Genetics of Dystonia

Dystonia is 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

Axis I. Clinical characteristics

Age at onset

Body distribution

Temporal pattern

Associated features

Axis II. Etiology

Nervous system pathology

Inherited or acquired


Combining the two axes, in general, in patients with a late-onset and a non-progressive focal form of dystonia, a primary cause is most likely. This form usually involves the neck or cranial muscles but spares the lower extremities. This late-onset variant affects more women than men and appears to be sporadic in most cases (for review see [4]), although some 15–30 % of patients do have a positive family history and genetic susceptibility has been proposed (see below).

In contrast, early-onset dystonia typically starts in the lower limbs, tends to generalize, and commonly has a genetic origin. Young-onset cases should thus be investigated further for genetic causes or treatable metabolic diseases. Altogether, the prevalence of primary dystonia has been estimated at 152 per million in a European prevalence study [5].

In recent years, a growing number of genetic causes associated with dystonia have been recognized which are reviewed in this chapter.

Genetic Forms of Dystonia

The monogenic forms of dystonia have been “classified” according to the gene locus. However, this list of differential diagnoses for dystonia is by far complete, as not all genes associated with dystonia have been assigned to a DYT locus (e.g., mutations in SPR associated with complicated dopa-responsive dystonia or SLC6A3 [6] associated with dopamine transporter deficiency syndrome, mutations in TIMM8A and other genes associated with dystonia deafness syndromes [7], or mutations in one of the several genes associated with dystonia parkinsonism [8], etc.). These often complicated syndromes where dystonia may be one (prominent) feature are beyond the scope of this chapter.

Currently, 25 DYT loci have been assigned referring to 23 genes (two loci have been abandoned because of redundancy or initial incorrect assignation due to erroneous linkage, e.g., DYT9 or DYT14; see below and Table 7.2 and Fig. 7.1). For most but not all loci, the correlating gene has been identified. With the exception of the five rare forms (DYT2, 3, 5b, 16, and 17), the DYT genes follow an autosomal-dominant pattern of transmission with reduced penetrance. In at least one form (DYT11), maternal imprinting also plays a role [9]. Notably, the designation of some loci has never been replicated and is of questionable significance (e.g., DYT7 or DYT13).

Table 7.2
Monogenic forms of dystonia (DYT1 – 20)


Dystonia phenotype

Mode of inheritance

Gene locus

Gene product


Early-onset generalized torsion dystonia (TD)

Autosomal dominant


Deletion in torsinA


Autosomal-recessive TD

Autosomal recessive




X-linked dystonia parkinsonism, “lubag”

X-chromosomal recessive


Disease-specific changes 3 in DYT3 region


Whispering dysphonia, focal or generalized dystonia, hobby horse gait

Autosomal dominant


TUBB4A (seems to be a private mutation)


Dopa-responsive dystonia, Segawa syndrome

Autosomal dominant


Autosomal recessive




Adolescent-onset TD of mixed type

Autosomal dominant




Adult-onset focal TD

Autosomal dominant


Unknown, locus questionable


Paroxysmal nonkinesigenic dyskinesia

Autosomal dominant




Paroxysmal choreoathetosis with episodic ataxia and spasticity

DYT9 recently omitted and reclassified as DYT18


Paroxysmal kinesigenic choreoathetosis (PKD)

Autosomal dominant





Autosomal dominant




Rapid-onset dystonia parkinsonism (allelic to alternating hemiplegia of childhood)

Autosomal dominanta




Multifocal/segmental dystonia

Autosomal dominant




DYT14 was recently omitted and reclassified as DYT5



Autosomal dominant




Generalized dystonia parkinsonism

Autosomal recessive




Young-onset generalized dystonia

Autosomal recessive




Paroxysmal exercise-induced dyskinesia

Autosomal dominant


SLC2A1 (glucose transporter 1)


Paroxysmal kinesigenic dyskinesia 2 (episodic kinesigenic dyskinesia 2)

Autosomal dominant




Paroxysmal non-kinesigenic dyskinesia 2

Autosomal dominant




Adult-onset mixed dystonia with generalization in one Swedish family

Autosomal dominant




Reserved, not published





Adult-onset (tremulous) craniocervical dystonia +/− upper limb tremor

Autosomal dominant


CIZ1 (not confirmed by others)


