when turning the head towards the normal posi- tion, is very common and can be the predominant feature. Patients may have a geste antagoniste, where they can partially relie ve their spasm by touching the chin or part of their face. Symptoms usually progress over 6 \200\22312 months and then plateau. Remission can occur in 10 \200\22315% of the patients, especially those with younger onset, and may be sustained. Another cause of young-onset primary dystonia is DYT6 dysto- nia due to heterozygous mutati ons in the gene THAP1 (thanatos- associated protein domain-containing apoptosis-associated pro- tein 1), initially described in three Amish-Mennonite families (41, 42). THAP1 is a tr anscription factor whose function in the brain remains unknown. More than 45 heterozygous m utations have been reported in THAP1 (43 \200\22347). Recently, THAP1 has been shown to bin d to the TOR1A promoter, repressing its expression, which links the molecular pathways unde rlying DYT1 and DYT6 dystonia (48). Th e typical DYT6 phenotype is characterized by young o nset (mean 13 years, range 2 \200\22362 years), most oft en in an arm (47%) followed by cra nial muscles (25%) or the neck (23%) but, in contrast with DYT1, rarely in the leg (5%), wi th spread to a generalized or multifocal distribution in over half and prominent speech inv olvement in more than 60% of cases (44 \200\22347). However, about 10 \200\22318% of cases have only focal dystonia, and in screening studies of adult-onset focal cases a low frequen cy (>1%) of THAP1 mutations has been reported (45). Blepharospasm causes contraction of the orbicularis oculi mus- cles; it tends to start late r than other craniocervical dystonias, with mean age at onset around 55 years (58, 59). Wom en are more com- monly aff ected than men. An uncomfortable feeling around the eyes, dry ey es, and photophobia may precede the spasm. Mild cases are characterized by increased blink rate with fl urries of blinking, whereas more severely aff ected patients have visual impai rment due to sustained forceful eye closure. In some patients there is an inability to acti vate the levator palpebri, so that the eyelid cannot open; this is called levator inhibitio n. About two-thirds of patients are signifi cantly disabled and 12 \200\22336% are consider ed functionally blind (60). Spasmodic dysphonia (SD) results from dystonia of the vocal cords and has a similar age at onset and sex ratio to cervical dystonia. Compared with other forms of cranial dystonia, it occurs less oft en in conjunction with other cranial dystonias (57). It is estimated that the majority of patients have isolated SD, about 10 \200\22315% progress to another cranial region, and about 5% progress to extracranial sites (61, 62). In adductor dysphonia (the m ost common form), which involves the thyroarytenoid muscles, there is excessive glottal clo - sure in a rigid fashion, preventing air fl ow and causing a strained, strangled voice. Ab ductor dysphonia (much less common) involves the posterior cricoarytenoid muscles; it is ch aracterized by open glottal confi guration and a paucity of vocal cord vibration so that th e voice sounds whispering and breathy. DYT2 is an autosomal recessive primary dystonia reported in consanguineous families of Span ish gypsy (49), Sephardic Jewish (50), and Arab descent (51). Th e phenotype is similar to DYT1 dystonia with young-onset limb dystonia followed by generaliza- tion. DYT4 is an autos omal dominant primary dystonia, reported in a single large Australian family, with prominen t whispering dys- phonia that begins in the second decade in most family members (52, 53). No chromosomal location or gene has been identifi ed for either disorder. DYT13 is an autosomal dominant disorder with reduced pen- etrance, mapped to chromosome 1p3 6 in an Italian family, with adolescence onset, mainly segmental, dystonia, and prominent c raniocervical involvement (54). In oromandibular dystonia (OMD) there is abnormal activity in lower facial, tongue, jaw, an d pharyngeal muscles. It has a similar Oxford Textbook of Movement Disorders 180 age at onset to blepharospasm, and women are more commonly aff ected than men. Jaw-closing dystonia has been considered to be the most common form, while simultanous movements