Genetics of Primary Torsion Dystonia

Genetics of Primary Torsion Dystonia

Norbert Brüggemann & Christine Klein

Published online: 24 March 2010# Springer Science+Business Media, LLC 2010

Abstract Advances in the genetics of dystonia have furtherelucidated the pathophysiology of this clinically andetiologically heterogeneous group of movement disorders.Currently, 20 monogenic forms of dystonia, designated bythe acronym DYT, are grouped as 1) pure dystonias, 2)dystonia-plus syndromes, and 3) paroxysmal dystonias/dyskinesias. We summarize recently discovered genes andloci, including the 1) detection of two primary dystoniagenes (DYT6, DYT16), 2) identification of the DYT17locus, 3) association of a dystonia/dyskinesia phenotypewith a gene previously linked to GLUT1 (glucose trans-porter of the blood–brain barrier) deficiency syndrome(DYT18), 4) designation of paroxysmal kinesigenic andnonkinesigenic dyskinesia as DYT19 and DYT20, and 5)redefinition of DYT14 as DYT5. Further, we review currentknowledge regarding genetic modifiers and susceptibilityfactors. Because recognizing and diagnosing monogenicdystonias have important implications for patients and theirfamilies with regard to counseling, prognosis, and treat-ment, we highlight clinical “red flags” of individualsubtypes and review guidelines for genetic testing.

Keywords Primary dystonia . Genetics . DYT1 . DYT6 .

DYT18

Introduction

Dystonia is characterized by sustained, nonsuppressiblecontractions of agonist and antagonist muscles, resulting in

twisting and repetitive movements that typically lead toabnormal postures. Dystonic syndromes commonly areclassified by their distribution of symptoms, age at onset,accompanying symptoms, and etiology. The categorizationby means of distribution comprises focal, segmental,multifocal, and generalized dystonia. With regard to theclassification by age at onset, the subgroup of early-onsetdystonia generally is infrequent, commonly has a geneticorigin, and tends to generalize. In contrast, late-onsetdystonias have a much higher prevalence, remain focal inmost cases, and usually spare the lower extremities. The“historical” threshold for early onset has been defined asthe age of 26 years because of distinct clinical character-istics [1]. The classification by etiology distinguishesprimary and secondary forms. In primary dystonia, thedystonic features usually are the only symptoms, with thepossible exception of accompanying tremor. By contrast,secondary dystonia is only one of several manifestationsand part of another underlying disease.

Monogenic forms of dystonia have been assigned theacronym DYT according to the gene or gene locus involved.This assortment of clinical rather than heterogeneousdystonias and dyskinesias is represented by a current list of20 DYTs, in which monogenic forms of dystonia areincluded in chronological order based on first appearancein the literature (Table 1, Fig. 1). Although this listing ofDYTs can serve as an orientation, it does not represent alogical classification in the strict sense of the word. Rather,the monogenic forms can be pragmatically grouped as 1)pure dystonias, 2) dystonia-plus syndromes, and 3) paroxys-mal dyskinesias (Fig. 1). The pure monogenic dystonias arepart of the primary forms and are thought to occur in theabsence of neuropathologic changes. Primary dystonias areconsidered mainly to alter the function of neuronal basalganglia circuits. Dystonia-plus syndromes are characterizedby additional neurologic manifestations, such as parkinson-ism and myoclonus [2]. Paroxysmal dyskinesias typically

N. Brüggemann : C. Klein (*)Schilling Section of Clinical and Molecular Neurogenetics,Department of Neurology, University of Lübeck,Ratzeburger Allee 160,23538 Lübeck, Germanye-mail: [email protected]

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manifest episodically, dystonia usually is only one of severalmovement disorders present, and there are no interictalneurologic abnormalities.

