Dystonia Overview

Klein C, Marras C, Münchau A.

Publication Details


Clinical characteristics.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements and/or postures. Dystonic movements are typically patterned and twisting, and may be associated with tremor. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia can be classified clinically according to age of onset, body distribution, temporal pattern, and associated features (i.e., isolated dystonia – in which it is the only motor feature except tremor; combined dystonia – in which another movement disorder is present; or complex dystonia – in which other neurologic or systemic manifestations are present).

Causes of dystonia.

Inherited dystonia can be classified by mode of inheritance and gene or chromosome locus. To date the underlying genetic cause has been unequivocally identified for 12 inherited forms of dystonia with a ‘DYT’ designation (isolated and combined forms of dystonia) and for numerous types of complex dystonia.

Genetic counseling.

Hereditary dystonias are usually inherited in an autosomal dominant manner and less commonly in an autosomal recessive or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific cause of an inherited dystonia in an individual.

Definition of Dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements and/or postures. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation [Albanese et al 2013].

In most cases, dystonia combines abnormal movements and postures. Some forms of dystonia, such as blepharospasm and laryngeal dystonia, are not associated with postures, but rather are characterized by focal involuntary contractions that interfere with physiologic opening or closing of the eyelids or the larynx, respectively [Albanese et al 2013].

Prevalence of Dystonia

The prevalence of isolated dystonia is estimated at 16.43:100,000 [Steeves et al 2012]. No systematic prevalence studies exist for other forms of dystonia. The most common type is adult-onset focal dystonia.

Clinical Classification of Dystonia

Dystonia can be classified clinically according to age of onset, body distribution, temporal pattern, and associated features (Table 1). Clinical classification in this manner allows the formulation of dystonia phenotypes (e.g., early-onset generalized isolated dystonia or focal isolated dystonia with onset in adulthood).

Age of onset

  • Infancy (neonatal – 2 years)
  • Childhood (3-12 years)
  • Adolescence (13-20 years)
  • Early adulthood (21-40 years)
  • Late adulthood (>40 years)

Body distribution

Table 1.

Table 1.

Classification of Dystonias by Affected Body Part

Temporal pattern

  • Persistent: dystonia persists to about the same extent throughout the day
  • Action-specific (e.g., musician’s dystonia, writer’s cramp)
  • Diurnal fluctuations (e.g., dopa-responsive dystonia)
  • Paroxysmal: dystonia/dyskinesia appear suddenly and are self-limited, usually induced by a specific trigger

Associated features

  • Isolated dystonia (formally referred to as ‘primary dystonia’): dystonia is the only motor feature with the exception of possible tremor (see Table 3)
  • Combined dystonia (formerly ‘dystonia-plus’): dystonia is combined with another movement disorder (e.g., myoclonus, parkinsonism) (see Table 3)
  • Complex dystonia (formerly ‘secondary dystonia’): dystonia co-occurs with other neurologic or systemic manifestations; dystonia is not necessarily the most prominent disease manifestation and may even be an inconsistent feature (see Table 4).

As a number of different etiologies have been identified for both isolated/combined and complex dystonia, the terms ‘primary’ and ‘secondary’ dystonia have led to some confusion and their use is no longer recommended.

Note that the clinical classification axis above and the following etiologic classification interrelated. For instance, while most forms of dystonia tend to worsen initially and some focal dystonias may spread and eventually generalize, forms of dystonia without neurodegeneration usually reach a plateau with stable findings, whereas those associated with neuronal loss progressively worsen over time.

Etiologic Classification of Dystonia

Disorders characterized by dystonia can be subdivided by anatomic changes (structural lesions, degeneration) and causation (inherited, acquired, or idiopathic [i.e., of unknown cause]).

Classification of Inherited Forms of Dystonia

Inherited dystonia can be classified by mode of inheritance and gene or chromosome locus. To date, the underlying genetic cause has been identified for 25 inherited forms of dystonia.

Initially these monogenic disorders were designated DYT followed by a number that represented the chronologic order in which the description of the phenotype and/or genetic discovery first appeared in the literature (Table 2). Although some of the inherited dystonias have a distinct phenotype, considerable phenotypic overlap can occur, making classification based on phenotype alone (e.g., DYT2) problematic.

Table 2.

Table 2.

