Julie Phukan, Alberto Albanese, Thomas Gasser, Thomas Warner

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1 Primary dystonia and dystonia-plus syndromes: clinical characteristics, diagnosis, and pathogenesis Julie Phukan, Alberto Albanese, Thomas Gasser, Thomas Warner Lancet Neurol 2011; 10: Published Online October DOI: /S (11) Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free Campus, Rowland Hill Street, London, UK (J Phukan MRCP, Prof T Warner FRCP); Istituto Neurologica Carlo Besta, Milan Universita Cattolica del Sacro Cuore, Milan, Italy (Prof A Albanese MD); and Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Tubingen, Germany (Prof T Gasser MD) Correspondence to: Prof Thomas Warner, Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK t.warner@ucl.ac.uk The dystonias are a heterogeneous group of hyper kinetic movement disorders characterised by involuntary sustained muscle contractions that lead to abnormal postures and repetitive movements. Dystonia syndromes represent common movement disorders and yet are often misdiagnosed or unrecognised. In recent years, there have been substantial advances in the understanding of the spectrum of clinical features that encompass dystonia syndromes, from severe generalised childhood dystonia that is often genetic in origin, to adult-onset focal dystonias and rarer forms of secondary dystonias, to dystonia as a feature of other types of CNS dysfunction. There has also been a rationalisation of the classification of dystonia and a greater understanding of the causes of dystonic movements from the study of genetics, neurophysiology, and functional imaging in the most prevalent form of dystonia syndrome, primary dystonia. Introduction 100 years have passed since Oppenheim first used the term dystonia to describe the altering muscle tone and postural abnormalities in a family with an autosomal dominant movement disorder. 1 The dystonias are now recognised as a group of hyperkinetic movement disorders whose main feature is involuntary sustained muscle contraction. This contraction results in twisting and repetitive movements or abnormal postures. 2 In addition to the abnormal postures and movements, other characteristic features include gestes antagonistes, mirror movements, and overflow dystonia. 3 Prevalence estimates of dystonia range from 15 to 30 per population. 4,5 In a study of a random sample of the population over 50 years of age, prevalence of primary dystonia was estimated to be 732 per , which suggests that, in the ageing population, dystonia is a common neurological disorder. 6 In this Review, we describe the primary forms of dystonia (which are the most common forms) and the more complex forms (dystonia-plus syndromes) that are caused by neuronal dysfunction but not neuronal death. We focus on the clinical phenomenology and diagnosis of dystonia and on current understanding of the pathogenesis of dystonia from genetic, cell biological, imaging, and neurophysiological studies. Classification of dystonia The classification of dystonia is controversial and has been through numerous revisions over time, influenced by a better understanding of clinical phenotype, genetics, and pathophysiology. However, this increased under standing of the complexity of dystonia has also led to increasingly confused classification schemes. Classi fication of dystonia is not helped by use of the term dystonia to describe a symptom, sign, syndrome, or specific diagnosis. Three basic parallel approaches are used to classify dystonia: age of onset, distribution of affected body parts, and cause. 2,3,7 The categories of age at onset and affected body distribution have clinical implications for prognosis and treatment and are mainly relevant for primary or idiopathic dystonia. The classification by cause attempts to describe all forms of dystonia and is the most contentious. Dystonia can develop at any age, although those with earlier onset are more likely to have a severe course. 2 Division into early (<26 years) and late (>26 years) onset is now used, on the basis of the age by which almost all carriers of the mutant DYT1 gene (see later) will have developed dystonia. 8 Distribution of affected body parts describes whether dystonia is localised to a single body region (focal) or has spread to contiguous (segmental) or non-contiguous (multifocal) regions. In generalised dystonia there is involvement of the legs, trunk, and another body part, whereas hemidystonia just affects the body and limbs on one side. Age at onset and distribution of affected body parts are linked: onset in the legs is most frequent during childhood, and with increasing age the site of onset ascends to the arms and hands, neck, and then cranial muscles. The third approach to classification is by cause. This approach has been revised several times over the years and, confusingly, involves use of both clinical and pathological features as well as reference to the presence or absence of genetic factors. Here, we outline the difficulties of current terminology but also refer to an alternative, descriptive, classification. At present, primary torsion dystonia (PTD) is perhaps the least contentious term and is commonly defined as a syndrome in which dystonia is the only clinical feature (except for tremor of the arms or head and neck) without evidence of neuro degeneration. However, some groups have used the term primary-plus dystonia to refer to conditions such as dopa-responsive dystonia (DRD) in which there can be additional features such as parkinsonism, whereas others keep them as a separate category, tradition ally known as dystonia-plus syndromes. The same disparity in classification applies to the unusual paroxysmal dyskinesias: certain forms are charac terised by almost pure dystonia, whereas others display a combination of dystonia, chorea, and athetosis, which might or might not be due to a single gene disorder Vol 10 December 2011