In addition to the dystonia-plus syndromes listed amongthe DYT loci, several syndromes with a mixed phenotypeof dystonia and parkinsonism recently were described butare not included in the list of DYTs. These syndromes shareseveral features with the monogenic forms DYT3, DYT12,and DYT16, which also are characterized by a combinationof dystonia and parkinsonism. Specifically, two recessivelyinherited forms featuring a combined phenotype of dystoniaand parkinsonism, classified as PARK14 and PARK15, arecaused by mutations in the genes for PLA2G6 and FBXO7,respectively [3].

In this review, we focus on recent findings related to newgenes, loci, and genetic modifiers that have been describedin the past 2 years. We review the contribution of genetic

factors to the development of non-mendelian primary focaldystonias. Finally, we discuss general considerations forgenetic testing and outline future perspectives regarding thegenetics of dystonia.

New Genes and Loci

The years 2008 and 2009 saw a particularly large numberof changes to the list of DYTs, including the 1) detection oftwo novel primary dystonia genes (DYT6 and DYT16); 2)identification of a new dystonia gene locus (DYT17); 3)association of a dystonia/dyskinesia phenotype with a genepreviously linked to GLUT1 (glucose transporter of theblood–brain barrier) deficiency syndrome (DYT18); 4)designation of paroxysmal kinesigenic and nonkinesigenicdyskinesia as DYT19 and DYT20, respectively; and 5)

Table 1 Monogenic forms of dystonia/dyskinesia

Designation Clinical presentation Inheritance OMIMidentifier

Genelocus

Gene Genetic testinga

DYT1 Early-onset generalized TD AD 128 100 9q TOR1A Commercially available

DYT2 AR TD AR 224 500 – – Unavailable

DYT3 X-linked dystonia parkinsonism;“lubag”

XR 314 250 Xq TAF1/DYT3 (genetranscription factor)

Available in selectresearch laboratories

DYT4 “Non-DYT1” TD; whisperingdysphonia

AD 128 101 – – Unavailable

DYT5a/DYT14b Dopa-responsive dystonia; Segawasyndrome

AD 128 230 14q GCH1 Commercially available

DYT5b Dopa-responsive dystonia; Segawasyndrome

AR 128 230 11p TH Available in selectresearch laboratories

DYT6 Adolescent-onset TD of mixed type AD 602 629 8p THAP1 Commercially available

DYT7 Adult-onset focal TD AD 602 124 18p – Unavailable

DYT8 Paroxysmal nonkinesigenic dyskinesia AD 118 800 2q PNKD1/MR1 Commercially available

DYT9 Paroxysmal choreoathetosis withepisodic ataxia and spasticity

AD 601 042 1p – Unavailable

DYT10 Paroxysmal kinesigenic choreoathetosis AD 128 200 16p-q – Unavailable

DYT11 Myoclonus-dystonia AD 159 900 7q SGCE Commercially available

DYT12 Rapid-onset dystonia-parkinsonism AD 128 235 19q ATP1A3 Available in selectresearch laboratories

DYT13 Multifocal/segmental dystonia AD 607 671 1p – Unavailable

DYT15 Myoclonus-dystonia AD 607 488 18p – Unavailable

DYT16 Young-onset dystonia-(parkinsonism) AR 612 067 2p PRKRA (stress-responseprotein)

Commercially available

DYT17 AR primary TD AR 612 406 20pq – Unavailable

DYT18 Paroxysmal exertion-induceddyskinesia 2

AD 612 126 1p SLC2A1 (glucosetransporter)

Commercially available

DYT19 Episodic kinesigenic dyskinesia 2 AD 611 031 16q – Unavailable

DYT20 Paroxysmal nonkinesigenicdyskinesia 2

AD 611 147 2q – Unavailable

AD autosomal dominant, AR autosomal recessive, OMIM online mendelian inheritance in man, TD torsion dystonia, XR X-linked recessivea For details, see www.genetests.orgb DYT14 recently was redefined as DYT5 [8•]

200 Curr Neurol Neurosci Rep (2010) 10:199–206

http://www.genetests.org

redefinition of a putatively new form (DYT14) of dopa-responsive dystonia (DRD) as the previously known formof DRD, DYT5. Following is a short summary of the mostrelevant new findings.

