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Etiology, clinical features, and diagnostic evaluation

of dystonia
�������: Andres Deik, MD, MSEd, Cynthia Comella, MD
������� ������: Howard I Hurtig, MD
������ ������: April F Eichler, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2024.

This topic last updated: May 09, 2023.

INTRODUCTION

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 and twisting, and may be tremulous. Dystonia is often
initiated or worsened by voluntary action and associated with overflow muscle activation
[1].

Dystonia may be inherited, acquired, or idiopathic. An increasing number of genetic

variants have been identified in familial dystonia syndromes.

This topic will review the classification, clinical features, and evaluation of dystonia.
Treatment options for dystonia are discussed elsewhere. Tardive dyskinesia, including
tardive dystonia, is also reviewed separately. (See "Treatment of dystonia in children and
adults" and "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis" and
"Tardive dyskinesia: Prevention, treatment, and prognosis".)

EPIDEMIOLOGY

Dystonia is a heterogeneous group of disorders with variable prevalence [2-8]. Focal

dystonia, affecting a single body region such as the neck, is the most commonly
encountered form and is approximately 10 times more frequent than generalized
dystonia. Among focal dystonias, cervical dystonia is the most common.

The prevalence of primary (ie, isolated) dystonia is estimated to be 16.4 per 100,000
persons [9]. The estimated carrier frequency of DYT-TOR1A, the most common genetic
form of dystonia, ranges from 18 to 26 per 100,000 persons [10]. In the United States,
there are between 54,000 and 81,000 DYT-TOR1A mutation carriers predicted, among
whom 16,000 to 25,000 would have dystonic symptoms based on decreased penetrance
[10].

There are ongoing efforts to develop a practical, reliable, and validated screening tool for
dystonia that can be applied to large populations [11-13]. In the absence of such an
instrument, underdiagnosis and misdiagnosis are limiting factors in most epidemiologic
studies. As an example, a study of familial dystonia found that one-half of the cases were
not previously diagnosed [14].

PATHOGENESIS

There are no consistent neuropathologic findings in isolated dystonia [15-19]. The lack of
cell degeneration suggests that isolated dystonia is a dynamic disorder, arising from
abnormal neuronal function.

The anatomic localization and specific neurotransmitter defects of dystonia have also
been elusive. In patients with hemidystonia, lesions of the basal ganglia or its outflow on
structural imaging or neuropathologic examination have been associated with
contralateral dystonia [20]. Advanced neuroimaging studies with positron emission
tomography (PET) and functional magnetic resonance imaging (MRI) have shown that
dystonia can be associated with abnormal activity in multiple regions of the brain,
including motor cortex, supplementary motor areas, brainstem, cerebellum, and basal
ganglia [21-23]. With the varied anatomic areas implicated in dystonia, dystonia is
increasingly considered to be a network disorder that may arise from dysfunction of one
or more of the nodes involved in the network [24-28].

Data from electrophysiologic testing (eg, blink reflex recovery) and functional imaging
studies suggest that the pathophysiology of dystonia, in particular the task-specific
dystonias, may arise from a decrease of central inhibitory mechanisms, an increase of
plasticity, or an impairment in sensory function [29,30].

Direct microelectrode recordings obtained in patients with dystonia during electrode

implantation for deep brain stimulation (DBS) have shown alterations in mean discharge
rates, somatosensory responsiveness, and altered patterns of neuronal activity in the
globus pallidus [31]. These recordings have given rise to new constructs for diagrams of
the basal ganglia and its involvement in dystonia, in which the modulating influences
within the basal ganglia change with activity, reflecting the movement-dependent nature
of dystonia.

The underlying neurochemistry of dystonia is not known, but dopaminergic, cholinergic,

gamma-aminobutyric acid (GABA)-ergic, and glutamatergic neurotransmitter systems may
be involved.

● Abnormal dopaminergic activity in the basal ganglia is indirectly suggested by

extrapolation from observations that dopamine receptor antagonism can cause
acute and chronic dystonic symptoms (eg, acute dystonic reactions, oculogyric crisis,
and tardive dystonia) and that dystonia may be a feature of Parkinson disease, a
disorder characterized by presynaptic dopamine depletion. In addition, striosomal
dysfunction and its downstream effect on dopamine release has been implicated in
the genesis of hyperkinetic movements, including dystonia [28]. The co-occurrence
of parkinsonism and dystonia in dopa-responsive dystonia (DRD) further implicates a
role for dopamine in the pathogenesis of dystonia.

● Cholinergic mechanisms are suggested by the success of anticholinergic therapy,

mainly in children with dystonia [32]. In mouse models, overexpression of mutant
torsinA, the protein associated with DYT1, in medium spiny neurons produces
complex alterations in nigrostriatal dopaminergic and intrastriatal cholinergic
function [33]. In DYT-TOR1A, animal models using a knock-in model suggest a
hypercholinergic state in the striatum [34].

ETIOLOGY

The etiologic categories for the classification of dystonia ( table 1) span inherited
( table 2), acquired ( table 3), and idiopathic forms [1]. Both degenerative and
nondegenerative causes of dystonia exist.

Genetic causes — Inherited dystonias are those with proven genetic origin [1]. Since the
discovery of DYT-TOR1A, the first dystonia gene mutation to be cloned, many additional
genetic forms of dystonia have been described ( table 4) [35-40]. The contemporary (but
still evolving) nomenclature ( table 2) uses the molecular genetic abnormality (if known)
in place of a numeral (eg, DYT-TOR1A rather than DYT1), with the goal of providing more
informative symbols that include only confirmed disease-causing mutations. New
dystonias are classified by the predominant phenotype and the specific gene variant
[40,41]. An updated list of genetically determined movement disorders is available on
the International Parkinson and Movement Disorder Society (MDS) website.

In the older system, chronologically assigned, consecutively numbered locus symbols

(DYT1 to DYT34) were used to represent the expanding list of hereditary dystonias
( table 4). However, this system proved unsatisfactory for many reasons, including
symbols of questionable significance, known pathogenic mutations whose genes did not
have DYT symbols, and assignment of syndromes with prominent dystonia to loci
suggesting other movement disorders (eg, PARK13) or assignment of other movement
disorders to loci suggesting dystonia (eg, DYT3) [35,37,39].

Acquired causes — Acquired dystonia (previously known as secondary dystonia) usually

arises from a specific underlying condition ( table 3), such as perinatal brain injury or
exposure to dopamine receptor-blocking drugs (eg, acute dystonic reactions, tardive
dystonia). Dystonia can be induced by lesions in a variety of brain regions, most
commonly basal ganglia, thalamus, or brainstem [42]. The presence of neurologic
abnormalities other than dystonia may provide the clue to the cause of acquired dystonia
[42-44].

Antibody-mediated syndromes, such as anti-N-methyl-D-aspartate (NMDA) receptor

encephalitis, can manifest with new-onset dystonia and other abnormal movements,
usually in combination with cognitive or behavioral symptoms [45]. (See "Autoimmune
(including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Anti-
NMDA receptor encephalitis'.)

Idiopathic — The cause of dystonia is unknown, or idiopathic, in many cases. The majority
of adult-onset isolated focal and segmental dystonias reviewed below fall into this
category. (See 'Adult-onset focal or segmental isolated dystonia' below.)

Idiopathic dystonias can be sporadic or have familial clustering. If a specific genetic cause
is identified, the dystonia is reclassified as inherited.

CLINICAL FEATURES

The clinical features important for the classification of dystonia are age of onset, body
distribution, temporal pattern, and associated features ( table 1) [1].

Defining motor features — The consensus definition of dystonia is as follows [1]:

● 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 and twisting, and may be tremulous.

● Dystonia is often initiated or worsened by voluntary action and associated with

overflow muscle activation. Overflow refers to unintentional muscle contraction in an
anatomically distinct site that commonly occurs at the peak of dystonic movements.
In most cases, dystonia combines abnormal movements and postures. Exceptions include
blepharospasm and laryngeal dystonia, which are not associated with abnormal posture
but rather with intermittent, involuntary muscle contractions that interfere with
physiologic muscle function.

The sustained movements of dystonia may have overlying spasms that are seemingly
rhythmic and are referred to as dystonic tremor. Dystonic tremor is produced by
contractions of dystonic muscles and often exacerbated by attempts to maintain a
primary or normal posture [1].

Dystonic tremor often accompanies both focal and generalized dystonia. The most
commonly involved body regions are neck, face, and upper limbs [46]. Compared with
essential tremor, dystonic tremor tends to be less rhythmic, more irregular or "jerky," and
more likely to be task specific when it affects the limbs. However, dystonic tremor can
mimic essential tremor, and some cases labeled as essential tremor are more likely to
have cervical dystonia with prominent limb dystonic tremor, or craniofacial dystonia with
prominent vocal dystonic tremor [47,48]. In such cases, the dystonia is often subtle, and
the tremor is the predominant symptom. (See "Essential tremor: Clinical features and
diagnosis".)

Nonmotor features — Nonmotor features of dystonia syndromes are increasingly

recognized and contribute to morbidity and decreased quality of life [49-54]. Psychiatric
comorbidity is common, especially depression and anxiety. Approximately one-third of
patients with cervical dystonia and other isolated dystonias experience poor sleep and/or
excessive daytime sleepiness [49,52,53]. Higher dystonia severity correlates not only with
adverse physical functioning but also with social and emotional dysfunction and
decreased health-related quality of life [51].