(Tremulous) craniocervical dystonia +/− upper limb tremor

Autosomal dominant




Segmental, mainly cervical dystonia, often facial involvement

Autosomal dominant



Some gene tests may (only) be available on a research basis. To choose the appropriate gene test, it is helpful clinically and genetically to think of autosomal-recessive syndromes, autosomal-dominant syndromes, and X-linked syndromes. Furthermore, genetic testing in general has implications not only for the diagnosis and therapy but also, of course, for family planning and counseling of family members

ANO3 anoctamin 3, ATP1A3 Na+/K+ ATPase alpha 3, CIZ1 CDKN1A-interacting zinc finger protein 1, GCH1 GTP-cyclohydrolase 1, GNAL guanidine nucleotide-binding protein, alpha-activating activity polypeptide of the olfactory type, HPCA hippocalcin, MR1 myofibrillogenesis regulator 1, PRKRA protein kinase interferon-inducible double-stranded RNA-dependent activator, PRRT2 proline-rich transmembrane protein 2, SGCE epsilon sarcoglycan, TH tyrosine hydroxylase, THAP1 thanatos-associated [THAP] domain containing apoptosis-associated protein 1, TUBB4A tubulin beta-4A

aOften de novo

bPlease note that there is some confusion in the literature with regard to assignment of these two loci (see main text for more details)


Fig. 7.1
An approach to different genetic forms of dystonia. Paroxysmal dyskinesia is not included in this figure. (1) Parkin-, PINK1-, and DJ-1-associated parkinsonism. (2) Including PANK2- and PLA2G6-associated neurodegeneration, neuroferritinopathy, and others

Some have criticized the DYT classification because it is an assortment of clinically and genetically heterogeneous disorders [10]. However, this owes to the historical evolution when loci were assigned chronologically according to appearance in the literature.

Targeted genetic testing for many dystonia genes is commercially available including using gene panels. However, it is important to realize that a negative gene test result does not fully exclude a mutation in the gene tested or an inheritable cause for that matter because introns and promoter regions are usually not sequenced and variations in these areas remain difficult to interpret. Furthermore, routine methods may only involve mutational analysis, while for some genes mutational screening per se may not be sufficient as entire or parts of genes may be deleted or multiplied (whole gene deletion, exon deletion, duplications, etc.), also referred to as gene dosage alterations, e.g., in the context of dystonia in GTP cyclohydrolase [11] or SGCE [12]. These are only detected if gene dosage analysis is performed.

Genetic testing can confirm the diagnosis in a patient. It can also be used to identify at-risk individuals based on their mutational status. For both symptomatic and non-symptomatic gene mutation carriers, knowledge about the genetic status may have implications for the prognosis and therapeutic management decisions and with respect to family planning. A special role plays prenatal testing which is beyond the focus of this chapter. For DYT1 dystonia testing guidelines have been proposed [13]. For the other forms, genetic testing guidelines are still being formulated.

Autosomal-Dominant Forms of Primary Dystonia with Known Genetic Defect

DYT1 Dystonia (Early-Onset Generalized Dystonia) Associated with TOR1A Gene Mutations

In the 1990s the first gene responsible for some cases of generalized torsion dystonia was identified, termed DYT1 [14]. DYT1 dystonia is the most common cause of monogenic dystonia. The mutation occurs particularly frequent in the Ashkenazi Jewish population (1/9,000), where it is 5–10-fold more common compared to non-Jewish populations [15]. DYT1 dystonia typically presents as early onset, generalized dystonia, starting in the legs. The clinical course varies, even within the same family (intrafamilial heterogeneity) ranging from severe generalized dystonia to mild focal dystonia (like writer’s dystonia) [16, 17]. Unusual phenotypes in gene-proven cases have been described [18, 19]. In addition to solely motor involvement, subclinical changes of the sensory system have been described [20, 21]. Notably, penetrance is markedly reduced: 60–70 % of mutation carriers remain unaffected in that they do not exhibit any dystonia at all. The natural course among the 30–40 % of symptomatic cases is influenced by clinical factors such as age of onset, site of onset, and distribution of symptoms which have prognostic significance, as well as genetic (see below) and extragenetic (such as complications of vaginal delivery) factors [22]. Clinical experience has shown that mutation carriers usually remain unaffected if symptoms have not developed before 28 years of age. In affected cases there is a tendency for stabilization of the clinical course after the age of 25 years without direct relationship to therapeutic modalities [23]. However, others [21] suggested that earlier treatment may slow disease progression.

