U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Monogenic Isolated Dystonia Overview

, PhD, , MD, , MD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: December 11, 2025.

Estimated reading time: 46 minutes

Summary

The purpose of this overview is to:

1.

Briefly describe the clinical characteristics of monogenic isolated dystonia;

2.

Review the genetic causes of monogenic isolated dystonia;

3.

Review the differential diagnosis of monogenic isolated dystonia with a focus on genetic conditions;

4.

Provide an evaluation strategy to identify a monogenic cause of isolated dystonia in a proband (when possible);

5.

Review management of monogenic isolated dystonia;

6.

Inform genetic counseling of family members of an individual with monogenic isolated dystonia.

1. Clinical Characteristics of Monogenic Isolated Dystonia

Dystonia is defined as a movement disorder characterized by sustained or intermittent abnormal movements, postures, or both. Dystonic movements and postures are typically patterned and repetitive and may be tremulous or jerky. They are often initiated or worsened by voluntary action and are frequently associated with overflow movements [Albanese et al 2025].

Similar to dystonia in general, monogenic forms of dystonia are categorized into two groups based on associated clinical features, following the recommendations of an international expert panel [Albanese et al 2025]:

  • Isolated dystonia (the subject of this GeneReview). Dystonia is the only presentation without other motor or neurologic features. Individuals with isolated dystonia may have dystonic tremor that accompanies dystonia and does not represent a separate movement disorder.
  • Combined dystonia. All other forms of dystonia are considered combined dystonia (see Differential Diagnosis) and are divided into three subgroups:
    • Combined with other separate movement disorder entities (e.g., myoclonus, tremor, chorea, parkinsonism, ataxia)
    • Combined with other neurologic features (e.g., corticospinal signs, epilepsy, developmental delay)
    • Combined with systemic features (e.g., liver disease, kidney disease)

The clinical diagnosis of isolated dystonia is based on a detailed clinical neurologic examination and the absence of additional features.

Dystonia can be further classified clinically based on age at onset, body distribution (see Table 1), temporal pattern, and associated features [Albanese et al 2025].

Age of onset

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

Body distribution. See Table 1.

Table 1.

Type of Dystonia by Affected Body Part

Type# of Body Parts AffectedComment
Focal 1 1Examples:
  • Eyelids (blepharospasm)
  • Mouth (oromandibular dystonia, musician's cramp)
  • Larynx (dystonic adductor dysphonia, "whispering dysphonia")
  • Neck (cervical dystonia, previously known as spasmodic torticollis)
  • Hand & arm (writer's cramp)
Segmental 2-3 contiguous body partsExamples:
  • Axial (neck & trunk)
  • Brachial (1 arm & trunk; both arms ± neck ± trunk)
  • Crural (1 leg & trunk; both legs ± trunk)
Multifocal 2-3 non-contiguous body partsExamples:
  • Faciobrachial (blepharospasm & writer's cramp)
  • Bibrachial (both hands)
Hemidystonia ≥2Unilateral involvement of the upper and the lower limbs (w/ or w/o trunk, neck, or cranial regions)
Generalized ≥3Dystonia distribution that goes beyond segmental or multifocal and does not qualify for hemidystonia. Examples:
  • Trunk + 2 additional regions
  • 3 or 4 limbs w/o trunk
1.

Some focal dystonias may spread and eventually generalize.

Temporal pattern. The most recent nomenclature has three temporal descriptors, referring to onset, disease course, and variability.

  • The onset of dystonia can be:
    • Acute (within minutes, often indicative of a functional [psychogenic] form);
    • Subacute (within days to a few weeks, often in the case of an autoimmune process);
    • Gradual (within several months or years, usually seen in common adult-onset focal dystonias).
    Onset indicates the first occurrence of symptoms or signs of dystonia until the first peak of severity. When possible, the age at onset should be indicative of the onset of dystonia rather than co-occurring problems (e.g., seizures and cognitive impairment). If this is not possible, the age at onset should indicate the age at which a motor disorder became evident.
  • The disease course (from inception until clinical evaluation) can be:
    • Static (persistent, with little or no variations in symptoms and signs during natural history);
    • Progressive (worsening, with signs and symptoms that increase over time, perhaps related to neurodegeneration);
    • Fluctuating (with variations in intensity or distribution of dystonia over several months).
    The course of dystonia may change with longer observation periods.
  • The disease variability indicates changes in intensity or phenomenology of dystonia over shorter time periods than are considered under disease course, typically measurable during a day. This includes:
    • Paroxysmal dystonia (short, self-limited episodes of dystonia, often induced by a trigger, with a return to the preexisting neurologic state);
    • Diurnal variability (circadian variations in the occurrence, severity, and phenomenology of dystonia, for instance, in GCH1-linked dopa-responsive dystonia.

When dystonic movements are the presenting or predominant sign, determining the form of dystonia (i.e., isolated or combined) can be challenging. Whereas gradual-onset focal or segmental dystonia can be classified as isolated in most adult-onset dystonia, this is true for fewer than half of those with childhood-onset dystonia [Zech et al 2020]. Therefore, the presence of dystonia in a child must be considered a potential sign of combined dystonia (and often more complicated disease) and warrants thorough assessment (see Differential Diagnosis).

Nomenclature

Initially, monogenic dystonias were designated DYT followed by a number that represented the chronologic order in which the description of the phenotype and/or genetic discovery first appeared in the literature. Although some monogenic dystonias have a distinct phenotype, considerable phenotypic overlap can occur, making classification based on phenotype alone problematic (for example, DYT-THAP1 and DYT-VPS16 can mimic each other).

Because of the inconsistencies in the numeric DYT nomenclature, a naming system that combines the DYT designation and the name of the associated gene was proposed by Marras et al [2012] and is recommended by the Nomenclature of Genetic Movement Disorders by the International Parkinson's Disease and Movement Disorder Society Task Force [Lange et al 2022] (see Table 2). This naming system eliminates previously listed loci that were erroneous, duplicated, or unconfirmed. Disorders that are not predominantly dystonic are not labeled with a DYT prefix. In addition, distinguishing paroxysmal movement disorders by replacing DYT with PxMD is recommended [Marras et al 2016]. Paroxysmal movement disorders are not discussed in this chapter.

Although dystonia combined with systemic features (e.g., liver disease, kidney disease) has been referred to as complex dystonia, use of this term is no longer recommended due to lack of consensus regarding findings that would warrant a diagnosis of complex dystonia rather than combined dystonia [Albanese et al 2025].