Previous Nomenclature System for Inherited (Monogenic) Forms of Dystonia/Dyskinesias (DYTs)

Because of the inconsistencies in the “DYT nomenclature” (Table 2), a new naming system that combines the “DYT” designation (to indicate the main clinical feature) and the name of the (confirmed) gene or chromosome locus has been proposed [Marras et al 2012] (Table 3). This new naming system eliminates previously listed loci that were erroneous, duplicated, or unconfirmed as well as disorders that were not predominantly dystonic. Of note, genes associated with an increased risk for dystonia – but not meeting a threshold to be considered a gene in which mutation is causative – are not included.

Table 3.

Table 3.

Proposed New Nomenclature System for Inherited (Monogenic) Forms of Isolated Dystonia and Combined Dystonia/Dyskinesias (DYTs)

Isolated Dystonias

DYT-TOR1A (Early-Onset Generalized Dystonia)

DYT-TOR1A typically first manifests in childhood (mean age 13 years, range 1-28 years) as twisting of an extremity. Symptoms tend to start in lower parts of the body, progressing to involve more rostral body parts. It progresses to involve other limbs and the torso, but usually not the face or neck [Bressman et al 2000]. Disease characterized by later-onset or onset in the arms tends to be less severe.

Penetrance is reduced: only about 30% of persons heterozygous for a TOR1A pathogenic variant are affected. Expressivity varies with respect to age of onset, site of onset, and progression. If manifestations are not evident in a person heterozygous for a TOR1A pathogenic variant by age 28 years, that individual will usually remain symptom free for life.

A specific TOR1A pathogenic variant, a three-base pair deletion (GAG) in the coding region, accounts for about 60% of generalized dystonia in the non-Jewish population and about 90% in the Ashkenazi Jewish population due to a founder effect [Ozelius et al 1997].

DYT-THAP1 (Adolescent-Onset Segmental/Generalized Dystonia)

DYT-THAP1 is manifest as focal and generalized primary dystonia. Although some phenotypic overlap with DYT-TOR1A is observed, the onset of DYT-THAP1 is later (mean 19 years; range 5-38 years) and cranial involvement is more prominent especially in muscles of the tongue, larynx, and face, with dysphonia being a predominant feature.

Penetrance is estimated at 40%.

DYT-THAP1 was first identified in three Mennonite families who are related to a common ancestor [Fuchs et al 2009]. Currently over 60 different missense and truncating THAP1 pathogenic variants have been reported – mainly in people from Europe but also from China and Brazil [Blanchard et al 2011].

DYT-GNAL (Adult-Onset Segmental Dystonia)

Cervical or cranial dystonia often begins in the fourth decade (range 7-54 years) [Fuchs et al 2013].

GNAL pathogenic variants were identified in six of 39 families with dystonia [Fuchs et al 2013]. This association was independently confirmed in a large African American family with dystonia [Vemula et al 2013] and in a number of familial cases and simplex cases (i.e., a single occurrence in a family) [Vemula et al 2013, Kumar et al 2014].

Of note, although GNAL is located within the DYT7 locus, it does not appear to be mutated in the original family reported with DYT7 and the existence of the DYT7 locus is questionable [Winter et al 2012].

Combined Dystonias

Dystonia plus Parkinsonism

DYT-TAF1 (X-linked dystonia-parkinsonism, lubag). DYT-TAF1 (also known as XDP; lubag), the only known X-linked form of dystonia, is endemic on Panay Island in the Philippines [Lee et al 2011]. It is characterized by a combination of dystonia and parkinsonism, and is the only known ‘DYT’ with documented neurodegeneration.

As an X-linked disorder, DYT-TAF1 predominantly affects males. Penetrance is complete in men with the disease haplotype. Although almost all women who are obligate heterozygotes are unaffected, 14 affected females with phenotypes of variable severity have been reported. Possible explanations for disease manifestations in females include homozygosity for the disease-causing change, non-random (“skewed”) X-chromosome inactivation, and mosaic monosomy X [Westenberger et al 2013].

The exact TAF1 pathogenic variant remains a matter of debate since several variants (disease haplotype) segregate with the phenotype. A disease-specific change (DSC) within TAF1 [Herzfeld et al 2013] or a retrotransposon (SVA) insertion [Kawarai et al 2013] are under discussion as potential disease-causing mechanisms.

DYT-GCH1, DYT-TH, and DYT-SPR (dopa-responsive dystonia). Dopa-responsive dystonia (DRD) is characterized by childhood onset of dystonia, diurnal fluctuation of symptoms, and a dramatic response to L-dopa therapy. Later in the course of the disease, parkinsonian features may occur and may, in rare cases, be the only sign of the condition.