of jaw openers (lateral pterygoids, digastric muscles) and closers (medial pterygoids, masseter a nd temporalis muscles) may result in jaw tremor (63). OMD may cause pain and diffi culty in speaking, chew- ing, and swallowing. Sensory tricks such as putting a fi nger in the mouth , chewing gum, or placing a toothpick in the mouth can par- tially help to reduce the sympt oms (64). An important diff erential diagnosis is OMD caused by neuroleptic drugs, since th is presents with a similar clinical picture. A combination of blepharospasm and OMD is call ed Meige \200\231s syndrome . four forms that have predominantly parkinsonism but also other features as part of their ph enotype (DYT3, 5/14, 12, 16). Myoclonus \200\223dystonia DYT11 myoclonus \200\223dystonia (MD) is an autosomal dominant c on- dition with reduced penetrance due to maternal imprinting, i.e. the selective silencing of the maternal allele, so that almost all aff ected individuals inherit a mutation from t heir father (84, 85). It is due to mutations in the SGCE (epsilon sarcoglycan) gene. SGCE f unction in the brain is largely unknown, but experimental studies express- ing pathogenic m issense mutations show impaired traffi cking of the mutant protein to the plasma membrane a nd degradation by the proteasome, which is enhanced by an interaction with torsinA (the pro tein encoded by TOR1A /DYT1). DYT11 MD is charac- terized typically by brief lightning-like myoclonic jerks and dys- tonia, and usually begins in childhood. Myoclonus is usually the presenting symptom and most oft en aff ects the neck, trunk, and upper limbs, with the legs aff ected less prominently. Th e myoclonic jerks show a dramatic response to alcohol in ma ny patients (86, 87) and they are not stimulus-sensitive, indicating a subcortical origin. About two-thirds of patients with DYT11 have dystonia, mostly cervical or writer \200\231s cramp, which tends to remain mild. Psychiatric manifest ations including depression, anxiet y, panic attacks, and obsessive \200\223compulsive disorder (OCD) have been reported, and, in particular, OCD has been found in those not aff ected with motor signs, suggesting that it is related to the genetic defect (88 \200\22390). Exonic deletion mutations and other la rger deletions result in more complex manifestations, including skeletal abnormalities, fac ial dysmorphism, developmental delay, or cavernous cerebral malfor- mations (91). Primary lingual dystonia is rare and may or may not be associated with OMD. Although severe tongue protrusion dystonia is more frequent in heredodegenerative disorders (65), it has a lso been described in APD (66). Tongue movements may be repetitive or protrusion may be sus tained. Movements are oft en action-induced, commonly by speaking (67), and the tongue may also curl instead of protruding (68). Th e most common adult-onset limb dystonia is writer \200\231s cramp, where the patient sho ws abnormal postures aff ecting the hand when writing, but not while performing other tasks . Age at onset is around 25 \200\22335 years and men are more commonly aff ected than women . Th e unaff ected hand may show mirror movements when the patient is writing with the aff ected hand. Other adult-onset limb dystonias include task-specifi c dystonias like musician s \200\231, typists \200\231, or golfers \200\231 dystonia. Adult-onset leg dystonia is ver y rarely reported as a primary phenomenon and is almost always due to a secondary/ heredode generative cause. Adult-onset primary truncal dystonia is also reported. Th e mean age of o nset is 41 and men seem to be slightly more commonly aff ected than women. It tends to rema in focal, although there may be an initial contiguous spread, some- times beginning in the craniocervical region and spreading axially or, rarely, vise versa (69). Although the SGCE gene appears to be a major locus for MD, sporadic and familial cases with out mutations in SGCE have been reported (92, 93), suggesting genetic heterogeneity. One of these families, with autosomal dominant inheritance and reduced pene- trance, was used to map a second locus for MD to chromosome 18p ( DYT15 ). Th e average age at onset is 9.6 yea rs (range 7 \200\22315 years) and the MD phenotype is alcohol responsive (94). Genetics of APD