REVIEW URRENT C OPINION

Dystonia: an update on phenomenology, classification, pathogenesis and treatment Bettina Balint a,b and Kailash P. Bhatia a

Purpose of review This article will highlight recent advances in dystonia with focus on clinical aspects such as the new classification, syndromic approach, new gene discoveries and genotype-phenotype correlations. Broadening of phenotype of some of the previously described hereditary dystonias and environmental risk factors and trends in treatment will be covered. Recent findings Based on phenomenology, a new consensus update on the definition, phenomenology and classification of dystonia and a syndromic approach to guide diagnosis have been proposed. Terminology has changed and ‘isolated dystonia’ is used wherein dystonia is the only motor feature apart from tremor, and the previously called heredodegenerative dystonias and dystonia plus syndromes are now subsumed under ‘combined dystonia’. The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia. Clinical and genetic heterogeneity underlie myoclonus-dystonia, dopa-responsive dystonia and deafness-dystonia syndrome. ALS2 gene mutations are a newly recognized cause for combined dystonia. The phenotypic and genotypic spectra of ATP1A3 mutations have considerably broadened. Two new genome-wide association studies identified new candidate genes. A retrospective analysis suggested complicated vaginal delivery as a modifying risk factor in DYT1. Recent studies confirm lasting therapeutic effects of deep brain stimulation in isolated dystonia, good treatment response in myoclonus-dystonia, and suggest that early treatment correlates with a better outcome. Summary Phenotypic classification continues to be important to recognize particular forms of dystonia and this includes syndromic associations. There are a number of genes underlying isolated or combined dystonia and there will be further new discoveries with the advances in genetic technologies such as exome and whole-genome sequencing. The identification of new genes will facilitate better elucidation of pathogenetic mechanisms and possible corrective therapies. Keywords approach, classification, dystonia, genetics, phenotype

INTRODUCTION The term dystonia dates back to 1911 when Oppenheim introduced it to describe a disorder in which involuntary muscle contractions lead to abnormal movements or postures [1]. Since then, the term has been used both to describe the hyperkinetic movement disorder itself and to embrace a group of disorders in which dystonia may be the only sign, or part of a syndrome. Hence, dystonia can occur in the absence of neurodegeneration or secondary causes (previously called idiopathic); or be because of heredodegenerative disorders; and also present as paroxysmal dystonia. Correspondingly, the aetiologies vary. The rapidly evolving field of genetics has broadened our knowledge in the last few years with the discovery of a number of new dystonia genes, www.co-neurology.com

such as CIZ1, ANO3, TUBB4A, GNAL and PRRT2 and linkage of known genes to new phenotypes [2]. This article is aimed as a follow-up to the previously mentioned [2] and will highlight the recent advances. We will review the new consensus update on the definition, phenomenology and classification of a Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, UK and bDepartment of Neurology, University Hospital, Heidelberg, Germany

Correspondence to Professor Kailash P. Bhatia, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Tel: +44 203 448 8723; fax: +44 207 419 1860; e-mail: [email protected] Curr Opin Neurol 2014, 27:468–476 DOI:10.1097/WCO.0000000000000114 Volume 27  Number 4  August 2014

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Update on dystonia genotypes and phenotypes Balint and Bhatia

KEY POINTS  The new dystonia classification refers to phenomenology rather than aetiology and provides new terminology: ‘isolated dystonia’ is used wherein dystonia is the only motor feature apart from tremor and replaces ‘primary’. The previously called heredodegenerative dystonias and dystonia plus syndromes (e.g. myoclonus-dystonia) are now subsumed under ‘combined dystonia’.  Recent gene discoveries: mutations in GNAL and ANO3 seem not to be a major cause of isolated dystonia; the pathogenicity of mutations in CIZ1 awaits confirmation.  Clinical and genetic heterogeneity underlie myoclonusdystonia, dopa-responsive dystonia and deafnessdystonia syndrome. The phenotypic and genotypic spectra of ALS2 and ATP1A3 gene mutations have broadened.  A case-control study suggested complicated vaginal delivery as an environmental risk factor in DYT1.  Recent studies confirm lasting therapeutic effects of deep brain stimulation in isolated dystonia, good treatment response in myoclonus-dystonia, and imply that early treatment correlates with a better outcome.

dystonia, which retains its roots in phenomenology [3 ] and the syndromic approach to guide diagnosis in dystonia [4 ]. We will discuss the new genes in terms of their clinical relevance and genotypephenotype correlations. Broadening of genotype and phenotype has been recognized for some of the previously described hereditary dystonias. The contribution of environmental risk factors to pathogenesis and advances in treatment of dystonia will also be discussed. &&