DYT-GCH1, the most common form of dopa-responsive dystonia, is usually caused by a heterozygous pathogenic variant in GCHI and, thus, inherited in an autosomal dominant manner [Ichinose et al 1994]. Autosomal dominant DYT-GCH1 shows reduced penetrance – particularly in men – and both inter- and intrafamilial phenotypic variability. Non-motor features (e.g., sleep disturbances, mood disorders, migraine) that are present in a considerable subset of affected individuals are probably due to involvement of the serotoninergic system [Tadic et al 2012].

To date, more than 100 different GCH1 pathogenic variants (spread across the entire coding region and untranslated regions) have been reported and include missense, nonsense, and splice-site variants and small and large (whole-exon and whole-gene) deletions.

DYT-TH and DYT-SPR, autosomal recessive forms of dopa-responsive dystonia, are rare. Their phenotypes --which are much more severe than that of autosomal dominant DYT-GCH1-- resemble autosomal recessive DYT-GCH1 (caused by biallelic GCH1 pathogenic variants) [Brüggemann et al 2012].

DYT-ATP1A3 (rapid-onset dystonia-parkinsonism). DYT-ATP1A3 is characterized by abrupt onset of dystonia with parkinsonism (primarily bradykinesia and postural instability); a rostra-caudal (face>arm>leg) gradient of involvement; bulbar involvement; and no response to an adequate trial of L-dopa therapy [Brashear et al 2007]. Anxiety, depression, and seizures have been reported. The age of onset ranges from four to 55 years. Fever, physiologic stress, or alcoholic binges often trigger the onset of symptoms. After their initial appearance, findings commonly stabilize, but with little improvement. Occasionally, subsequent episodes cause abrupt worsening.

Penetrance is incomplete.

Of note, the phenotypic spectrum associated with heterozygous mutation of ATP1A3 has recently expanded to include alternating hemiplegia of childhood (AHC), a severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. In one study 74% of alternating hemiplegia of childhood (AHC) was attributed to mutation of ATP1A3 [Heinzen et al 2012]. Of the seven recurrent ATP1A3 pathogenic variants identified in AHC, one was observed in 35% of affected individuals [Heinzen et al 2012].

Dystonia with Myoclonus

DYT-SGCE (myoclonus-dystonia). DYT-SGCE is characterized by a combination of myoclonus and (in most cases) dystonia [Zimprich et al 2001]. Many heterozygotes for a SGCE pathogenic variant develop psychiatric features in addition to or instead of the movement disorder [Weissbach et al 2013].

Reduced penetrance on maternal transmission of the pathogenic variant is explained by maternal genomic imprinting of SGCE [Müller et al 2002]. Maternal imprinting of SGCE explains the observation that the vast majority of affected individuals inherit their pathogenic variant from their fathers; in contrast, those inheriting the variant from their mothers will likely remain unaffected throughout their lives.

Dystonia with Other Dyskinesia (Paroxysmal)

DYT-MR-1 (paroxysmal non-kinesigenic dyskinesia). Paroxysmal nonkinesigenic dyskinesia (PNKD) attacks are usually a combination of dystonia, chorea, athetosis, and ballismus; last from minutes to hours; and in the most severe cases may occur several times daily. Attacks can be precipitated by alcohol and caffeine, as well as by stress, hunger, fatigue, and tobacco.

Two PNKD (formerly MR-1) pathogenic missense variants (p.Ala7Val and p.Ala9Val) are causative [Lee et al 2004]. Another pathogenic variant, p.Ala33Pro, cosegregated with the phenotype in a single family [Ghezzi et al 2009].

DYT-PRRT2 (paroxysmal kinesigenic dyskinesia). Paroxysmal kinesigenic dyskinesia (PKD) attacks are mostly dystonia and choreoathetosis triggered by sudden movement. Attacks usually last several minutes and may occur up to 100 times per day. Onset is usually in childhood or adolescence [Bhatia 2011].

Heterozygous missense and truncating PRRT2 variants were identified as the cause of PKD [Chen et al 2011] as well as the allelic disorders benign familial infantile seizures (BFIS) and the syndrome of rolandic epilepsy, paroxysmal exercise-induced dyskinesia, and writer's cramp [Schmidt et al 2012, Heron & Dibbens 2013].