2 A category of secondary dystonia has also been used to describe cases in which dystonia is symptomatic of an identifiable acquired cause (eg, exposure to specific drugs, damage to the basal ganglia). However, by definition, this category should include all so-called non-primary dystonias, including heredodegenerative disorders in which dystonia is part of a more complex phenotype caused by underlying neurodegeneration. Other groups have defined heredodegenerative dystonia as a separate category that defines cause. There is no easy solution to this historic, and sometimes geographic, debate, but we show one strategy recently put forward to encompass the various forms of dystonia syndrome (table 1). 7 This strategy would best be called a descriptive classification of dystonia, rather a than causative classification. Diagnosis of dystonia The diagnosis of dystonia is clinical; the key characteristics are abnormal postures (with or without tremor) and presence of specific features. The absence of specific diagnostic tests means that expert clinical examination is recommended for diagnosis. A dystonic posture flexes, extends, or twists a body part often along its longitudinal axis. Dystonic movements are usually irregular and sustained at their peak, although they can include regular, tremor-like movements. Movements are repetitive and predictable (affecting the same body part), sometimes rhythmic, and are aggravated by task-specific (eg, writing) or non-specific movement (action dystonia). Over time, the dystonia can occur with less specific movements and can lead to sustained abnormal postures that are present at rest. Gestes antagonistes are sensory tricks, typically described in cervical dystonia, whereby light touch to the face or chin can alleviate the neck muscle spasm. The mechanism of gestes is uncertain but they can affect most body parts and help to relieve both dystonic postures and movements. Overflow and mirroring are also useful diagnostic clinical features. Overflow describes the spread of involuntary muscle contraction from the primary site of dystonia to an unaffected, usually contiguous, body part. Mirror dystonia occurs on the affected side of the body when a specific task is done by the opposite unaffected body part eg, in patients with writer s cramp, mirror dystonia of the dominant hand is seen while writing with the opposite unaffected hand. Although in most cases the recognition of dystonia is based on clinical features, electromyogram (EMG) mapping can be useful for detection of coactivation of agonist and antagonist muscles, the presence of phasic and tonic components of the movements, and the effect of gestes. EMG mapping is also helpful for differentiating dystonic tremor from other tremors. 9 Clinical features of PTD PTD accounts for around 75% of cases of dystonia and has a broad clinical spectrum, from childhood-onset generalised dystonias to adult-onset focal PTD. 3 Early-onset PTD is a progressive, disabling disorder that often begins in a limb with subsequent involvement of the other limbs and trunk. Most cases are genetic in origin. Primary dystonia Dystonia-plus syndromes Primary paroxysmal dyskinesia and dystonia Heredodegenerative dystonias Symptomatic (secondary) dystonia Dystonia as a feature of another neurological disease Characteristics Table 1: A descriptive classification of dystonia No other neurological abnormalities, except tremor No known cause apart from genetic factors in some cases No evidence of neurodegeneration Prominent torsion dystonia associated with another movement disorder No evidence of neurodegeneration Brief episodes of dyskinesia and dystonia with no dystonia in between Idiopathic (mainly familial although sporadic cases also occur) Dystonia occurs in the context of a genetic neurodegenerative disorder with additional clinical features Dystonia arises from other disease states or brain injury Features that suggest a secondary dystonia include abnormal birth or perinatal history, developmental delay, atypical site for age at onset (eg, leg onset in adults or cranial onset in children), dystonia at rest at onset (rather than with action), seizures, exposure to drugs, continuous progression of symptoms, prominent bulbar involvement, hemidystonia, additional neurological symptoms (with the exception of tremor), or multisystem involvement Usually seen in the presence of another movement disorder, both degenerative and non-degenerative Not usually the major clinical feature Examples Focal dystonias: cervical, blepharospasm, and writer s cramp Genetic dystonia (eg, DYT1 and DYT6 dystonia) Dopa-responsive dystonia, rapid-onset dystonia parkinsonism, and myoclonus dystonia syndrome Paroxysmal kinesigenic dystonia (DYT9), paroxysmal exercise-induced dystonia, and paroxysmal non-kinesigenic dystonia (DYT8) Wilson s disease, Huntington s disease, and neuroferritinopathy CNS tumour, congenital malformation, or stroke CNS trauma Perinatal cerebral injury, eg, Reye s syndrome Viral encephalitis, subacute sclerosing panencephalitis, prion disease, tuberculosis, lupus, antiphospholipid syndrome, syphilis, or SjÖgren s syndrome Drug induced: levodopa, dopamine antagonists (eg, neuroleptics, prochlorperazine, metoclopramide), selective serotonin reuptake inhibitors, buspirone, cocaine, monoamine oxidase inhibitors, flecainide, calcium antagonists, ergots, or anaesthetic drugs Toxins, eg, carbon monoxide, managanese, cyanide, methanol, disulfiram, carbondisulphide, and methanol Metabolic: hypoparathyroidism Paraneoplastic syndromes Central pontine myelinosis Parkinson s disease, progressive supranuclear palsy, corticobasal ganglionic degeneration, and tic disorders Vol 10 December

3 Focal PTD is about ten times as common as generalised forms, has onset in adulthood, and usually involves craniocervical muscles or arms. Generalisation is unusual, although dystonia can become segmental in less than 30% of cases, depending on the site of onset. 10 Focal dystonia affecting the craniocervical region is more common in women than in men, and the converse is true for focal limb dystonia. 11,12 Cervical dystonia Cervical dystonia is the most common form of focal dystonia, usually with onset in the fifth decade. 4 Variable involvement of sternocleidomastoid, trapezius, and posterior cervical muscles results in abnormal head, neck, and shoulder positions, most frequently involving horizontal turning (torticollis) and head tremor. 12 Initial symptoms include pulling, pain, or stiffness of the neck. Muscle tone and bulk are increased in the dystonic muscles. Cervical dystonia often progresses within the first 5 years before stabilising. Spontaneous symptom remission occurs in less than 20% of patients and most of those who do have remission subsequently relapse. Cervical dystonia adversely affects quality of life. 13 Blepharospasm Blepharospasm is caused by dystonic contractions of the orbicularis oculi. 14 Onset is usually insidious in the sixth decade, with eye irritation or dryness followed by excessive blinking, especially in bright light. Symptoms worsen over years, leading to sustained eye closure, and severe symptoms can lead to functional blindness. The spasms are sometimes accompanied by perioral muscle involvement. Prolonged remission is rare. Oromandibular dystonia Oromandibular dystonia affects the jaw muscles, with prominent jaw opening or closing. 