APD is complex, with family studies suggesting autosomal domi- nant inherit ance but with very low penetrance (about 12 \200\22315% compared with 30% for early-onset d ystonia) (70, 71). Th e role of specifi c genes in the etiology of APD is not fully elucida ted. Th ere are some descriptions of large families with highly penetrant autosomal dominan t APD (72 \200\22374) which have resulted in the map- ping of two genes for APD: DYT7 (75) and DYT21 (76) (see Table 17.2) . DYT7 is mapped to chromosome 18p in a German family with adult-onset cervical dystonia (mean 43 years), some of whom also had brachial and cranial i nvolvement (75). DYT21 was linked to a region on chromosome 2q14.3-q21.3 in a Swedish famil y (76) phenotypically characterized by later-onset (mean 27 years) mainly generalized or mu ltifocal dystonia with onset in the craniocervical muscles in most and the hands in about 2 5%. DYT6 has been asso- ciated with adult-onset focal dystonia (45), and cervical dystonia as well as writer \200\231s cramp cases with DYT1 mutations (77 \200\22379). Reports with r egard to an association of torticollis and blepharospasm with a polymorphism in the dopamin e D5 receptor ( DRD5 ) gene are contradictory (77, 80 \200\22383). Dystonia \200\223parkinsonism DYT3 is the only form of dystonia that is inherited as an X-l inked trait. Th e disease originated on the island of Panay in the Philippines due to a fou nder mutation in the TAF1 (TATA-binding protein-associated factor 1) gene and primarily aff ects males, although a few females have been reported (95 \200\22398). Disease onset occur s in the mid-thirties (range 12 \200\22352 years) with complete pen- etrance by the end of the fi ft h decade. Th e symptoms start as focal dystonia in almost any part of the body an d progress to multifocal or generalized dystonia, in most cases within 5 years. Parkinsonis m evolves later in the disease in about 50% of patients (99, 100). However, DYT3 dystonia i s unique among the DYT loci in that neuronal degeneration, consisting mainly of neuronal lo ss and a multifocal mosaic pattern of astrocytosis restricted to the caudate and lateral pu tamen, has been noted on post-mortem analysis (95, 96, 98). DYT5 was initially described by Segawa in 1976 (101), and later by Nygaard and colleagues a s dopa-responsive dystonia (DRD) because of the dramatic and sustained response to a low do se of levodopa (102). Th e disease is inherited as an autosomal dominant trait with reduced penetrance that appears to be gender Dystonia-plus syndromes Within the dystonia-plus syndromes there are two forms that have pr edominantly myoclonus in addition to dystonia (DYT11, 15) and CHAPTER 17 Dystonia: an overview 181 dependent, with females expressing symptoms more frequently. It is caused by mutations in t he GTPCH1 (GTP cyclohydrolase 1) gene (103). GTPCH1 is the rate-limiting enzyme in the syn- thesis of tetrahydrobiopterin, an essential co-factor for tyrosine hydroxylase (TH) which, in turn, is needed to synthesize dopamine (Fig. 17.1). Comprehensive screening of the GTPC H1 gene iden- tifi es mutations in approximately 80% of \200\230typical \200\231 DRD patie nts (103, 104), and comprehensive molecular testing is available. Th e typical phenotype in cludes childhood (average 6 years) limb onset dystonia with diurnal variation (i.e. worseni ng of symptoms as the day progresses), improvement aft er sleep, and dramatic response to l evodopa. With identifi cation of the causative gene, the clinical spectrum of DRD has expan ded to include oromandibular dysto- nia, spasticity with developmental delay mimicking cere bral palsy, psychiatric abnormalities, and generalized hypotonia with proxi- mal weakness ( 105, 106). disease is inherited as an autosomal dominant trait with reduced penetrance. Six heterozygo us missense mutations have been identi- fi ed in the Na + , K + -ATPase ATP1A3 (alpha 3 sub unit) gene, and all are shown to impair cell viability in cell culture experiments (109). A total of ten novel mutations in 17 families, and eight de novo cases have been reported (1 10, 111). Th e disease phenotype is designated rapid-onset dystonia \200\223parkinsonism be cause key clinical features include abrupt onset, within hours to weeks, of dystonia with