ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Etiology, clinical features, and diagnostic evaluation of dystonia

Etiology, clinical features, and diagnostic evaluation of dystonia
Literature review current through: Jan 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 about a given condition. These articles are best for patients who want a general overview 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 12th grade reading level and are best for patients who want in-depth information and are 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.)

  1. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: A consensus update. Mov Disord 2013; 28:863.
  2. Nutt JG, Muenter MD, Melton LJ 3rd, et al. Epidemiology of dystonia in Rochester, Minnesota. Adv Neurol 1988; 50:361.
  3. Nutt JG, Muenter MD, Aronson A, et al. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 1988; 3:188.
  4. Butler AG, Duffey PO, Hawthorne MR, Barnes MP. An epidemiologic survey of dystonia within the entire population of northeast England over the past nine years. Adv Neurol 2004; 94:95.
  5. Defazio G, Abbruzzese G, Livrea P, Berardelli A. Epidemiology of primary dystonia. Lancet Neurol 2004; 3:673.
  6. Le KD, Nilsen B, Dietrichs E. Prevalence of primary focal and segmental dystonia in Oslo. Neurology 2003; 61:1294.
  7. Fukuda H, Kusumi M, Nakashima K. Epidemiology of primary focal dystonias in the western area of Tottori prefecture in Japan: Comparison with prevalence evaluated in 1993. Mov Disord 2006; 21:1503.
  8. Almasy L, Bressman S, de Leon D, Risch N. Ethnic variation in the clinical expression of idiopathic torsion dystonia. Mov Disord 1997; 12:715.
  9. Steeves TD, Day L, Dykeman J, et al. The prevalence of primary dystonia: A systematic review and meta-analysis. Mov Disord 2012; 27:1789.
  10. Park J, Damrauer SM, Baras A, et al. Epidemiology of DYT1 dystonia: Estimating prevalence via genetic ascertainment. Neurol Genet 2019; 5:e358.
  11. Saunders-Pullman R, Soto-Valencia J, Costan-Toth C, et al. A new screening tool for cervical dystonia. Neurology 2005; 64:2046.
  12. Bressman SB, Raymond D, Wendt K, et al. Diagnostic criteria for dystonia in DYT1 families. Neurology 2002; 59:1780.
  13. Lagos AE, García-Huidobro FG, Ramos PH, et al. Spasmodic Dysphonia: Standardized Spanish Tool for Ambulatory Consult Diagnosis. J Voice 2021; 35:809.e7.
  14. Klein C, Ozelius LJ. Dystonia: Clinical features, genetics, and treatment. Curr Opin Neurol 2002; 15:491.
  15. Altrocchi PH, Forno LS. Spontaneous oral-facial dyskinesia: Neuropathology of a case. Neurology 1983; 33:802.
  16. Zweig RM, Hedreen JC, Jankel WR, et al. Pathology in brainstem regions of individuals with primary dystonia. Neurology 1988; 38:702.
  17. Gibb WR, Lees AJ, Marsden CD. Pathological report of four patients presenting with cranial dystonias. Mov Disord 1988; 3:211.
  18. McNaught KS, Kapustin A, Jackson T, et al. Brainstem pathology in DYT1 primary torsion dystonia. Ann Neurol 2004; 56:540.
  19. Holton JL, Schneider SA, Ganesharajah T, et al. Neuropathology of primary adult-onset dystonia. Neurology 2008; 70:695.
  20. Marsden CD, Obeso JA, Zarranz JJ, Lang AE. The anatomical basis of symptomatic hemidystonia. Brain 1985; 108 (Pt 2):463.
  21. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998; 44:303.
  22. Carbon M, Su S, Dhawan V, et al. Regional metabolism in primary torsion dystonia: Effects of penetrance and genotype. Neurology 2004; 62:1384.
  23. Sharma N. Neuropathology of dystonia. Tremor Other Hyperkinet Mov (N Y) 2019; 9:569.
  24. Jinnah HA, Hess EJ. Evolving concepts in the pathogenesis of dystonia. Parkinsonism Relat Disord 2018; 46 Suppl 1:S62.
  25. Corp DT, Joutsa J, Darby RR, et al. Network localization of cervical dystonia based on causal brain lesions. Brain 2019; 142:1660.