3 There is often additional involvement of the tongue, facial, and pharyngeal muscles. Oromandibular dystonia worsens on eating or talking, with dysarthria and dysphagia. It is a visible, distressing, and painful condition that can result in temporomandibular joint impairment. Laryngeal dystonia Laryngeal dystonia is a rare task-specific dystonia that affects speech and occurs in late adult life. 15 Adductor laryngeal dystonia results in strained or strangled voice quality caused by hyperadduction of the vocal cords. Abductor spasmodic dysphonia presents with breathy breaks in speech, especially with consonants. Voice tremor can occur with both types of laryngeal dystonia. Writer s cramp Writer s cramp is the commonest form of task-specific dystonia, with onset between the ages of 30 and 50 years. Patients describe tension and aching in the fingers and forearm progressing to persistent cramp on writing, with abnormally forceful grip. 16 Excessive flexion of the thumb OMIM code Gene or locus Phenotype Transmission Primary torsion dystonias DYT TOR1A Generalised early-limb-onset dystonia AD DYT None Early-onset generalised dystonia with prominent cranial-cervical involvement AR DYT None Whispering dysphonia AD DYT THAP1 Craniocervical and limb dystonia AD DYT p Adult-onset cervical dystonia AD DYT p Craniocervical, laryngeal, and limb dystonia AD DYT p11.2-q13.12 Segmental or generalised dystonia with severe dysphonia AR DYT21 2q14.3-q21.3 Adult-onset generalised or multifocal dystonia, often starting with blepharospasm AD Dystonia-plus syndromes DYT GCH1 Dopa-responsive dystonia AD THD TH Dopa-responsive dystonia AR DYT SGCE Myoclonus-dystonia AD DYT ATP1A3 Rapid-onset dystonia parkinsonism AD DYT p11 Myoclonus-dystonia AD DYT PRKRA Early-onset dystonia parkinsonism AR Paroxysmal dyskinesias DYT MR1 Paroxysmal dystonic choreoathetosis (non-kinesigenic) AD DYT p13.3-p21 Paroxysmal dyskinesias with episodic ataxia and spasticity AD DYT p11.2-q12.1 Paroxysmal kinesigenic choreoathetosis AD DYT GLUT1 Paroxysmal exercise-induced dystonia 2 AD DYT q Paroxysmal kinesigenic dyskinesia 2 AD DYT q Paroxysmal non-kinesigenic dyskinesia 2 AD (Continues on next page) Vol 10 December 2011

4 OMIM code Gene or locus Phenotype Transmission (Continued from previous page) Heredodegenerative syndromes Ataxia-telangiectasia ATM Cerebellar ataxia and telangiectases AR Choreoacanthocytosis VPS13A Parkinsonian features and orofacial dyskinesias AR Ceroid-lipofuscinosis CLN3 Cerebral atrophy and macular degeneration AR Dystonia-deafness TIMM8A Progressive deafness and dystonia XR syndrome Dentatorubralpallidoluysian ATN1 Ataxia, chorea, and dementia AD atrophy DYT TAF1 Dystonia-parkinsonism XR Fucosidosis FUCA1 Mental retardation, seizures, and neuropathy AR Glutaricacidaemia GCDH Infantile encephalopathy with dystonic choreoathetosis AR Huntington s disease IT-15 Chorea, dystonia, and dementia AD Leber hereditary optic Several genes Optic atrophy, tremor, and dystonia M neuropathy Lesch-Nyhan syndrome HPRT Mental retardation, motor delay, and spasticity XR Leigh syndrome Several genes Early onset, rapid progression, and clinical heterogeneity M or AR Metachromatic ARSA Mental retardation, spasticity, and bulbar palsies AR leukodystrophy Neuroferritinopathy FTL Neurodegeneration with brain iron accumulation type 2 AD NPC NPC1 Mental retardation, motor delay, and spasticity AR NPC HE1 Mental retardation, motor delay, and spasticity AR PARK14 PLA2G6 Neurodegeneration with brain iron accumulation type 2 AR PARK PRKN Early-onset parkinsonism AR PARK DJ1 Early-onset parkinsonism AR PKAN PANK2 Neurodegeneration with brain iron accumulation type 1 AR Pelizaeus-Merzbacher PLP1 Progressive pyramidal and cerebellar signs, and rolling head tremor XR disease Rett syndrome MECP2 Mental retardation, motor delay, autism, and epilepsy XD SCA TBP Parkinsonism, chorea, and dementia AD SCA ATXN3 Ataxia, spasticity, and ocular movement abnormalities AD Tay-Sachs disease HEXA Infancy onset, paralysis, dementia, and blindness, fatal by age 2 3 years AR Wilson s disease ATP7B Tremor, dystonia, and parkinsonian features AR AD=autosomal dominant. AR=autosomal recessive. ARSA=arylsulfatase A. ATM=ataxia-telangiectasia mutated gene. ATN1=atrophin 1. ATP1A3=ATPase, Na+/K+ transporting. ATP7B=ATPase, Cu²+-transporting beta polypeptide. ATXN3=ataxin-3. CLN3=ceroid-lipofuscinosis, neuronal 3. DJ1=oncogene DJ1. FTL=ferritin light chain. FUCA1=alpha-L-fucosidase 1. GCDH=glutaryl-CoA dehydrogenase. GCH1=guanosine triphosphate cyclohydrolase 1. GLUT1=glucose transporter 1. HE1=epididymal secretory protein. HEXA=hexosaminidase A alpha polypeptide. HPRT=hypoxanthine guanine phosphoribosyl-transferase 1. IT-15=important transcript 15 (Huntingtin). M=mitochondrial. MECP2=methyl-CpG-binding protein 2. MR1=myofibrillogenesis regulator 1. NPC1=Niemann-Pick type C1. NPC2=Niemann-Pick type C2. PANK2=pantothenate kinase 2. PKAN=pantothenate kinase-associated neurodegeneration. PLA2G6=phospholipase A2 group VI. PLP1=proteolipid protein 1. PARK=Parkinson disease or parkinsonism. PRKN=parkin. PRKRA=double-stranded RNA-activated protein kinase. SCA=spinocerebellar ataxia. SGCE=ε-sarcoglycan. TAF1=TATA boxing-binding protein associated factor. TBP=TATA box-binding protein. TH=tyrosine hydroxylase. THAP1=thanatos associated protein. THD=tyrosine hydroxylase deficiency. TIMM8A=translocase of inner mitochondrial membrane 8. TOR1A=torsin A gene. VPS13A=vacuolar protein sorting 13. XD=X-linked dominant. XR=X-linked recessive. Table 2: Molecular classification of genetic dystonias and index finger, with pronation of the hand and ulnar deviation of the wrist, often occurs, with arm tremor in less than 50% of patients. Other task-specific dystonias include musician s dystonia and dystonia in those performing highly learned motor skills, such as professional craftsmen and sportsmen (eg, tennis, snooker, golf) whose work involves frequent, repetitive and precise movements of particular muscle groups. 17 Genetics of PTD Many forms of dystonia have an underlying genetic basis, with clear monogenic inheritance in more severe forms and potential genetic susceptibility factors in primary focal dystonia. Table 2 lists the various DYT loci and genes, which include primary, dystonia-plus, and paroxysmal and heredodegenerative forms. It also shows that classification of dystonia by DYT locus is impractical and confusing. The following sections describe the best characterised DYT genes that cause PTD. DYT1 PTD A mutation in the DYT1 gene is the commonest cause of early-onset primary dystonia (typical onset age 9 15 years). 18 It accounts for less than 50% of childhood Vol 10 December