Inheritance of DYT1 dystonia is autosomal dominant. It is caused by a mutation (typically a 3 base pair deletion (GAG)) in the TOR1A gene located on chromosome 9. Penetrance may be influenced by a “trans” allele. Precisely, the D216H polymorphism in trans (inherited from the non-affected parent) may be protective [24].

The encoded protein, torsinA, is a member of the superfamily of ATPases. Functions include protein processing and degradation, organelle biogenesis, intracellular trafficking, and vesicle recycling [25]. A functional link to DYT6 dystonia has been suggested with repression of DYT1 by the transcription factor THAP1 [26]. Brain pathology is generally normal in DYT1 dystonia except perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray [27]. However, this could not be replicated in another case series [28]. The inclusions were located within cholinergic and other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephali and stained positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. Additional tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and locus coeruleus were observed [27].

DYT4 (Whispering Dysphonia) Associated with TUBB4A Gene Mutations

DYT4 dystonia is characterized by whispering dysphonia, craniocervical or, more frequently, generalized dystonia, and a unique ataxic (hobby horse) gait with normal MRI. In 2013 the condition was first described in a large Australian family with more than 30 affected individuals [29]. In 2013, the underlying gene was then identified by two independent research groups [30, 31]. A single missense (p.Arg2Gly) TUBB4A mutation in exon 1 located within the autoregulatory methionine–arginine–glutamic acid–isoleucine (MREI) domain was identified as the underlying cause in the original family. So far, no further patients with TUBB4A mutations have been identified. It was concluded that the mutation may be private, and the classification as primary dystonia was criticized [32].

Notably, there is allelic association with the distinct syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). This is a rare sporadic leukodystrophy characterized by developmental delay, a variety of extrapyramidal movement disorders, ataxia, progressive spastic tetraplegia, and seizures with a variable age of onset. Indeed, it has been suggested that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations [33, 34, 35].

The encoded protein, tubulin, beta 4A class IVa of the β-tubulin protein family forms heterodimers with α-tubulins, which ultimately assemble into microtubules, a major cytoskeletal component. TUBB4A is primarily expressed in the nervous system. Functional studies suggested reduced levels (rather than functional changes) of TUBB4 which play a key role in the pathophysiology [31].

DYT5 Dystonia (Dopa-Responsive Dystonia or Segawa Syndrome)

Dopa-responsive dystonia (DRD) is characterized by the triad of childhood-onset dystonia (in the first decade of life) with or without parkinsonism, diurnal fluctuation of symptoms, and a dramatic and sustained response to levodopa [36]. Atypical phenotypes including late-onset parkinsonism have been reported [36]. Some motor features (e.g., writer’s cramp, dysphonia, truncal dystonia) may remain levodopa resistant, but overall dopamine treatment is very effective and safe for long-term use including during pregnancy without suggestion that it may cause fetal abnormalities [36].

Cerebrospinal fluid analysis may demonstrate decreased catecholamine metabolites. The most common form of DRD (DYT5a) is dominantly inherited and associated with mutations in the GTP cyclohydrolase 1 (GCH1) gene, a gene which encodes the enzyme GTPCH that catalyzes the first step in the dopamine synthesis. Mutations in GCH1 can be identified in 40–60 % of clinically typical DRD patients [37]. In addition, exon deletions have been demonstrated [11] that are not detectable by conventional screening methods and may account for at least another 10 % of the “mutation-negative” cases. Notably, heterozygous variants in GCH1 [38] are associated with an increased risk for Parkinson’s disease (even in the absence of a family history for DRD).

Recessive forms of DRD also occur, but their clinical presentation is usually strikingly more complex, characterized by mental retardation, oculogyric crises, and parkinsonism (dopa-responsive dystonia-plus syndromes). Mutations in various genes involved in metabolic pathways of biopterin and dopamine synthesis may be the cause, such as tyrosine hydroxylase (TH) (DYT5b) but also 6-pyruvoyl-tetrahydropterin synthase (6PTPS), sepiapterin reductase (SPR), dihydropteridine reductase (DHPR), and aromatic Lamino acid decarboxylase (AADC) (for review see [39]). Notably, mutations in genes involved in distinct (non-dopamine synthesis) metabolic pathways may sometimes also clinically present as DRD phenocopies, e.g., recently, biallelic mutations in the ATM gene (traditionally associated with ataxia telangiectasia) were described as one cause of a (recessive) DRD presentation [40].