2. Causes of Monogenic Isolated Dystonia

Genes

The Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders currently recognizes more than 50 established dystonia genes, most of which are occasionally implicated in isolated dystonia [Lange et al 2022]. With ongoing sequencing efforts, the list of dystonia candidate genes continues to grow, with more than 400 potential dystonia-associated genes to date [Thomsen et al 2025].

Of the established dystonia-related genes, 12 genes are confirmed to be primarily associated with isolated dystonia (see Table 2). Collectively, pathogenic variants in the 12 known isolated dystonia-related genes account for less than 10% of isolated dystonia [Thomsen et al 2025]. This includes DYT-TOR1A as the most prevalent form (~2% of individuals), DYT-ANO3, DYT-GNAL, DYT-THAP1, and DYT-VPS16 (each ~1%), and DYT-KMT2B (~0.5-1%), while the six other forms are very rare (<0.1%).

Table 2.

Monogenic Isolated Dystonia: Genes and Key Features

Gene 1Disorder 2MOIMedian Age at Onset (IQR)PhenotypeReference 2Genetically Related (Allelic) Disorders
ANO3 DYT-ANO3AD26 yrs (11-45)Mixed presentation w/generalized infantile-onset or focal/segmental adult-onset dystonia Lange et al [2021]
AOPEP DYT-AOPEPAR20 yrs (17-24)Early-onset, progressive, generalized dystonia Thomsen et al [2023]
EIF2AK2 DYT-EIF2AK2AD5 yrs (3-10)Childhood-onset generalized dystonia, sometimes w/cognitive impairment Thomsen et al [2023] EIF2AK2-NDD (w/o prominent dystonia) 3
EIF4A2 DYT-EIF4A2AD22 yrs (12-53)Variable onset; upper-body dystonia w/tremor Harrer et al [2023] EIF4A2-NDD 4
GNAL DYT-GNALAD
(AR) 5		40 yrs (25-47)Mostly adult-onset cervical dystonia (focal/segmental)DYT-GNAL; Lange et al [2021]Dystonic features in chromosome 18p deletion syndrome (OMIM 146390) are attributed to involvement of GNAL. 6
HPCA DYT-HPCAAR2 yrs (1-8)Childhood-onset, generalized, isolated/combined dystoniaLange et al [2021], Magrinelli et al [2022]Combined dystonia phenotypes (e.g., dystonia & chorea; dystonia & DD/ID, seizures, cognitive decline, & psychiatric comorbidities) 7
KMT2B DYT-KMT2BAD6 yrs (0-43)Childhood-onset, progressive, isolated/combined dystonia KMT2B-Related Disorders KMT2B-NDD (non-dystonic)
PRKRA DYT-PRKRAAR7 yrs (3-13)Childhood- or adolescence-onset generalized dystonia Lange et al [2021]
THAP1 DYT-THAP1AD
(AR) 5		14 yrs (8-25)Adolescent-onset segmental/generalized dystonia Lange et al [2021]
TOR1A DYT-TOR1AAD9 yrs (7-12)Childhood-onset generalized dystoniaDYT-TOR1A; Lange et al [2021]Arthrogryposis multiplex congenita has been reported in persons w/biallelic pathogenic variants (OMIM 618947)
TUBB4A DYT-TUBB4AAD22 yrs (18-25)Adult-onset laryngeal dystonia, often assoc w/cervical & upper-limb dystonia & frequent generalizationBally et al [2021]; Bally et al [2022]TUBB4A-related hypomyelinating leukodystrophy (OMIM 612438; see TUBB4A-Related Neurologic Disorders)
VPS16 DYT-VPS16AD
(AR) 5		14 yrs (9-24)Early-onset generalized dystonia, often w/craniocervical & axial involvement Thomsen et al [2023]

AD = autosomal dominant; AR = autosomal recessive; DYT = dystonia; MOI = mode of inheritance; IQR = interquartile range; NDD = neurodevelopmental disorder

1.

Genes are listed in alphabetical order.

2.
3.
4.
5.

Typically inherited in an autosomal dominant manner; autosomal recessive inheritance has been reported in a few families.

6.
7.

Disorders

DYT-ANO3

Number of affected individuals reported. To date, about 100 individuals have been reported. Pathogenic or likely pathogenic variants or variants of uncertain significance in ANO3 can be detected in up to 1% of individuals with dystonia [Olschewski et al 2019].

Age at onset. The median age at onset is 26 years (interquartile range [IQR]: 11-45 years; range: <1-69 years) with two peaks: one in the first decade of life and the second in the fifth decade of life (MDSGene).

Clinical manifestations at onset and disease progression. The initial report described individuals with tremulous cervical dystonia with variably associated upper-limb dystonic tremor, with onset often in the fourth decade of life [Charlesworth et al 2012]. Subsequent reports have described other findings ranging from infantile-onset generalized dystonia, sometimes associated with myoclonus [Tunc et al 2019], to adult-onset focal (cervical) dystonia, often accompanied by tremor [Ma et al 2015]. Cervical involvement is typical. Head tremor can be the initial manifestation. Other commonly involved sites are the limbs (upper more than lower) and the craniofacial and laryngeal regions. Axial involvement is rare.

Non-motor signs and symptoms are rarely reported in DYT-ANO3 [Lange et al 2021].

Mode of inheritance is autosomal dominant.

Molecular genetics. DYT-ANO3 is caused by heterozygous pathogenic variants in ANO3 (previously C11orf25 and TMEM16C). ANO3 encodes anoctamin-3 and seems to directly interact with sodium-activated potassium channels that are involved in maintenance of the resting membrane potential and, therefore, neuronal excitability [Kim et al 2022].

The interpretation of pathogenicity of variants, usually missense variants, is challenging since pedigrees are often small and a wide spectrum of rare benign missense variants can be found in variant databases and in healthy individuals. Tests for protein function are available but are labor intensive and are not routinely applied [Charlesworth et al 2012]. Notably, in some individuals, the presence of a de novo ANO3 variant supports the pathogenicity of that variant [Zech et al 2017].

DYT-AOPEP

Number of affected individuals reported. Biallelic pathogenic variants in AOPEP were described for the first time in individuals with dystonia in four families by Zech et al [2022]. To date, almost 20 individuals from 10 families have been reported with overlapping phenotypes [Boesch & Zech 2025].

Age at onset. The median age at onset is 20 years (IQR: 17-24 years; range: 9-36 years) (MDSGene).