5 PTD in non-jews and about 80% in Ashkenazi Jews. 19 The increased prevalence in Ashkenazi Jews is the result of a founder mutation that appeared about 350 years ago. 20 DYT1 dystonia has a typical phenotype that presents in childhood with limb onset and subsequently generalises, usually sparing cranio cervical muscles. 8 DYT1 dystonia is an autosomal dominant trait with penetrance of around 30%. All cases of DYT1 dystonia are caused by a 3 bp (GAG) deletion in the coding region of the TOR1A (DYT1) gene. 18 The deletion results in loss of one of a pair of glutamic acid residues in a conserved region at the C terminus of the protein torsina. Penetrance is lower (3%) in those with histidine at aminoacid 216 of torsina, suggesting that this single nucleotide polymorphism acts as a genetic modifier of DYT1. 21 Two other potential TOR1A mutations have been reported in atypical cases of dystonia. 22,23 TorsinA is a 332 aminoacid protein typical of the superfamily of ATPase chaperone-like proteins, which are involved in protein trafficking, membrane fusion, protein refolding, and degradation. 24 TorsinA is ubiquitously expressed and is restricted to neurons, especially in the substantia nigra, cerebellar Purkinje cells, thalamus, globus pallidus, hippocampus, and cerebral cortex. 25 TorsinA is predominantly found in the endoplasmic reticulum and nuclear envelope, but also in the cytoplasm, neurite processes, and growth cones. 26,27 Mutant torsina is redistributed to the nuclear envelope and accumulates in perinuclear membranous inclusions. 28,29 These inclusions have been found in neurons of animal models and the midbrain reticular formation and periaqueductal grey in brain tissue from patients with DYT1 dystonia, which suggests that they are relevant to the pathogenesis of DYT1 dystonia The finding of perinuclear inclusions in brain tissue from patients is clearly important but has been reported only once and needs to be replicated to show its validity. 30 TorsinA binds to the nuclear envelope protein LAP1, endoplasmic reticulum protein LULL1/NET9, and kinesin light chain 1, which suggests that torsina has a role in regulating nuclear envelope organisation or in regulating microtubule-based movement of membrane compartments, or both. 27,33 Other interactions might lead to stress-induced endoplasmic reticulum abnormalities. Findings from a recent study suggested that mutant torsina reduces endoplasmic reticulum-associated protein degradation, which might underlie increased endoplasmic reticulum stress. 34 Defects in synaptic function and vesicle recycling have also been reported, suggesting that mutant torsina might lead to abnormal neurotransmission and disrupt the highly organised neuronal firing in the motor pathways in the brain. DYT6 PTD DYT6 dystonia is also autosomal dominant, with reduced penetrance and late onset (mean age 18 years), typically involving cranial or cervical muscles; laryngeal involvement is also frequent. 38 Heterozygous insertion/ deletion mutations in the thanatos-associated protein 1 gene (THAP1; DYT6) have been identified in several families. 39,40 Typical onset was in childhood or adolescence but also in adulthood (<49 years). In further studies in Germany and the UK, additional cases have been identified, usually with early-onset craniocervicalonset or limb-onset segmental dystonia with prominent laryngeal involvement. 41,42 Findings from a recent study showed homozygous THAP1 mutations in a family with autosomal recessive generalised dystonia, implying a loss of function mechanism. 43 The mechanism by which mutant THAP1 protein causes dystonia is unclear, although recent work showed that THAP1 is a transcription factor and that mutant THAP1 leads to altered transcription of TOR1A, implying a linked mechanism. 44,45 DYT13 PTD The DYT13 gene was mapped to chromosome 1p36 in an Italian family with autosomal dominant PTD. 46 Most cases had juvenile-onset segmental craniocervical dystonia, which occasionally generalised. The DYT6 gene has been excluded in this family and no other gene has yet been identified. DYT21 PTD The DYT21 gene has recently been mapped to chromosome 2q14.3-q21.3 in a large Swedish family with autosomal dominant inheritance and high penetrance (90%). 47 Age at onset varied from 13 to 50 years, often starting with blepharospasm or hand dystonia before becoming generalised. Late-onset PTD: genetic and environmental factors The genetics of late-onset focal PTDs are complex and most cases seem to be sporadic. Families with autosomal dominant inheritance and low penetrance have been described In a large German family with late-onset cervical and laryngeal dystonia, the DYT7 locus was mapped to chromosome 18p. 51 Allelic association to polymorphisms in this region was reported in patients with sporadic adult-onset focal dystonia from northwestern Germany, suggesting the existence of a founder mutation. 52 However, other studies could not replicate these findings and their relevance remains uncertain. 53 Support for a monogenic cause of late-onset focal PTD came from a recent study that used the neurophysiological temporal discrimination test (TDT) as a marker for the dystonia endophenotype of 24 families of index cases who had focal PTD had at least one relative with an abnormal TDT result, implying that dystonia was caused by an autosomal dominant gene with low penetrance. More work is needed to confirm these findings and verify the suitability of the TDT as a marker for dystonia Vol 10 December 2011

6 Adult-onset focal PTD is probably multifactorial, with several genes, along with environmental factors, combining to reach the threshold for dystonia. There might be particular genes that are common to various clinical types, which, when combined with other specific genes or environmental factors, contribute to the variability of clinical expression. 55 An association between common DYT1 haplotypes (including the D216H single nucleotide polymorphism) and adult focal PTD has been reported 56,57 but not replicated elsewhere. 58 The same is true for the association with a multiallelic polymorphism of the dopamine D5 receptor gene in cervical dystonia and blepharospasm. 59,60 Genome-wide association studies should help resolve these inconsistencies and enable identification of other potential loci. There have been limited case-control studies that have suggested that environmental factors might play a part in the development of focal PTD. These factors include disease of the anterior segment of the eye for blepharospasm, neck trauma and scoliosis for cervical dystonia, and repetitive motor tasks for upper limb dystonia. 61,62 Differences in prevalence, age of onset, and sex distribution in the focal dystonias are likely to be a result of age-related and sex-related exposure to environmental factors against a background of genetic susceptibility. 