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CONSENSUS UPDATE ON DEFINITION, PHENOMENOLOGY AND CLASSIFICATION OF DYSTONIA In 2013, an international panel of experts provided a consensus update on definition, phenomenology and classification of dystonia [3 ]. The new definition specifies dystonia as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Previously, dystonia syndromes were classified along three main axes: aetiology, age at onset and body distribution [5,6]. The new classification encompasses only two, &&

more refined axes, namely ‘clinical characteristics’ and ‘aetiology’ (Fig. 1). Axis I, regarding clinical characteristics, includes age at onset, body distribution, temporal pattern, coexistence of other movement disorders and other neurological manifestations. The age at onset may give important clues to the underlying aetiology, and was subdivided into infancy (birth to 2 years), childhood (3–12 years), adolescence (13–20 years), early adulthood (21–40 years) and late adulthood (>40 years). The body distribution is described as focal, segmental, multifocal, generalized (with or without leg involvement) or hemidystonia. The temporal pattern includes both the disease course, which may be static or progressive, and the variability of symptoms, which may persist, fluctuate diurnally or occur only on specific actions or in paroxysms. Associated features distinguish dystonia combined with another movement disorder (e.g. myoclonusdystonia) or with other neurological or systemic manifestations. Axis II allows further division according to the presumed aetiology; the proposed two criteria are nervous system pathology (evidence of degeneration/structural lesions/neither of both) and inherited or acquired causes, respectively (such as perinatal brain injury, infections, drugs among others) or idiopathic (sporadic/familial), which may be reclassified to inherited if new genes are recognized. Notably, the term ‘primary’ was abandoned, as it is currently used to describe isolated dystonia in both genetic (with known cause) or idiopathic cases and hence does not facilitate clear communication. The new terminology uses ‘isolated dystonia’ to describe cases in which dystonia is the only motor feature apart from tremor. Similarly, the previously called heredodegenerative dystonias and dystonia plus syndromes (e.g. myoclonus-dystonia) are now subsumed under ‘combined dystonia’, which again refer only to phenomenology rather than aetiology.

ASSESSMENT OF PATIENTS WITH ISOLATED OR COMBINED DYSTONIA: A SYNDROMIC APPROACH Similarly, also based on the phenomenology, recently an updated syndromic approach was suggested [4 ]. Briefly, first steps comprise establishing the presence of dystonia, identifying any associated movement disorders (‘isolated’ versus ‘combined’ dystonia) and defining which is the dominant movement disorder. It is important to establish associated neurological features and, as highlighted before [3 ], the temporal pattern (age at onset; tempo of the disease). Finally, evaluation of other systemic features (e.g. endocrine or haematological abnormalities, solid organ involvement) as well as results of

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Old classification (2011) Axis I -aetiology Primary pure Primary plus

New classification (2013) Axis I -clinical characteristics

Infancy (birth–2 yrs) Childhood (3–12 yrs)

Age at onset

Adolescence (13–20 yrs) Early adulthood (21–40 yrs)

Primary paroxysmal

Late adulthood (>40 yrs)

Heredodegenerative Secondary

Focal Segmental

Axis II -age at onset

Body distribution

Multifocal

Early onset

Generalised

Late onset

Hemidystonia

Axis III -body distribution

Disease course

Static Progressive

Focal Segmental

Temporal pattern

Persistent

Multifocal

Variability

Generalised

Action specific Diurnal Paroxysmal

Hemidystonia Isolated

Combined with other movement disorder(s)

Associated features

Other co-occurring neurological or systemic manifestations Axis II -aetiology Degeneration Nervous system pathology

Structural lesion No evidence AD Inherited

ar X-linked Mitochondrial

Inherited or acquired

PerinataI brain injury Infection Drug Acquired

Toxic Vascular Neoplastic Brain injury Psychogenic

Idiopathic

Sporadic Familial

FIGURE 1. Comparison of the old and the new classification (adapted from [3 ,6]). AD, autosomal dominant; AR, autosomal recessive. &&

brain imaging, basic diagnostic tests and neurophysiological investigations are taken into consideration when formulating the dystonia syndrome. For clinical purposes, the authors suggest a list of six groups of dystonia syndromes, on the basis of which an aetiological differential diagnosis may be generated and specific tests (e.g. genetic tests, tissue biopsy) can be arranged. Similarly, a symptomoriented review of genetically determined dystonias 470

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and disorders with dystonia as a central feature can be found here [7].

ISOLATED DYSTONIAS: THE RECENT GENE DISCOVERIES AND THEIR REPERCUSSION Mutations in ANO3, GNAL and CIZ1 were recently described to cause isolated (previously so-called Volume 27  Number 4  August 2014

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Update on dystonia genotypes and phenotypes Balint and Bhatia

‘primary’) dystonia, and were reviewed elsewhere [2]. Here we discuss the subsequent studies searching to define the respective phenotype, frequency and relevance. Also TUBB4A mutations were thought to cause isolated dystonia, but recent evidence suggests a more complex phenotype.