Clinical manifestations at onset and disease progression. A disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles [Zech et al 2022]. Manifestations often start in the hands [Thomsen et al 2023]. Most individuals show generalized dystonia.

Note: Intrafamilial variability and interfamilial variability are considerable.

Non-motor signs and symptoms have not been reported in DYT-AOPEP.

Mode of inheritance is autosomal recessive.

Molecular genetics. AOPEP (previously C9orf3) encodes aminopeptidase O, a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance [Zech et al 2022].

Almost all reported variants are truncating, loss-of-function variants (frameshift, splice site, or nonsense).

DYT-EIF2AK2

Number of affected individuals reported. Pathogenic variants in EIF2AK2 were initially reported in a large family with early-onset generalized dystonia [Kuipers et al 2021]. To date, about 25 individuals with pathogenic variants in EIF2AK2 have been reported.

Age at onset is usually in the first or second decade of life (median: 5 years; IQR: 3-10 years; range: 1-18 years).

Clinical manifestations at onset and disease progression. Manifestations most frequently start in the limbs, often with subsequent generalization. Both upper limbs and lower limbs are involved with equal frequency [Thomsen et al 2023].

Other findings include spasticity (reported in several individuals) as well as developmental delay and cognitive impairment in some individuals (MDSGene).

Reduced penetrance has been reported in heterozygous adults, including unaffected older family members [Kuipers et al 2021].

Mode of inheritance is autosomal dominant.

Molecular genetics. EIF2AK2 (previously PRKR) encodes a kinase responsible for phosphorylation of EIF2A (eukaryotic translation initiation factor 2A).

Most reported individuals are heterozygous for the recurrent missense variant NM_001135651.3:c.388G>A (p.Gly130Arg) (de novo in some individuals).

All pathogenic EIF2AK2 variants reported to date are located within one of the double-stranded RNA-binding motifs of the protein that is also the site of interaction with PRKRA (encoded by PRKRA, in which pathogenic variants cause the isolated dystonia DYT-PRKRA) [Thomsen et al 2024a].

In both DYT-EIF2AK2 and DYT-EIF4A2, the proteins encoded by the respective genes are part of a protein complex that mediates microRNA-dependent translational repression and, thus, is considered to have a role in the regulation of protein synthesis.

To date, no truncating variants have been described in individuals with DYT-EIF2AK2.

DYT-EIF4A2

Number of affected individuals reported. To date, DYT-EIF4A2 has been reported in one study of 11 individuals from four families [Harrer et al 2023].

Age at onset. The median age at onset is 22 years with high variability (IQR: 12-53 years; range: 3-65 years).

Clinical manifestations at onset and disease progression. Dystonia mainly affects the upper body. Onset in almost all individuals was in the upper limbs with additional cervical involvement. Cranial involvement is also frequent. Dystonic features of varying severity can include tremor and jerky movements resembling myoclonus.

Other findings in about half of affected individuals often include mild, nonprogressive cognitive impairment or behavioral abnormalities [Harrer et al 2023].

Mode of inheritance is autosomal dominant.

Molecular genetics. EIF4A2 encodes eukaryotic initiation factor 4A-II (also referred to as eukaryotic translation initiation factor 4A2), which is part of a protein complex that mediates microRNA-dependent translational repression and thus is considered to have a role in the regulation of protein synthesis [Harrer et al 2023]. Two different frameshift variants and one in-frame deletion have been reported [Harrer et al 2023].

DYT-GNAL

Number of affected individuals reported. Pathogenic variants in GNAL were initially reported in families with adult-onset cervical dystonia that spread to involve cranial regions [Fuchs et al 2013]. To date, more than 100 individuals have been reported.

Age at onset. The median age at onset is 40 years (IQR: 25-47 years, range: 2-68 years) (MDSGene).

Clinical manifestations at onset and disease progression. Onset is usually focal or segmental, and rarely generalized [Lange et al 2021]. Dystonia usually manifests first in the neck and commonly progresses to the cranial region (oromandibular/jaw, larynx, eyelids) and/or to one arm.

Note: Intrafamilial variability and interfamilial variability are considerable.

Reduced penetrance has been reported in heterozygous adults from several families, including family members age 9 to 51 years [Vemula et al 2013].

Mode of inheritance is typically autosomal dominant. Autosomal recessive inheritance has been reported in a few families.

Molecular genetics. GNAL encodes guanine nucleotide-binding protein G(olf) subunit alpha, an alpha subunit of functional G protein-coupled receptors, considered to be involved in striatal dopamine signaling [Thomsen et al 2024a].The spectrum of pathogenic variants is broad, including missense and truncating variants but also whole-gene deletions.

A labor-intensive bioluminescence resonance energy transfer (BRET) assay is available to test the functionality of missense variants [Fuchs et al 2013].

DYT-HPCA

Number of affected individuals reported. Biallelic pathogenic variants in HPCA are a rare cause of dystonia that was first reported in 2015 in two families [Charlesworth et al 2015]. Since then, only about five additional families have been described in the literature (MDSGene).

Age at onset. The median age at onset is two years (IQR: 1-8 years; range: 0-20 years).

Clinical manifestations at onset and disease progression. Although dystonia usually starts in the first decade of life, onset in one individual was reported in the early 20s.

Onset sites are variable (neck, trunk, or limbs). Dystonia is typically severe, often involving the craniocervical region, all limbs, and the trunk.

Mode of inheritance is autosomal recessive.

Molecular genetics. HPCA encodes neuron-specific calcium-binding protein hippocalcin. Truncating and missense variants, usually homozygous, have been reported. Most reported missense variants are in the calcium-binding EF-hand 2 domain.

DYT-KMT2B

Number of affected individuals reported. Pathogenic heterozygous KMT2B variants were first reported by two independent groups at the end of 2016 and in early 2017 [Zech et al 2016, Meyer et al 2017]. To date, more than 200 individuals heterozygous for a KMT2B pathogenic variant have been described.

Age at onset. The median age at onset is six years (range: 0-43 years) [Lange et al 2021].

Clinical manifestations at onset and disease progression. Dystonia typically evolves from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties secondary to articulation difficulties (dysarthria) and low speech volume (hypophonia) are common. Bulbar dysfunction can lead to impaired swallowing with an increased risk of aspiration and need for gastrostomy tube placement in some. Approximately 27% of individuals have additional movement disorders including spasticity (~10%), myoclonus (~7%), tremor (~7%), chorea (~2%), and ataxia (~1.5%).