55 Pathogenesis of PTD Loss of inhibition Dystonia is characterised by excessive co-contraction of agonist and antagonist muscles during action, resulting in overflow of muscle contractions and unwanted muscle spasm. A loss of motor inhibitory function has been noted at spinal, brainstem, and cortical levels. 63 Reciprocal inhibition between opposing muscles is reduced at the spinal level during movement of the arm in patients with writer s cramp, generalised dystonia, cervical dystonia, and blepharospasm compared with control individuals. 64 Assessment of other spinal and brainstem inhibitory reflexes (eg, blink and perioral reflexes) also confirmed that patients with primary dystonia have a reduction in inhibitory processes within the motor system compared with control individuals. 65 Abnormalities of sensory input The importance of the sensory system to dystonic movements is evident from the occurrence of gestes antagonistes to suppress dystonia. Additionally, indi viduals with dystonia have abnormal somatosensory spatial and temporal discrimination (the shortest time during which two successive stimuli are perceived as separate) compared with control individuals. 66 The amount of temporal discrimination impairment is related to the severity of dystonia. 67,68 A third line of evidence for the role of the sensory system comes from the investigation of muscle spindle afferents, which can produce or reinforce dystonia. In patients with writer s cramp, vibration that stimulates these afferents can induce dystonic postures, and local anaesthetic block of large afferent fibres in the hand and forearm can reduce this vibration-induced dystonia. 69 Abnormal motor and sensory cortex excitability Findings from neurophysiological and functional imaging studies have shown increased cortical excitability in regions that represent unaffected body parts of patients with focal PTD compared with age-matched control individuals, 70 which has also been confirmed by use of transcranial magnetic stimulation. 71 Use of the paired pulse method of transcranial magnetic stimulation showed that the cortical silent period a pause in the ongoing voluntary EMG activity elicited by a single magnetic stimulus was reduced in affected muscles from patients with cranial, cervical, and hand dystonia compared with controls. 72 This finding supported the idea of motor cortex over-excitability in dystonia. Findings from a functional imaging study showed that increased cortical excitability in patients with dystonia compared with control individuals is not restricted to the sensorimotor cortex, and that higher order motor and sensory integration areas might also be involved. 73 Intracortical inhibition is reduced in both the affected and unaffected hands in patients with focal hand dystonia compared with age-matched control individuals, and even in patients with blepharospasm without hand dystonia. 74 One consequence of decreased inhibition is a loss of surround inhibition, which might explain the phenomenon of overflow in dystonia. 75 Surround inhibition is the suppression of unwanted movements when undertaking a specific motor task and is essential for the production of precise, functional movement. Disturbed surround inhibition has been noted in the hand muscles of patients with writer s cramp, with significantly enhanced motor-evoked potentials in uninvolved muscles of patients compared with control individuals. 76 Reduced intracortical inhibition, a shorter silent period, and abnormal spinal reciprocal inhibition have also been reported in both manifesting and non-manifesting carriers of the abnormal DYT1 gene compared with healthy control individuals, showing that these neurophysiological abnor malities occur in the full spectrum of PTD. 77 Reduced intracortical inhibition and silent period have been recorded in individuals with psychogenic dystonia compared with age-matched control individuals, suggesting that this reduced inhibition might represent a marker of dystonic movements irrespective of cause. 78 The excessive muscle contractions that occur in dys tonia are believed to be generated by loss of inhibition, particularly surround inhibition. One hypothesis is that altered basal ganglia input to the motor cortex causes reduced excitability of cortical inhibitory circuits. 63 Increased motor cortical excitability then causes the excessive and inappropriate muscle contraction that occurs during motor tasks. The Vol 10 December

7 abnormal inhibitory integration of afferent inputs coming from adjacent body parts that is found in dystonia might be due to altered surround inhibition and might contribute to the genesis of dystonic movements. 79 Neural networks Substantial evidence from pathological studies and the therapeutic effects of deep brain stimulation point to the basal ganglia as a major site of dysfunction in dystonia. 80,81 Inhibitory control of basal ganglia output to thalamocortical projections plays an important part in normal cortical activity. The basal ganglia have output that can influence cortical inhibition and are anatomically organised to work in a centre-surround pattern, which would allow surround inhibition. 82 Evidence from PET studies suggests that abnormal basal ganglia circuitry, in which there is an imbalance between the direct and indirect pathways, leads to a loss of cortical inhibition in dystonia compared with controls. 82 Bilateral increases in metabolism in lateral frontal and paracentral cortices have been associated with hypermetabolism of the contralateral lentiform nuclei, pons, and midbrain in patients with idiopathic torsion dystonia compared with control individuals. 83 Studies in DYT1 and other genetic forms of PTD have suggested a potential endophenotype of abnormal neural networks in asymptomatic mutation carriers. 83,84 Both manifesting and non-manifesting carriers of DYT1 mutations have increased resting metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor area compared with controls. 84 Sequence learning defects with concomitant increases in cerebellar activation have also been reported. 85 These changes seem to be specific to DYT1 dystonia, because they were not present in carriers of mutations in the DYT6 gene. This specificity suggests that asymptomatic carriers of DYT1 mutations have an abnormal motor system, which might result in clinical dystonia. Functional MRI has also shown that, in the absence of a specific dystonia-inducing task, patients with blepharospasm and focal hand dystonia have overactivity of the primary sensorimotor cortex and caudal part of the supplementary motor area compared with healthy control individuals. 86 This concept of cortical reorganisation is supported by a primate model in which repetitive hand activityinduced dystonia was associated with enlargement of somato sensory receptive fields in the primary sensory cortex and with overlapping representations of individual digits. 