unrelated families; and because six out of the 39 screened families featured mutations in this gene, GNAL mutations were expected to be common in familial dystonia [11]. Subsequently, screening of 760 subjects with familial and sporadic primary dystonia identified, however, only three further pedigrees with GNAL mutations [12 ]. Hence, the question of the frequency and relevance of GNAL mutations was raised. A screening for GNAL in two German cohorts comprising 137 and 342 patients with mainly sporadic isolated dystonia identified two more cases with pathogenic mutations [10,13], thus confirming GNAL mutations as cause of dystonia in approximately less than 0.5 of the cases as suggested by Vemula et al. [12 ]. In another study, two putatively pathogenic mutations in GNAL were found in two cases, which represented approximately 1% of patients with cervical dystonia in this sample [14]. In the UK population, however, GNAL mutations do not appear to be a common cause of dystonia, as no pathogenic mutations were found in one study screening 192 dystonia patients [15]. Similarly, GNAL mutations were not found in familial cervical dystonia in 12 Chinese Han families [16]. In a cohort of 76 Amish-Mennonites with isolated dystonia, a novel GNAL mutation was identified in one case with craniocervical dystonia onset at age 21 years, and her son who had arm tremor [17]; the seven other individuals with GNAL mutations in this cohort have been previously reported [11]. The craniocervical region was affected in the vast majority, with generalization in 10% of the cases. Dystonic head tremor was not infrequent. Some patients had laryngeal onset or developed spasmodic dysphonia. A distinguishing feature and useful diagnostic clue may be hyposmia, which occurred to variable extent in four of 11 individuals described by Vemula et al. [12 ]. Onset ranged from 7 to 63 years. GNAL encodes guanine nucleotide-binding protein, alpha activating activity polypeptide, olfactory type Ga(olf), a protein that was originally discovered in the olfactory neuroepithelium and striatum and that is involved in olfactory signal transductions and in dopamine (D1) signalling [18]. Mice deficient in GNAL are anosmic and displayed motor hyperactivity [18]. &

ANO3 Mutations in the anoctamin 3 gene (ANO3) were recently identified to cause autosomal dominant isolated dystonia [8] and have been assigned to the locus dystonia-24 (DYT24). The gene is highly expressed in the striatum and hitherto existing data point to an important role in calcium signalling and mediating neuronal excitability [8]. Now Stamelou et al. [9 ] have expanded on the clinical spectrum based on the genetically identified cases. Age at onset ranged from early childhood to the forties. The predominant phenotype was tremulous cervical dystonia, whereas cranial and laryngeal dystonia were present to a variable degree. Mild dystonia of the arms was present in some cases; generalized dystonia however was never observed. Importantly, tremor was present in all identified patients, mostly as head and arm tremor. Also, there were two patients with myoclonic jerks of the head or the arms, and electrophysiological studies in one of them revealed a subcortical origin. Hence, amongst the isolated dystonias, the phenotype of DYT24 may be distinguished by cranciocervical onset from DYT1 and by tremor from DYT6. There are two more interesting aspects worth pointing out: firstly, the prominent tremor, even without signs of dystonia at onset, sheds a new light on the discussion about the definition of dystonic tremor, and the differential diagnosis of so-called essential tremor; secondly, the notion of myoclonus in some of these patients suggests that DYT24 should be included in the list of myoclonus-dystonias. The phenotype of carriers of ANO3 mutations seems distinct from those with epsilon-sarcoglycan gene mutations (DYT11), as in the latter, the jerks have a characteristic ‘lightning’, shock-like appearance. Further studies are warranted to assess frequency and role of ANO3 mutations in the pathogenesis of dystonia. To date, two novel missense variants of ANO3 were detected in a German cohort of 342 patients with sporadic cervical dystonia (0.6%); their pathogenic relevance, however, remains unclear, as in-silico analysis yielded contradictory results [10]. &

GNAL In 2012, GNAL gene mutations were identified as a cause of isolated familial dystonia (DYT25) in two

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CIZ1 In 2012, missense mutations of the CIZ1 (Cip1interacting zinc finger protein 1; DYT23) gene were reported to cause cervical dystonia with age of onset varying between 18 and 66 years [19]. However, this has not been replicated in other cohorts (reviewed in [2] and recently investigated also in [17]). Further

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studies are warranted to clarify the role of CIZ1 mutations in the pathogenesis of dystonia.

TUBB4A A missense mutation in the TUBB4A gene has been shown to cause ‘whispering dysphonia’ (DYT4) in the same Australian kindred by two groups [20,21], the phenotype of which is that of an autosomal-dominant laryngeal dysphonia, craniocervical or generalized dystonia and a peculiar ‘hobby horse’ gait, with onset in the second to third decade. Apart from the original family, only one other familial case of segmental dystonia with spasmodic dysphonia harbouring another missense mutation was hitherto described [21]. A recent study investigating 575 subjects with primary laryngeal, segmental or generalized dystonia did not detect any TUBB4A mutations [22]. Even though not a common cause of isolated dystonia, TUBB4A mutations are fascinating, as there is a newly described allelic disorder of de-novo mutations at a different site of the gene causing hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). This rare and sporadic leukodystrophy is characterized by infantile to childhood onset, developmental delay with cerebellar ataxia, dystonia, progressive spastic tetraplegia and epilepsy [23 ]. Whereas the hypomyelination and the atrophy of the basal ganglia are hallmark features of H-ABC syndrome, no MRI abnormalities were reported in the DYT4 kindred [24]. A recent report of a case with a new mutation expands both phenotype and genotype of TUBB4A mutations: the patient had a milder phenotype both clinically and radiologically. Perambulation was retained and there was only mild regional hypomyelination without atrophy of the basal ganglia [25]. &&

THE COMBINED DYSTONIAS: A BROADENING SPECTRUM WITH CLINICAL AND GENETIC HETEROGENEITY According to the new classification, the combined dystonias comprise a group wherein dystonia is accompanied by another movement disorder, for example myoclonus-dystonia, dopa-responsive dystonia, and dystonia with parkinsonism. There are also other syndromes wherein dystonia is combined with other neurological or systemic disorders, which will be also included in this section, for example deafness-dystonia or dystonia with spasticity.