Age of onset — Age of dystonia onset is clinically important for both diagnostic
evaluation and prognosis. As an example, dystonia that begins in childhood is more likely
to have a discoverable cause and is more likely to progress from focal to generalized [1].

● Early-onset – Early-onset dystonia refers to dystonia that begins in infancy (birth to 2

years), childhood (3 to 12 years), or adolescence (13 to 20 years). The best
characterized syndrome in this age range is early-onset isolated dystonia, which
most often begins in the legs and often spreads slowly to other body areas to
become generalized. Most of these syndromes are genetic or idiopathic. (See 'Early-
onset isolated dystonia' below.)

● Adult-onset – Dystonia that begins in early (age 21 to 40 years) or late (age >40
years) adulthood is usually focal or segmental and typically affects the upper part of
 the body (neck, arm, or face) [55]. The initial body area affected by isolated focal
dystonia determines the risk and pattern of dystonia spread to other areas. (See
'Adult-onset focal or segmental isolated dystonia' below.)

Generalized-onset dystonia in adulthood is unusual and suggests an acquired cause

( table 3), such as exposure to dopamine receptor-blocking agents. Even in
generalized cases in adults, the dystonia usually begins focally with spread. (See
'Adult-onset focal or segmental isolated dystonia' below.)

Body distribution — Dystonia can affect any part of the body, and the distribution can
change over time, including spread to contiguous or distant body parts. Body distribution
often provides clues to etiology and guides treatment. For classification purposes, the
following regions are defined [1]:

● Focal – Focal dystonia affects one body region. Examples of focal dystonias include
blepharospasm (affecting the periocular muscles), oromandibular dystonia (affecting
the jaw and tongue), laryngeal dystonia, and brachial dystonia (ie, writer's "cramp,"
when limited to the hand). Cervical dystonia, affecting the neck, is also considered a
focal dystonia, although the shoulder may be involved.

● Segmental – Segmental dystonia affects two or more contiguous body regions.

Examples include cranial dystonia (blepharospasm plus involvement of the jaw or
tongue) or dystonia involving the neck and arm.

● Generalized – Generalized dystonia refers to dystonia affecting the trunk and at

least two other sites. Some forms affect the legs and some do not, but involvement
of the trunk is the key feature of generalized dystonia. Involvement of the trunk
results in abnormal flexion, leaning, or extension postures.

● Multifocal – Multifocal dystonia refers to dystonia affecting two or more

noncontiguous body regions, without meeting criteria for generalized dystonia. It is
most commonly seen in early-onset isolated dystonia that begins focally, then
spreads to another body region. (See 'Early-onset isolated dystonia' below.)

● Hemidystonia – Hemidystonia refers to dystonia that affects multiple body regions

on one side of the body only. Hemidystonia is uncommon and is usually due to an
acquired cause with a lesion in or around the contralateral basal ganglia. (See
'Diagnostic evaluation' below.)

Dynamic and temporal features — Dystonia is a dynamic disorder that changes in

severity depending upon activity and posture. In some cases, dystonia follows a temporal
pattern or has recognizable triggers, which can suggest an underlying etiology. Examples
include the following:

● Action or task specificity – Some dystonias occur only during a particular activity or
task. An example is writer's dystonia, a task-specific hand dystonia that is present
only during the action of writing but not during any other activity. (See 'Task-specific
dystonia' below.)

● Overflow phenomenon – Activation of an unaffected body part can trigger or

worsen dystonic symptoms in a contiguous or distant region; this is known as the
"overflow" phenomenon. So-called "mirror movements," in which movement of an
unaffected limb results in dystonic movement of the affected limb, fall within the
spectrum of overflow movements.

● Diurnal variation – Dystonia may fluctuate in occurrence or severity with

recognizable circadian variation. Dopa-responsive dystonia (DRD) classically has a
diurnal pattern, with worsening over the course of the day and improvement after
sleep. However, this pattern is not specific to DRD. (See 'Dopa-responsive dystonia'
below.)

● Sensory trick – A common feature of dystonia is the sensory trick or "geste

antagoniste." The sensory trick is a maneuver (eg, lightly touching the affected body
part) that temporarily reduces or abolishes the dystonic symptoms. It is found in
approximately 60 percent of patients with dystonia. In some patients, these tricks
may be effective if imagined but not performed physically [56,57].

Isolated versus combined — Isolated dystonia is the classification term used when
dystonia is the only motor feature (this term allows for accompanying tremor). A number
of isolated dystonia syndromes are recognized ( table 5), including early-onset
generalized isolated dystonia and many of the focal and segmental dystonias of
adulthood. (See 'Early-onset isolated dystonia' below and 'Adult-onset focal or segmental
isolated dystonia' below.)

Combined dystonia refers to dystonia that occurs with other movement abnormalities,
such as parkinsonism or myoclonus [1]. There may be other neurologic signs as well, such
as weakness, ataxia, ocular motility abnormalities, retinal abnormalities, cognitive
impairment, or seizures. (See 'Combined dystonia' below.)

SPECIFIC SYNDROMES

Early-onset isolated dystonia — Early-onset isolated dystonia (previously known as

primary dystonia, primary torsion dystonia, dystonia musculorum deformans, and
Oppenheim dystonia) presents in childhood with signs related solely to dystonia. Aside
from associated tremor, there are no additional neurologic, laboratory, or imaging
abnormalities. Cognition and intellectual abilities remain intact despite the presence of
severe movement abnormalities ( table 6).

Early-onset isolated dystonia usually begins in a leg, often as inversion of the foot [58].
Initially, the dystonia might be triggered only by vigorous physical activity such as
running. Over time, the posturing becomes susceptible to triggering by minimal physical
activity, such as walking or standing. Subsequently, the dystonia may be present even at
rest.

Dystonia with focal onset in childhood often will progress to generalized dystonia [1]. With
early-onset focal dystonia, spread from one leg to other body areas, including the other
leg, torso, arms, and upper body, occurs in approximately 50 to 90 percent of children,
usually within five years of onset. However, when early-onset dystonia begins in the arm
in late childhood and adolescence, it tends to have a lower likelihood of subsequent
spread.

Early-onset isolated dystonia may be sporadic or inherited ( table 2 and table 4).
Most early-onset isolated generalized dystonia is inherited in an autosomal-dominant
pattern with reduced penetrance. Some of the more common inherited syndromes are
discussed below.

DYT-TOR1A dystonia — Many patients with hereditary isolated dystonia have early-onset
generalized DYT-TOR1A dystonia (previous gene symbol DYT1), which is caused by a
mutation in the torsin family 1 member A (TOR1A) gene that maps to chromosome 9q34
and encodes torsinA, an adenosine triphosphate (ATP) binding protein [59]. A three-base
pair deletion (c.907_909delGAG) results in loss of a glutamic acid residue in the C-terminal
region of the torsinA protein [60].

DYT-TOR1A dystonia typically begins in childhood with limb onset, often but not always
followed by progression to generalized dystonia. However, the phenotypic spectrum of
DYT-TOR1A dystonia is broad, even within families, and late onset can occur. In one study
with 97 genetically confirmed TOR1A carriers, the mean age at onset was 14 years, with a
range from 4 to 44 years [61].

DYT-TOR1A dystonia accounts for approximately 40 to 65 percent of early-onset isolated

generalized dystonia in non-Jewish populations and 90 percent of early-onset limb
dystonia in the Ashkenazi Jewish population [62]. Inheritance is autosomal dominant, but
penetrance is reduced to approximately 30 percent [63]. Thus, most mutation carriers do
not express clinically apparent disease. Because of the reduced penetrance, DYT-TOR1A
should be considered even when there is no apparent family history to suggest a
hereditary form of dystonia.

The pathogenic mechanism for DYT-TOR1A dystonia is uncertain. Although the function of
torsinA protein product is not known, it has been hypothesized to play an important role
in protein folding. In one study, using human neuroblastoma cells in culture, wildtype
torsinA colocalized to the endoplasmic reticulum (ER) and nuclear envelope, whereas
mutant torsinA showed perinuclear staining and formed distinct globular inclusions
containing vesicular monoamine transporter 2 (VMAT2) [64]. Since VMAT2 plays an
important role in the exocytosis of monoamines in neurons, it may be that mutant torsinA
may interfere with VMAT2 expression and dopamine release.

Other studies have associated the expression of mutant TOR1A to dysregulation of

eukaryotic initiation factor 2α (eIF2α), which is a vital component of the cellular response
to stress. In particular, animal models of DYT-TOR1A dystonia suggest there is increased
basal phosphorylation of eIF2α, and that this is associated with an abnormal response to
acute ER stress [65]. Interestingly, mutations in the eukaryotic translation initiation factor
2 alpha kinase 2 (EIF2AK2) gene (which encodes the kinase that phosphorylates eIF2α)
have been found to cause early-onset generalized dystonia (DYT-EIF2AK2, or DYT33)
( table 4) [66].

Cholinergic signaling may also play a role. In a mouse model of DYT-TOR1A dystonia, there
was a significant increase in the vesicular acetylcholine transporter (VAChT) protein level
[67]. VAChT is responsible for loading acetylcholine from the cytosol into synaptic vesicles
and suggests that there may be an altered cholinergic tone in DYT-TOR1A dystonia.

DYT-THAP1 dystonia — Adolescent-onset dystonia of mixed type (DYT-THAP1, previous

gene symbol DYT6) was initially described in Amish-Mennonite families and characterized
as an early-onset, cranial-cervical dystonia with autosomal-dominant inheritance, rostro-
caudal progression (head to feet), and a penetrance of 60 percent [68,69]. Causative
mutations in the THAP domain containing 1 (THAP1) gene on chromosome 8 were
discovered as founder mutations in the Amish-Mennonite families [69,70]. Involvement of
cranial muscles, leading to disabling dysarthria or dysphonia, was thought to be
characteristic of DYT-THAP1 dystonia.