63 Rapid, repetitive, highly stereotypic movements might actively degrade cortical represen tations of the sensory information that guides fine motor hand movements, which map inappropriately onto neuronal networks, causing dystonic movements. 87 Slowly evolving reorganisational changes have also been identified in the primary motor cortex in patients with writer s cramp and cervical dystonia. 88 These reorganisational changes were thought to be secondary to altered afferent inputs from both clinically affected and unaffected muscles. In musicians, expanded spatial integration of proprioceptive input into the hand motor cortex (sensorimotor organisation) is believed to support their fine motor skills. 89 However, in musician s dystonia, this expansion was even larger than in healthy pianists and disrupted rather than assisted task-specific motor control. 89 Intervention with proprioceptive training restored sensorimotor organisation in pianists with dystonia to the pattern seen in healthy pianists. Crucially, task-specific motor control also improved. Brain plasticity and motor learning Neuroplasticity refers to the capacity of neuronal circuits to undergo enduring morphological and functional changes in connectivity. The theory that repetitive activity or excessive sensory stimulation can lead to dystonia is supported by studies that show plasticity to be abnormal. Results of a study of paired associative stimulation, which produces motor learning similar to long-term potentiation, have shown that patients with focal hand dystonia had abnormal motor cortical plasticity compared with age-matched control individuals. 90 These findings have been replicated in patients with writer s cramp, blepharospasm, and limb dystonia. 91 Professional musicians have increased recruitment of corticospinal and intracortical connections as well as enhanced synaptic plasticity compared with non-musicians. 92 Assessment of manifesting and non-manifesting DYT1 mutation carriers also revealed abnormal motor cortex plasticity in the manifesting carriers only, suggesting that in genetically susceptible individuals this plasticity is important in the pathogenesis of dystonia. 93 Structural imaging studies Neuroimaging studies have enabled identification of structural and functional abnormalities in both focal and generalised PTD. Volumetric imaging of the basal ganglia has shown significantly larger putamina in patients with cranial and focal hand dystonia than in healthy control individuals. 94 Findings from voxel-based morphometry studies have shown changes in grey matter density in patients with blepharospasm, cervical dystonia, and focal hand dystonia compared with control individuals. 95 Bilateral increases in grey matter density were identified in primary somatosensory and motor cortices of patients with focal hand dystonia, whereas basal ganglia changes were seen in patients with blepharospasm and cervical dystonia. Diffusion tensor imaging has also shown subtle morphological and microstructural abnormalities in sensorimotor circuitry. Abnormal fractional anisotropy has been found in subgyral white matter in both manifesting and non-manifesting carriers of the DYT1 mutation. 96 It was also found in the thalamus, lentiform nucleus, and surrounding white matter in patients with focal hand dystonia and cervical dystonia. 97,98 These changes reversed after treatment with botulinum toxin, Vol 10 December 2011

8 suggesting that the microstructural changes seen might be secondary to metabolic or structural alterations in fibres as a result of dystonic symptoms. Findings from a diffusion tensor imaging study showed reduced integrity of cerebellothalamic connectivity in both manifesting and clinically non-manifesting DYT1 mutation carriers. 96 This diminished cerebellothalamic connectivity was associated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Dystonia-plus syndromes In dystonia-plus disorders, dystonia is associated with another movement disorder, for example myoclonus or parkinsonism. There is no evidence of neurodegeneration. Dopa-responsive dystonia DRD is a rare form of dystonia. The classic phenotype is of early-onset lower limb dystonia that causes gait disturbance, with diurnal fluctuation and an excellent response to levodopa. 99 Parkinsonism can develop later or can be an early feature in adult-onset cases. Diurnal fluctuation describes worsening of symptoms towards the evening and improvement after sleep. Other features include brisk reflexes and extensor plantar responses. DRD shows a dramatic and sustained response to doses of levodopa as low as mg, and this response is usually apparent within days to weeks. The motor complications of levodopa treatment that are seen in Parkinson s disease rarely develop. Association of DRD with anxiety, depression, obsessive-compulsive disorder, sleep disturbances, or a combination thereof has been reported. 100 Inheritance of DRD is autosomal dominant with reduced penetrance (30%); females are two to four times more likely to be affected than males. Most cases of DRD are caused by heterozygous mutations in the GCH1 gene. 101 The gene encodes GTP cyclohydrolase 1, an enzyme that catalyses the first step in the biosynthesis of tetrahydrobiopterin, the essential cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme for dopamine synthesis. Other rare forms of DRD are caused by autosomal recessive mutations in genes for tyrosine hydroxylase and sepiapterin reductase. 102 These forms usually have additional features such as parkinsonism, cognitive impairment, spastic paraplegia, hypotonia, myoclonus, seizures, and progressive neurological deterioration. 103 Myoclonus dystonia syndrome Myoclonus dystonia syndrome (MDS) is characterised by myoclonic jerks and dystonia affecting mainly the neck, trunk, and arms, with onset in the first or second decade. 104 Dystonia occurs in about two-thirds of patients, typically in the form of cervical dystonia and writer s cramp. The jerks show dramatic response to alcohol and benzodiazepines, often with a rebound effect. Depression, anxiety, obsessive-compulsive disorder, and panic attacks have been reported in patients with MDS. 105 Inheritance of MDS is autosomal dominant and mutations have been identified in the epsilon-sarcoglycan gene (SGCE; DYT11) in many individuals. 106 Penetrance is reduced, with evidence of maternal imprinting of the SGCE gene. 107 Sarcoglycans are transmembrane proteins that are part of the dystrophin-associated glycoprotein in cardiac and skeletal muscle. In the brain, SGCE is found in midbrain monaminergic neurons, cerebellar Purkinje cells, the hippocampus, and cortex. 