Most individuals have additional neurologic or systemic manifestations including intellectual disability / developmental delay, other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities), and neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.)

Mode of inheritance is autosomal dominant.

Molecular genetics. KMT2B encodes histone-lysine N-methyltransferase 2B (KMT2B), a ubiquitously expressed lysine-specific histone methyltransferase. KMT2B, a member of the SET/MLL protein family, is specifically involved in histone H3 lysine 4 (H3K4) methylation. Histone methylation is a post-translational epigenetic mechanism that either represses or activates gene transcription in a residue-specific manner [Shi & Whetstine 2007, Shilatifard 2008]. The histone methylation is accompanied by characteristic DNA methylation (episignature), which can serve as a functional readout to differentiate pathogenic KMT2B variants from benign variants [Mirza-Schreiber et al 2022, da Silva Carvalho et al 2024, Thomsen et al 2024b].

About 88% of affected individuals have a heterozygous pathogenic (or likely pathogenic) variant involving KMT2B; about 12% have a heterozygous deletion of 19q13.11-19q13.12 involving KMT2B.

DYT-PRKRA

Number of affected individuals reported. First described by Camargos et al [2008], DYT-PRKRA has been reported in about 30 individuals from 15 families.

Biallelic pathogenic variants in PRKRA were initially reported in Brazilian individuals with combined dystonia-parkinsonism [Camargos et al 2008]. However, reevaluation of the phenotype and literature reviews revealed that parkinsonism is neither a predominant nor a consistent finding, although the number of reported individuals is low (about 30 individuals from 15 families) [Lange et al 2021].

Age at onset. The median age at onset is seven years (IQR: 3-13 years; range: 1-53 years) (MDSGene).

Clinical manifestations at onset and disease progression. Manifestations usually start in the first or second decade of life, most often in a limb (upper limb more often than lower limb). Most individuals have generalized dystonia, including limb dystonia and laryngeal, craniofacial, cervical, and axial involvement. Laryngeal dystonia is often associated with dysphonia and/or dysarthria [Lange et al 2022].

Developmental delay and/or cognitive impairment have been described in about one third of individuals.

Mode of inheritance is autosomal recessive.

Molecular genetics. PRKRA encodes interferon-inducible double-stranded RNA-dependent protein kinase activator A, a kinase that is involved in the eIF2a pathway and, thus, linked to the integrated stress response [Calakos & Caffall 2024].

Most affected individuals are homozygous for the missense variant NM_003690.4:c.665C>T (p.Pro222Leu). To date, only missense variants have been identified in DYT-PRKRA.

DYT-THAP1

Number of affected individuals reported. Heterozygous pathogenic variants in THAP1 were initially reported in three Amish Mennonite families with a clinical presentation of mostly segmental or generalized dystonia [Fuchs et al 2009].

DYT-THAP1 is probably the third most frequent monogenic isolated dystonia, with about 300 reported individuals to date. A large-scale exome sequencing study found pathogenic THAP1 variants in almost 1% of individuals with dystonia [Thomsen et al 2025].

Age at onset is usually in the first or second decade of life but very rarely in infancy (median: 14 years; IQR: 8-25 years; range: 1-63 years) (MDSGene).

Clinical manifestations at onset and disease progression. The onset site varies and includes the upper limbs, neck, or craniofacial/laryngeal regions. Manifestations are mainly in the upper body with prominent craniocervical, arm, and axial involvement. A segmental/multifocal or generalized distribution is more frequent than focal dystonia. Dystonia affecting the tongue, larynx, and face is common, with many individuals having dysphonia or dysarthria.

Additional manifestations are rarely reported in DYT-THAP1.

Note: There is considerable interfamilial variability and intrafamilial variability [Lange et al 2021].

Mode of inheritance is typically autosomal dominant. Occasionally, autosomal recessive inheritance has been reported.

Several pathogenic variants were demonstrated to be de novo.

Penetrance is highly reduced and estimated at ~50%.

Molecular genetics. THAP1 encodes THAP domain-containing 1, a transcription factor. Pathogenic variants either lack nuclear localization or the capacity to bind to DNA [Thomsen et al 2024a]. The heterozygous variants causing autosomal dominant DYT-THAP1 include truncating and missense variants as well as a whole-gene deletion.

DYT-TOR1A

Number of affected individuals reported. A pathogenic recurrent TOR1A variant, the first identified monogenic cause of isolated dystonia [Ozelius et al 1997], was identified in the Ashkenazi Jewish population due to a founder effect. To date, more than 750 individuals from different ancestries have been reported in the literature.

Age at onset. The median age at onset is nine years (IQR: 7-12 years; range: 0-70 years), with the majority having childhood onset (MDSGene).

Clinical manifestations at onset and disease progression. DYT-TOR1A often starts as twisting of an extremity, usually in the upper limb and sometimes also in the lower limb; other onset sites are rare. Most individuals develop generalized dystonia; however, some present with multifocal/segmental dystonia, and even fewer with a focal distribution. Over the course of the disease, limb involvement is characteristic. While axial and cervical involvement is also seen in many individuals, only a few individuals have craniofacial or laryngeal involvement.

Like other monogenic isolated dystonias, there is considerable interfamilial variability and intrafamilial variability.

Penetrance is highly reduced (estimated to be only 30%) [Lange et al 2021].

Mode of inheritance is autosomal dominant.

Molecular genetics. TOR1A (previously DYT1) encodes torsin-1A, a member of the AAA family of adenosine triphosphatases (ATPases) associated with diverse cellular activities. Torsin-1A dysfunction has been linked to alterations of the nuclear envelope [Goodchild et al 2005].

More than 98% of affected individuals have an in-frame 3-bp deletion c.907_909delGAG involving the highly conserved GAGGAG sequence in exon 5 (NM_000113.3:c.907_909delGAG [p.Glu303del]). The variant seems to be a mutation hotspot, and de novo occurrence has been demonstrated several times.

A few additional missense variants and another in-frame deletion have also been described.

Note: A benign missense TOR1A variant (NM_000113.3:c.646G>C [p.Asp216His]) seems to modulate the penetrance of the GAG deletion and reduces it to only about 3% [Risch et al 2007].

DYT-TUBB4A

Number of affected individuals. A TUBB4A pathogenic heterozygous missense variant was first reported in a clinically well-defined multigenerational United Kingdom / Australian pedigree by two independent research teams in 2013 [Hersheson et al 2013, Lohmann et al 2013]. To date, about 20 individuals from eight families have been described, all with missense variants, including one unrelated individual with the same missense variant as the original family (NM_006087.4:c.4C>G [p.Arg2Gly]) [Keritam et al 2025].