DYT6 Associated with THAP1 Gene Mutations

Another locus associated with generalized dystonia is DYT6 dystonia, originally described in Mennonite families [41]. The underlying gene, THAP1, was identified in 2009 [42, 43]. Since then more than 100 patients have been described in the literature (for review see [44]). Clinically, it presents as focal or generalized dystonia with a mean age at onset of 24 years. Limbs are the most common site at onset (in about 45 % of patients), followed by the cervical region [44]. However, in contrast to DYT1 dystonia, there seems to be a rostrocaudal gradient, and bulbar findings (present in 60 % of patients) may be prominent (which are typically absent in DYT dystonia). Similar to DYT1 dystonia, changes beyond the motor system (i.e., affecting spatial discrimination) have been reported [45].

Inheritance of DYT6 dystonia is autosomal dominant. Notably though, homozygous mutations have also rarely been reported [46]. The penetrance is reduced to about 40 % [10].

THAP1 is a small gene containing 3 exons. Variants mostly affect the THAP1 domain (exon 1 and 2). More than 60 THAP1 mutations have been reported, mostly missense (>65 %) [44], but small insertions/deletions, nonsense mutations, and splice-site mutations have also been described. No definite obvious genotype–phenotype correlations have yet emerged. However, in a recent review of the literature, Xiromerisiou et al. [44] re-analyzed the pathogenicity of mutations computationally. Interestingly, in the generalized dystonia, 84 % of patients harbored likely damaging mutations versus 4 % that presented with benign variants. On the other hand, in focal dystonia, 65 % harbored benign variants versus 14 % with likely damaging mutations.

The THAP1-encoded THAP1 protein belongs to the family of sequence-specific DNA-binding factors. THAP1 regulates endothelial cell proliferation and is a transcription factor [47, 48]. A functional link between THAP1 and torsinA has been suggested: THAP1 binds to the core promoter of TOR1A, and wild-type THAP1 represses the expression of TOR1A [26, 49].

DYT11 (Myoclonus-Dystonia) Associated with SGCE Gene Mutations

As the name suggests, myoclonus-dystonia is characterized by the combination of dystonia and myoclonic jerks, thus rapid, brief lightning-like muscle contractions [50, 51]. Dystonia usually remains focal or segmental as cervical or arm dystonia [50]. Legs are less prominently affected, in contrast to DYT1 dystonia. Myoclonus also most often affects the neck, trunk, and upper limbs. Myoclonus is often dramatically responsive to alcohol, however, with rebound effect.

Again there may also be non-motor features, particularly psychiatric features (including obsessive–compulsive disorder, anxiety, and addiction but also depression, panic attacks, and personality disorders) [52, 53]. In fact, a recent study reported psychiatric symptoms in almost 80 % of cases [53].

Mutations in the underlying epsilonsarcoglycan (SGCE) gene [52] are inherited in an autosomal-dominant manner with reduced penetrance due to maternal genomic imprinting [54]. However, family history is positive in more than 80 % of cases with genetically confirmed DYT11 dystonia [12]. Gene function remains unknown. All sorts of mutations have been reported in the SGCE gene including nonsense and missense, as well as deletions and insertions leading to frame shifts and splicing errors, but also larger deletions of entire exons and de novo mutations without obvious genotype–phenotype correlations [12, 50, 52, 54]. Notably, such larger deletions may affect areas beyond the SGCE gene and involve neighboring genes (“genomic deletions”). This may impinge on the clinical phenotype. For example, if the adjacent COL1A2 gene is also affected, patients may be affected by additional osteoarthritis, osteoporosis, or delayed skeletal development [12, 55]. Other clinical manifestations associated with neighboring genes include split-hand/split-foot malformations, sensorineural hearing loss, and cavernous cerebral malformations [55]. Such findings emphasize the importance of a careful clinical examination which also includes other (non-motor) features [12].

Finally, there is evidence of genetic heterogeneity after mutations in the SGCE gene were excluded in a large Canadian family with a clinical presentation compatible with typical myoclonus-dystonia. This family was linked to chromosome 18p, and this was designated the DYT15 locus, but the gene is yet unknown [56, 57].