108 Mutations in SGCE seem to lead to its mislocalisation from the plasma membrane to the endoplasmic reticulum and to promotion of its degradation by the proteasome. 109 TorsinA binds and promotes degradation of SGCE, and mice with a double mutation in SGCE and torsina have an earlier onset of the motor deficit compared with those that have just mutant SGCE or torsina alone. 110 Rapid-onset dystonia parkinsonism Rapid-onset dystonia parkinsonism is a rare condition that has onset in childhood or early adulthood, with dystonic spasms, bradykinesia, postural instability, dysarthria, and dysphagia developing over hours to weeks, followed by little progression. 111 Mild limb dystonia can precede onset by several years. 112 Potential triggers include emotional trauma, extreme heat, or physical exertion. Inheritance is autosomal dominant with reduced penetrance. Neurodegeneration has not been identified in the few pathological studies that have been done, 113 suggesting that rapid-onset dystonia parkinsonism results from neuronal dysfunction. Missense mutations in the gene for the Na + /K + -ATPase 3 subunit (ATP1A3; DYT12) have been identified in patients with rapid-onset dystonia parkinsonism. Mutations seem to decrease the activity of the Na + /K + pump, which is crucial for maintaining the electrochemical gradient across the cell membrane. 114 A mouse model showed that blocking the sodium pump with the inhibitor ouabain produced dystonia when injected into the cerebellum and parkinsonism if injected into the basal ganglia. Simultaneous perfusion of the cerebellum and basal ganglia led to mild symptoms, which rapidly transformed into persistent dystonia and rigidity after stress, mimicking the clinical features of rapid-onset dystonia parkinsonism. 115 An autosomal recessive young-onset dystonia parkinsonism disorder (DYT16) has been reported in two Brazilian families. 116 The patients have progressive, early-onset dystonia with axial muscle involvement, oromandibular and laryngeal dystonia, and parkinsonian features. Mutations in the stress-response gene doublestranded RNA-activated protein kinase (PRKRA; DYT16) were found. Recently, the clinical and molecular characteristics of dopamine transporter deficiency syndrome have Vol 10 December

9 DYTI DYT6 GTPCH1 Figure: Pathogenetic mechanisms in primary dystonia GTPCH1=GTP cyclohydrolase 1. SMA=supplementary motor area. Search strategy and selection criteria References for this Review were identified through searches of PubMed from 1985 to September, 2011, with the terms dystonia, pathogenesis, and DYT. Articles were also identified from the authors own files. Only papers published in English were considered. been described. 117 This autosomal recessive disorder manifested in infancy with severe parkinsonismdystonia associated with an eye movement disorder and pyramidal signs. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in their CSF. Loss of function mutations were identified in the gene encoding the dopamine transporter (SLC6A3). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Conclusions and future directions Dystonia syndromes are common disorders of CNS inhibition that have considerable clinical and genetic heterogeneity. In recent years, improvements in genetic, imaging, and neurophysiological technology has led to significant advances in our understanding of the nosology and pathogenesis of the primary dystonias. The existence of a disease spectrum is clear, starting with more severe early-onset dystonias, which are often monogenic, through to adult-onset focal PTD, which might develop as a result of a greater interaction between genetic and environmental factors (figure). However, the net result of the underlying pathogenic changes in PTD is a defect in neural networks involving the basal ganglia, sensorimotor cortex, and cerebellum, which contribute to motor control. The abnormalities lead to reduced inhibition at cortical, brainstem, and spinal levels and result in abnormal sensorimotor cortical plasticity. The cumulative effect of these changes leads to the generation of excessive uncontrolled muscle spasms that are the hallmark of dystonia, which seem to be associated with enduring functional changes in neural networks and subtle structural changes. The sensorimotor circuits seem to be impaired in dystonia and can be disrupted by many causes at numerous levels, resulting in a susceptibility state that might allow secondary insults (eg, physiological stress, environmental insults, increased sensory input, and repetitive activity) to push these pathways into a dystonic state. A situation is then created in which this imbalance in circuitry becomes perpetuated by feedback reinforcement. Therefore, in some ways, the dystonia could be described as abnormally learned. The vast increase in our understanding of the abnormal cellular, circuitry, and neural networks in dystonia might lead to new therapeutic targets. If dystonia is caused by abnormal motor learning, can it be unlearned? This unlearning might be the process that is seen in those patients with generalised dystonia in whom globus pallidus internus deep brain stimulation is successful, or in patients with focal taskspecific hand dystonia who benefit from constraintinduced therapy, whereby non-dystonic digits are immobilised and the dystonic digits are retrained. 118 Fundamentally, understanding of the genetic and cellular pathogenesis of dystonia might lead to specific therapies at a protein or enzymatic level. Gene therapy might also have a role to switch off abnormal genes or introduce wild-type versions in cases such as DRD with GCH1 mutations, in which the mutation leads to reduced concentrations or function of the protein. Thus, just as there might be multiple ways in which the sensorimotor control of voluntary movements can be altered in dystonia, there might also be many ways that these pathways can be specifically targeted by therapy. Contributors JP and TW coordinated the Review, did the literature search, and prepared the first draft. All authors revised and modified this and subsequent drafts. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We thank Sian Warner for assistance in creating the figure. References 1 Oppenheim H. Uber eine eigenartige Krampfkrankheit des kindlichen und jugendlichen Alters (dysbasia lordotica progressiva, dystonia musculorum deformans). Neurologie Centralblatt 1911; 30: Fahn S. Concept and classification of dystonia. Adv Neurol 1988; 50: Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 2011; 18: Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group. A prevalence study of primary dystonia in eight European countries. J Neurol 2000; 247: Vol 10 December 2011