Subsequent investigations of patients with non-DYT-TOR1A, familial, early-onset,

generalized dystonia showed that there were additional mutations in the THAP1 gene
besides the initially reported ones [71-73]. These additional THAP1 mutations were found
in 25 percent of the families studied [71], suggesting that THAP1 mutations could be
responsible for a substantial proportion of familial non-DYT-TOR1A early-onset isolated
dystonia in patients of European descent, including those of German, Irish, and Italian
ancestry. In another study, the phenotype of the patients with DYT-THAP1 dystonia was
highly variable, with age of onset ranging from 8 to 69 years (mean 48 years), and with
site of onset predominantly cervical and laryngeal [74]. The dystonia remained focal in 15
of 18 patients (83 percent).

THAP1 encodes for a transcription regulating protein that modulates other target genes,
including the TOR1A gene associated with DYT-TOR1A dystonia [75,76]. Genetic studies in
humans and animals have shown that the wildtype THAP1 protein binds to the TOR1A
gene promoter region and represses the expression of torsinA, while pathogenic THAP1
mutations abolish the interaction between THAP1 protein and the TOR1A promoter,
leading to decreased repression of TOR1A [75,76]. Thus, these findings suggest a common
molecular pathway linking DYT-TOR1A and DYT-THAP1. This link has been further
strengthened by identification of molecular and electrophysiologic defects in the eIF2α
pathway in DYT-THAP1 mice that resemble those seen in DYT-TOR1A, including
abnormalities in baseline activating transcription factor 4 (ATF4; a downstream effector of
eIF2α) and in long-term depression [77].

Pathogenic mutations in THAP1 may have other downstream effects. In near-isogenic

neural stem cells, mutations in THAP1 led to dysregulation of genes involved in
neurodevelopment, lysosomal lipid metabolism, and myelination [78]. Others have
proposed that THAP1 mutations lead to dysregulation of genes mainly through regulation
of Sp1 transcription factor (SP1) family members, SP1 and SP4, in a cell-type-dependent
manner [79,80].

DYT-KMT2B dystonia — DYT-KMT2B (DYT28) is estimated to account for up to 10 percent

of early-onset generalized dystonia. It is a limb-onset childhood dystonia with secondary
generalization caused by pathogenic variants in the lysine methyltransferase 2B (KMT2B)
gene [81,82]. Most mutations are de novo, and the reported mutations include frameshift,
nonsense, splice-site, missense, and deletions. Chromosomal deletions and protein-
truncating variants have been associated with a more severe phenotype [83].

DYT-KMT2B dystonia can closely resemble that of DYT-TOR1A (including a moderately

favorable response to deep brain stimulation [DBS] surgery), except that patients often
also exhibit intellectual disability. The median age of symptom onset is five years [83].
Most patients present with lower limb symptoms (foot posturing, new-onset toe walking
or gait difficulties), with progression to generalized dystonia over a median of two years.
Laryngeal, oromandibular, and cervical involvement is a prominent feature in most
patients, often disabling. Developmental delay may precede dystonia in approximately
one-third of patients. In addition to intellectual disability, which occurs in approximately
half of patients, other common features include dysmorphism (eg, elongated face,
bulbous nasal tip, and abnormal angulation of a finger, known as clinodactyly), short
stature, and endocrinopathies.

Brain imaging can be helpful in establishing an accurate genetic diagnosis. The presence
of symmetric bilateral pallidal hypointensities with a hypointense lateral streak of the
globus pallidum externa on susceptibility-weighted imaging strongly suggests DYT-KMT2B
[83]. However, in the absence of these imaging findings, pediatric patients who are
clinically thought to have DYT-TOR1A but are negative for TOR1A gene mutations should
be tested for DYT-KMT2B [84,85].

Adult-onset focal or segmental isolated dystonia — Adult-onset (age >21 years)

isolated focal or segmental dystonias usually involve the upper body and begin after the
age of 30 years. Most cases are sporadic without identifiable cause.

Common and/or important types of focal dystonia include:

● Cervical dystonia (dystonia of neck and shoulders)

● Blepharospasm (dystonia of periocular muscles)

● Oromandibular, lingual, or facial dystonia (dystonia of jaw, oral muscles, tongue, or

facial muscles)

● Laryngeal dystonia (dystonia of laryngeal muscles)

● Limb dystonia (dystonia of arm or leg)

● Task-specific or occupational dystonia (dystonia that occurs only with certain

activities such as writing, typing, running, or playing a musical instrument)

Although symptoms may worsen in the area of involvement or spread to contiguous body
regions (segmental dystonia), adult-onset isolated dystonias rarely become generalized
[58]. Regional spread to contiguous body areas is most frequently observed with
blepharospasm [55,86,87]. In a prospective international cohort, the risk of spread was 50
percent in patients with blepharospasm, most commonly to jaw and neck; 8 percent in
patients with cervical dystonia, most commonly to hand; 17 percent in patients with hand
dystonia, most commonly to neck; and 16 percent for patients with laryngeal dystonia,
mostly to neck [87].

Infrequently, late-onset isolated dystonia begins in the leg. However, onset in the leg in an
adult is usually secondary to an underlying etiology such as early-onset Parkinson disease
[88].

The genetics of late-onset focal and segmental isolated dystonia have been more difficult
to delineate than early-onset isolated dystonia. One confirmed form is adult-onset cranial-
cervical dystonia (DYT-GNAL), as discussed below. Other rare genetic forms of focal and/or
segmental dystonia have also been reported, some of which still require confirmation
[89,90]. Additional gene loci linked to dystonia are certain to be identified in the future.

Cervical dystonia — Cervical dystonia, previously known as spasmodic torticollis, is the

most common isolated focal dystonia seen in clinical practice. It affects the muscles of the
neck and shoulders. It may appear as horizontal turning of the head (torticollis), lateral tilt
of the neck (laterocollis), flexion of the head (anterocollis), extension of the head
(retrocollis), or a combination of directions. Many patients have associated neck pain and
tremor.

The clinical features and diagnosis of cervical dystonia are discussed in more detail
separately. (See "Cervical dystonia: Etiology, clinical features, and diagnosis".)

DYT-GNAL dystonia — Adult-onset cranial-cervical dystonia (DYT-GNAL, previous gene

symbol DYT25) is caused by a mutation in the G protein subunit alpha L (GNAL) gene. In the
initial report of eight families of mixed European ancestry with 28 affected individuals, the
mean age of onset was 31 years (range 7 to 54) [91]. Subsequent reports have
independently confirmed DYT-GNAL dystonia in Japanese and African-American
individuals [73,92,93]. The usual presentation is that of focal neck involvement, although
the dystonia may progress to other sites. Response to DBS has been reported for these
patients [94].

Blepharospasm — Blepharospasm is a focal dystonia involving the orbicularis oculi

muscles and other periocular muscles, including the procerus and corrugator muscles
[95,96]. Clinical manifestations include increased blinking and spasms of involuntary eye
closure. Symptoms are usually bilateral, synchronous, and symmetric, but may be
asymmetric. Involuntary eye closure caused by forcible dystonic spasms of the orbicularis
oculi should be distinguished from eyelid-opening apraxia. With an apraxia, the eyelid
closure is described as smooth and "curtain-like" because the levator palpebrae fails to
contract. In some patients (particularly those with atypical parkinsonian syndromes), the
two conditions can coexist.

Proposed criteria for the diagnosis of blepharospasm, which are supported by a

multicenter, international study of blepharospasm in multiethnic, multicenter cohorts [97],
are as follows [98]:

● The presence of stereotyped, bilateral, and synchronous orbicularis oculi spasms

inducing eyelid narrowing/closure

● At least one of the following:

 • Presence of an effective "sensory trick" (ie, a maneuver, such as lightly touching
the affected body part, that reduces or abolishes the dystonic symptoms)

• Increased blinking

Blepharospasm may be mild and nondisabling, or it may cause significant disability

through interference with vision as a result of the eye closure. Patients with
blepharospasm typically complain of increased spasms under conditions of bright light or
stress, such as driving a car in traffic. Pain is infrequently associated with blepharospasm,
although a feeling of irritation in the eyes (foreign body sensation) may be one of the first
symptoms [99].

Blepharospasm may be associated with dystonia of the lower face and/or jaw (Meige
syndrome or Brueghel syndrome) [87,100].

Oromandibular dystonia and facial dystonia — Oromandibular dystonia and facial

dystonia are characterized by involuntary movements involving masticatory, lingual, and
pharyngeal muscles [101].

Oromandibular dystonia can manifest as jaw clenching, jaw opening, jaw deviation, a
combination of the three, or tongue protrusion. It is often found in combination with
dystonia of adjacent body regions, including blepharospasm and cervical dystonia.
Symptoms can result in difficulty speaking and swallowing and may be cosmetically
disfiguring.

Laryngeal dystonia — Laryngeal dystonia, formerly called spasmodic dysphonia, is a

task-specific focal dystonia involving the laryngeal muscles [102-104]. It is characterized by
irregular and involuntary voice breaks that interrupt normal speech. Delays of several
years before diagnosis are common, and symptoms are often confused with muscle
tension dysphonia or essential vocal tremor. Most cases are sporadic, although rare
genetic forms, such as DYT-TUBB4A, have been identified, usually as part of a segmental
or generalized dystonia [104-107].