Age at onset is often in the third decade of life (median: 22 years; IQR: 18-25 years; range: 2-60 years).

Clinical manifestations at onset and disease progression. Laryngeal involvement is a hallmark feature of DYT-TUBB4A, and the larynx is often also the site of onset. Dystonia often affects other body parts also, including the neck and the upper limbs, with a tendency to generalize. A characteristic "hobby horse" gait has been reported in at least two unrelated families [Wilcox et al 2011, Bally et al 2021].

Penetrance. Although penetrance in the original family [Wilcox et al 2011] appeared to be complete, reduced penetrance has subsequently been reported in two additional families [Bally et al 2021].

Mode of inheritance is autosomal dominant.

Molecular pathogenesis TUBB4A encodes the brain-specific tubulin beta-4A chain isotope, an important component of the microtubule network. Pathogenic variants have been shown to impair microtubule-associated transport, including the transport of mitochondria [Vulinovic et al 2018].

DYT-VPS16

Number of affected individuals. VPS16 heterozygous variants were first reported as causal for dystonia by Steel et al [2020]. To date, more than 70 individuals have been described.

DYT-VPS16 is one of the most common monogenic forms of isolated dystonia on a global scale. A large-scale exome sequencing study found pathogenic VPS16 variants in ~1% of individuals [Thomsen et al 2025].

Age at onset is usually in the first or second decade of life (median: 14 years; IQR: 9-24 years; range: 0-70 years) (MDSGene).

Clinical manifestations at onset and disease progression. Onset is mostly in the upper body, involving the hand, neck, or oromandibular region. Over the course of the disease, limb involvement is prominent; cervical, laryngeal, and axial dystonia are common. In most individuals, dystonia is generalized [Thomsen et al 2023].

Additional features include cognitive impairment in about 10% and anxiety in about 5% (MDSGene).

Penetrance. Older unaffected individuals who are heterozygous for a VPS16 pathogenic variant have been described, suggesting reduced penetrance in DYT-VPS16.

Mode of inheritance. DYT-VPS16 is mostly inherited in an autosomal dominant manner.

Autosomal recessive inheritance has also been described, usually with biallelic missense variants that may individually (monoallelically) exert a milder effect. Cai et al [2016] suggested that homozygosity for a relatively frequent missense variant (supported by functional studies) in the Asian population was the cause of dystonia in a Chinese family with four affected sibs. Several additional individuals with biallelic pathogenic variants have been identified [K Lohmann & M Zech, unpublished data].

Molecular pathogenesis. VPS16 encodes vacuolar protein sorting-associated protein 16 homolog, a core subunit of the CORVET and HOPS (homotypic fusion and protein sorting) complexes, and thus links this form of isolated dystonia to autophagy and lysosomal function. The HOPS complex mediates the fusion of late endosomes and autophagosomes with lysosomes and, therefore, plays a fundamental role in removing misfolded or aggregated proteins and damaged cellular organelles [Thomsen et al 2024a].

Autosomal dominant inheritance is often associated with loss-of-function variants such as nonsense, frameshift, and splice site changes.

3. Differential Diagnosis of Monogenic Isolated Dystonia

Dystonias are clinically and genetically highly heterogeneous, which complicates the genetic diagnosis and leads to a long list of differential diagnoses.

Pathogenic variants in genes that usually present with combined dystonia or even other movement disorders may also, albeit rarely, be found in individuals with isolated dystonia, including GCH1, PRKN, SGCE, SLC2A1, and CACNA1A [Thomsen et al 2025]. Among these differential diagnoses, DYT/PARK-GCH1 (see GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia) has great importance because it is responsive to levodopa treatment [Weissbach et al 2021].

Despite a positive family history in about 25% of individuals with dystonia, the diagnostic yield of genome sequencing is <50% and depends on age at onset (higher in individuals with early onset than in those with late onset), family history (higher when multiple family members have dystonia), distribution of dystonia (highest in generalized dystonia), and presence of additional features (lower in isolated dystonia than in combined dystonia) [Thomsen et al 2025].

The absence of an identifiable genetic cause in most individuals with isolated dystonia suggests that (1) additional, as-yet unidentified genes are associated with dystonia, (2) digenic and oligogenic contributions may play a role, and (3) acquired causes of dystonia may account for a proportion of isolated dystonia, particularly among individuals with later-onset focal dystonia (the most common dystonia phenotype observed in epidemiologic studies) [Zech et al 2020].

Table 3.

Differential Diagnosis: Acquired Causes of Isolated Dystonia

CauseEtiologyExamples
Acquired brain lesions Hypoxic insultsLesion-induced cerebral palsy, bronchopulmonary dysplasia
InfectionsCreutzfeldt-Jakob disease, mycoplasma pneumonia, Japanese B encephalitis, tuberculosis
Parainfectious disordersReye syndrome, subacute sclerosing panencephalitis
Autoimmune disordersMultiple sclerosis, antiphospholipid-antibody syndrome
Metabolic disordersKernicterus, hypoparathyroidism, central pontine myelinolysis
Vascular insultsStroke, arteriovenous malformation
Traumatic brain injury
Space-occupying lesions
IntoxicationsCarbon monoxide, manganese
Drug-induced dystonia Neuroleptics
Anticonvulsants
Psychogenic dystonia UnknownSee Geroin et al [2024] & Cherian et al [2025].

4. Evaluation Strategies to Identify the Cause of Monogenic Isolated Dystonia in a Proband

Genomic/Genetic Testing

Genetic testing is an essential component of establishing a specific dystonia diagnosis and initiating appropriate treatment (see Genetic Counseling).

Molecular genetic testing approaches, in general, can include a combination of gene-targeted testing (multigene panel, single gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved; genomic testing does not.

Comprehensive genomic testing. Exome sequencing is most commonly used; genome sequencing is also possible [Zech et al 2025].

Given the extensive genetic heterogeneity of monogenic isolated dystonia, diagnostic gene-specific approaches or panels are often impractical, making comprehensive genomic methods like exome or genome sequencing the most efficient path to diagnosis [Thomsen et al 2025]. These screening strategies can also be reanalyzed to include novel disease genes, increasing the diagnostic yield in the long term [Laurie et al 2025].