s igns of parkinsonism usually triggered by physical or emotional stress (fever, childbirth, running, alcohol binging). Th e age of onset var- ies from 4 to 58 years, but typically pre sents in the teens or early twenties, and the distribution follows a rostrocaudal (face > a rm > leg) gradient with prominent bulbar involvement. An autosomal recessive form of dystonia-parkinsonism, DYT16, was assigned to chromosome 2q3 1 and the same homozygous missense mutation (P222L) was identifi ed in the PRKRA (protein k inase, interferon-inducible double-stranded RNA-dependent acti- vator) gene in the six aff ected family members as well as in one spor- adic case (112). Th e phenotype in these patie nts is characterized by early (2 \200\22318 years) limb onset, with progression to generali zed dystonia including prominent bulbar involvement with spasmodic dysphonia, dysarthria, a nd even dysphagia. Some aff ected mem- bers also had parkinsonism. A heterozygous frameshif t mutation leading to a protein truncation was identifi ed in a sporadic German case with e arly-onset dystonia (113, 114). In a minority of cases DRD can also be inherited as an autosomal recessive disorder with mu tations in the genes coding for other enzymes involved in dopamine synthesis, including TH (oft en referred to as DYT5b) (106, 107) and sepiapterin reductase (SR) (Fig. 17.1) (108). Th e clinical manifestations are oft en more severe and can include mental retardation, ocu logyria, hypotonia, severe bradykinesia, ptosis, and seizures. A further dystonia \200\223parkinsonism syndrome, which has been des- ignated the DYT12 loc us, was mapped to chromosome 19q13. Th e Guanosine triphosphate (GTP) Dopa-responsive dystonia (DYT5) GTP cyclohydrolase 1 (GTPCH1) Dihydroneopterin triphosphate 6-Pyruvoyl-tetrahydropterin synthase SR de \201ciency Partially dopa responsive 6-Pyruvoyl-tetrahydropterin triphosphate Sepiapterin reductase Tryptophan Phenylalanine Phenylalanine hydroxylase Tryptophan dydroxylase TETRAHYDROPTERIN TRIPHOSPHATE (BH4) Tyrosine Tyrosine Lavodopa 5-OH-tryptophan Tyrosine hydroxylase AADC Serotonin Dopamine TH de \201ciency (dopa-responsive but mostly partially) Homovanillic acid (HVA) 5-Hydroxyindolacetic acid (5-HIAA) AADC de \201ciency (rarely dopa-responsive dopamine-agonists responsive) Fig. 17.1 Dopamine, tyrosine, and serotonin metabolic synthesis pathway and enzyme de \201 ciencies with corresponding disorders. Oxford Textbook of Movement Disorders 182 Paroxysmal dystonia Th is is a heterogeneous group of disorders characterized by parox- ysm al attacks of involuntary movements. Th ey are subdivided into kinesigenic (PKD) (DYT10, 19 ), non-kinesigenic (PNKD) (DYT8, 20), and exercise-induced forms (PED) (DYT9, 18). or stroke. In cases of a precipitating event dystonia may sometimes develop some time aft e r the event. Secondary dystonia is typically not progressive; however, it could be that the re is an initial worsen- ing of symptoms aft er the event for up to some years before the c ondition becomes static. Continuous progression should raise sus- picion of a heredodegener ative cause of dystonia (134, 135). Past medical history, abnormalities in the neurological examination, neuroimaging, or laboratory evaluation, distribution (e.g. hemidys- tonia), a ge at onset, and distribution which is unusual for primary dystonia, such as young-onset cr anial dystonia or late-onset lower limb dystonia, are clues for the diagnosis of secondary dystonia. Paroxysmal non-kinesigeni c dyskinesia (PNKD) is characterized by attacks of dystonia, chor ea, ballism, or athetosis, oft en provoked by alcohol or caff eine. Th e episodes last from minutes to hours, with a frequency ranging from once per day to one or two per year. Th e age of onset is typically in childhood or adolescents, but can be as late as 50 years (115) . DYT8 (PNKD1) is inherited as an auto- somal dominant trait with high penetrance. Th e loc us was localized to chromosome 2q33 \200\22336 (116 \200\223118) and mutations were identi- fi ed in the MR1 (myofi brillogenesis regulator 1) gene (119 \200\223121). Th e DYT20 (PNK D2) locus designates a second form of paroxys- mal non-kinesigenic dyskinesia, which was de scribed in a single Canadian family, in which linkage analysis assigned