DYT-SLC2A1 (paroxysmal exertion-induced dyskinesia). The attacks are characterized by the combination of chorea, athetosis, and dystonia in excessively exercised body regions. The legs are most frequently affected. A single attack lasts from a few minutes to an hour and occurs after prolonged physical exercise. In addition to the movement disorder, other disease manifestations can include epilepsy, hemolytic anemia, and migraine.

Allelic disorders include:

Complex Dystonias

Although complex dystonias share dystonia as a manifestation, atypical features and additional neurologic signs are often observed. These may include:

  • Sustained dystonia at rest (whereas isolated or combined dystonia is usually action- or posture-dependent);
  • Prominent tongue and peri-oral involvement leading to a “risus sardonicus” (i.e., fixed, exaggerated, or distorted smiling);
  • Pyramidal or cerebellar signs;
  • Ataxia;
  • Oculomotor abnormalities;
  • Cognitive disturbances.

Although the list of complex dystonias is long and unwieldy, certain rules and patterns help to make an accurate diagnosis and tailor management.

Grouping the complex dystonias into those that are hereditary neurodegenerative or metabolic disorders (Table 4) and those that are acquired due to brain lesions, drugs, or psychological causes (Table 5) has proven useful.

Complex Dystonia in Hereditary Neurodegenerative or Metabolic Disorders

Hereditary neurodegenerative or metabolic disorders characterized by complex dystonia are summarized in Table 4.

When dystonic movements are the presenting or predominant sign, the class of dystonia (i.e., isolated, combined, or complex) may be difficult to identify. Whereas gradual-onset focal or segmental dystonia can be classified as isolated in the vast majority of adult-onset dystonia, this is true for fewer than half of those with childhood-onset dystonia [Fahn et al 1987]. Therefore, the presence of dystonia in a child must be considered a potential sign of complex and often severe disease, and warrants thorough assessment.

Of note, both autosomal dominant and autosomal recessive spinocerebellar ataxias (SCAs) can be associated with dystonia (see Hereditary Ataxia). The most common of the autosomal dominant SCAs (i.e., SCA1, SCA2, SCA3, and SCA6) together account for more than half of all affected families. Signs of cerebellar dysfunction are often accompanied by other clinical features [Schmitz-Hübsch et al 2008]. Dystonia is sometimes present and can be the most prominent sign.

Dystonia is also part of the clinical presentation in some autosomal recessive SCAs including Friedreich ataxia, ataxia with vitamin E deficiency, ataxia-telangiectasia (A-T), ataxia with oculomotor apraxia type 1 (AOA1), and ataxia with oculomotor apraxia type 2 (AOA2). Dystonia in these disorders typically involves the cranio-cervical region and the arms [Fogel & Perlman 2007]. In A-T, AOA1, and AOA2 difficulty with head-eye coordination related to saccadic failure is common.

Table 4.

Table 4.

Complex Dystonias: Inherited Neurodegenerative/Metabolic Disorders

Neurodegenerative diseases

  • Huntington disease. The cardinal movement disorder in Huntington disease is chorea, at least in adults. However, about 10% of individuals with Huntington disease have childhood onset (called the Westphal variant), which typically manifests as (1) focal or segmental dystonia (rather than chorea) that gradually becomes generalized and (2) parkinsonism [Bruyn & Went 1986]. Cranio-cervical dystonia including risus sardonicus is common and is often accompanied by speech and swallowing problems. Childhood-onset Huntington disease is more common when the pathogenic variant is paternally inherited. It is accompanied by larger numbers of CAG repeats [Went et al 1984].
  • Chorea-acanthocytosis (ChAc, choreoacanthocytosis) and McLeod neuroacanthocytosis syndrome (MLS) have overlapping findings [Danek et al 2001].
    • Chorea-acanthocytosis is characterized by severe oro-lingual dystonia leading to chewing problems and sometimes mutilation of the lips, tongue, or cheeks (so called “eating dystonia”) [Schneider et al 2007]. Other characteristic movement abnormalities include generalized chorea, motor and vocal tics, intermittent head drop, and sometimes parkinsonism.
    • MLS is defined as absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens causing red blood cell acanthocytosis and compensated hemolysis. It is a multisystem disorder manifesting with sensorimotor axonopathy, muscle weakness, neuropsychiatric and cognitive disturbances, and movement disorders, particularly generalized chorea and oro-lingual dystonia.
  • Rett syndrome. Asymmetric crural or generalized dystonia is common in Rett syndrome [Temudo et al 2008]. It occurs almost exclusively in girls because it is embryonic lethal in males. Following a near-normal early development affected girls develop autism, dementia, epilepsy, spastic paraparesis or tetraparesis, and characteristic stereotypies (hand clapping, knitting movements, or body rocking). After an initial rapid progression symptoms usually stabilize so that these patients often survive into adulthood.