When answered in the affirmative, screening questions that raise suspicion for laryngeal
dystonia include the following:

● Does it take a lot of effort for you to talk?

● Does your speech sound more normal when you shout, whisper, or sing?

Additional features that may help distinguish laryngeal dystonia from muscle tension
include the presence of vocal tremor, a female predominance, and lack of response to
voice therapy alone [108].
Symptom severity fluctuates depending on which sounds are being spoken, and a clinical
speech evaluation aims to detect voice breaks during spoken sentences that emphasize
different types of sounds (eg, vowels and glottal stops like "uh-oh," voiceless consonants
like p, t, and k) and types of speech (eg, speaking, shouting, whispering, singing). The
most common type of laryngeal dystonia is the adductor type, in which voice breaks and a
strained pattern of vocalization occur because the vocal cords forcefully and involuntarily
adduct, especially during production of vowel sounds (especially long "e"). Abductor
laryngeal dystonia is characterized by an abduction of the vocal cords during vocalization,
resulting in a voice that is whispering and breathy. Mixed adductor-abductor, adductor
respiratory, and singer's laryngeal dystonia forms are also recognized.

The diagnosis of laryngeal dystonia is made by history, clinical speech examination, and
nasolaryngoscopy to exclude other laryngeal pathologies or structural defects that would
account for an abnormal voice [109].

Upper limb dystonia — Upper limb dystonia is manifested as a posturing of the hand
and/or arm. This problem may be variably present with arms outstretched, but is often
not present at rest. Overlying dystonic spasms may occur and resemble essential tremor.
However, in contrast to essential tremor, dystonia is often unilateral, jerky, and triggered
by specific activities, such as writing or typing. (See "Overview of tremor", section on
'Essential tremor'.)

Arm dystonia may be focal or segmental and usually affects the dominant arm (even
when non-task-specific) [110,111]. Most cases are idiopathic with a median age of onset in
the early sixth decade [110].

Task-specific dystonia — Task-specific or occupational dystonia is manifested only

during particular activities [112].

Writer's dystonia (also known as writer's cramp, although it is not painful) is the most
common form of task-specific hand dystonia [111,113]. It is elicited by the act of writing
and appears as an involuntary flexion, extension, and/or rotation of the fingers, the wrist,
and, less frequently, the elbow and shoulder. The act of writing is increasingly effortful,
and handwriting may become so distorted that it is no longer legible [114]. In a case-
control study of patients with focal hand dystonia, writing with the contralateral (normal)
hand was associated with dystonic movements of the affected hand (mirror movements)
in 67 percent [115].

Other types of task-specific dystonia include typist's dystonia, golfer's dystonia (yips),
runner's dystonia, and musician's dystonia. Embouchure dystonia is a dystonia of the lips,
jaw, or tongue that affects musicians only during the act of playing reed or brass
instruments and is absent during other activities such as eating or speaking [116].

Combined dystonia — Combined dystonias are those in which dystonia is combined with
other movement disorders, most often parkinsonism or myoclonus; combined dystonia
also includes paroxysmal dyskinesia with dystonia [37].

Dystonia-parkinsonism — Dystonia syndromes in the dystonia-parkinsonism group

combine dystonia and parkinsonian features. These are sometimes accompanied by
pyramidal tract involvement and/or nonmotor features, including cognitive decline. Many
are inherited. Some important types include:

● Dopa-responsive dystonia (DRD). (See 'Dopa-responsive dystonia' below.)

● Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural
history", section on 'Neurologic involvement'.)

● Parkin-associated parkinsonism. (See "Epidemiology, pathogenesis, and genetics of

Parkinson disease", section on 'PRKN-associated PD'.)

● PTEN-induced kinase 1 (PINK1) associated parkinsonism. (See "Epidemiology,

pathogenesis, and genetics of Parkinson disease", section on 'PINK1-associated PD'.)

● DJ-1-associated parkinsonism. (See "Epidemiology, pathogenesis, and genetics of

Parkinson disease", section on 'DJ-1-associated PD'.)

● X-linked dystonia-parkinsonism (DYT-TAF1), also known as Lubag dystonia, is

characterized by progressive dystonia, often accompanied by parkinsonism.
Parkinsonism becomes the predominant movement disorder during the later stages
of the disease. This disorder mainly affects Filipino men in their fifth decade, but
women can also be affected [117]. Prominent pathologic findings include
pronounced atrophy of the caudate and putamen. The disorder is poorly responsive
to medication (although symptoms have been reported to respond to DBS [118]),
and patients usually survive for only 10 to 12 years. However, a case series found
that the clinical course is much more benign in women [119]. The responsible
mutation involves the TATA-box binding protein-associated factor 1 (TAF1) gene on
chromosome Xq13.1 [120,121].

● Rapid-onset dystonia-parkinsonism (DYT-ATP1A3) is an autosomal-dominant,

adolescence and early adulthood disorder in which dystonia, parkinsonism,
prominent dysarthria, and dysphagia emerge and evolve over a period of hours to
weeks. Because the onset of symptoms can be acute and follow an emotional
stressor, these patients can be misdiagnosed as having functional dystonia. The
 disorder is linked to chromosome 19q13, and six missense mutations in the ATP1A3
gene that encodes the Na+/K+-ATPase alpha 3 subunit have been described
[122,123]. Genetic testing for the ATP1A3 gene is recommended when abrupt onset,
rostrocaudal gradient, and prominent bulbar findings are present [124]. Despite
reduced cerebrospinal homovanillic acid levels, this syndrome responds poorly to
dopaminergic agents or DBS. Of note, the spectrum of neurologic diseases linked to
ATP1A3 mutations is broad, with overlapping phenotypes that can also include
alternating hemiplegia of childhood, cerebellar ataxia, and early infantile epileptic
encephalopathy [125,126]. (See "Types of migraine and related syndromes in
children", section on 'Alternating hemiplegia of childhood'.)

● Neurodegeneration with brain iron accumulation (see "Bradykinetic movement

disorders in children", section on 'Neurodegeneration with brain iron accumulation'):

• Pantothenate kinase-associated neurodegeneration (pantothenate kinase 2

[PANK2] gene)
• Infantile neuroaxonal dystrophy (phospholipase A2 group VI [PLA2G6] gene)
• Mitochondrial membrane protein-associated neurodegeneration (chromosome
19 open reading frame 12 [C19orf12] gene)
• Beta-propeller protein-associated neurodegeneration, also known as static
encephalopathy of childhood with neurodegeneration in adulthood (WD repeat
domain 45 [WDR45] gene)
• Fatty acid hydroxylase-associated neurodegeneration (fatty acid 2-hydroxylase
[FA2H] gene)
• Kufor-Rakeb syndrome (ATPase cation transporting 13A2 [ATP13A2] gene)
• Neuroferritinopathy (ferritin light chain [FTL] gene)
• Aceruloplasminemia (ceruloplasmin [CP] gene)
• Woodhouse-Sakati syndrome (DDB1 and CUL4 associated factor 17 [DCAF17]
gene)

Dopa-responsive dystonia — DRD, also known as Segawa disease, manifests in

most cases as a generalized dystonia with onset in early childhood [127-130].
Parkinsonism, including rigidity and bradykinesia, may be present at onset or develop
during the course of untreated disease. Often, children with DRD experience a long delay
in diagnosis [131] or are initially misdiagnosed as having an isolated dystonia or cerebral
palsy [132,133]. Atypical presentations include adult onset with predominantly
parkinsonian symptoms and signs [130].

In the original description of DRD, the investigators observed a diurnal fluctuation in

symptoms, which worsened over the course of a day and improved following sleep [127].
However, this diurnal fluctuation may not be present in all patients with DRD [134].
The hallmark of DRD is a clinically significant, sustained response to levodopa. (See
"Treatment of dystonia in children and adults".)

The most frequent form of DRD is autosomal-dominant DYT-GCH1 dystonia caused by a

mutation in the guanosine triphosphate (GTP) cyclohydrolase 1 gene (GCH1) [135]. The
GTP cyclohydrolase 1 protein encoded by this gene is involved in the biosynthesis of
tetrahydrobiopterin, which is a cofactor for tyrosine hydroxylase, the rate-limiting enzyme
in the synthesis of dopamine. It is also a cofactor for phenylalanine and tryptophan
hydroxylase. Numerous mutations of the GCH1 gene can cause DRD.

An autosomal-recessive form of DRD (DYT-TH) is caused by mutation in the tyrosine

hydroxylase (TH) gene [136-138]. Another rare entity (DYT-SPR) with a phenotype of DRD
involves mutations in the sepiapterin reductase (SPR) gene [139].

In the clinical setting, the most practical and useful diagnostic test for DRD is a markedly
positive response to a trial of levodopa, slowly increased up to doses of 600 to 1000 mg
daily. Most patients exhibit robust responses at doses that can be as low as 200 mg per
day. However, a positive response to levodopa does not differentiate DRD from juvenile-
onset Parkinson disease. Typically, patients with DRD will have a sustained benefit from
low doses of levodopa (sometimes as low as 100 mg) without developing motor
fluctuations and dyskinesia, in contrast to juvenile Parkinson disease, in which these
motor complications are a frequent occurrence.

Although off label, striatal dopamine transporter imaging (eg, DaTscan) has been reported
as an objective neuroimaging method able to distinguish juvenile Parkinson disease from
DRD [140], where a normal DaTscan result would suggest DRD and an abnormal result
would suggest Parkinson disease. Sensitivity and specificity of DaTscan in this context
have not been established, however.