the locus to chromo some 2q31 with no mutations in the MR1 gene (122). Th e clinical symptoms in this family ar e very similar to those described in the DYT8 families. One major cause of secondary dystonia is brain injury or infection (e.g. perinatal injury, stroke, head trauma or peripheral trauma, brain tumor, exposure to neurotoxic agents, Japan ese B encephali- tis, encephalitis lethargica, brain abscesses) especially involving the ba sal ganglia (mostly putamen), cerebellum, and thalamus (136). Perinatal hypoxic injury oft en leads to severe generalized dysto- nia, with or without spasticity. Th is is oft en call ed athetoid cerebral palsy and should be diff erentiated from DRDs (106, 137, 138). Exposure to dopamine-receptor-blocking drugs (DRBs) or other agents (amine depleters, serot onin-reuptake inhibitors, monoamine oxidase inhibitors, calcium antagonists, benzodiazepine s, general anesthetic agents, carbamazepine, phenytoin, triptans, raniti- dine, cocaine, ec stasy) is a common cause of secondary dystonia. Acute dystonic reactions may occur in up to 2% of patients begin- ning treatment with DRBs. Time to onset is variable, but 50% will de velop dystonia within 1 \200\2232 days and 90% within 5 days. Common presentations are OMD, oculogyric crisis, cervical dys- tonia, and laryngeal dystonic spasm. Tardive dystonia is caused by chronic exposure to DRBs. All neuroleptic drugs including so-called atypical agen ts, with the exception of clozapine, can cause tardive dystonia (139). In contrast with acu te dystonic reac- tions, amine depleters (e.g. tetrabenazine) do not cause tardive syndrome s. Clinically, the dystonia is characterized by axial dys- tonia with hyperextension of the spine and retrocollis. Th e mean time from exposure to onset is around 6 years, but the sh ortest exposure time to onset reported is 4 days. Around 10% of patients show spontaneous r emission, while the prognosis of the others depends on the prompt discontinuation of the DR B and the total duration of the exposure (139). Paroxysmal kinesigenic dyskinesia (PKD) is characterized by short (seconds to minutes) freq uent (up to 100 times per day) attacks of dystonic or choreiform movements precipitated by sudden move- ments. Age of onset is usually during childhood or adolescence, but symptoms c an resolve in adulthood. PKD is inherited as an autosomal dominant trait. Th e DYT10 locus was mapped to chro- mosome 16p11.2-q12.1 (123, 124) and mutations have been iden- tifi ed i n the PRRT2 (proline-rich transmembrane protein 2) gene (125, 126). A second locus for PKD, designated DYT19 , maps to an overlapping region and thus could represent the same locus ( 127). Another PKD pedigree has been excluded from linkage analysis to chromosome 16 and thu s most likely represents a diff erent PKD locus (128). Paroxysmal exercise-induce d dyskinesia (PED) is characterized by exercise-induced attacks of dystonic, choreoathetotic, and bal- listic movements aff ecting the exercised limbs whic h last from a few minutes to an hour. Th e disease usually has its onset in child- hood, an d can have other disease manifestations including epilepsy, migraine, developmental delay, and haemolytic anemia. It shows an autosomal dominant inheritance pattern with slightly red uced pen- etrance. Th e locus is designated DYT18 (129, 130) and mutations in the SLC2A1 ge ne encoding glucose transporter 1 (GLUT1) have been identifi ed (129). Mutations in SLC2A1 have also been found in sporadic cases of PED (131) and in a family with dystonic tremor as the presenting feature (132). SLC2A1 /GLUT1 is the main glucose transporter in the brain. PED is thought to be caused by reduced glucose transportation into the brain, particularly when energy demand is high aft er prolonged exercise. Paroxysmal choreoathetosis/spas- tici ty (DYT9), originally described in a large German pedigree with autosomal dominant inherita nce, was linked to chromosome 1p. Recently, re-examination of this family revealed a causat ive muta- tion in SLC2A1 ; thus DYT9 and DYT18 are allelic disorders (133). Heredodegenerative dystonia Inherited degenerative diseases that can cause dystonia include many autosomal dominant and autosomal recessive conditions, X-linked dominant and recessiv e conditions, and