Myoclonus-dystonia The term myoclonus-dystonia was initially coined to describe an entity characterized by a combination 472

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of dystonia and shock-like jerks mainly in the neck and upper limbs, responsive to alcohol, and apparently autosomal-dominant inheritance [26,27]. Later, mutations in the epsilon-sarcoglycan gene (DYT11) have been found to account for approximately 30% of the familial cases [28–30]. Additionally, another locus (DYT15) causing myoclonusdystonia was identified [31]. The association of myoclonus and dystonia opens now a broader differential diagnosis – as pointed out above, ANO3 mutations can give rise to craniocervical or segmental dystonia with myoclonus. Furthermore, two recent reports of two other genetic conditions also need to be kept in mind. The first is tyrosine hydroxylase deficiency, an autosomal-recessive condition. Tyrosine hydroxylase is an enzyme of the tetrahydrobiopterin-dopamine pathway. The usual presentation is either infantile onset of progressive, hypokinetic-rigid parkinsonism with dystonia or neonatal onset of a complex encephalopathy with parkinsonism, hypotonia, ptosis and mental retardation, epilepsy, dystonia with oculogyric crises and dysautonomia [32]. Recently, predominant myoclonus and dystonia have been described in a family with tyrosine hydroxylase deficiency because of compound heterozygosity of one previously reported mutation in the promoter region and a novel mutation in the other allele [33]. Oculogyric, dystonic or dysautonomic crises may be clues to this differential diagnosis, which is particularly important as outcome may be better if treatment with L-Dopa is started early. Benign hereditary chorea is an autosomal dominant disorder presenting in infancy with chorea. It is because of mutations of NKX2–1 (or TITF1), a gene that is essential for organogenesis of the basal ganglia, thyroid and lungs [34]. During evolution, the chorea can disappear and be replaced by myoclonus-dystonia [35,36]. Hence, awareness of this possible differential diagnosis should prompt enquiry about clues from history, namely thyroid and lung disease, and presence of chorea in childhood.

Dopa-responsive dystonia Following up a previously reported family with young-onset dopa-responsive cervical dystonia [37], Charlesworth et al. [38] by exome sequencing revealed biallelic mutations in the ataxia telangiectasia (ATM) gene. Typically, mutations in this gene inherited as an autosomal recessive disorder cause progressive ataxia, oculomotor apraxia, oculocutaneous telangiectasias and tendency to malignancies. Further features include dystonia, chorea and axonal neuropathy (reviewed in [39]). In light of the new report, testing for ATM mutations should be Volume 27  Number 4  August 2014

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Update on dystonia genotypes and phenotypes Balint and Bhatia

considered also in dopa-responsive dystonia, particularly with craniocervical predominance, more so as it entails important management implications in identified cases [39]. Moreover, some patients with ataxia telangieactasia and dystonia may benefit from a trial of L-Dopa because of an unexplained mechanism. Another recent case report of a patient with established GLUT1 mutation suggests that also some of the paroxysmal exercise-induced dyskinesias may be dopa-responsive [40]. Response to L-Dopa treatment was also reported in another patient with paroxysmal exercise-induced dyskinesias, however without established gene mutation, previously [41].

Deafness-dystonia The combination of deafness and dystonia as a dominant syndromic feature is rare. A recent series of 20 patients with deafness and dystonia highlights that the aetiology remains undetermined in the majority of the cases [42]. The cause was found only in seven patients and comprised methylmalonic aciduria, Mohr-Tranebjaerg syndrome, Woodhouse-Sakati syndrome and a large deletion of 7.q21, (including the epsilon-sarcoglycan gene), meningoencephalitis and perinatal hypoxic-ischemic injury. In the majority of the patients, however, no cause could be identified, but two clinical patterns became apparent: patients with childhood onset had generalized dystonia with prominent bulbar involvement, whereas patients with onset in adulthood had segmental dystonia and laryngeal involvement. In all cases, hearing impairment preceded the dystonia, and the disease course was overall benign with a static course after initial progression. Apart from a sibling pair with childhoodonset generalized deafness-dystonia syndrome, brain imaging was normal. Even though rare, the distinctness of the disorder suggests underlying genetic pathomechanisms, likely involving interference with mitochondrial function, still to be identified, and more research is warranted.