Disorders leading to brain calcification. Primary familial brain calcification (PFBC) can present with dystonia in addition to cognitive and psychiatric symptoms. Vascular and brain parenchymal calcification, consisting primarily of calcium phosphate, is found in the basal ganglia and other brain areas including the cerebellum, thalamus, and brain stem.

  • Mutation of SLC20A2 (encoding for the inorganic phosphate transporter PIT2) causes approximately 50% of PFBC, suggesting that impaired phosphate transport is an important underlying disease mechanism [Wang et al 2011, Keller et al 2013].
  • Mutation of PDGFRB (encoding platelet-derived growth factor receptor-beta [PDGF-Rβ]) [Nicolas et al 2013] and mutation of PDGFB (encoding its ligand, platelet-derived growth factor beta (PDGFB) [Keller et al 2013] are responsible for an unknown proportion of PFBC. Mutation of PDGFB compromises pericyte functions and cause disruptions of the blood-brain barrier.

Disorders of copper metabolism. Wilson disease typically includes cranio-cervical dystonia that can be severe, early speech and swallowing problems, and other bulbar signs.

Disorders of manganese metabolism. Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC) resembles Wilson disease but is caused by disturbances of manganese metabolism. It is characterized by early-onset generalized dystonia, adult-onset parkinsonism, liver cirrhosis, polycythemia, and hypermanganesemia [Quadri et al 2012, Tuschl et al 2012]. Serum manganese levels are elevated and brain MRI shows hyperintensities in the basal ganglia as well as in the subthalamic and dentate nuclei typical for hypermanganesemia.

Neurodegeneration with brain iron accumulation (NBIA)

  • NBIA is a group of disorders characterized by progressive iron storage in the brain and abnormal iron accumulation in the basal ganglia which is evident as hypointense lesions predominantly (but not exclusively) in the globus pallidus and substantia nigra pars reticulata on T2-weighted images. On T1-weighted images, these regions are isointense.
  • Pantothenate kinase associated neurodegeneration (PKAN), the major form of NBIA, accounts for approximately 50% of NBIA. In classic PKAN, onset is early, usually before age six years and progression is rapid. Affected children often present with dystonic gait, dysarthria, and limb rigidity. Corticospinal tract involvement results in spasticity. A central region of hyperintensity in the globus pallidus with surrounding hypointensity on T2-weighted images (“eye-of-the-tiger sign”) is pathognomonic for PKAN and is highly correlated with the presence of biallelic PANK2 pathogenic variants.
  • PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. Progressive dystonia associated with dysarthria and behavioral abnormalities including hyperactivity and impulsivity is common in NAD (onset age ~4 years), but not in INAD. PLA2G6-related dystonia-parkinsonism is characterized by juvenile parkinsonism associated with pyramidal signs, dementia, psychiatric features, and cerebral and cerebellar atrophy without brain iron accumulation on MRI [Paisan-Ruiz et al 2009, Hayflick et al 2013].
  • Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized by dystonia that frequently involves limbs and occasionally becomes generalized [Hogarth et al 2013]. Associated features are parkinsonism with varying combinations of bradykinesia, rigidity, tremor and postural instability, cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and motor neuronopathy.
    Brain MRI shows a distinctive pattern of brain iron accumulation with T2-weighted/gradient echo hypointensities in the substantia nigra and globus pallidus, often with unique T2-weighted hyperintense streaking between the hypointense internal and external globus pallidus.
  • Fatty acid hydroxylase-associated neurodegeneration (FAHN) presents in childhood with spastic tetraparesis, ataxia, and often generalized dystonia, followed by episodic neurologic decline. Brain MRI typically demonstrates T2-weighted hypointensity in the globus pallidus, confluent T2-weighted white matter hyperintensities, and profound pontocerebellar atrophy [Kruer et al 2010].
  • Beta-propeller protein-associated neurodegeneration (BPAN) is characterized by global developmental delay with further regression in early adulthood and by progressive dystonia, parkinsonism, and dementia. Seizures, spasticity, and disordered sleep are also common.
    Although the parkinsonism is L-dopa responsive, nearly all affected individuals have early motor fluctuations and develop disabling dyskinesia. Brain MRI shows iron deposition in the substantia nigra and globus pallidus, with a characteristic ‘halo’ of T1-weighted hyperintense signal in the substantia nigra [Hayflick et al 2013].
  • Neuroferritinopathy typically presents with progressive adult-onset chorea or dystonia and subtle cognitive deficits. The movement disorder involves additional limbs within five to ten years and becomes more generalized within 20 years. When present, asymmetry remains throughout the course of the disease. The majority of affected individuals develop a characteristic orofacial action-specific dystonia induced by speech leading to dysarthria and dysphonia. Frontalis overactivity, orolingual dyskinesia, and dysphagia are also common.
    Brain MRI often shows cystic lesions in the basal ganglia and bilateral pallidal necrosis, in addition to iron accumulation in the caudate, globus pallidus, putamen, substantia nigra, and red nuclei.