DYT12 Dystonia (Rapid-Onset Dystonia Parkinsonism, Allelic to Alternating Hemiplegia of Childhood) Associated with ATP1A3 Gene Mutations

Rapid-onset dystonia parkinsonism is characterized by sudden onset (within hours to weeks) with a rostral–caudal (face > arm > leg) gradient in response to physical or mental stress without evidence of neurodegeneration on brain pathology [58, 59]. The phenotypic spectrum includes dystonic spasms predominantly in the upper limbs, orofacial dystonia, dysarthria, dysphagia, slowness of movement, rigidity and postural instability, and non-responsiveness to levodopa [60]. Notably, intermittent hemidystonia, paroxysmal dystonia, and seizures have been described (see below) [58, 60, 61]. Onset is usually early in life (in adolescence or young adulthood but may be as late as 55 years), and symptoms persist throughout life. Fever, prolonged exercise, childbirth, and even giving oral presentations have been described as triggering factors [58, 59].

Inheritance follows an autosomal-dominant manner with reduced penetrance. The causative gene, ATP1A3, located on chromosome 19q13 (23 exons), encodes Na+/K+ATPase alpha 3 [62], a subunit of a sodium pump responsible for maintenance of ionic gradients across cell membranes. Interestingly, there is phenotypic variability as mutations in this gene are also the major cause of alternating hemiplegia of childhood (AHC) [6365], a rare, usually sporadic syndrome (due to frequent de novo mutations) with early onset characterized by episodes of hemiplegia on alternating body sides, dystonia or ataxia, seizures, and developmental delay. See also Fig. 7.2 and Chap. 10 for more detailed discussion of this syndrome.


Fig. 7.2
The main phenotypic variability of genes associated with paroxysmal movement disorders

DYT231: Dystonia Associated with Mutations in the CIZ1 Gene

Recently, mutations in CIZ1 located at the long arm of chromosome 9 were described in several cases of autosomal dominant adult-onset cervical dystonia as identified by exome sequencing [66]. However, this finding has not yet been confirmed by others [67].

DYT231/24: Dystonia with Dystonic Tremor (ANO3-Related Dystonia)

Recently, the combination of linkage analysis with whole-exome sequencing led to identification of ANO3 as a new cause of autosomal-dominant dystonia [68]. The age at onset ranged from early childhood to the forties [69]. The clinical picture consisted of focal dystonia affecting the neck, laryngeal muscles, and upper limbs accompanied by 6-Hz dystonic tremor with or without superimposed myoclonus in some. The duration of the myoclonic bursts was most consistent with a subcortical type. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor [69]; however, genetic studies in an independent cohort of essential tremor patients (with a positive autosomal-dominant family history) did not identify further ANO3 mutations [70].

The ANO3 gene, located at chromosome 11p14, encodes a protein called anoctamin 3, a predicted Ca2+-gated chloride channel with high expression in the striatum. Notably, related genes from the ANO family have also been linked to neurological disease (ANO5 to several forms of muscular dystrophy and ANO10 to autosomal-recessive spinocerebellar ataxia) [68].

DYT25: Dystonia Associated with Mutations in the GNAL Gene

Recently, using exome sequencing, mutations in GNAL were identified in two families with primary torsion dystonia [71]. A handful of other patients from different ethnic backgrounds were since reported [7275], while other researchers did not detect any changes in their cohort [76]. The clinical phenotype consists of focal or segmental, mainly cervical dystonia, with a relatively broad range in the age of onset and spreading to other muscles, especially the facial muscles [71].

GNAL has 12 exons and encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation.

The Paroxysmal Dyskinesia (DYT8, DYT9, and DYT10 as well as DYT19 and DYT20)

The group of paroxysmal dyskinesia is defined as abnormal involuntary movements of intermittent or episodic nature. The phenotype varies but tends to be dystonic and/or choreic and may be complex. Episodes are sudden in onset and without change in consciousness. Subtypes include the nonkinesigenic variant (PNKD), the kinesigenic variant (PKD), and the exercise-induced variant (PED) according to the triggering factors (for review see [77, 78]). While secondary causes should be excluded, genetic forms, usually with autosomal-dominant inheritance, are recognized. They are discussed in detail in Chap. 10.

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Jun 14, 2017 | Posted by in NEUROLOGY | Comments Off on Genetics of Dystonia
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