Other proposed diagnostic methods for DRD include assessment of tetrahydrobiopterin

and neopterin in the cerebrospinal fluid, and the phenylalanine-loading test [141,142].
However, most clinicians rely on confirmation with levodopa and do not undertake more
extensive laboratory testing. Genetic testing for GCH1 is available, and additional rarer
genes that may give rise to the disorder should be tested if GCH1 testing is negative and
clinical suspicion is high [143].

Myoclonus-dystonia — Myoclonus-dystonia is a genetically heterogeneous autosomal

dominant movement disorder characterized by myoclonic jerks primarily affecting the
neck, arms, and axial muscles, combined with variable features of dystonia. Onset is
typically in the second decade. The dystonia may be mild, is often task specific (eg, writer's
cramp), and may improve dramatically after alcohol intake. Several forms of myoclonus
dystonia (DYT-SGCE, DYT-KCTD17, and DYT-KCNN2) have been genetically established
[144-146].

Myoclonus-dystonia is discussed in greater detail separately. (See "Classification and

evaluation of myoclonus", section on 'Myoclonus-dystonia'.)

Paroxysmal dyskinesia with dystonia — Several rare genetic forms of dystonia are
characterized by episodes of spontaneous or induced dyskinesia with dystonia
( table 4):

● Paroxysmal nonkinesigenic dyskinesia (PNKD) is characterized by spontaneous

episodes of dystonia and/or choreoathetosis not triggered by exercise or physical
activity. Alcohol, coffee, tea, fatigue, stress, or excitement may be precipitating
factors. Episodes last minutes to hours and recur two or three times a month. One
type of PNKD (DYT-MR1) is caused by mutations in the myofibrillogenesis 1 regulator
gene on chromosome 2q35 [147,148]. There may be other responsible genes [149].
Of note, patients with functional movement disorders may present with otherwise
unexplained, spontaneous dyskinesias, and may be misdiagnosed as having clinical
PNKD.

● Paroxysmal kinesigenic choreoathetosis, also known as paroxysmal kinesigenic

dyskinesia, is characterized by episodic choreoathetosis and dystonia brought on by
voluntary movement [150,151]. One confirmed form, episodic kinesigenic dyskinesia
1 (DYT-PRRT2), is caused by inherited or sporadic mutations in the proline rich
transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2 [152-158].

● Paroxysmal exertion-induced dyskinesia (DYT-SLC2A1) is an autosomal-dominant

disorder with reduced penetrance that begins in childhood with dyskinesia and
dystonia induced by prolonged exertion (eg, ≥15 minutes), fasting, and stress
[159-161]. Associated features include absence and/or partial complex seizures.
Affected members of one family also had hemolytic anemia [162]. The condition is
linked to mutation or deletion of the solute carrier family 2 member 1 (SLC2A1) gene
on chromosome 1p35-p31.3 that encodes the GLUT1 facilitated glucose transporter
[162]. Patients with this condition are often found to have low glucose in
cerebrospinal fluid (hypoglycorrhachia).

DIFFERENTIAL DIAGNOSIS

Mimics of dystonia — Some conditions ( table 7) may result in abnormal movements,

postures, or spasms that mimic dystonia (ie, pseudodystonia), including gastroesophageal
reflux in infants (Sandifer syndrome) [44]. In addition, dystonia may be erroneously
attributed to a postural deformity that results from common musculoskeletal or
orthopedic problems such as congenital torticollis, atlantoaxial or temporomandibular
subluxation, or scoliosis.

Functional dystonia — Functional dystonia, also referred to as psychogenic dystonia,

may be focal or generalized. Features include inconsistent movements over time without
the typical features of dystonia, such as changes with posture or activity. Patients with
functional dystonia should not have marked signs of overflow, although some overflow
can be seen among healthy individuals. Fixed postures following trauma that are not due
to structural causes have been considered as psychogenic, although this remains
controversial. Functional movement disorders are reviewed separately. (See "Functional
movement disorders".)

DIAGNOSTIC EVALUATION

Dystonia is a clinical diagnosis based on history and neurologic examination.

Classification, including determination of underlying etiology, is based on clinical features,
a levodopa trial in many cases, and laboratory and neuroimaging studies in selected
patients.

History and neurologic examination — The diagnosis of dystonia is based mainly upon
clinical features. In the absence of specific diagnostic tests, expert observation by a
movement disorder specialist is suggested to confirm the diagnosis of dystonia in cases
where there is uncertainty or confusion [163,164].

Isolated dystonia is separated from dystonia attributable to another underlying condition

by the absence of additional neurologic abnormalities (with the exception of tremor) and
the lack of a possible acquired cause ( table 6). Medications should be carefully reviewed
for exposure to dopamine receptor-blocking agents as a cause of tardive dystonia,
including first- and second-generation antipsychotic drugs and metoclopramide. Since
tardive syndromes can be permanent, past medication use is also important to review.
(See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis", section on
'Causative agents'.)

The age and anatomic distribution of dystonia at onset are important clinical clues for
diagnosis. Atypical presentations (eg, a child with onset of dystonia in the neck or face, an
adult with onset in the leg, or an adult who develops generalized dystonia) are not
characteristic of isolated dystonia or the most common genetically determined form (DYT-
TOR1A); they indicate the need to evaluate for another genetic or acquired cause.

Infrequently, late-onset isolated dystonia begins in the leg. However, onset in the leg in an
adult is usually secondary to an underlying etiology such as early-onset Parkinson disease
[88].

Generalized dystonia is rare with adult onset. In such cases, an acquired etiology should
be sought ( table 3), such as exposure to dopamine receptor antagonists. Hemidystonia
is infrequent at all ages and is usually due to an acquired cause, such as a contralateral
structural brain abnormality.

Levodopa trial — A trial of levodopa is recommended to suggest or exclude the diagnosis

of dopa-responsive dystonia (DRD) for patients with young-onset (ie, in infancy, childhood,
or adolescence) focal or generalized dystonia of unknown etiology, particularly for those
with a family history of dystonia or parkinsonism. (See 'Dopa-responsive dystonia' above
and "Treatment of dystonia in children and adults", section on 'Levodopa trial'.)

A levodopa trial should also be considered in adults with new-onset dystonia of unknown
cause, although there is less consensus in this age group and the likelihood of DRD is
lower in this age range [165]. At a minimum, a levodopa trial is appropriate in adults with
a family history of DRD or parkinsonism and in adults with an uncertain duration of
dystonia (eg, a possibility that the dystonia has been present for much longer than
originally thought). Patients with equivocal or minimal symptomatic response to levodopa
probably do not have DRD.

Laboratories and neuroimaging — Laboratory testing in patients with dystonia is part of

the etiologic evaluation for suspected acquired and hereditary dystonias or dystonia with
atypical features. The specific workup varies depending on age and associated clinical
findings.

When there is clinical suspicion for acquired ( table 3), inherited, or neurodegenerative
cause for dystonia, we generally suggest obtaining the following studies:

● Computed tomography (CT) and/or MRI of brain (looking for basal ganglia
calcifications or necrosis and other abnormalities)

● Complete blood count

● Electrolytes

● Renal and liver function tests

● Antinuclear antibodies

● Serum ceruloplasmin and copper levels, a slit-lamp examination for Kayser-Fleischer

rings, and a 24-hour urinary copper excretion determine the need for additional
 testing for Wilson disease (see "Wilson disease: Clinical manifestations, diagnosis,
and natural history")

● Erythrocyte sedimentation rate

● Rapid plasma reagin (RPR)

● Striatal dopamine transporter imaging using 123I-FP-CIT single-photon emission

computed tomography (DaTscan) only in patients in whom the possibility of an
evolving parkinsonian syndrome cannot be confidently excluded

Genetic testing — In patients with early-onset dystonia, or those with late onset who
have an affected relative with early-onset dystonia, TOR1A gene testing is indicated with
appropriate genetic counseling [61,164], particularly in individuals with Ashkenazi Jewish
heritage. In most patients with late-onset dystonia, TOR1A testing is not recommended
unless there is a family history of early-onset dystonia. (See 'DYT-TOR1A dystonia' above.)

Multigene panel testing is also possible for DRD (DYT-GCH1), myoclonus-dystonia (DYT-
SGCE), rapid-onset dystonia-parkinsonism (DYT-ATP1A3), and deafness-dystonia-optic
neuronopathy syndrome, among others [166]. In patients with adult-onset dystonia, rare
but treatable genetic causes to consider testing for include ( table 8) [44]:

● Dopa-responsive dystonia due to variants in GCH1, TH, or SPR (see 'Dopa-responsive

dystonia' above)
● Dystonia with brain manganese deposition due to variants in SLC30A10 or SLC9A14
● Glucose transporter type 1 deficiency due to variants in SLC2A1 (see 'Paroxysmal
dyskinesia with dystonia' above)
● Rapid-onset dystonia-parkinsonism due to variants in ATP1A3 (not treatable, but
prevention of worsening can be attempted by avoidance and treatment of
intercurrent illness) (see 'Dystonia-parkinsonism' above)
● Wilson disease due to variants in ATP7B (see "Gene test interpretation: ATP7B (Wilson
disease gene)")

Next-generation sequencing may allow for the identification of genetic variants that may
be causative, as well as phenotypic variations of more common genetic forms of dystonia.
The diagnostic yield of whole-exome or whole-genome sequencing in tertiary care cohorts
of patients with idiopathic dystonia is approximately 10 to 20 percent [167,168]. In one
large multicenter study the yield was highest in patients with childhood-onset symptoms,
generalized or segmental body distribution, and concurrent non-movement disorder
neurologic symptoms [169]. A scoring algorithm predicting the diagnostic utility of whole-
exome sequencing based on individual phenotypic aspects has also been validated [170].
SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Dystonia
in children and adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
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and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
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comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Dystonia (The Basics)")

● Beyond the Basics topics (see "Patient education: Laryngeal dystonia (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Definition – 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 and twisting, and may
be tremulous. Dystonia is often initiated or worsened by voluntary action. (See
'Defining motor features' above.)