Dystonia and spasticity Mutations in the ALS2 gene are known to cause three forms of autosomal recessive motor neuron diseases. Now they have been found to underlie an autosomal-recessive syndrome with progressive generalized dystonia and ascending spasticity in two consanguineous families [43 ]. Onset was in early childhood at approximately 2 years of age; the patients developed spastic tetraparesis and significant muscle wasting, marked bulbar involvement with anarthria and dysphagia and scoliosis; &

the two index cases became wheelchair-bound during adolescence. In one family, there were also cerebellar signs and microcephaly. The brain MRI findings were normal in one index case and showed white matter signal changes compatible with delayed myelination in the other index case.

Dystonia and parkinsonism The previously recognized presentation of dopamine transporter deficiency syndrome (DTDS) because of recessively inherited SLC63 gene mutations was that of infantile-onset parkinsonism-dystonia with a rapidly progressive disease course [44]. A recent report expands the phenotypic spectrum now to a later onset (childhood or adolescence) and a slower disease course [45]. DTDS may feature oculogyric crisis and thus broaden the differential diagnosis of disorders of the dopamine synthesis pathway and should be kept in mind in patients with juvenile parkinsonism. An important diagnostic clue is the characteristic CSF profile with a ratio of homovanillic acid to 5-hydroxyindoleacetic acid usually in excess of 4.0. Mutations in ATP1A3 were primarily described in rapid-onset dystonia parkinsonism (RODP; DYT12), but were shown to also cause alternating hemiplegia of childhood (AHC) (reviewed in [2]). Since then, it became clear that the two disorders share many clinical features like rostrocaudal gradient, asymmetry of symptoms and the susceptibility to triggering factors [46,47 ]. The hitherto held view of AHC causing paroxysmal episodes with recovery, and an earlier onset (before 18 months of age) contrasting to RODP with a later onset of stable symptoms has been challenged by the many intermediate phenotypes reported [47 ,48,49]. Moreover, other symptoms associated with ATP1A3 mutations have been recognized and comprise developmental delay [48], cognitive [50] and psychiatric disturbances [51,52], epilepsy and unusual manifestations like adult-onset limb dystonia [51] or exercise-induced dystonia [49]. Besides, there have been reports on improvement of symptoms in AHC with ketogenic diet [53,54]. Asystole has been reported as a dominant feature in a case of AHC and may be explained by expression of ATP1A3 in cardiomyocytes and atrioventricular node cells [55]. Lastly, quite different from the AHC-RODP spectrum, heterozygous missense mutations of the ATP1A3 gene were found to cause CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome, a rare disorder of autosomal dominant inheritance described in one family to date [56].

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In terms of management, there is a suggestion that treatment with flunarizine in AHC should not be discontinued, as this was associated with motor deterioration thereafter [57 ]. Recent studies have shown a considerable genotype-phenotype correlation [47 ,57 ], but the broad phenotypic spectrum with the same mutation occurring within one family suggests that other factors (epigenetic, environmental) are relevantly modifying the disease course [52]. ATP1A3 encodes the a3 isoform of the sodium-potassium ATPase pump, which is highly expressed in the basal ganglia, the cerebellum, thalamic nuclei, hippocampus and several areas of the pons [58]. Usage of its specific blocker ouabain in an animal model resulted in an aberrant activity of the cerebellum that altered basal ganglia function, which in turn caused dystonia [59], thus contributing to the growing body of evidence pointing at an important role of the cerebellum in dystonia (reviewed in [2]). &&

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GENOME-WIDE ASSOCIATION STUDIES IN DYSTONIA, AND POTENTIAL RISK FACTORS BEYOND GENES More research may also follow the identification of two recently published genome-wide association studies, which identified the arylsulfatase G locus as a possible risk variant at the arylsulfatase G locus in musician’s dystonia [60]. Another GWAS study of cervical dystonia showed a possible association with a sodium leak channel gene [61]. Despite the advances in our understanding of the genetics of dystonia, some questions remain unsettled, for example which factors may modify the clinical penetrance. A recent study explored the role of extragenetic factors in DYT1 dystonia by comparing 39 manifesting carriers of the DGAG mutation, 23 nonmanifesting carriers and 48 noncarriers from 28 families [62]. The retrospective analysis was based on elaborated statistical analyses to account for potentially confounding factors. Complications of vaginal delivery were positively associated with manifestation of dystonia, whereas there was no significant association between presence of dystonia and the other investigated variables such as other perinatal adversities (preterm birth, urgent caesarean section), previous childhood infections and prior general anaesthesia or physical trauma. A possible interpretation of this finding might be that mild perinatal asphyxia facilitates manifestation of dystonia in genetically predisposed individuals. This view would be supported by a previous report of signal changes on MRI similar to those detectable in postanoxic encephalopathy in 68% of a cohort of DYT1 patients [63]. 474