  26. Sedov A, Usova S, Popov V, et al. Feedback-dependent neuronal properties make focal dystonias so focal. Eur J Neurosci 2021; 53:2388.
  27. Sedov A, Usova S, Semenova U, et al. Pallidal Activity in Cervical Dystonia with and Without Head Tremor. Cerebellum 2020; 19:409.
  28. Brüggemann N. Contemporary functional neuroanatomy and pathophysiology of dystonia. J Neural Transm (Vienna) 2021; 128:499.
  29. Phukan J, Albanese A, Gasser T, Warner T. Primary dystonia and dystonia-plus syndromes: Clinical characteristics, diagnosis, and pathogenesis. Lancet Neurol 2011; 10:1074.
  30. Hallett M. Pathophysiology of writer's cramp. Hum Mov Sci 2006; 25:454.
  31. Vitek JL. Pathophysiology of dystonia: A neuronal model. Mov Disord 2002; 17 Suppl 3:S49.
  32. Pisani A, Bernardi G, Ding J, Surmeier DJ. Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci 2007; 30:545.
  33. Gonzalez-Alegre P, Beauvais G, Martin J, et al. A Novel Transgenic Mouse Model to Investigate the Cell-Autonomous Effects of torsinA(ΔE) Expression in Striatal Output Neurons. Neuroscience 2019; 422:1.
  34. Scarduzio M, Zimmerman CN, Jaunarajs KL, et al. Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia. Exp Neurol 2017; 295:162.
  35. Charlesworth G, Bhatia KP, Wood NW. The genetics of dystonia: New twists in an old tale. Brain 2013; 136:2017.
  36. Waugh JL, Sharma N. Clinical neurogenetics: Dystonia from phenotype to genotype. Neurol Clin 2013; 31:969.
  37. Klein C. Genetics in dystonia. Parkinsonism Relat Disord 2014; 20 Suppl 1:S137.
  38. 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.
  39. 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.
  40. Lange LM, Junker J, Loens S, et al. Genotype-Phenotype Relations for Isolated Dystonia Genes: MDSGene Systematic Review. Mov Disord 2021; 36:1086.
  41. Thomsen M, Lange LM, Klein C, Lohmann K. MDSGene: Extending the List of Isolated Dystonia Genes by VPS16, EIF2AK2, and AOPEP. Mov Disord 2023; 38:507.
  42. Corp DT, Greenwood CJ, Morrison-Ham J, et al. Clinical and Structural Findings in Patients With Lesion-Induced Dystonia: Descriptive and Quantitative Analysis of Published Cases. Neurology 2022; 99:e1957.
  43. Friedman J, Standaert DG. Dystonia and its disorders. Neurol Clin 2001; 19:681.
  44. van Egmond ME, Lagrand TJ, Lizaitiene G, et al. A novel diagnostic approach for patients with adult-onset dystonia. J Neurol Neurosurg Psychiatry 2022; 93:1039.
  45. Balint B, Vincent A, Meinck HM, et al. Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology. Brain 2018; 141:13.
  46. Shaikh AG, Beylergil SB, Scorr L, et al. Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort. Neurology 2021; 96:e563.
  47. Quinn NP, Schneider SA, Schwingenschuh P, Bhatia KP. Tremor--some controversial aspects. Mov Disord 2011; 26:18.
  48. Albanese A, Sorbo FD. Dystonia and tremor: The clinical syndromes with isolated tremor. Tremor Other Hyperkinet Mov (N Y) 2016; 6:319.
  49. Ray S, Kutty B, Pal PK, Yadav R. Sleep and other Non-motor Symptoms in Patients with Idiopathic Oromandibular Dystonia and Meige Syndrome: A Questionnaire-based Study. Ann Indian Acad Neurol 2021; 24:351.
  50. Monaghan R, Cogley C, Burke T, et al. Non-motor features of cervical dystonia: Cognition, social cognition, psychological distress and quality of life. Clin Park Relat Disord 2021; 4:100084.
  51. Junker J, Berman BD, Hall J, et al. Quality of life in isolated dystonia: non-motor manifestations matter. J Neurol Neurosurg Psychiatry 2021.
  52. Wadon ME, Bailey GA, Yilmaz Z, et al. Non-motor phenotypic subgroups in adult-onset idiopathic, isolated, focal cervical dystonia. Brain Behav 2021; 11:e2292.