● Etiology and pathogenesis – Dystonia can be inherited ( table 2 and table 8),
acquired ( table 3), and idiopathic [1]. Both degenerative and nondegenerative
causes of dystonia exist. (See 'Etiology' above.)

The pathogenesis of most forms of isolated dystonia is largely unknown. There are
no consistent neuropathologic features. Multiple brain areas may be involved,
including basal ganglia, motor cortex, supplementary motor areas, cerebellum, and
 their connections. Abnormalities in dopaminergic and cholinergic neurotransmitter
systems may play a role. (See 'Pathogenesis' above.)

● Clinical features – Dystonia is classified based upon clinical characteristics and

etiology ( table 1). Important clinical characteristics are age at onset, body
distribution (ie, focal, segmental, multifocal, generalized, or hemidystonia), temporal
pattern, and associated features (eg, isolated dystonia or dystonia combined with
another movement disorder) ( table 5). (See 'Clinical features' above.)

• Early-onset isolated dystonia presents in childhood or young adulthood. It most

often begins with symptoms in the limbs, typically the leg, often as intorsion of
the foot. It spreads to other body areas to become generalized in over 50 percent,
usually within five years of onset. Cases may be inherited/genetic or idiopathic.
(See 'Early-onset isolated dystonia' above.)

• Adult-onset focal or segmental isolated dystonias may involve different body

areas and extend to contiguous regions, but progression to generalized dystonia
is rare. Onset is usually after age 30 years. Most cases are idiopathic. Common
and/or important types include cervical dystonia, blepharospasm, and task-
specific dystonias. (See 'Adult-onset focal or segmental isolated dystonia' above.)

• Combined dystonias are those in which dystonia is combined with other

movement disorders, such as parkinsonism or myoclonus. These are sometimes
accompanied by pyramidal tract involvement and/or nonmotor features,
including cognitive decline. Many are inherited. (See 'Combined dystonia' above.)

● Diagnosis – The diagnosis of dystonia is mainly clinical. Expert observation by a

movement disorder specialist is suggested to confirm the diagnosis of dystonia in
cases where there is uncertainty or confusion ( table 6). Atypical presentations
and/or suspicion for secondary etiologies should prompt further investigations. (See
'Diagnostic evaluation' above.)

• Role of levodopa trial – For patients with focal or generalized dystonia of

unknown etiology, a trial of levodopa should be performed to suggest or exclude
the diagnosis of dopa-responsive dystonia (DRD) ( table 8). (See 'Levodopa trial'
above.)

• Genetic testing – Genetic testing for TOR1A is recommended for patients with
early-onset dystonia, or those with late onset who have an affected relative with
early-onset dystonia. (See 'Genetic testing' above.)
 Use of UpToDate is subject to the Terms of Use.

Topic 4886 Version 45.0

GRAPHICS

Classification of dystonia by clinical characteristics and etiology

Clinical characteristics
Age of onset Infancy: birth to 2 years

Childhood: 3 to 12 years

Adolescence: 13 to 20 years

Early adulthood: 21 to 40 years

Late adulthood: >40 years

Body distribution Focal: involving a single body region

Segmental: involving two or more contiguous body regions

Multifocal: involving two noncontiguous or more (noncontiguous or not)

body regions

Generalized: involving the trunk and at least two other sites

Hemidystonia: involving more regions restricted to one body side

Temporal pattern Disease course:

Static

Progressive

Variability:

Persistent: dystonia that persists to approximately the same extent

throughout the day

Action-specific: dystonia that occurs only during a particular activity or

task

Diurnal: dystonia fluctuates during the day, with recognizable circadian

variations in occurrence, severity, and phenomenology

Paroxysmal: sudden self-limited episodes of dystonia usually induced by

a trigger with return to preexisting neurologic state

Associated features Isolated or combined with another movement disorder:

Isolated: dystonia is the only motor feature, with the exception of tremor

Combined: dystonia is combined with other movement disorders (such as

myoclonus, parkinsonism, etc)

Occurrence of other neurologic or systemic manifestations

Etiology
Nervous system Evidence of degeneration (progressive structural abnormality, such as
pathology neuronal loss)
 Evidence of structural (often static) lesions

No evidence of degeneration or structural lesion

Inherited or Inherited (dystonia forms of proven genetic origin):

acquired
Autosomal dominant

Autosomal recessive

X-linked recessive

Mitochondrial

Acquired (dystonia due to a known specific cause):

Cerebrovascular (infarction or hemorrhage)

Perinatal brain injury

Traumatic brain injury

Infection

Drug

Toxic

Neoplastic

Psychogenic

Idiopathic Sporadic
(unknown cause)
Familial

Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: A consensus update. Mov Disord
2013; 28:863.

Graphic 59278 Version 4.0

Inherited forms of dystonia*

Locus
Usual onset Gene locus Gene symbol
symbol

Autosomal dominant

Dystonia is the presenting or predominant manifestation

Early-onset Childhood to DYT1 9q34 TOR1A

generalized adolescence
dystonia (DYT-
TOR1A)

Dopa-responsive Childhood DYT5a 14q22 GCH1

dystonia; Segawa
syndrome (DYT-
GCH1)

Adolescent-onset Adolescence DYT6 8p11.21 THAP1

dystonia of mixed
type (DYT-THAP1)

Cranial-cervical Adulthood DYT25 18p11.21 GNAL

dystonia (DYT-
GNAL)

Early-onset Childhood DYT28 19q13.12 KMT2B

generalized
dystonia (DYT-
KMT2B)

Dystonia is an associated or secondary feature

Paroxysmal Adolescence to DYT8 2q35 MR1

nonkinesigenic adulthood
dyskinesia 1 (DYT-
MR1)

Episodic Childhood to DYT10 16p11.2 PRRT2

(paroxysmal) adolescence
kinesigenic
dyskinesia 1 (DYT-
PRRT2)

Myoclonus-dystonia Childhood to DYT11 7q SGCE

(DYT-SGCE) adolescence

Myoclonus-dystonia Childhood to DYT26 22q.12.3 KCTD17

(DYT-KCTD17) early adulthood

Rapid-onset Childhood to DYT12 19q ATP1A3

dystonia- adulthood
parkinsonism (DYT-
 ATP1A3)

Paroxysmal Childhood DYT18 1p34.2 SLC2A1

exercise-induced
dyskinesia (DYT-
SLC2A1)

Dentatorubral- Adulthood N/A 12p13.31 ATN1

pallidoluysian
atrophy

Friedreich ataxia Adolescence to N/A 9q21.11 FXN

adulthood

Huntington disease Adolescence to N/A 4p16.3 HTT

adulthood

Idiopathic basal Adulthood N/A 8p11.21 SLC20A2

ganglia calcification
1

Neuroferritinopathy Adulthood NBIA3 19q13.33 FTL

Spinocerebellar Childhood to SCA3 14q32.12 ATXN3

ataxia 3 (Machado- adulthood
Joseph disease)

Spinocerebellar Adulthood SCA17 6q27 TBP

ataxia 17

Autosomal recessive

Dystonia is the presenting or predominant manifestation

Dopa-responsive Infancy to DYT5b 11p15.5 TH

dystonia; Segawa childhood
syndrome (DYT-TH)

Dopa-responsive Infancy to N/A 2p14-p12 SPR

dystonia (DYT-SPR) childhood

Dystonia is an associated or secondary feature

Aromatic L-amino Infancy N/A 7p12.1 DDC (AADC)

acid decarboxylase
deficiency

Ataxia- Childhood N/A 11q22.3 ATM

telangiectasia

Chorea- Adulthood N/A 9q21 VPS13A

acanthocytosis

Fucosidosis Infancy N/A 1p36.11 FUCA1

Glutaric acidemia Infancy N/A 19p13.2 GCDH

Huntington Childhood HDL3 4p15.3 ?

disease-like 3
 Infantile Infancy NBIA2a 22q13.1 PLA2G6
neuroaxonal
dystrophy

Juvenile Adolescence to PARK2 6q26 PRKN

parkinsonism adulthood

Kufor-Rakeb Childhood to PARK9 1p36.13 ATP13A2

syndrome adulthood

Methylmalonic Infancy N/A 6p12.3 MUT

aciduria
2q23.2 MMADHC

Niemann-Pick Infancy to N/A 18q11-q12 NPC1

disease type C adulthood
14q24.3 NPC2 (HE)

Pantothenate Childhood NBIA1 20p13 PANK2

kinase-associated
neurodegeneration

Tay-Sachs disease Infancy to N/A 15q23 HEXA

adulthood

Wilson disease Childhood to N/A 13q14.3 ATP7B

adulthood

Woodhouse-Sakati Adolescence N/A 2q31.1 DCAF17

syndrome

X-linked

Dystonia is an associated or secondary feature

X-linked dystonia- Adulthood DYT3 XR TAF1

parkinsonism;
Lubag (DYT-TAF1)

Lesch-Nyhan Childhood N/A Xq26.2-q26.3 HPRT

syndrome

Mohr-Tranebjaerg Childhood to N/A Xq22.1 TIMM8A (DDP)

dystonia-deafness adulthood
syndrome

Pelizaeus- Infancy N/A Xq22.2 PLP1

Merzbacher disease

Rett syndrome Infancy N/A Xq28 MECP2

Mitochondrial

Dystonia is an associated or secondary feature

Leber optic atrophy Childhood to N/A N/A Multiple

adolescence mitochondrial-
encoded genes
 Leigh syndrome ¶ Infancy N/A N/A Multiple nuclear
and
mitochondrial-
encoded genes

N/A: not assigned.