DYT6 (Adolescent-Onset Torsion Dystonia of Mixed Type)

Mutations in the THAP1 (Thanatos-associated proteindomain-containing apoptosis-associated protein 1) genewere shown to be associated with DYT6, an autosomaldominantly inherited form of generalized dystonia with anestimated penetrance of approximately 60%. First describedin patients with Amish-Mennonite ancestry [4••], mutationsalso were found in German, Irish, and Italian dystoniapatients, accounting for up to 25% of non-DYT1 general-ized dystonia cases [5, 6]. The THAP1 mutation frequencywas much lower, with only one detected carrier of aheterozygous missense mutation, in a sample of 158patients from southern Europe with sporadic DYT1-negative primary focal dystonia, 76 of whom had nonfocaldystonia and onset before 22 years of age [7]. Thefrequency of THAP1 mutations may have been overesti-mated in the original screening study and seems to be muchlower in at least some populations. The spectrum of THAP1

mutations includes missense, nonsense, and frameshiftmutations of all three exons. Unlike DYT1, this form ofdystonia usually starts in the upper limbs, followed bygeneralization, with relative sparing of the lower extremi-ties but with prominent craniocervical and speech involve-ment (Fig. 1). Onset typically is in adolescence, with an agerange of 9 to 49 years, and may be rather rapid, as seen inDYT12 dystonia (rapid-onset dystonia parkinsonism[RDP]). Apart from these two forms, a rapid onset ofdystonic features usually points toward a secondary causeof dystonia, such as a lesion following a vascular event.The DYT6 gene product THAP1 is a member of the familyof sequence-specific DNA-binding factors. Its function isstill poorly understood.

Implications and Perspectives

THAP1-associated DYT6 dystonia appears to be a relativelyfrequent cause of DYT1-negative generalized and segmentaldystonia. On average, age at onset is later than in DYT1dystonia, and the distribution of symptoms differs betweenboth forms (Fig. 1). Future research will help elucidate theyet unknown function of the gene product and involvedpathways. Further, genetic and nongenetic disease modifiers

Monogenic dystonias/dyskinesias

Dystonia plus

Plus parkinsonism Plus myoclonus

Paroxysmaldyskinesias

Pure dystonia

DYT1 (TOR1A)DYT2DYT4DYT6 (THAP1)DYT7DYT13DYT16 (PRKRA)DYT17

DYT3 (TAF1)DYT5 (GCH1/TH)DYT12 (ATP1A3)

DYT1 DYT6

DYT11 (SGCE)DYT15

DYT8 (MR1)DYT9DYT10DYT18 (SLC2A1)DYT19DYT20

Fig. 1 Monogenic dystonias/dyskinesias and symptom distri-bution of the most commonmonogenic forms of generalizeddystonia, DYT1 and DYT6.Known genes are listed inparentheses. The mostcommonly/most severelyaffected body regions are shadedin black in the lower panel. Notethe “caudal-to-rostral” gradientin DYT1 dystonia and the“rostral-to-caudal” gradient inDYT6 dystonia

Curr Neurol Neurosci Rep (2010) 10:199–206 201

must be unraveled to explain the incomplete penetrance ofthis dominantly inherited form of dystonia.

Redefining DYT14 as DYT5

A putatively new form of DRD (DYT14) was found to beidentical to classic DRD (DYT5) [8•]. Misclassification ofone patient from the putative DYT14 family had led to falselocus assignment to an area outside the GCH1 gene. Thispatient with dystonia later was identified to be a phenocopy.After exclusion of this patient, linkage became compatiblewith DYT5, and a novel multiexonic deletion of the GCH1gene was found as the disease cause.


An accurate clinical diagnosis and comprehensive genetictesting, including both qualitative and quantitative analyses,are necessary to successfully map and identify genes.Phenocopies are an unresolved problem in genetic studies.