  53. Han V, Skorvanek M, Smit M, et al. Prevalence of non-motor symptoms and their association with quality of life in cervical dystonia. Acta Neurol Scand 2020; 142:613.
  54. Matteo C, Daniele B, Isabella B, et al. Motor and non-motor subtypes of cervical dystonia. Parkinsonism Relat Disord 2021; 88:108.
  55. Weiss EM, Hershey T, Karimi M, et al. Relative risk of spread of symptoms among the focal onset primary dystonias. Mov Disord 2006; 21:1175.
  56. Greene PE, Bressman S. Exteroceptive and interoceptive stimuli in dystonia. Mov Disord 1998; 13:549.
  57. Ramos VF, Karp BI, Hallett M. Tricks in dystonia: ordering the complexity. J Neurol Neurosurg Psychiatry 2014; 85:987.
  58. Greene P, Kang UJ, Fahn S. Spread of symptoms in idiopathic torsion dystonia. Mov Disord 1995; 10:143.
  59. Ozelius LJ, Hewett JW, Page CE, et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet 1997; 17:40.
  60. Ozelius LJ, Page CE, Klein C, et al. The TOR1A (DYT1) gene family and its role in early onset torsion dystonia. Genomics 1999; 62:377.
  61. Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines for diagnostic testing. Neurology 2000; 54:1746.
  62. Bressman SB, Heiman GA, Nygaard TG, et al. A study of idiopathic torsion dystonia in a non-Jewish family: Evidence for genetic heterogeneity. Neurology 1994; 44:283.
  63. Bressman SB. Dystonia genotypes, phenotypes, and classification. Adv Neurol 2004; 94:101.
  64. Misbahuddin A, Placzek MR, Taanman JW, et al. Mutant torsinA, which causes early-onset primary torsion dystonia, is redistributed to membranous structures enriched in vesicular monoamine transporter in cultured human SH-SY5Y cells. Mov Disord 2005; 20:432.
  65. Beauvais G, Rodriguez-Losada N, Ying L, et al. Exploring the interaction between eIF2α dysregulation, acute endoplasmic reticulum stress and DYT1 dystonia in the mammalian brain. Neuroscience 2018; 371:455.
  66. Kuipers DJS, Mandemakers W, Lu CS, et al. EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia. Ann Neurol 2021; 89:485.
  67. Tassone A, Martella G, Meringolo M, et al. Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia. Mov Disord 2021; 36:2768.
  68. Almasy L, Bressman SB, Raymond D, et al. Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families. Ann Neurol 1997; 42:670.
  69. Saunders-Pullman R, Raymond D, Senthil G, et al. Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites. Am J Med Genet A 2007; 143A:2098.
  70. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 2009; 41:286.
  71. Bressman SB, Raymond D, Fuchs T, et al. Mutations in THAP1 (DYT6) in early-onset dystonia: A genetic screening study. Lancet Neurol 2009; 8:441.
  72. Djarmati A, Schneider SA, Lohmann K, et al. Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: A genetic screening study. Lancet Neurol 2009; 8:447.
  73. Saunders-Pullman R, Fuchs T, San Luciano M, et al. Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Mov Disord 2014; 29:812.
  74. Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence variants in primary dystonia. Neurology 2010; 74:229.
  75. Gavarini S, Cayrol C, Fuchs T, et al. Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann Neurol 2010; 68:549.
  76. Kaiser FJ, Osmanoric A, Rakovic A, et al. The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Ann Neurol 2010; 68:554.
  77. Zakirova Z, Fanutza T, Bonet J, et al. Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. PLoS Genet 2018; 14:e1007169.
  78. Domingo A, Yadav R, Shah S, et al. Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin. Am J Hum Genet 2021; 108:2145.
  79. Cheng F, Walter M, Wassouf Z, et al. Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia. J Mol Neurosci 2020; 70:999.
  80. Cheng F, Zheng W, Barbuti PA, et al. DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family. Brain 2022; 145:3968.
  81. Zech M, Boesch S, Maier EM, et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet 2016; 99:1377.
  82. Meyer E, Carss KJ, Rankin J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 2017; 49:223.
  83. Cif L, Demailly D, Lin JP, et al. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain 2020; 143:3242.
  84. Zech M, Lam DD, Winkelmann J. Update on KMT2B-related dystonia. Curr Neurol Neurosci Rep 2019; 19:92.
  85. Gorman KM, Meyer E, Kurian MA. Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B. Eur J Paediatr Neurol 2018; 22:245.