* This list is not comprehensive. An updated list of genetically determined movement disorders is
maintained by the International Parkinson and Movement Disorder Society (MDS) at
www.mdsgene.org.

¶ Leigh syndrome inheritance may be autosomal recessive or mitochondrial.

Data from:
1. Online Mendelian Inheritance in Man (OMIM).
2. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov
Disord 2013; 28:863.
3. Waugh JL, Sharma N. Clinical neurogenetics: dystonia from phenotype to genotype. Neurol Clin 2013; 31:969.
4. Klein C. Genetics in dystonia. Parkinsonism Relat Disord 2014; 20 Suppl 1:S137.
5. Moghimi N, Jabbari B, Szekely AM. Primary dystonias and genetic disorders with dystonia as clinical feature of the
disease. Eur J Paediatr Neurol 2014; 18:79.
6. Marras C, Lohmann K, Lang A, Klein C. Fixing the broken system of genetic locus symbols: Parkinson disease and
dystonia as examples. Neurology 2012; 78:1016.

Graphic 70477 Version 6.0

Causes of acquired dystonia

Cause Examples

Perinatal brain injury ▪ Delayed-onset dystonia

▪ Dystonic cerebral palsy

Cerebrovascular ▪ Arteriovenous malformation and aneurysm

▪ Hemorrhage
▪ Ischemia

Brain injury ▪ Brain surgery (including stereotactic ablations)

▪ Electrical injury
▪ Head trauma

Medications ▪ Antihistamines
▪ Antimalarials
▪ Antiseizure medications
▪ Calcium channel blockers
▪ Cholinergic agonists
▪ Disulfiram
▪ Dopamine agonists
▪ Dopamine depleting agents (eg, tetrabenazine)
▪ Dopamine receptor blocking agents, including antipsychotic drugs
and metoclopramide
▪ Levodopa
▪ Lithium
▪ Selective serotonin reuptake inhibitors
▪ Stimulants (eg, methylphenidate)
▪ Tricyclic antidepressants

Infection ▪ Encephalitis lethargica

▪ Human immunodeficiency virus (HIV) infection
▪ Subacute sclerosing panencephalitis
▪ Syphilis
▪ Tuberculosis
▪ Viral encephalitis

Neoplastic and ▪ Brain tumor

paraneoplastic ▪ Paraneoplastic or autoimmune encephalitis

Toxins and drugs of abuse ▪ 3-nitropropionic acid

▪ 3,4-methylenedioxymethamphetamine (MDMA; ecstasy)
▪ Amphetamine
▪ Carbon disulfide
▪ Carbon monoxide
 ▪ Cobalt
▪ Cocaine
▪ Cyanide
▪ Manganese
▪ Mercury
▪ Methamphetamine
▪ Methanol
▪ Methcanthinone
▪ Organophosphate

Functional ▪ Functional movement disorder

References:
1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: A consensus update. Mov
Disord 2013; 28:863.
2. van Egmond ME, Lagrand TJ, Lizaitene G, et al. A novel diagnostic approach to patients with adult-onset dystonia. J
Neurol Neurosurg Psychiatry 2022; 93:1039.

Graphic 51622 Version 7.0

DYT locus symbols for dystonia

Chromosome,
Mode of Clinical
Locus Designation mutation, and
inheritance features
gene product

DYT1 Dystonia 1, AD Typically begins 9q34; GAG

torsion in childhood; deletion in TOR1A
onset in limb gene causes
often with abnormality in
progression to ATP-binding
generalized protein, torsinA
dystonia

DYT2 Dystonia 2, AR Childhood onset, 1p35.1; HPCA

torsion generalized or gene that
segmental; Roma encodes
families hippocalcin

DYT3 X-linked dystonia- X-linked recessive Segmental or Xq13.1; TAF1 gene

parkinsonism generalized
(Lubag) dystonia with
parkinsonism;
predominantly in
males from
Panay island in
Philippines

DYT4 Whispering AD Laryngeal and 19p13.3;

dysphonia cervical dystonia, mutations in the
often with TUBB4A gene
progression to
generalized
dystonia

DYT5 Dopa-responsive AD Dystonia with or 14q22; GCH1

dystonia/ without locus; mutations
parkinsonism parkinsonism; in GTP
dramatic cyclohydrolase I
response to gene
levodopa

Segawa AR Dystonia with or 11p15.5;

syndrome without mutations in the
parkinsonism; tyrosine
diurnal variation, hydroxylase gene;
with worst tyrosine
symptoms in hydroxylase
evening; marked deficiency
response to
 levodopa

DYT6 Dystonia 6, AD Adolescent-onset 8p11.21;

torsion dystonia of mixed mutations in the
type; mostly THAP1 gene
segmental
dystonia; mixed
limb, cervical,
cranial; Amish-
Mennonite,
German, Irish,
Italian families

DYT7 Dystonia 7, AD Adult-onset focal 18p; gene and

torsion dystonia with product unknown
cervical dystonia,
limb dystonia,
dysphonia, or
blepharospasm;
German family

DYT8 Paroxysmal AD Episodes of 2q35; MR1 gene

nonkinesigenic dystonia/ involved in
dyskinesia 1 choreoathetosis myofibrillogenesis
not precipitated regulation
by exercise or
activity

DYT9 (allelic with Paroxysmal AD Episodes of 1p34.2; mutations

DYT18) choreoathetosis dystonia, in the SLC2A1
with episodic diplopia, and gene that
spasticity and paresthesia with encodes the
ataxia spastic glucose
paraplegia transporter type 1
between attacks

DYT10 Episodic AD Episodic 16p11.2;

kinesigenic choreoathetosis mutations in the
dyskinesia 1 and dystonia PRRT2 gene
(paroxysmal brought on by
kinesigenic exercise/activity
dyskinesia)

DYT11 Myoclonus- AD Myoclonic jerks 7q; epsilon-

dystonia associated with sarcoglycan gene
variable features (SGCE)
of dystonia; very
alcohol
responsive

DYT12 Rapid-onset AD Onset of dystonia 19q; ATP1A3 gene

dystonia- and parkinsonism that encodes the
 parkinsonism over days to Na+/K+ -ATPase
months alpha3 subunit

DYT13 Dystonia 13, AD Early adult-onset 1p36.32-p36.13;

torsion multifocal and gene and product
segmental unknown
dystonia with
cervical, cranial,
and arm dystonia

DYT14 Dopa-responsive
dystonia (now
included under
DYT5)

DYT15 Dystonia 15, AD Myoclonus and 18p11; gene and

myoclonic dystonia product unknown

DYT16 Dystonia 16 AR Early-onset 2q31.3; PRKRA

generalized gene
dystonia; some
cases with
parkinsonism
unresponsive to
levodopa

DYT17 Dystonia 17, AR Adolescent onset 20p11.2-q13.12;

torsion in neck with gene and product
regional spread unknown

DYT18 (allelic Paroxysmal AD Episodes of 1p34.2; mutations

with DYT9) exercise-induced dystonia, in the SLC2A1
dyskinesia with diplopia, gene that
or without paresthesias with encodes the
epilepsy and/or spastic glucose
hemolytic anemia paraplegia transporter type 1
(GLUT1 deficiency between attacks
syndrome 2)

DYT19 Episodic AD Episodic 16q13-q22.1;

kinesigenic choreoathetosis gene and product
dyskinesia 2 and dystonia unknown
(paroxysmal brought on by
kinesigenic exercise/activity
dyskinesia)

DYT20 Paroxysmal AD Spontaneous 2q31; gene and

nonkinesigenic episodes of product unknown
dyskinesia 2 dystonia
DYT21 Dystonia 21 AD Adolescent to 2q14.3-q21.3;
adult onset; gene and product
generalized or unknown
multifocal

DYT23 Dystonia 23 AD Adult-onset 9q34, CIZ1 gene

cervical dystonia

DYT24 Dystonia 24 AD Adult-onset 11p14.2, ANO3

craniocervical gene
dystonia affecting
the neck,
laryngeal
muscles, and
arms

DYT25 Dystonia 25 AD Adult-onset 18p11.21, GNAL

cervical dystonia gene
with regional
spread

DYT26 Dystonia 26, AD Myoclonus in the 22p12.3; KCTD17

myoclonic first decades of gene encoding
life; craniocervical the BTB/POZ
dystonia domain-
develops containing
eventually protein KCTD17

DYT27 Dystonia 27 AR Segmental 2q37.3; COL6A3

isolated gene encoding
craniocervical the collagen type
and limb dystonia VI alpha 3 chain
in the first
decades of life

DYT28 Dystonia 28, AD Childhood-onset 19q13.12; KMT2B

childhood onset caudal dystonia gene encoding
with rostral the histone-lysine
progression, N-
intellectual methyltransferase
disabilities, and 2B protein
dysmorphia