Lipid storage disorders. The juvenile variant of Niemann-Pick type C, a sphingomyelin storage disease with onset in preschool or early school years, is characterized by splenomegaly, behavioral abnormalities, ataxia, and supranuclear gaze palsy. Progressive generalized dystonia typically involving the orofacial muscles is also common.

Mitochondrial disorders

  • Leigh syndrome (subacute necrotizing encephalomyopathy) is a progressive neurodegenerative disorder with characteristic neuropathologic features of symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optic nerves [Lera et al 1994]. The most frequent clinical features of Leigh syndrome are developmental regression and signs of brain stem dysfunction including respiratory abnormalities and nystagmus. Other common manifestations include optic atrophy, ophthalmoparesis, failure to thrive, hypotonia, weakness, spasticity, ataxia, seizures, bulbar problems, and dystonia. Leigh syndrome is caused by altered oxidative phosphorylation secondary to mitochondrial dysfunction. Pathogenic variants in both mitochondrial and nuclear genes have been reported [Schapira 2002].
  • Leber hereditary optic neuropathy (LHON) typically presents in young adults as painless subacute bilateral visual failure. Dystonia can be part of the clinical presentation [Wang et al 2009]. Ninety-five percent of individuals with LHON have one of three pathogenic variants of mitochondrial DNA (mtDNA): m.11778G>A, m.1448T>C, or m.3460G>A.
  • Deafness-dystonia-optic neuronopathy syndrome (Mohr-Tranebjaerg syndrome) is characterized by profound sensorineural hearing loss (SNHL) in early childhood that precedes the onset of dystonia which ranges from the first to the sixth decades (peaking in the second and third decades). Dystonia tends to be focal, segmental, or multifocal in distribution at onset, with a predilection for the upper body, variably involving the head, neck, and upper limbs [Ha et al 2012]. In most affected males dystonia generalizes regardless of the onset age.
    The deafness-dystonia-optic neuronopathy syndrome occurs as either a single-gene disorder resulting from mutation of TIMM8A or a contiguous gene deletion syndrome at Xq22, which also includes X-linked agammaglobulinemia secondary to disruption of BTK located telomeric to TIMM8A [Jin et al 1996].

Organic acidurias. In glutaric aciduria type 1 (caused by glutaryl-CoA-dehydrogenase deficiency) accumulation of toxic metabolites typically affects basal ganglia structures resulting in dystonia [Harting et al 2009]. The classic clinical scenario is acute encephalopathy triggered by infection or immunization with rapid onset of chorea and hypotonia, followed in months and years by the gradual development of severe generalized dystonia. Dystonia at rest with action-induced exacerbation, which profoundly interferes with any voluntary movement, is often incapacitating. Dysarthria and dysphagia are also common, whereas cognitive functions can be preserved. Early diagnosis and special diet can prevent encephalopathic crises and have improved the prognosis considerably.

Disorders of thiamine metabolism. Biotin-responsive basal ganglia disease (BBGD) typically presents in childhood with subacute episodes of encephalopathy triggered by febrile illness and characterized by confusion, dysarthria, dysphagia, and external ophthalmoplegia. The disease is progressive and leads to persistent severe dystonia, quadriparesis, or coma and death if untreated. Symptoms resolve within a few days following administration of high doses of biotin and thiamine. The precise mechanism by which biotin and thiamine improve symptoms is unclear.

Brain MRI typically shows symmetric and bilateral lesions in the caudate nucleus and putamen, infra- and supratentorial brain cortex, and brain stem [Tabarki et al 2013].