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TREATMENT As yet, the last advances in the field have not yet yielded new therapeutic strategies, and the drug regimens remain the same, an extensive review of which can be found here [64 ]. Deep brain stimulation (DBS) targeting the globus pallidus internus is well established in generalized or segmental idiopathic dystonia after failure of medical treatment, or in craniocervical dystonia after failure of botulinum toxin injections [6,65]. Studies with long-term follow-up confirm here lasting therapeutic effects [66 ,67 ,68], and there is accumulating evidence that a shorter disease duration correlates with a better outcome [67 ,69,70 ]. A better outcome was also associated with a positive DYT1 status [68], whereas patients positive for DYT6 seem to benefit less [71–73]. A recent review of existing data furthermore suggests that patients with myoclonus-dystonia respond well to DBS [74 ]. Myoclonus improved in all patients, and more than dystonia. As however, dystonia was more responsive to GPi stimulation than to stimulation of the ventral intermediate nucleus, overall results were better with pallidal stimulation. Otherwise, pallidal DBS seems less effective in other combined dystonias with the exception of tardive dystonia [75]. A comprehensive review of the latest developments in DBS can be found elsewhere [76 ]. &

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CONCLUSION There are a number of genes underlying isolated or combined dystonia and there will be further new discoveries with the advances in genetic technologies such as exome and whole-genome sequencing. Phenotypic classification continues to be important to recognize particular forms of dystonia and this includes syndromic associations. The identification of new genes will facilitate better elucidation of pathogenetic mechanisms and possible corrective therapies. Acknowledgements K.P.B. holds grants from the Bachmann-Strauss Dystonia and Parkinson Foundation, the Dystonia Society UK and the Halley Stewart Trust. K.P.B. and B.B. hold a grant from the Gossweiler Foundation. This work was funded by the Bachmann-Strauss Dystonia and Parkinson Foundation. Conflicts of interest K.P.B. has received honoraria/financial support to speak / attend meetings from GSK, Boehringer-Ingelheim, Ipsen, Merz, and Orion pharmaceutical companies. B.B. has no conflicts of interest. Volume 27  Number 4  August 2014

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Update on dystonia genotypes and phenotypes Balint and Bhatia

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Oppenheim H. About a rare spasm disease of childhood and young age (Dysbasia lordotica progressiva, dystonia musculorum deformans). Neurologische Centralblatt 1911; 30:1090–1107. 2. Charlesworth G, Bhatia KP. Primary and secondary dystonic syndromes: an update. Curr Opin Neurol 2013; 26:406–412. 3. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification && of dystonia: a consensus update. Mov Disord 2013; 28:863–873. Consensus update of the new definition and classification of dystonia. 4. Fung VS, Jinnah HA, Bhatia K, Vidailhet M. Assessment of patients with & isolated or combined dystonia: an update on dystonia syndromes. Mov Disord 2013; 28:889–898. This is a syndromic approach with a helpful list to guide differential diagnosis in combined dystonias. 5. Fahn S. Classification of movement disorders. Mov Disord 2011; 26:947– 957. 6. Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 2011; 18:5–18. 7. Moghimi N, Jabbari B, Szekely AM. Primary dystonias and genetic disorders with dystonia as clinical feature of the disease. Eur J Paediatr Neurol 2014; 18:79–105. 8. Charlesworth G, Plagnol V, Holmstro¨m KM, et al. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet 2012; 91:1041–1050. 9. Stamelou M, Charlesworth G, Cordivari C, et al. The phenotypic spectrum of & DYT24 due to ANO3 mutations. Mov Disord 2014. doi: 10.1002/mds.25802. The report highlights the clinical features of DYT-24. 10. Zech M, Gross N, Jochim A, et al. Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls. Mov Disord 2014; 29:143– 147. 11. Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2012; 45:88–92. 12. Vemula SR, Puschmann A, Xiao J, et al. Role of G((olf) in familial and sporadic & adult-onset primary dystonia. Hum Mol Genet 2013; 22:2510–2519. This study confirms GNAL mutations as a cause in familial and sporadic adultonset cervical and segmental dystonia. 13. Dufke C, Sturm M, Schroeder C, et al. Screening of mutations in GNAL in sporadic dystonia patients. Mov Disord 2014. doi: 10.1002/mds.25794. 14. Kumar KR, Lohmann K, Masuho I, et al. Mutations in GNAL: a novel cause of craniocervical dystonia. JAMA Neurol 2014; 71:490–494. 15. Charlesworth G, Bhatia KP, Wood NW. No pathogenic GNAL mutations in 192 sporadic and familial cases of cervical dystonia. Mov Disord 2014; 29:154–155. 16. Ma L, Chen R, Wang L, et al. No mutations in CIZ1 in twelve adult-onset primary cervical dystonia families. Mov Disord 2013; 28:1899–1901. 17. Saunders-Pullman R, Fuchs T, San Luciano M, et al. Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Mov Disord 2014; 29:812–818. 18. Belluscio L, Gold GH, Nemes A, Axel R. Mice deficient in G(olf) are anosmic. Neuron 1998; 20:69–81. 19. Xiao J, Uitti RJ, Zhao Y, et al. Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann Neurol 2012; 71:458–469. 20. Hersheson J, Mencacci NE, Davis M, et al. Mutations in the autoregulatory domain of (-tubulin 4a cause hereditary dystonia. Ann Neurol 2013; 73:546– 553. doi:10.1002/ana.23832. 21. Lohmann K, Wilcox RA, Winkler S, et al. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann Neurol 2013; 73:537–545. doi:10.1002/ana.23829. 22. Vemula SR, Xiao J, Bastian RW, et al. Pathogenic variants in TUBB4A are not found in primary dystonia. Neurology 2014; 82:1227–1230. 23. Simons C, Wolf NI, McNeil N, et al. A de novo mutation in the b-tubulin && gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. Am J Hum Genet 2013; 92:767–773. Unravelling the genetic cause of the HABC syndrome. 24. Wilcox RA, Winkler S, Lohmann K, Klein C. Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal. Mov Disord 2011; 26:2404–2408. 25. Blumkin L, Halevy A, Ben-Ami-Raichman D, et al. Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene. Neurogenetics 2014; 15:4107–4113. 26. Obeso JA, Rothwell JC, Lang AE, Marsden CD. Myoclonic dystonia. Neurology 1983; 33:825–830. 27. Quinn NP, Rothwell JC, Thompson PD, Marsden CD. Hereditary myoclonic dystonia, hereditary torsion dystonia and hereditary essential myoclonus: an area of confusion. Adv Neurol 1988; 50:391–401.