DYT29 Dystonia 29, AR Onset of dystonia 1p35.3; MECR

childhood onset and optic atrophy gene
with optic in the first
atrophy and decade of life
basal ganglia
abnormalities

DYT30 Dystonia 30 AD Early-onset upper 20p13; VPS16

body dystonia gene encoding
with eventual the VPS16 core
 generalization subunit of
CORVET and
HOPS complexes

DYT31 Dystonia 31 AR Progressive 9q22.32; AOPEP

generalized gene encoding
dystonia with aminopeptidase
orofacial O
dyskinesias
causing
dysarthria and
dysphagia

DYT32 Dystonia 32 AR Adult-onset, 11q23.3; VPS11

slowly gene encoding
progressive the VPS11 core
dystonia with subunit of
eventual CORVET and
generalization HOPS complexes
complicated by
dysarthria and
dysphagia

DYT33 Dystonia 33 AD, AR Childhood- to 2p22.2; EIF2AK2

adolescent-onset, gene encoding
slowly the eukaryotic
progressive focal translation
or generalized initiation factor 2-
dystonia alpha kinase 2

DYT34 Myoclonic AD Childhood-onset 5q22.3; KCNN2

dystonia 34 dystonia gene encoding
involving the potassium
hands and neck calcium-activated
with tremor and channel subfamily
superimposed N member 2
myoclonus

AD: autosomal dominant; ATP: adenosine triphosphate; AR: autosomal recessive.

Graphic 56658 Version 17.0

Dystonia syndromes

Isolated dystonias

Early-onset generalized isolated dystonia

Description: dystonia with focal onset beginning in childhood that often progresses to generalized
involvement; cases may be sporadic, familial, genetically defined, or without known cause

Early-onset generalized dystonia (DYT-TOR1A)

Adolescent-onset dystonia of mixed type (DYT-THAP1)

Focal or segmental isolated dystonia with onset in adulthood

Description: focal or segmental isolated dystonias usually begin after age 30 years; most are
sporadic without identifiable cause, and rarely progress to generalized dystonia, but can extend to
contiguous body regions

Adult-onset segmental dystonia (DYT-GNAL)

Cervical dystonia

Blepharospasm

Writer's cramp

Oromandibular dystonia

Laryngeal dystonia (spasmodic dysphonia)

Limb dystonia

Other syndromes of late adult-onset focal isolated dystonia

Combined dystonias

Dystonia-parkinsonism

Description: disorders that combine dystonia and parkinsonian features, sometimes accompanied
by pyramidal tract involvement, and/or nonmotor features, including cognitive decline; many are
inherited

Dopa-responsive dystonia (DYT-GCH1, DYT-TH, and DYT-SPR)

Wilson disease

Early-onset parkinsonism (PARK-PARKIN)

Early-onset parkinsonism (PARK-PINK1)

Early-onset parkinsonism (PARK-DJ1)

X-linked dystonia-parkinsonism/Lubag (DYT-TAF1)

Rapid-onset dystonia-parkinsonism (DYT-ATP1A3)

Neurodegeneration with brain iron accumulation:

Pantothenate kinase-associated neurodegeneration (PANK2 gene)

Infantile neuroaxonal dystrophy (PLA2G6 gene)

 Mitochondrial membrane protein-associated neurodegeneration (C19ORF12 gene)

Beta-propeller protein-associated neurodegeneration, also known as static encephalopathy of

childhood with neurodegeneration in adulthood (WDR45 gene)

Fatty acid hydroxylase-associated neurodegeneration (FA2H gene)

Kufor-Rakeb syndrome (PARK-ATP13A2)

Neuroferritinopathy (FTL gene)

Aceruloplasminemia (ceruloplasmin gene)

Woodhouse-Sakati syndrome (DCAF17 gene)

Myoclonus-dystonia

Description: disorders in which there is a combination of dystonia and myoclonus; dystonia may be
mild, and myoclonus generally predominates

Myoclonus-dystonia (DYT-SGCE)

Paroxysmal dyskinesia with dystonia

Description: disorders characterized by episodes of spontaneous or induced dyskinesia with

dystonia

Paroxysmal nonkinesigenic dyskinesia (DYT-MR1)

Paroxysmal kinesigenic choreoathetosis (DYT-PRRT2)

Paroxysmal exertion-induced dyskinesia (DYT-SLC2A1)

Data from:
1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: A consensus update. Mov
Disord 2013; 28:863.
2. Klein C. Genetics in dystonia. Parkinsonism Relat Disord 2014; 20 Suppl 1:S137.
3. Marras C, Lohmann K, Lang A, Klein C. Fixing the broken system of genetic locus symbols: Parkinson disease and
dystonia as examples. Neurology 2012; 78:1016.

Graphic 59044 Version 5.0

Clinical features of isolated dystonia

Presence of:
Sustained involuntary movement, sometimes overlying spasms

Consistent directional quality

Involves same body region(s)

Enhanced or produced by activity of involved area

Varies with change in activity or posture

Sensory tricks (geste antagoniste) may reduce symptoms

May have associated tremor

Absence of:
Weakness

Amyotrophy

Spasticity

Ataxia

Ocular abnormalities

Abnormal eye movements

Retinal changes

Cognitive impairment

Seizures

Graphic 70065 Version 4.0

Mimics of dystonia

Type of dystonia Mimics

Facial dystonia ▪ Tics

▪ Hemifacial spasm (tonic component)
▪ Apraxia of eyelid opening (levator inhibition)
▪ Ptosis
▪ Trismus
▪ Hemimasticatory spasm
▪ Myotonia
▪ Tetanic spasms
▪ Hypoglossal nerve damage
▪ Functional movement disorder

Cervical dystonia ▪ Klippel-Feil syndrome

▪ Atlanto-axial subluxation
▪ Congenital muscular torticollis
▪ Tics
▪ Vestibulopathy ("vestibular torticollis")
▪ Trochlear/abducens nerve palsy (head tilt)
▪ Space-occupying lesion in posterior fossa or spinal cord
▪ Retropharyngeal abscess
▪ Sternocleidomastoid injuries
▪ Upper spinal cord syringomyelia
▪ Arnold Chiari malformation
▪ Dropped head syndrome in neuromuscular disease
▪ Kyphosis
▪ Functional movement disorder

Truncal dystonia ▪ Scoliosis

▪ Camptocormia
▪ Ventral hernia
▪ Stiff-person syndrome
▪ Functional movement disorder

Limb dystonia (posturing) ▪ Contracture

▪ Spasticity
▪ Rigidity
▪ Abnormal posture due to paresis or atrophy
▪ Shoulder subluxation
▪ Dystonic (tonic) tics
▪ Trigger finger
▪ Myotonia or neuromyotonia
 ▪ Sensory ataxia and/or pseudoathetosis
▪ Stiff-person syndrome
▪ Tonic spasms (hypocalcemia, hypomagnesemia, alkalosis)
▪ Focal tonic seizures
▪ Functional movement disorder

Hemidystonia ▪ Stiff-person syndrome

▪ Functional movement disorder

Generalized dystonia ▪ Progressive encephalomyelitis with rigidity and myoclonus (PERM)

▪ Carpopedal spasms
▪ Myelopathy
▪ Peripheral neuropathy
▪ Subacute combined degeneration (B12 deficiency)
▪ Functional movement disorder

Paroxysmal dystonia ▪ Focal tonic epilepsy

▪ Multiple sclerosis
▪ Tonic spasms (hypocalcemia, hypomagnesemia, alkalosis)
▪ Periodic paralyses
▪ Functional movement disorder

Adapted with permission from: van Egmond ME, Lagrand TJ, Lizaitene G, et al. A novel diagnostic approach to patients
with adult-onset dystonia. J Neurol Neurosurg Psychiatry 2022; 93:1039. Copyright © 2022 BMJ Publishing Group Ltd.

Graphic 141015 Version 1.0

Treatable genetic causes of adult-onset dystonia

Disorder Gene(s) Diagnostic tests Treatment

Dopa-responsive GCH1 ▪ Levodopa Levodopa

dystonia, classic challenge
▪ CSF pterins and
biogenic amines
▪ Genetic testing

Dopa-responsive TH, PTPS, SPR ▪ Levodopa Levodopa, 5-

dystonia, complex challenge hydroxytryptophan, or
▪ CSF HVA, 5-HIAA, tetrahydrobiopterin
and sepiapterin
▪ Genetic testing

Dystonia with brain SLC30A10, SLC9A14 ▪ Serum manganese Chelation therapy

manganese deposition and iron
▪ Peripheral blood
smear
▪ Genetic testing

Glucose transporter SLC2A1 ▪ Serum and CSF Ketogenic diet or

type 1 deficiency glucose triheptanoin
▪ Genetic testing

Rapid-onset dystonia- ATP1A3 ▪ CSF HVA Avoid or treat

parkinsonism intercurrent illness to
prevent
encephalopathic crises

Wilson disease ATP7B ▪ Slit lamp Zinc or

examination tetrathiomolybdate
▪ Plasma copper and
ceruloplasmin
▪ 24-hour urine
copper

CSF: cerebrospinal fluid; HVA: homovanillic acid; 5-HIAA: 5-hydroxyindoleacetic acid.

Adapted from: van Egmond ME, Lagrand TJ, Lizaitene G, et al. A novel diagnostic approach to patients with adult-onset
dystonia. J Neurol Neurosurg Psychiatry 2022; 93:1039.

Graphic 141014 Version 1.0