Since nucleotide repeat expansions have not been identified to be associated with (isolated) dystonia to date, and complex structural rearrangements are only rarely identified as pathogenic mechanisms in genetic dystonias, short-read next-generation sequencing approaches are currently considered a sufficient approach. The diagnostic yield of long-read sequencing (LRS) in dystonia is not yet well-known and is an area under investigation [Wirth et al 2025]. In a pilot study, LRS was shown to improve resolution and/or interpretation of specific variant types related to dystonia such as structural variants and unphased variants [Sorrentino et al 2025].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

A multigene panel that includes some or all the genes listed in Table 2 may identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. However, such panels are not flexible enough to easily include newly discovered dystonia genes and may lack genes that need to be considered in the differential diagnosis. Thus, multigene panels are not recommended, and an exome or genome sequencing approach with targeted analysis of a panel of genes might be more cost efficient and applicable. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Candidate gene testing. Specific genetic testing in isolated monogenic dystonias, i.e., a candidate gene approach, is complicated by the highly heterogeneous nature of genetic dystonias, the ever-expanding number of dystonia-associated genes, and reliance on clinical findings due to the absence of established biomarkers [Thomsen et al 2025].

If a candidate gene approach is required, for instance, due to limited resources, the following should be considered:

  • DYT-TOR1A, DYT-THAP1, and DYT-VPS16 are the most common monogenic isolated dystonias, with just one specific recurrent variant in the case of DYT-TOR1A.
  • Ancestry might guide genetic testing due to founder variants for DYT-TOR1A in the Ashkenazi Jewish population and for DYT-PRKRA in the Brazilian population (MDSGene).

Clinical findings that could be considered to guide testing include the following:

  • In contrast to other monogenic isolated dystonias, DYT-ANO3 and DYT-GNAL often (1) manifest in adulthood (median age at onset >25 years) and (2) remain focal with predominant cervical involvement, making it clinically difficult to distinguish between them and from non-genetic dystonia.
  • The presence of myoclonus, a recurrent feature of DYT-ANO3, is also often present in DYT-VPS16 but is rare in DYT-GNAL and dystonia of unknown cause.
  • Dystonia combined with developmental delay and/or cognitive impairment makes DYT-KMT2B or DYT-EIF2AK2 more likely.
  • Onset of dystonia in infancy makes DYT-HPCA a consideration.
  • All monogenic isolated dystonias except DYT-GNAL and DYT-TUBB4A frequently affect the limbs.
  • Laryngeal dystonia is most frequent in DYT-THAP1 and DYT-TUBB4A.

5. Management

No clinical practice guidelines for monogenic isolated dystonia have been published. In the absence of published guidelines, the following recommendations are based on the literature, which is scarce, and the authors' personal experience managing individuals with these disorders. A neurologist specializing in movement disorders should be involved soon after diagnosis and subsequently over the disease course to assess and discuss therapeutic options, including pharmacologic and potential surgical treatments.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a monogenic isolated dystonia, the evaluations summarized in Table 4 are recommended.

Table 4.

Monogenic Isolated Dystonia: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Dystonic movement disorder Thorough neurologic examTo assess for:
  • Dystonia, coexistence of tremor, jerky movements
  • Dystonia progression &/or spread to other body regions w/standardized scale 1
  • Candidacy for deep brain stimulation therapy
Speech involvement Eval by speech therapist &/or ENT specialistsTo assess need for:
  • Augmentative or alternative means of communication
  • Speech therapy
  • Specific treatment of laryngeal or oromandibular dystonia
Dysphagia Eval by swallowing specialist &/or ENT specialistConsider endoscopic eval of swallowing to identify persons at ↑ risk for aspiration.
Cognitive function / Psychiatric comorbidity Assessment of cognitive complaints & neuropsychiatric testing if concernsConsider more structured assessment of behavioral & cognitive functioning for genetic isolated dystonia w/reported neurobehavioral/cognitive involvement (e.g., ANO3, EIF2AK2, EIF4A2, HPCA, KMT2B, PRKRA, VPS16), w/eval for mood disorders, anxiety, & fatigue & assessment of need for pharmacologic & psychotherapeutic interventions.
Development
(if diagnosed in young children)		Eval by developmental pediatricianConsider developmental assessment more routinely for genetic isolated dystonia w/reported possible neurodevelopmental comorbidity (e.g., ANO3, EIF2AK2, EIF4A2, HPCA, KMT2B, PRKRA, VPS16).
Activities of daily living Eval by physiatrist, PT, &/or OTConsider more detailed assessment of functionality in generalized dystonia or more widespread body distribution.
Musculoskeletal Eval w/detailed neurologic exam &/or eval by orthopedistTo assess for:
  • Fixed deformity
  • Contractures
  • Joint dislocation
  • Kyphoscoliosis
Pain Eval of acute & chronic pain by neurologist or in interdisciplinary pain centerConsider use of pain assessment tools & systematic pain eval processes to identify need for pain treatment.
Genetic counseling By genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of monogenic isolated dystonia to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist

1.

E.g., Burke-Fahn-Marsden Dystonia Rating Scale-Motor/Disability (BFMDRS-M/D), Unified Dystonia Rating Scale, Global Dystonia Rating Scale

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for monogenic isolated dystonia. Targeted therapies addressing the specific underlying mechanisms of disease causation are not available.

Supportive care to reduce symptom severity, maximize function, and improve quality of life is recommended. Supportive care can also reduce complications, including deformities and pain. Depending on the clinical picture and degree of disability, affected individuals can benefit from multidisciplinary care involving specialists in relevant fields, including neurologists, physical therapists, occupational therapists, orthopedists, speech-language specialists, otolaryngologists, and psychiatrists.