DYT16 (Dystonia-Parkinsonism)

DYT16 dystonia is a recessively inherited form of early-onset generalized dystonia associated with a homozygousmissense mutation in the PRKRA gene [9]. Affectedmembers from three Brazilian families shared the sameP222L mutation, inherited from a common founder. Thismutation is associated with prominent bulbar involvement,with dysphonia, dysarthria, and even dysphagia, reminis-cent of DYT6 dystonia or the acute phase of RDP. Asmentioned by the authors, parkinsonism is a less prominentfeature [10]. Shortly after the initial report, a patient withearly-onset generalized dystonia was described as carryinga heterozygous frameshift mutation in PRKRA, pointingtoward a possible influence of single mutations in thisputatively recessive disorder [11]. Importantly, there havebeen no bona fide reports of DYT16 dystonia with twomutated PRKRA alleles since the initial description of thecondition. Currently, little is known about the function ofthe PRKRA protein, short for protein kinase, interferon-inducible double-stranded RNA-dependent activator.PRKRA binds double-stranded RNA and also may beactivated by cellular protein activators.


To confirm PRKRA mutations as a cause of early-onsetgeneralized dystonia (with or without parkinsonism),screening of patients with recessively inherited and otherforms of dystonia seems warranted. Likewise, identificationof heterozygous mutation carriers may help clarify thepossible impact of heterozygous mutations in this putatively

recessive disorder. Interestingly, the genes involved in DYT16and DYT6 dystonia are binding partners of RNA and DNA,respectively. Future research will add to our knowledge aboutdisease mechanisms, which may be related to regulatoryprocesses and may not directly affect the function of cellularproteins.

DYT17 (Recessive Torsion Dystonia)

A new dystonia gene locus (DYT17) has been mapped to a20.5-Mb interval on chromosome 20, recently described ina single large consanguineous Lebanese family with threesisters suffering from recessively inherited primary focaltorsion dystonia with onset in adolescence, between theages of 14 and 19 years [12]. Site of onset was cervical,with progression to segmental in two of the sisters andgeneralized dystonia in one. Prominent features includeddystonia and dysarthria. Dystonic symptoms were notlevodopa responsive in this family.

DYT18 (Paroxysmal Exertion-Induced Dyskinesia 2)

The SLC2A1 gene, previously linked to GLUT1 deficiencysyndrome, was identified to also cause paroxysmalexertion-induced dyskinesia and was designated DYT18[13•, 14•]. The attacks in this disorder are clinicallycharacterized by the combination of chorea, athetosis, anddystonia in excessively exercised body regions. The legsare most frequently affected. A single attack lasts from afew minutes to an hour and occurs after prolonged physicalexercise. In addition to the movement disorder, severalpatients have other disease manifestations, such as epilepsy,hemolytic anemia, and migraine. A ketogenic diet is aneffective therapeutic option. Of note, the clinical pictureassociated with paroxysmal choreoathetosis with episodicataxia and spasticity (DYT9) closely resembles that ofDYT18 and has been linked to an overlapping region on theshort arm of chromosome 1 [15]. It remains to be seenwhether DYT18 and DYT9 are the same condition.

DYT19 and DYT20 (Paroxysmal Kinesigenicand Nonkinesigenic Dyskinesia 2)

A second form of paroxysmal kinesigenic dyskinesia(PKD2) was mapped to chromosome 16p and designatedDYT19 [16]. The clinical characteristics mimic those ofDYT10-associated PKD1. The DYT19 region lies close tothe DYT10 locus and overlaps with this locus in onefamily. One may speculate whether both forms are the samecondition or are genetically heterogeneous.