mitochondrial defects. As per the defi nition, there are other symptoms a nd signs, and dystonia occurs as part of neurodegeneration. Th e most important conditions, along with the responsible genes, are given in Table 17.3. A logical approach in these pat ients is to look for syndromic associations that help to narrow down the diff erential diag nosis (Table 17.3). Of particular note is Wilson disease (WD), because it is treatable. It is caused by mutations in the ATP7B (ATPase, Cu 2+ transporting, beta polypeptide) gene on chromo- some 13, which produce a defect in copper metabolism, leading to the insidious deve lopment of neurological, psychiatric, or hepatic dysfunction. Inheritance is autosomal rece ssive; more than 200 diff erent mutations have been reported, making genetic testing imprac tical. In childhood, WD usually presents with hepatic dys- function, while neurological pre sentation is typical in adult-onset Secondary/heredodegenerative dystonia Secondary dystonia Secondary dystonias require the pr esence of a causative lesion, exposure, or event, such as an abscess, dopamine blocking age nts, CHAPTER 17 Dystonia: an overview 183 Table 17.3 Syndromic associations in diagnosing some of the most important heredodegenerati ve dystonias Syndrome Dystonia \200\223parkinsonism Disorder Parkinson \200\231s disease (PD) Gene esp. PRKN (PARK2), DJ- 1 (PARK7) \200\223 Trans mission AR Sporadic PD, CBD, PSP, MSA \200\223 Wilson disease AR ATP7B Neurodegeneration with brain iron accumulation (NBIA) AR PANK2 PLA2G6 (PARK14) Kufor \200\223Rakeb (PARK9) ATP13A2 AR AR AR FA2H Aceruloplasminaemia ( ceruloplasmin gene) Neuroferritinopathy ( FTL ) AR AR Huntington \200\231s disease AD IT-1 5 SCA2 ( ATXN2 ), SCA3 ( ATXN3 ) Spinocerebellar ataxia AD GM1 gangliosidosis AR LacZ Mitochondrial AD, AR POLG \200\223 Dystonia \200\223 ataxia MSA Spinocerebellar ataxia SCA2 ( ATXN2 ), SCA3 ( ATXN3 ) AD Wilson disease AR ATP7B Neuroacanthocytosis AD VPS13A Huntington \200\231s disease AD IT-1 5 Dentatorubral-pallidoluysian atrophy (DRPLA) AR ATN1 GM2 gangliosidosis AR HEXB3 Dystonia \200\223eye movement disorder Ataxia telangiectasia AR ATM Ataxia oculomotor apraxia 1,2 AR APTX, SETX Niemann \200\223Pick C AD NPC1, NPC2 Kufor \200\223Rakeb disease AD ATP13A2 SCA2 ( ATXN2 ) Spinocerebellar ataxia AR Huntington \200\231s disease AR IT-1 5 \200\223 See above PSP Dystonia \200\223bulbar involvement NBIA Neuroacanthocytosis Wilson disease Dystonia \200\223peripheral neuropathy Spinocerebellar ataxia Neuroacanthocytosis GM2 gangliosidosis See above AR Metachromatic leucodystrophy ARSA disease (see Chapter 23 for more details). Dystonia can be general- ized, segmental, or mul tifocal, but cranial involvement is character- istic; other common signs include a \200 \230sardonic \200\231 smile, wing-beating tremor, dysarthria, dysphagia, drooling, ataxia, and dementia. In addition to brain and liver involvement (cirrhosis, acute hepatitis), syst emic fi ndings can involve the eye (Keyser \200\223Fleischer rings), heart, kidney, bones, joints, glands, and muscles. protein. Examples include impaired temporal discrimination threshold in DYT1 manifesting an d non-manifesting mutation carriers (140) and higher temporal and spatial discrimination th reshold in adult-onset primary focal dystonia (141 \200\223143), also in unaff ected body r egions (141, 142, 144) and in patients \200\231 unaf- fected fi rst- and second-degree rela tives (145 \200\223147), suggesting a primary endophenotypic defi cit rather than a defi ci t second- ary to the presence of dystonic contractions. Kinaesthesia and vibration-induced illusion of movement have been found to be impaired in patients with APD in the aff ected a nd unaff ected body regions (148 \200\223151) and in asymptomatic fi rst-degree rela- tives , again indicating the probable primary origin of this feature. Mental rotation of corporea l objects, refl ecting mental simula- tion of movements, is abnormal in both focal hand dys tonia and cervical dystonia (152). Th is suggests that, apart from the motor defi cit, ther e is also a primary defi cit in sensory processing in primary dystonia (7). Pathophysiology of dystonia Th e pathophysiology of dystonia is unknown. Most research has focused on the