  86. Svetel M, Pekmezović T, Jović J, et al. Spread of primary dystonia in relation to initially affected region. J Neurol 2007; 254:879.
  87. Berman BD, Groth CL, Sillau SH, et al. Risk of spread in adult-onset isolated focal dystonia: A prospective international cohort study. J Neurol Neurosurg Psychiatry 2020; 91:314.
  88. Schneider SA, Edwards MJ, Grill SE, et al. Adult-onset primary lower limb dystonia. Mov Disord 2006; 21:767.
  89. Chouery E, Kfoury J, Delague V, et al. A novel locus for autosomal recessive primary torsion dystonia (DYT17) maps to 20p11.22-q13.12. Neurogenetics 2008; 9:287.
  90. Lohmann K, Klein C. Genetics of dystonia: What's known? What's new? What's next? Mov Disord 2013; 28:899.
  91. Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013; 45:88.
  92. Kumar KR, Lohmann K, Masuho I, et al. Mutations in GNAL: A novel cause of craniocervical dystonia. JAMA Neurol 2014; 71:490.
  93. Vemula SR, Puschmann A, Xiao J, et al. Role of Gα(olf) in familial and sporadic adult-onset primary dystonia. Hum Mol Genet 2013; 22:2510.
  94. Sarva H, Trosch R, Kiss ZHT, et al. Deep brain stimulation in isolated dystonia with a GNAL mutation. Mov Disord 2019; 34:301.
  95. Hallett M, Evinger C, Jankovic J, et al. Update on blepharospasm: Report from the BEBRF International Workshop. Neurology 2008; 71:1275.
  96. Defazio G, Hallett M, Jinnah HA, et al. Blepharospasm 40 years later. Mov Disord 2017; 32:498.
  97. Defazio G, Jinnah HA, Berardelli A, et al. Diagnostic criteria for blepharospasm: A multicenter international study. Parkinsonism Relat Disord 2021; 91:109.
  98. Defazio G, Hallett M, Jinnah HA, Berardelli A. Development and validation of a clinical guideline for diagnosing blepharospasm. Neurology 2013; 81:236.
  99. Jankovic J, Ford J. Blepharospasm and orofacial-cervical dystonia: Clinical and pharmacological findings in 100 patients. Ann Neurol 1983; 13:402.
  100. Marsden CD. Blepharospasm-oromandibular dystonia syndrome (Brueghel's syndrome). A variant of adult-onset torsion dystonia? J Neurol Neurosurg Psychiatry 1976; 39:1204.
  101. Comella CL. Systematic review of botulinum toxin treatment for oromandibular dystonia. Toxicon 2018; 147:96.
  102. Brin MF, Blitzer A, Stewart C. Laryngeal dystonia (spasmodic dysphonia): Observations of 901 patients and treatment with botulinum toxin. Adv Neurol 1998; 78:237.
  103. Jinnah HA, Berardelli A, Comella C, et al. The focal dystonias: current views and challenges for future research. Mov Disord 2013; 28:926.
  104. Simonyan K, Barkmeier-Kraemer J, Blitzer A, et al. Laryngeal Dystonia: Multidisciplinary Update on Terminology, Pathophysiology, and Research Priorities. Neurology 2021; 96:989.
  105. Lohmann K, Wilcox RA, Winkler S, et al. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann Neurol 2013; 73:537.
  106. Hersheson J, Mencacci NE, Davis M, et al. Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia. Ann Neurol 2013; 73:546.
  107. Bally JF, Camargos S, Oliveira Dos Santos C, et al. DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations. Neurology 2021; 96:e1887.
  108. Hintze JM, Ludlow CL, Bansberg SF, et al. Spasmodic dysphonia: A review. Part 2: Characterization of pathophysiology. Otolaryngol Head Neck Surg 2017; 157:558.
  109. Ludlow CL, Adler CH, Berke GS, et al. Research priorities in spasmodic dysphonia. Otolaryngol Head Neck Surg 2008; 139:495.
  110. Defazio G, Ercoli T, Erro R, et al. Idiopathic Non-task-Specific Upper Limb Dystonia, a Neglected Form of Dystonia. Mov Disord 2020; 35:2038.