DYT20 dystonia/dyskinesia, a second form of paroxys-mal nonkinesigenic dyskinesia (PKND2), was described ina single Canadian family with clinical features similar to


those of DYT8 dystonia/dyskinesia (PKND1) [17]. Bothforms map to the short arm of chromosome 2. Conventionalsequencing revealed no mutations in the myofibrillogenesisregulator 1 gene (MR-1/DYT8); gene dosage studies werenot performed. Identification of the DYT20 gene will berequired to confirm the existence of a new form of PKND.


New sequencing techniques, such as next-generationsequencing, are promising new tools to discover thecausative mutations in monogenic forms of dystonia withyet unidentified genes.

Genetic Modifiers: Influence on the Penetranceof Monogenic Dystonias

Genetic variants have the potential to modify the pene-trance, age at onset, expressivity, and progression ofneurogenetic disorders. They may be localized within thedisease-causing gene or in genes that share commonpathophysiologic pathways. Currently, the best-studiedgenetic modifier for dystonias is situated in the DYT1 geneinfluencing the penetrance of DYT1 dystonia. In thefollowing paragraph, we give a general overview of thistype of monogenic dystonia and describe the modifyingproperties of a single nucleotide polymorphism (SNP) inthe DYT1 gene in more detail.

Disease Modifier in DYT1 Dystonia (DystoniaMusculorum Deformans, Oppenheim Dystonia,Early-Onset Generalized Dystonia)

The first signs of the most common form of hereditarydystonias typically start in childhood, most commonly inthe lower limbs, with a tendency to spread to otherextremities and the torso (mean age at onset, 13 years;range, 1–28 years; Fig. 1) [1]. The disease may generalizewithin years, but the neck and head usually are spared. Thehigh prevalence of 1 in 9000 among Ashkenazi Jewscompared with 1 in 160,000 in non-Jews is explained by afounder mutation in this population. DYT1 dystonia isinherited in an autosomal dominant fashion, with amarkedly reduced penetrance of only around 30% andvariable expressivity. As an example, some mutationcarriers develop writer’s cramp only, without subsequentdisease progression [1]. The risk of developing the diseaseis minimal for mutation carriers older than 28 years. Thevast majority of patients carry a heterozygous deletion ofthree nucleotides (GAG) in the coding region of the fiveexon–containing DYT1 gene, leading to the loss of aglutamic acid residue in the carboxy-terminal region of

the gene product torsinA [18•]. This member of thesuperfamily of ATPases associated with a variety ofactivities (AAA+) is located predominantly in the lumenof the endoplasmic reticulum and is thought to play a rolein protein transport, degradation, intracellular trafficking,vesicle recycling, and cytoskeletal dynamics. The mutatedform has been shown to be dislocated to the nuclearenvelope [19]. Postmortem studies revealed absence ofneuronal cell loss in brains of DYT1 mutation carriers [20,21]. However, more sophisticated histologic examinationsof the brainstem showed perinuclear inclusion bodies in themidbrain reticular formation and periaqueductal gray, butnot in the striatum [22]. In accordance with these findings,recent in-vitro studies demonstrated that overexpression ofthe DYT1 GAG deletion induced the formation of cyto-plasmic inclusion bodies [19]. The rare variant of the onlyknown nonsynonymous SNP in the DYT1 gene, D216H,was capable of inducing similar inclusions. The codingsequence for residue 216 of the torsinA protein encodeseither aspartic acid (D, wild type) in 88% or histidine (H) in12% of the general population. Coexpression of the GAG-deleted and 216H-encoding alleles led to a decrease ininclusion bodies compared with the exclusive overexpres-sion of the DYT1 mutation, suggesting a protective effect ofthe 216H allele in this scenario. Clinical–genetic studiesconfirmed this hypothesis and identified a considerablyhigher proportion of unaffected DYT1 mutation carriersamong individuals who also carried the 216H allele in transwith the GAG deletion than among those bearing the D216allele [23, 24•]. Trans refers to the fact that two geneticvariants are located on different alleles. This constellationwith “compound-heterozygous” genetic variations partlyexplains the substantially reduced penetrance of thisdominantly transmitted dystonia.