primary dystonias and the role of genetic suscep- tibility in disease mechan isms. Imaging and neurophysiological abnormalities have been identifi ed in unaff ected DYT 1 mutation carriers. Th ese endophenotypic traits may require additional genetic or environ mental factors to become fully penetrant, or they may simply refl ect stochastic expression of the mutant Oxford Textbook of Movement Disorders 184 Motor, sensory, and sensorimotor integration abnormalities are thought to derive from two c lear abnormalities that have been repeatedly demonstrated across diff erent forms of the di sorder using electrophysiological and neuroimaging studies. Th e fi rst is that mechanisms that usually produce inhibition within the motor system are underfunctioning; this has been demonstrated at a cor- tical, brainstem, and spinal cord level (153). Increased motor cort i- cal excitability then causes the excessive and inappropriate muscle contraction that occ urs during motor tasks. However, such abnor- malities can be present in clinically unaff ec ted body parts and in non-manifesting DYT1 gene carriers, indicating that additional factor s are necessary to produce the clinical symptoms of dystonia (154). Th e second abnormality is that there is an excessive response to experimental protocols that produce plastic chan ges within the motor system (155 \200\223157). Again, such abnormalities are present in cli nically unaff ected body parts, but importantly are not present in non-manifesting DYT1 gen e carriers (158), where a subnormal response to plasticity protocols is seen. Th is suggest s that abnormal brain plasticity may be an essential component of the clinical mani- festat ion of dystonia. bones, ligaments, or joints can result in abnormal postures. In Sandifer syndrome, patients (typically young boys) with hiatus hernia develop head tilt in association with gastro-oes ophageal refl ux. Once the presence of dystonia is established, the next diag- nostic step is to diff erentia te between primary and secondary/ heredodegenerative dystonia. Distribution and age at onse t provide important clues for this diff erential. Primary dystonia has an ana- tomical dist ribution which depends on age at onset. Young-onset primary dystonia tends to be generalize d or multifocal, with onset of dystonia typically in a limb (typically lower), sparing cran ial muscles. Adult-onset dystonia is more commonly focal or seg- mental and oft en in an up per limb (such as task-specifi c writer \200\231s cramp), or it may aff ect the neck and he ad, while legs are almost never aff ected. Th erefore an unusual pattern (e.g. adult-onset lower limb dystonia) is a clue pointing to secondary/heredo- degenerative dystonia. If dystonia is primary, genetic testing for DYT1 dystonia is indi- cated for patients with onset of dystonia before 26 years of age, as well as for patients with later onset who have a relative with young-onset dystonia. Data to guide DYT6 testing are insuffi - cient at pr esent, but may be indicated in DYT1-negative individu- als with early-onset arm, cranial, o r cervical involvement. Most patients with clinically typical DRD will have identifi ed mut a- tions in GTPCH1 if comprehensive analysis is performed, includ- ing testing for deletion s. Genetic testing for myoclonus \200\223dystonia is available, although many sporadic case s do not harbor SGCE mutations. Evaluation of secondary/heredodegenerative dystonia is dict ated by clues provided by the history and examination. Routine blood tests, kidney, liver, thyroid function, iron, ferritin, copper, ceruloplasmin, white cell enzymes, acanthocytes, lactate, pyruvate, creatine kinase, and antinuclear antibody screen may be indicated. Speci fi c clinical fi ndings or laboratory abnormalities may dictate further investigations, inc luding electrophysiological studies, lum- bar puncture, muscle or skin biopsy, metabolic st udies of blood, urine, or cerebrospinal fl uid, MRI brain imaging with sequences to detect iron, and dopamine transporter imaging. Genetic testing is also available for many of the h eredodegenerative dystonias (see Table 17.3). Lastly, one should keep in mind the possibili ty of psy- chogenic dystonia which could be diagnosed based on established clinical criteri a (20).