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Monogenic Isolated Dystonia: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Dystonic movement disorder Pharmacologic treatment by a neurologist who is a movement disorder specialist
  • Use of oral anti-dystonic agents incl anticholinergics (e.g., trihexyphenidyl), GABAergic drugs (e.g., baclofen), benzodiazepines, & ASMs (e.g., gabapentin) may result in variable improvement of motor manifestations; however, because there are often no long-term benefits, side effects (e.g., drowsiness & negative impact on cognitive abilities, esp during anticholinergic therapy) should be considered w/any positive treatment outcomes.
  • An initial trial w/oral medications would be considered reasonable depending on individualized mgmt decisions; however, a few reports on their effects specifically in monogenic isolated dystonia are available.
  • Use of oral pharmacologic treatment requires monitoring of benefits & side effects.
  • Treatment should start at a low dose according to published guidelines & then titrated up slowly to lowest effective dose w/o side effects.
  • Levodopa (up to 600-1,000 mg/day in adults, 20 mg/kg/day in children) was partially beneficial in a few persons w/DYT-ANO3, DYT-EIF2AK2, & DYT-VPS16, even though these conditions do not belong to the group of dopa-responsive dystonias.
Chemodenervation by a neurologist who is a movement disorder specialist
  • Botulinum neurotoxin (BoNT) injections can produce satisfactory relief of dystonia in local muscle groups while avoiding systemic side effects.
  • BoNT is effective in ↓ excess muscle activity in cervical, eyelid, oromandibular, laryngeal, & focal limb dystonia.
  • Types of BoNT type A most used are onabotulinumtoxinA, abobotulinumtoxinA, & incobotulinumtoxinA.
  • Specific injection schedules are tailored to affected person's presentation & manifestations.
Bilateral globus pallidus interna deep brain stimulation (GPi-DBS) by a neurologist who is a movement disorder specialist & a neurosurgeon
  • GPi-DBS is useful to treat isolated dystonia based on individualized treatment plans.
  • The genetic subtypes have been shown to respond differentially.
  • DYT-TOR1A had a 68% improvement in BFMDRS-M compared to 37% improvement DYT-THAP1. 1
  • Mean improvement in BFMDRS-M was 42% in DYT-VPS16 2 & 43% in DYT-KMT2B. 3
  • For other monogenic isolated dystonias, response to DBS has not been systematically investigated to date. Variable benefit was reported for a few affected persons only w/DYT-ANO3, 4 DYT-AOPEP, 5 DYT-EIF2AK2, 6 DYT-GNAL, 7 DYT-HPCA, 8 & DYT-PRKRA. 9
  • Worse outcomes from DBS in monogenic isolated dystonia are often associated w/longer duration since initial onset of dystonia &/or higher baseline BFMDRS scores.
By physiatrist, PT, &/or OT
  • Early initiation of PT & a tailored exercise program can avoid secondary complications & improve function & independence in mobility.
  • Adaptative aids (e.g., walkers, ankle-foot orthoses) can support & maintain ambulation.
Speech involvement By a speech-language therapist familiar w/treatment of speech manifestations in persons w/dystonia
  • Consider BoNT therapy for laryngeal or oromandibular dystonia.
  • Consider augmentative & alternative communication methods as needed (e.g., writing pads & digital devices).
Dysphagia By a speech-language therapist, swallowing therapist, &/or ENT specialist
  • Modify food consistency to ↓ aspiration risk.
  • Consider endoscopic eval to meet optimal swallowing needs.
Cognitive impairment / Psychiatric manifestations
  • Psychotherapeutic interventions
  • Neuropsychological rehab
  • Pharmacologic treatment of mood disorders, anxiety, & fatigue
Refer to psychiatrist if needed to initiate treatment per standard practice.
Developmental delay Early intervention program for access to occupational, physical, speech, & feeding therapy as well as infant mental health services & special educatorsRefer to developmental pediatrician if needed.
Fixed deformities / Scoliosis Surgical interventionRefer to orthopedic surgeon if needed.
Pain Interdisciplinary pain treatmentRefer to specialized pain center if needed.

ASM = anti-seizure medication; BFMDRS-M = Burke-Fahn-Marsden Dystonia Rating Scale-Motor; OT = occupational therapist/therapy; PT = physical therapist/therapy

1.
2.
3.
4.
5.
6.
7.
8.
9.

Different monogenic forms of dystonia respond differently to treatment options. Key findings are summarized in Table 6.

Table 6.

Monogenic Isolated Dystonia: Gene-Based Management of Dystonia

DisorderManagement Based on Systematic Literature Reviews 1
DYT-ANO3
  • Botulinum toxin injections are effective, esp for focal presentations.
  • Possibly good response to dopaminergic treatment in some persons
  • Anticholinergics & ASMs may be beneficial.
  • Several individuals responded to DBS.
DYT-AOPEP
  • DBS is beneficial in a few reported persons.
  • Pharmacologic treatment attempts have been mostly unsuccessful.
  • Limited data are available.
DYT-EIF2AK2
  • Dopaminergic treatment has had variable outcomes.
  • Partially responsive to DBS
DYT-EIF4A2No information available
DYT-GNAL
  • DBS seems to be effective.
  • Botulinum toxin injections are effective, esp for focal presentations.
  • Dopaminergic drugs have had no effect.
DYT-HPCAPoor or no response to common anti-dystonic medications 2
DYT-KMT2B
  • Anticholinergic treatment has been beneficial in about half of treated persons.
  • DBS often has good benefit.
  • Variable effects from botulinum toxin injections, benzodiazepines, baclofen, neuroleptics, & ASMs
  • Dopaminergic drugs are mostly ineffective.
DYT-PRKRA
  • DBS may be helpful.
  • Botulinum toxin injections, baclofen, & benzodiazepines have had no effect.
DYT-THAP1
  • Botulinum toxin injections & anticholinergic medication have had fairly good outcomes.
  • DBS has had variable outcomes.
  • Dopaminergic drugs have not been effective.
DYT-TOR1A
  • DBS has been used in >200 individuals, often with good to excellent response.
  • Other surgical methods (thalamotomy, pallidotomy) were effective in about half of the few treated individuals.
  • Botulinum toxin injections, anticholinergics, & baclofen have had a beneficial effect in some individuals (but the numbers are small).
  • Benzodiazepine & dopamine are rather ineffective.
DYT-VPS16
  • Partial response to levodopa, anticholinergics, &/or botulinum toxin injections 3
  • DBS has been beneficial with some improvement. 4

ASM = anti-seizure medication; DBS = deep brain stimulation

1.
2.
3.
4.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Genetic Isolated Dystonia: Recommended Surveillance

System/ConcernEvaluationFrequency
Dystonic movement disorder Assess for progression & spread to other body regions.2-4x/yr depending on severity of manifestations
Speech involvement Monitoring by speech therapistAssess for new manifestations at follow-up visits
Dysphagia Monitoring by ENT specialist
Cognitive function / Psychiatric comorbidity Assessment for cognitive impairment, mood disorders, & behavioral disorders
Developmental delay
(if diagnosed in young children)		Monitoring of developmental progress & educational needs
Activities of daily living Assessment of self-help skills by PTAt each visit
Musculoskeletal Monitor for foot deformities, contractures, dislocations, & scoliosis.
Pain Assess pain w/pain rating scales, & use interdisciplinary pain care.
Family/Community Assess needs of individual & family & need for care coordination.