28. Zimprich A, Grabowski M, Asmus F, et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat Genet 2001; 29:66–69. 29. Spatola M, Wider C. Overview of primary monogenic dystonia. Parkinsonism Relat Disord 2012; 18 (Suppl 1):S158–S161. 30. Carecchio M, Magliozzi M, Copetti M, et al. Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus-dystonia: a reappraisal of genetic testing criteria. Mov Disord 2013; 28:787–794. 31. Grimes DA, Han F, Lang AE, et al. A novel locus for inherited myoclonusdystonia on 18p11. Neurology 2002; 59:1183–1186. 32. Willemsen MA, Verbeek MM, Kamsteeg EJ, et al. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 2010; 133 (Pt 6):1810–1822. 33. Stamelou M, Mencacci NE, Cordivari C, et al. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 2012; 79:435– 441. 34. Breedveld GJ, van Dongen JW, Danesino C, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet 2002; 11:971– 979. 35. Armstrong MJ, Shah BB, Chen R, et al. Expanding the phenomenology of benign hereditary chorea: evolution from chorea to myoclonus and dystonia. Mov Disord 2011; 26:2296–2297. 36. Gras D, Jonard L, Roze E, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry 2012; 83:956–962. 37. Schneider SA, Mohire MD, Trender-Gerhard I, et al. Familial dopa-responsive cervical dystonia. Neurology 2006; 66:599–601. 38. Charlesworth G, Mohire MD, Schneider SA, et al. Ataxia telangiectasia presenting as dopa-responsive cervical dystonia. Neurology 2013; 81: 1148–1151. 39. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med 2012; 366:636–646. 40. Baschieri F, Batla A, Erro R, et al. Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report. J Neurol 2014; 261:615–616. 41. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995; 38:571–579. 42. Kojovic M, Paree´s I, Lampreia T, et al. The syndrome of deafness-dystonia: clinical and genetic heterogeneity. Mov Disord 2013; 28:795–803. 43. Sheerin UM, Schneider SA, Carr L, et al. ALS2 mutations: juvenile amyo& trophic lateral sclerosis and generalized dystonia. Neurology 2014; 82: 1065–1067. This is the first description of ALS2 gene mutations as a cause of dystonia and spasticity. 44. Kurian MA, Zhen J, Cheng SY, et al. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J Clin Invest 2009; 119:1595–1603. 45. Ng J, Zhen J, Meyer E, et al. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. Brain 2014; 137 (Pt 4): 1107–1119. 46. Ozelius LJ. Clinical spectrum of disease associated with ATP1A3 mutations. Lancet Neurol 2012; 11:741–743. 47. Rosewich H, Ohlenbusch A, Huppke P, et al. The expanding clinical and && genetic spectrum of ATP1A3-related disorders. Neurology 2014; 82:945– 955. This is a thorough analysis of the phenotype, genotype-phenotype correlation and mutation clusters of AHC and ROPD to ATP1A3 mutations based on their own cohort and meta-analysis of hitherto published cases. 48. Brashear A, Mink JW, Hill DF, et al. ATP1A3 mutations in infants: a new rapidonset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol 2012; 54:1065–1067. 49. Roubergue A, Roze E, Vuillaumier-Barrot S, et al. The multiple faces of the ATP1A3-related dystonic movement disorder. Mov Disord 2013; 28:1457– 1459. 50. Cook JF, Hill DF, Snively BM, et al. Cognitive impairment in rapid-onset dystonia-parkinsonism. Mov Disord 2014; 29:344–350. 51. Brashear A, Cook JF, Hill DF, et al. Psychiatric disorders in rapid-onset dystonia-parkinsonism. Neurology 2012; 79:1168–1173. 52. Barbano RL, Hill DF, Snively BM, et al. New triggers and nonmotor findings in a family with rapid-onset dystonia-parkinsonism. Parkinsonism Relat Disord 2012; 18:737–741. 53. Ulate-Campos A, Fons C, Artuch R, et al. Alternating hemiplegia of childhood with a de novo mutation in ATP1A3 and changes in SLC2A1 responsive to a ketogenic diet. Pediatr Neurol 2013; 50:377–379. [Epub ahead of print] 54. Roubergue A, Philibert B, Gautier A, et al. Excellent response to a ketogenic diet in a patient with alternating hemiplegia of childhood. JIMD Rep 2014. [Epub ahead of print] 55. Novy J, McWilliams E, Sisodiya SM. Asystole in alternating hemiplegia with de novo ATP1A3 mutation. Eur J Med Genet 2014; 57:37–39. 56. Demos MK, van Karnebeek CD, Ross CJ, et al. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet J Rare Dis 2014; 9:15. doi: 10.1186/1750-1172-9-15.