  111. Norris SA, Jinnah HA, Klein C, et al. Clinical and Demographic Characteristics of Upper Limb Dystonia. Mov Disord 2020; 35:2086.
  112. Sadnicka A, Kassavetis P, Pareés I, et al. Task-specific dystonia: Pathophysiology and management. J Neurol Neurosurg Psychiatry 2016; 87:968.
  113. Torres-Russotto D, Perlmutter JS. Task-specific dystonias: A review. Ann N Y Acad Sci 2008; 1142:179.
  114. Thompson PD. Writers' cramp. Br J Hosp Med 1993; 50:91.
  115. Sitburana O, Wu LJ, Sheffield JK, et al. Motor overflow and mirror dystonia. Parkinsonism Relat Disord 2009; 15:758.
  116. Frucht SJ. Focal task-specific dystonia in musicians. Adv Neurol 2004; 94:225.
  117. Evidente VG, Advincula J, Esteban R, et al. Phenomenology of "Lubag" or X-linked dystonia-parkinsonism. Mov Disord 2002; 17:1271.
  118. Miravite J, Deik A, Swan M, et al. Parkinsonism and dystonia in Lubag disease respond well to high pulse width/low-frequency globus pallidus interna DBS. Neurol Clin Pract 2015; 5:480.
  119. Evidente VG, Nolte D, Niemann S, et al. Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ("lubag") in women. Arch Neurol 2004; 61:1956.
  120. Wilhelmsen KC, Weeks DE, Nygaard TG, et al. Genetic mapping of "Lubag" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome. Ann Neurol 1991; 29:124.
  121. Makino S, Kaji R, Ando S, et al. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 2007; 80:393.
  122. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, et al. Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 2004; 43:169.
  123. Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, CAPOS and beyond. Pediatr Neurol 2015; 52:56.
  124. Brashear A, Dobyns WB, de Carvalho Aguiar P, et al. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 2007; 130:828.
  125. Wei W, Zheng XF, Ruan DD, et al. Different phenotypes of neurological diseases, including alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism, caused by de novo ATP1A3 mutation in a family. Neurol Sci 2022; 43:2555.
  126. Vezyroglou A, Akilapa R, Barwick K, et al. The Phenotypic Continuum of ATP1A3-Related Disorders. Neurology 2022; 99:e1511.
  127. Segawa M, Hosaka A, Miyagawa F, et al. Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 1976; 14:215.
  128. Segawa M, Nomura Y, Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 2003; 54 Suppl 6:S32.
  129. Nygaard TG, Trugman JM, de Yebenes JG, Fahn S. Dopa-responsive dystonia: The spectrum of clinical manifestations in a large North American family. Neurology 1990; 40:66.
  130. Trender-Gerhard I, Sweeney MG, Schwingenschuh P, et al. Autosomal-dominant GTPCH1-deficient DRD: Clinical characteristics and long-term outcome of 34 patients. J Neurol Neurosurg Psychiatry 2009; 80:839.
  131. Tadic V, Kasten M, Brüggemann N, et al. Dopa-responsive dystonia revisited: Diagnostic delay, residual signs, and nonmotor signs. Arch Neurol 2012; 69:1558.
  132. Boyd K, Patterson V. Dopa responsive dystonia: A treatable condition misdiagnosed as cerebral palsy. BMJ 1989; 298:1019.
  133. Jan MM. Misdiagnoses in children with dopa-responsive dystonia. Pediatr Neurol 2004; 31:298.
  134. Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsive dystonia. Adv Neurol 1988; 50:377.
  135. Ichinose H, Ohye T, Takahashi E, et al. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 1994; 8:236.
  136. Lüdecke B, Dworniczak B, Bartholomé K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum Genet 1995; 95:123.
  137. Knappskog PM, Flatmark T, Mallet J, et al. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum Mol Genet 1995; 4:1209.
  138. Verbeek MM, Steenbergen-Spanjers GC, Willemsen MA, et al. Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. Ann Neurol 2007; 62:422.
  139. Steinberger D, Blau N, Goriuonov D, et al. Heterozygous mutation in 5'-untranslated region of sepiapterin reductase gene (SPR) in a patient with dopa-responsive dystonia. Neurogenetics 2004; 5:187.
  140. Brajkovic LD, Svetel MV, Kostic VS, et al. Dopamine transporter imaging (123)I-FP-CIT (DaTSCAN) SPET in differential diagnosis of dopa-responsive dystonia and young-onset Parkinson's disease. Hell J Nucl Med 2012; 15:134.
