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 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].

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 (6–PTPS), sepiapterin reductase (SPR), dihydropteridine reductase (DHPR), and aromatic L–amino 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].

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].

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 epsilon–sarcoglycan (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].

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) [63–65], 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.

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].

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].

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 [72–75], 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].

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.