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Movement disorders 57. Sasaki M, Ishii A, Saito Y, et al. Genotype-phenotype correlations in alternating hemiplegia of childhood. Neurology 2014; 82:482–490. This is a comprehensive analysis of the clinical course and phenotype-genotype correlation in a cohort of 33 patients with AHC. 58. Bøttger P, Tracz Z, Heuck A, et al. Distribution of Na/K-ATPase alpha 3 isoform, a sodium-potassium P-type pump associated with rapid-onset of dystonia parkinsonism (RDP) in the adult mouse brain. J Comp Neurol 2011; 519:376–404. 59. Calderon DP, Fremont R, Kraenzlin F, Khodakhah K. The neural substrates of rapid-onset Dystonia-Parkinsonism. Nat Neurosci 2011; 14:357– 365. 60. Lohmann K, Schmidt A, Schillert A, et al. Genome-wide association study in musician’s dystonia: a risk variant at the arylsulfatase G locus? Mov Disord 2013. doi: 10.1002/mds.25791. [Epub ahead of print] 61. Mok KY, Schneider SA, Trabzuni D, et al. Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel. Mov Disord 2014; 29:245–251. 62. Martino D, Gajos A, Gallo V, et al. Extragenetic factors and clinical penetrance of DYT1 dystonia: an exploratory study. J Neurol 2013; 260:1081 – 1086. 63. Gavarini S, Vayssie`re N, Delort P, et al. Stereotactic MRI in DYT1 dystonia: focal signal abnormalities in the basal ganglia do not contraindicate deep brain stimulation. Stereotact Funct Neurosurg 2008; 86:245– 252. 64. Jankovic J. Medical treatment of dystonia. Mov Disord 2013; 28:1001– & 1012. This is a comprehensive review of medical treatment of dystonia. 65. Bronte-Stewart H, Taira T, Valldeoriola F, et al. Inclusion and exclusion criteria for DBS in dystonia. Mov Disord 2011; 26 (Suppl 1):S5–S16. 66. Volkmann J, Wolters A, Kupsch A, et al. Pallidal deep brain stimulation in && patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol 2012; 11:1029–1038. This is an important long-term study of DBS in dystonia. &&

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67. Yamada K, Hamasaki T, Hasegawa Y, Kuratsu J. Long disease duration interferes with therapeutic effect of globus pallidus internus pallidal stimulation in primary cervical dystonia. Neuromodulation 2013; 16:219–225. This study contributes to the growing body of evidence that early treatment of dystonia with DBS correlates with a better outcome. 68. Walsh RA, Sidiropoulos C, Lozano AM, et al. Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years. Brain 2013; 136 (Pt 3):761–769. 69. Andrews C, Aviles-Olmos I, Hariz M, Foltynie T. Which patients with dystonia benefit from deep brain stimulation? A metaregression of individual patient outcomes. J Neurol Neurosurg Psychiatry 2010; 81:1383–1389. 70. Markun LC, Starr PA, Air EL, et al. Shorter disease duration correlates with & improved long-term deep brain stimulation outcomes in young-onset DYT1 dystonia. Neurosurgery 2012; 71:325–330. This study contributes to the growing body of evidence that early treatment of dystonia with DBS correlates with a better outcome. 71. Zittel S, Moll CK, Bru¨ggemann N, et al. Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families. Mov Disord 2010; 25:2405–2412. 72. Groen JL, Ritz K, Contarino MF, et al. DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Mov Disord 2010; 25:2420–2427. 73. Panov F, Tagliati M, Ozelius LJ, et al. Pallidal deep brain stimulation for DYT6 dystonia. J Neurol Neurosurg Psychiatry 2012; 83:182–187. 74. Rughani AI, Lozano AM. Surgical treatment of myoclonus dystonia syndrome. & Mov Disord 2013; 28:282–287. This is a review of hitherto published studies of DBS in myoclonus-dystonia. 75. Mentzel CL, Tenback DE, Tijssen MA, et al. Efficacy and safety of deep brain stimulation in patients with medication-induced tardive dyskinesia and/or dystonia: a systematic review. J Clin Psychiatry 2012; 73:1434–1438. 76. Moro E, Gross RE, Krauss JK. What’s new in surgical treatment for dystonia? & Mov Disord 2013; 28:1013–1020. This is a comprehensive review of recent developments in DBS in dystonia. &

Volume 27  Number 4  August 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Dystonia: an update on phenomenology, classification, pathogenesis and treatment.

This article will highlight recent advances in dystonia with focus on clinical aspects such as the new classification, syndromic approach, new gene di...
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