  141. Bandmann O, Goertz M, Zschocke J, et al. The phenylalanine loading test in the differential diagnosis of dystonia. Neurology 2003; 60:700.
  142. Saunders-Pullman R, Blau N, Hyland K, et al. Phenylalanine loading as a diagnostic test for DRD: Interpreting the utility of the test. Mol Genet Metab 2004; 83:207.
  143. Furukawa Y. GTP cyclohydrolase 1-deficient dopa-responsive dystonia. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1508/ (Accessed on April 11, 2011).
  144. Peall KJ, Kurian MA, Wardle M, et al. SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype. J Neurol 2014; 261:2296.
  145. Pandey S, Bhattad S, Dinesh S. Tremor in Primary Monogenic Dystonia. Curr Neurol Neurosci Rep 2021; 21:48.
  146. Lavenstein B, McGurrin P, Attaripour S, et al. KCNN2 Mutation in Pediatric Tremor Myoclonus Dystonia Syndrome with Electrophysiological Evaluation. Tremor Other Hyperkinet Mov (N Y) 2022; 12:2.
  147. Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol 2004; 61:1025.
  148. Bruno MK, Lee HY, Auburger GW, et al. Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia. Neurology 2007; 68:1782.
  149. Spacey SD, Adams PJ, Lam PC, et al. Genetic heterogeneity in paroxysmal nonkinesigenic dyskinesia. Neurology 2006; 66:1588.
  150. Müller U, Steinberger D, Németh AH. Clinical and molecular genetics of primary dystonias. Neurogenetics 1998; 1:165.
  151. Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology 1967; 17:680.
  152. Tomita Ha, Nagamitsu S, Wakui K, et al. Paroxysmal kinesigenic choreoathetosis locus maps to chromosome 16p11.2-q12.1. Am J Hum Genet 1999; 65:1688.
  153. Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011; 43:1252.
  154. Méneret A, Grabli D, Depienne C, et al. PRRT2 mutations: A major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 2012; 79:170.
  155. van Vliet R, Breedveld G, de Rijk-van Andel J, et al. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 2012; 79:777.
  156. Silveira-Moriyama L, Gardiner AR, Meyer E, et al. Clinical features of childhood-onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations. Dev Med Child Neurol 2013; 55:327.
  157. Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138:3476.
  158. Ekmen A, Meneret A, Valabregue R, et al. Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia. Neurology 2022; 98:e1077.
  159. Plant GT, Williams AC, Earl CJ, Marsden CD. Familial paroxysmal dystonia induced by exercise. J Neurol Neurosurg Psychiatry 1984; 47:275.
  160. Margari L, Perniola T, Illiceto G, et al. Familial paroxysmal exercise-induced dyskinesia and benign epilepsy: A clinical and neurophysiological study of an uncommon disorder. Neurol Sci 2000; 21:165.
  161. Münchau A, Valente EM, Shahidi GA, et al. A new family with paroxysmal exercise induced dystonia and migraine: A clinical and genetic study. J Neurol Neurosurg Psychiatry 2000; 68:609.
  162. Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 2008; 118:2157.
  163. Logroscino G, Livrea P, Anaclerio D, et al. Agreement among neurologists on the clinical diagnosis of dystonia at different body sites. J Neurol Neurosurg Psychiatry 2003; 74:348.
  164. Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: Report of an EFNS/MDS-ES Task Force. Eur J Neurol 2006; 13:433.
  165. Maas RPPWM, Wassenberg T, Lin JP, et al. l-Dopa in dystonia: A modern perspective. Neurology 2017; 88:1865.
  166. Nemeth AH. Dystonia overview. In: GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1155/ (Accessed on January 18, 2013).
  167. Powis Z, Towne MC, Hagman KDF, et al. Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions. Clin Genet 2020; 97:305.
  168. Kumar KR, Davis RL, Tchan MC, et al. Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes. Parkinsonism Relat Disord 2019; 69:111.
  169. Zech M, Jech R, Boesch S, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 2020; 19:908.
  170. Zech M, Jech R, Boesch S, et al. Scoring Algorithm-Based Genomic Testing in Dystonia: A Prospective Validation Study. Mov Disord 2021; 36:1959.
Topic 4886 Version 45.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