Non-Genetic Causes of Dystonia

Table 5.

Table 5.

Non-Genetic Causes of Dystonia

Complex dystonias caused by brain lesions. Typically, acquired brain lesions that cause dystonia affect the ipsilateral putamen, thalamus, and/or globus pallidus, resulting in contralateral hemidystonia [Marsden et al 1985, Münchau et al 2000] (i.e., as a rule hemidystonia results from circumscribed contralateral brain lesions). For unknown reasons dystonia resulting from such brain lesions develops months after the initial insult. Although aberrant reorganization has been postulated, it is unproven. Also, although the distribution of weakness and sensory symptoms can usually be predicted on the basis of lesion location, the development of dystonia after basal ganglia lesions are identified is not predictable as most individuals with such lesions do not develop dystonia.

The most common and clinically relevant cause of dystonia due to (gross or subtle) brain lesions is cerebral palsy (CP). Dystonia (along with chorea) is the presenting and prevailing finding in persons with dyskinetic CP, but can also be observed in other forms of CP (e.g., spastic hemiparesis, spastic paraparesis, or spastic tetraparesis) [Johnston 2004]. In children with dyskinetic CP, generalized dystonia often evolves between ages two and six years; however, onset of dystonia can be delayed for several years [Saint Hilaire et al 1991]. Involvement of oro-mandibular, lingual, and pharyngeal muscles is common, leading to characteristic risus sardonicus, speech problems, and dysphagia. In addition, limb and axial dystonia can be common. Physical disability can be very severe; cognitive ability is often not impaired.

Drug-induced dystonia can occur in adults and children. The two main forms are acute dystonic reactions and tardive dystonia.

  • Acute dystonic reactions result within hours or days of taking a dopamine-blocking medication (mostly neuroleptics). They usually manifest as oro-mandibular or cervical dystonia and subside when the causative medication is discontinued.
  • Tardive dystonia results from use of all classes of neuroleptics and usually can manifest at any time (ranging from several days to many years after beginning use of the medication) [Kiriakakis et al 1998]. At its onset, tardive dystonia is usually focal but it often progress over months or years. The cranio-cervical region is typically involved.
    The manifestations of tardive dystonia are often indistinguishable from those of primary focal dystonia; however, retrocollis and axial involvement are characteristic. Like DYT1 dystonia, the site of onset tends to ascend from the lower limbs cranially as the mean age of onset increases [Kiriakakis et al 1998]. Other abnormal movements can include oro-facial-lingual dyskinesias, abnormal breathing rhythm due to involvement of the diaphragm, and truncal hypokinesia. Tardive dystonia tends to persist and is difficult to treat. Chances of remission are greater in persons who have taken neuroleptics for shorter periods or in whom neuroleptics are discontinued.

Psychogenic dystonia. Diagnostic criteria for psychogenic dystonia have been proposed [Williams et al 1995]: “clinically definite” psychogenic dystonia is diagnosed in individuals: (1) with persistent symptom relief by psychotherapy, suggestion, or placebo; or (2) who fail to manifest dystonia when they feel that they are not being observed. Other criteria for “clinically definite” psychogenic dystonia, such as “dystonia is incongruent with classic dystonia, or inconsistencies are noted in the examination,” are more equivocal.

Positive signs of psychogenic dystonia include: sudden onset and remissions (e.g., following a psychological or physical trauma); a history of somatization; co-contraction of agonists and antagonists without abnormal postures; distractibility; suggestibility; fluctuating severity within short periods; discrepancies between objective signs and disability; and psychopathologic abnormalities. None of these signs, however, is diagnostic.

In confirmed cases, psychotherapy should undertaken promptly since early initiation of treatment is associated with a better prognosis.

Criteria mentioned above and knowledge about the natural history of psychogenic dystonia are predominantly based on studies in adults; however, reports in children with psychogenic movement disorders including dystonia suggest that similar “rules” also apply to children [Schwingenschuh et al 2008].

Evaluation Strategy

Once the diagnosis of dystonia has been established in an individual, the following approach can be used to determine the specific cause of dystonia to aid in discussions of prognosis and genetic counselling. Establishing the specific cause of dystonia for a given individual usually involves a medical history, physical examination, neurologic examination, and neuroimaging, as well as detailed family history and use of molecular genetic testing. It is especially important to look for treatable causes of dystonia such as dopa-responsive dystonia (DYT-GCH1, DYT-TH, and DYT-SPR), Wilson disease, and other rare metabolic disorders and toxic or drug-related associations.