Identification of Susceptibility Factors

There are different ways to identify genetic susceptibilityfactors in sporadic diseases: 1) case-control studies ofcandidate genes, 2) genome-wide association studies(GWAS), and 3) genome-wide expression studies (GWES).First, genetic association studies are performed to determinethe frequency of genetic variants in patients with a distinctphenotype compared with healthy controls. An associationmay indicate not only a statistical but also a pathophysio-logic relationship between the analyzed gene and the givencondition. While currently there are no published GWAS orGWES for dystonia, all studies aiming to identify geneticsusceptibility factors used a candidate gene approach andfocused mostly on late-onset dystonia, which usuallybegins in mid-adulthood, often with focal onset and alimited tendency to generalize. Although this form of


dystonia often appears sporadic, a positive family history ofdystonia is present in a considerable proportion of patients,and expert neurologic examination has revealed signs ofdystonia in up to 25% of first-degree relatives [25].Consistent with these observations, a recent study detecteda high proportion of affected relatives of patients withmusician’s dystonia, a classical type of focal task-specificdystonia previously thought to be purely occupational innature [26•].

Several different candidate genes have been suggested tobe involved in the development of dystonia, including thoseinvolved in brain plasticity and dopaminergic transmission,as well as common variants in genes known to causemonogenic dystonia. Although all these genes representattractive candidates, few of the suggested associationshave stood the test of replication. This likely is explainedby the various problems inherent in this approach, such asthe highly variable genotype frequency across differentethnic and geographic populations and confinement to oneor a few candidates despite the widely held view thatseveral different genetic and environmental factors acttogether to cause focal, late-onset dystonia.

The rare variant of the common Val66Met SNP in thegene coding for brain-derived neurotrophic factor (BDNF)is associated with decreased activity-dependent BDNFrelease and was shown to modulate short-term andexperience-dependent plasticity of the human cortex. Inanother study, this SNP failed to show a difference ingenotype distribution between adult-onset cranial-cervicaldystonia patients and controls from an Italian cohort [27].Contradictory findings also were reported for a micro-satellite polymorphism in the gene for the dopamine D5receptor (DRD5), with a twofold increased risk for dystoniain Italian cervical dystonia patients carrying a specific allele[28] but not in independent cohorts of Italian and NorthAmerican patients with primary blepharospasm [29] andGerman patients with various forms of primary dystonia[30]. Numerous studies explored the influence of poly-morphisms in the DYT1 gene. The common D216H SNPhas been shown to increase the risk for patients withprimary dystonia who have a positive family history [31].In contrast, the H216 variant was protective in anotherstudy including only a few Indian patients [32] and showedno correlation at all in other reports [30, 33]. However, twoother polymorphisms close to the 3′ untranslated region, aswell as a specific DYT1 haplotype, were strongly associatedwith idiopathic dystonia in a mixed German/Austrian [33]and an Icelandic study population [34]. Spread of primaryblepharospasm recently was shown to be associated with anSNP located in the 3′ untranslated region (rs1182) in Italianand North American patients [35]. Given the inconsistentfindings of these candidate studies, hypothesis-free GWASor genome-wide, next-generation sequencing may represent

the most promising approach to the identification of geneticrisk factors for focal dystonia, the most common type ofdystonia.