10 5 Nutt JG, Muenter MD, Melton LJ, et al. Epidemiology of dystonia in Rochester, Minnesota. Adv Neurol 1988; 50: Müller J, Kiechl S, Wenning GK, et al. The prevalence of primary dystonia in the general community. Neurology 2002; 59: Fahn S. Classification of movement disorders. Mov Disord 2011; 26: Bressman SB, Raymond D, Wendt K. Diagnostic criteria for dystonia in DYT1 families. Neurology 2002; 59: Albanese A, Lalli S. Is this dystonia? Mov Disord 2009; 24: Weiss EM, Hershey T, Karimi M. Relative risk of spread of symptoms among the focal onset primary dystonias. Mov Disord 2006; 21: Sex-related influences on the frequency and age of onset of primary dystonia. Epidemiologic Study of Dystonia in Europe (ESDE) Collaborative Group. Neurology 1999; 53: Chan J, Brin MF, Fahn S. Idiopathic cervical dystonia: clinical characteristics. Mov Disord 1991; 6: Camfield L, Ben-Shlomo Y, Warner TT. Impact of cervical dystonia on quality of life. Mov Disord 2002; 17: Grandas F, Elston J, Quinn N, et al. Blepharospasm: a review of 264 patients. J Neurol Neurosurg Psychiatry 1988; 51: Ludlow CL. Spasmodic dysphonia: a laryngeal control disorder specific to speech. J Neurosci 2011; 31: Sheehy MP, Rothwell JC, Marsden CD. Writer s cramp. Adv Neurol 1988; 50: Pont-Sunyer C, Martí MJ, Tolosa E. Focal limb dystonia. Eur J Neurol 2010; 17: Ozelius L, Kramer P, Page CE, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997; 17: Valente EM, Warner TT, Jarman PR, et al. The role of DYT1 in primary torsion dystonia in Europe. Brain 1998; 121: Risch N, de Leon D, Ozelius L, et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 1995; 9: Kamm C, Fischer H, Garavaglia B, et al. Susceptibility to DYT1 dystonia in European patients is modified by the D216H polymorphism. Neurology 2008; 70: Zirn B, Grundmann K, Huppke P, et al. Novel TOR1A mutation p.arg288gln in early-onset dystonia (DYT1). J Neurol Neurosurg Psychiatry 2008; 79: Calakos N, Patel V, Gottron M, et al. Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia. J Med Genet 2010; 47: Vale RD. AAA proteins. Lords of the ring. J Cell Biol 2000; 150: F Augood SJ, Keller-McGandy CE, Siriani A, et al. Distribution and ultra-structural localization of torsina immunoreactivity in the human brain. Brain Res 2003; 986: Kustedjo K, Bracey MH, Cravatt BF. Torsin A and its torsion dystonia-associated mutant forms are lumenal glycoproteins that exhibit distinct subcellular localizations. J Biol Chem 2000; 275: Granata A, Schiavo G, Warner TT. TorsinA and dystonia: from nuclear envelope to synapse. J Neurochem 2009; 109: Hewett J, Gonzalez-Agosti C, Slater D, et al. Mutant torsina, responsible for early onset torsion dystonia, forms membrane inclusions in cultured neural cells. Hum Mol Genet 2000; 22: Goodchild RE, Dauer WT. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsina mutation. Proc Natl Acad Sci USA 2004; 101: McNaught KS, Kapustin A, Jackson T, et al. Brainstem pathology in DYT1 primary torsion dystonia. Ann Neurol 2004; 56: Shashidharan P, Sandu D, Potla U, et al. Transgenic mouse model of early-onset DYT1 dystonia. Hum Mol Genet 2005; 14: Grundmann K, Reischmann B, Vanhoutte G, et al. Overexpression of human wildtype torsina and human DeltaGAG torsina in a transgenic mouse model causes phenotypic abnormalities. Neurobiol Dis 2007; 27: Goodchild RE, Kim CE, Dauer WT. Loss of the dystonia-associated protein torsina selectively disrupts the neuronal nuclear envelope. Neuron 2005; 48: Nery F, Armata I, Farley J, et al. TorsinA participates in endoplasmic reticulum-associated degradation. Nat Comm 2011; 2: Granata A, Koo SJ, Haucke V, et al. CSN complex controls the stability of selected synaptic proteins via a torsina-dependent process. EMBO J 2011; 30: Granata A, Watson R, Collinson L, Schiavo G, Warner TT. The dystonia-associated protein torsina modulates synaptic vesicle recycling. J Biol Chem 2008; 283: Bragg DC, Armata IA, Nery FC, et al. Molecular pathways in dystonia. Neurobiol Dis 2011; 42: Almasy L, Bressman SB, Kramer PL, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonote families. Ann Neurol 1997; 42: Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 2009; 41: Bressman SB, Raymond D, Fuchs T, et al. Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol 2009; 8: Djarmati A, Schneider SA, Lohmann K, et al. Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study. Lancet Neurol 2009; 8: Houlden H, Schneider SA, Paudel R, et al. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology 2010; 74: Schneider SA, Ramirez A, Shafiee K, et al. Homozygous THAP1 mutations as cause of early-onset generalized dystonia. Mov Disord 2011; 26: Kaiser FJ, Osmanoric A, Rakovic A, et al. The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Ann Neurol 2010; 68: Gavarini S, Cayrol C, Fuchs S, et al. Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann Neurol 2010; 68: Valente EM, Bentivoglio AR, Cassetta E, et al. DYT13, a novel primary torsion dystonia locus, maps to chromosome 1p in an Italian family with cranial-cervical or upper limb onset. Ann Neurol 2001; 49: Norgren N, Mattson E, Forsgren L, Holmberg M. A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q Neurogenetics 2011; 12: Defazio G, Brancati F, Valente EM, et al. Familial blepharospasm is inherited as an autosomal dominant trait and relates to a novel unassigned gene. Mov Disord 2003; 18: Waddy HM, Fletcher NA, Harding AE, Marsden CD. A genetic study of idiopathic focal dystonias. Ann Neurol 1991; 29: Stojanović M, Cvetković D, Kostić VS. A genetic study of idiopathic focal dystonias. J Neurol 1995; 242: Leube B, Doda R, Ratzlaff T, et al. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal inheritance and purely focal distribution. Hum Mol Genet 1996; 5: Leube B, Kessler KR, Goecke T, Auberger G, Benecke R. Frequency of familial inheritance among 488 index patients with idiopathic torsion focal dystonia and clinical variability in a large family. Mov Disord 1997; 12: Klein C, Ozelius L, Hagenah J, Breakefield X, Risch N, Vieregge P. Search for a founder mutation in idiopathic focal dystonia from northern Germany. Am J Hum Genet 1998; 63: Kimmich O, Bradley D, Whelan R, et al. Sporadic adult onset primary torsion dystonia is a genetic disorder by temporal discrimination testing. Brain 2011; 143: Defazio G, Berardelli A, Hallett M. Do primary adult-onset focal dystonias share aetiological factors? Brain 2007; 130: Clarimon J, Asgeirsson H, Singleton A, et al. Torsin A haplotype predisposes to idiopathic dystonia. Ann Neurol 2005; 57: Kamm C, Asmus F, Mueller J, et al. Strong genetic evidence for association of TOR1A-TOR1B with idiopathic dystonia. Neurology 2006; 67: Hague S, Klaffke S, Clarimon J, et al. Lack of association with TorsinA haplotype in German patients with sporadic dystonia. Neurology 2006; 66: Vol 10 December