History. Prenatal and birth history should be documented, particularly any history of birth asphyxia or drug history, and especially the use of antidopaminergic agents or L-dopa.

Clinical findings. Important features are age of onset, site of onset, presence or absence of other neurologic abnormalities, and presence of non-neurologic abnormalities (e.g., developmental delay, dysmorphic features). Presence or absence of associated findings may help distinguish among isolated dystonia, combined dystonia, and complex dystonia.

Delineation of the dystonia phenotype and the clinical course, the first step when evaluating persons with dystonia, can be diagnostic. For example,

  • Sudden onset of dystonia over a range of ages is compatible with rapid-onset dystonia-parkinsonism (DYT-ATP1A3) (formerly DYT12).
  • Many dystonias can be triggered or exacerbated by nonspecific factors, such as stress, fatigue, action, or certain postures.
  • A “therapeutic” response to alcohol is characteristic of myoclonus-dystonia (DYT-SGCE), and improvement with L-dopa supports a diagnosis of dopa-responsive dystonia (DYT-GCH1, DYT-TH, and DYT-SPR).

Family history. A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records including the results of molecular genetic testing, neuroimaging studies, and the results of autopsy examinations.

Testing. Non-DNA-based clinical tests for the following are available:

Molecular genetic testing

  • One molecular genetic testing strategy is serial single-gene molecular genetic testing based on the individual’s clinical findings, ethnicity, and/or the order in which mutation of a given gene most commonly occurs.
  • An alternative molecular genetic testing strategy is use of a multi-gene panel focused on dystonia that includes the gene(s) of interest. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary dystonias are usually inherited in an autosomal dominant manner, and less commonly in an autosomal recessive or X-linked manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Individuals with an autosomal dominant dystonia inherit the pathogenic variant from one parent or have the disorder as the result of a de novo pathogenic variant.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant may include clinical evaluation and molecular genetic testing when available.
  • An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although some individuals diagnosed with autosomal dominant dystonia have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance of the mutated allele in an asymptomatic parent.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Because many of the inherited dystonias demonstrate incomplete penetrance, not all individuals who inherit the pathogenic variant will develop dystonia.

Offspring of a proband

  • Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the pathogenic variant.
  • Because many of the inherited dystonias demonstrate incomplete penetrance, not all individuals who inherit the pathogenic variant will develop dystonia.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents are obligate heterozygotes and, therefore, carry a single copy of a pathogenic variant.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. All offspring are obligate carriers.

Risk to Family Members — X-Linked Inheritance

Parents of a proband

  • Women who have an affected son and another affected male relative are obligate heterozygotes.
  • If pedigree analysis reveals that an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
    • He has a de novo pathogenic variant and his mother is not a carrier.
    • His mother has a de novo pathogenic variant either (a) as a "germline variant" (i.e., occurring at the time of her conception and thus present in every cell of her body); or (b) as "germline mosaicism" (i.e., occurring in some of her germ cells only).
    • His mother has a pathogenic variant that she inherited from a maternal female ancestor.

Sibs of a proband. The risk to sibs depends on the genetic status of the proband's mother:

  • A female who is a carrier has a 50% chance of transmitting the pathogenic variant with each pregnancy. Sons who inherit the variant will be affected; daughters who inherit the variant are carriers and will not be affected.
  • If the mother is not a carrier, the risk to sibs is low but may be greater than that of the general population because the risk for germline mosaicism in mothers is not known.

Offspring of a proband. Affected males will pass the pathogenic variant to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant(s) in the family.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • Medline Plus
  • Global Dystonia Registry


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Chapter Notes

Author History

Christine Klein, MD (2014-present)
Connie Marras, MD, PhD (2014-present)
Alexander Münchau, MD (2014-present)
Andrea H Nemeth, MRCP, DPhil; Churchill Hospital and Institute of Molecular Medicine (2003-2014)

Revision History

  • 1 May 2014 (me) Comprehensive update posted live
  • 23 January 2006 (me) Comprehensive update posted to live Web site
  • 27 May 2005 (cd) Revision: information on neuroferritinopathy
  • 21 December 2004 (cd) Revision: information on Mcleod neuroacanthocytosis syndrome
  • 3 June 2004 (cd) Revision: change in test availability
  • 5 February 2004 (cd) Revision: change in test availability
  • 28 October 2003 (me) Review posted to live Web site
  • 8 April 2003 (an) Original submission