Genetic Testing

In other familial movement disorders, such as monogenicparkinsonism, spastic paraplegia, and autosomal dominantataxia, it is difficult, if not impossible, to distinguish amongdifferent “PARKs,” “HSPs,” and “SCAs” on clinicalgrounds. In the dystonias, however, knowledge of impor-tant clinical “red flags” may lead to the correct diagnosis ofa specific genetic form even before molecular testing.These red flags include diurnal variation of symptoms andresponse to levodopa in DRD (DYT5); prominent orobul-bar and speech involvement (DYT6); a combination ofdystonia with myoclonus, ameliorated by alcohol intake inmyoclonus-dystonia (DYT11); and abrupt onset of severedystonia and parkinsonism in RDP (DYT12)—to name justa few. An inherited dystonia also should be considered inthe case of an early onset and when a certain ethnicbackground and positive family history are present (eg, ahigh prevalence of DYT1 dystonia in Ashkenazi Jews andof DYT3 X-linked dystonia-parkinsonism [XDP, “lubag”]in Filipinos). Notably, the presence of a heritable conditionmay be masked by a small number of family members,nonpaternity, or adoption. Similarly, reduced penetrance,variable expressivity, and de novo mutations are potentialreasons for a “pseudo”-negative family history. With theexception of five rare forms (DYT2, DYT3, DYT5b,DYT16, and DYT17), all monogenic dystonias follow anautosomal dominant pattern of transmission with reducedpenetrance.

Mutational screening has become available on a com-mercial basis for most of the known dystonia-causing genes(www.genetests.org). For 10 of the 20 DYT loci (DYT1,DYT3, DYT5a, DYT5b, DYT6, DYT8, DYT11, DYT12,DYT16, and DYT18), genes have been identified (Table 1).Current guidelines for genetic testing and counseling arebased on criteria established by the European Federation ofNeurological Societies that were revised in 2009: 1)Molecular testing for the GAG deletion in the DYT1 geneis recommended in patients with limb-onset generalizeddystonia and symptom onset before the age of 26 years,regardless of family history. 2) Comprehensive mutationalanalysis for GCH1 mutations, including gene dosagestudies, is recommended in patients with early-onsetgeneralized dystonia and clear symptom relief followinglevodopa therapy, irrespective of family history. 3) Muta-tional screening for SGCE mutations is recommended onlyin cases with the typical combination of dystonia andmyoclonus and a suggestive family history. iv) RDP


http://www.genetests.org

(DYT12) and tyrosine hydroxylase (TH)–associated DRD(DYT5b) are exceedingly rare. XDP (DYT3) is restricted toa specific population. Therefore, no general recommenda-tions have been proposed for these forms [36].

Conclusions and Future Perspectives

The dystonias are a clinically and genetically heterogeneousgroup of movement disorders. Several genes and gene locihave been shown to be associated with monogenicdystonias. One may expect that new dystonia gene lociwill be added while others will be “merged” or even“disappear.” It is difficult even for the dystonia specialist tokeep up with these rapid changes in locus assignment, andthere is an urgent need for a more rigorous and consistentclassification scheme for monogenic forms of dystonia. Theidentification of new dystonia genes will improve ourunderstanding of the rare monogenic forms and of dystoniain general. Recent technologic advances, particularly next-generation sequencing, will further accelerate the process ofidentifying new dystonia-causing genes. Although geneticslikely also plays an important role in focal and segmentaldystonia, no such factor has yet been identified. Genome-wide association or genome-wide sequencing efforts areexpected to lead to rapid advances in this important field ofdystonia research as well. Because of the relative rarityeven of focal forms of the disease, large-scale internationalcollaborations will be necessary to achieve this importantgoal. In future research, transcriptome analysis andgenome-wide transcription factor binding-site profilingmay provide insight into the regulatory processes andinteraction of different genes in dystonia. Finally, mRNAexpression profiles may potentially be used as “finger-prints” in a variety of applications, such as identifying drugtargets.

Disclosure No potential conflicts of interest relevant to this articlewere reported.

Glossary

Allele One of a series of different forms of agene

Haploinsufficiency Only a single functional copy of thegene is available, mostly leading to alack of adequate protein(gene product) levels

Linkage analysis Common method for the search fordisease-causing genes

Gene locus Specific location of a gene on achromosome

Penetrance Describes the proportion of mutationcarriers who develop a distinctphenotype

Expressivity Phenotypic variations in individualscarrying a distinct genotype

Haplotype Combination of alleles at multiplegene loci transmitted together on thesame chromosome

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Genetics of Primary Torsion Dystonia