PT = physical therapist

6. Genetic Counseling

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

Mode of Inheritance

Monogenic isolated dystonias are inherited in an autosomal dominant and/or autosomal recessive manner.

  • Autosomal dominant inheritance: DYT-ANO3, DYT-EIF2AK2, DYT-EIF4A2, DYT-KMT2B, DYT-TOR1A, and DYT-TUBB4A
  • Autosomal recessive inheritance: DYT-AOPEP, DYT-HPCA, and DYT-PRKRA
  • Autosomal dominant or, rarely, autosomal recessive inheritance: DYT-GNAL, DYT-THAP1, DYT-VPS16
    DYT-GNAL, DYT-THAP1, and DYT-VPS16 are usually inherited in an autosomal dominant manner; autosomal recessive inheritance has been reported in a few families.

Genetic counseling and risk assessment depend on determination of the specific cause of monogenic isolated dystonia in an individual.

A basic view of monogenic isolated dystonia risk assessment for at-risk family members is presented in this section; issues that may be specific to a given family or genetic cause of dystonia are not comprehensively addressed.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with autosomal dominant monogenic isolated dystonia inherited a causative pathogenic variant from a parent. Because many of the monogenic isolated dystonias demonstrate reduced penetrance, a parent who is heterozygous for a pathogenic variant associated with autosomal dominant isolated dystonia may or may not have manifestations of the disorder.
  • Some individuals diagnosed with isolated dystonia have the disorder as the result of a de novo pathogenic variant. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of manifestations, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a monogenic isolated dystonia-related pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant.
  • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

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

Offspring of a proband. Each child of an individual with autosomal dominant isolated dystonia has a 50% chance of inheriting the dystonia-related pathogenic variant; because many of the monogenic dystonias demonstrate reduced penetrance, offspring who inherit a monogenic isolated dystonia-related pathogenic variant may or may not develop dystonia.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the monogenic isolated dystonia-related pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a dystonia-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygous sibs of an individual with autosomal recessive monogenic isolated dystonia are asymptomatic and are, to current knowledge, not at risk of developing monogenic isolated dystonia.

Offspring of a proband. The offspring of an individual with autosomal recessive monogenic isolated dystonia are obligate heterozygotes (carriers) for a dystonia-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a monogenic isolated dystonia-related pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the monogenic isolated dystonia-related pathogenic variants in the family.

Related Genetic Counseling Issues

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands (and potentially other family members) in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the monogenic isolated dystonia-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for dystonia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

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

Chapter Notes

Author Notes

PD Dr Michael Zech, Institute of Human Genetics, TUM University Hospital, Technical University of Munich, Munich, Germany and Institute of Neurogenomics, Helmholtz Munich, Munich, Germany. Email: ed.mut.irm@hcez.leahcim; web page: www.humangenetik.mri.tum.de

Dr Lara M Lange, Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. Email: ed.kcebeul-inu@egnal.al

Acknowledgments

The authors would like to thank Clara Krüger, BSc, for her support with the MDSGene-related literature review.

KL's dystonia work has been supported by the German Research Foundation (DFG), the Dystonia Medical Research Foundation (DMRF), and the German Ministry of Education and Sciences. MZ's dystonia work has been supported by the German Research Foundation, the Else Kröner-Fresenius-Stiftung, the German Federal Ministry of Education and Research, the European Joint Programme on Rare Diseases, and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder as well as Technical University of Munich – Institute for Advanced Study. LML's research related to dystonia was supported by a dystonia fellowship stipend from the Bachmann-Strauss Dystonia and Parkinson Foundation. CK's dystonia research was supported by the DFG, the DMRF, and GP2.

Author History

Christine Klein, MD (2014-present)
Lara Lange, MD (2025-present)
Katja Lohmann, PhD (2017-present)
Connie Marras, MD, PhD; University of Toronto (2014-2025)
Alexander Münchau, MD; University of Lübeck (2014-2025)
Andrea H Nemeth, MRCP, DPhil; Churchill Hospital and Institute of Molecular Medicine (2003-2014)
Michael Zech, MD (2025-present)

Revision History

  • 11 December 2025 (bp) Comprehensive update posted live
  • 22 June 2017 (sw) Comprehensive update posted live
  • 1 May 2014 (me) Comprehensive update posted live
  • 23 January 2006 (me) Comprehensive update posted live
  • 28 October 2003 (me) Review posted live
  • 8 April 2003 (an) Original submission

References

Literature Cited

  • Albanese A, Bhatia KP, Fung VSC, Hallett M, Jankovic J, Klein C, Krauss JK, Lang AE, Mink JW, Pandey S, Teller JK, Tijssen MAJ, Vidailhet M, Jinnah HA. Definition and classification of dystonia. Mov Disord. 2025;40:1248-59. [PMC free article: PMC12273609] [PubMed: 40326714]
  • Artusi CA, Dwivedi A, Romagnolo A, Bortolani S, Marsili L, Imbalzano G, Sturchio A, Keeling EG, Zibetti M, Contarino MF, Fasano A, Tagliati M, Okun MS, Espay AJ, Lopiano L, Merola A. Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2020;91:426-33. [PubMed: 32079672]
  • Bally JF, Camargos S, Oliveira Dos Santos C, Kern DS, Lee T, Pereira da Silva-Junior F, Puga RD, Cardoso F, Barbosa ER, Yadav R, Ozelius LJ, de Carvalho Aguiar P, Lang AE. DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations. Neurology. 2021;96:e1887-e1897. [PMC free article: PMC8105968] [PubMed: 32943487]
  • Bally JF, Kern DS, Fearon C, Camargos S, Pereira da Silva-Junior F, Barbosa ER, Ozelius LJ, de Carvalho Aguiar P, Lang AE. DYT-TUBB4A (DYT4 dystonia): clinical anthology of 11 cases and systematized review. Mov Disord Clin Pract. 2022;9:659-75. [PMC free article: PMC9274350] [PubMed: 35844288]
  • Boesch S, Zech M. AOPEP-related autosomal recessive dystonia: update on Zech-Boesch syndrome. J Med Genet. 2025;62:388-95. [PubMed: 40147878]
  • Braccia A, Carecchio M, Sciacca FL, Castagna A, Elia AE, Romito LM. Tremulous dystonia due to GNAL haploinsufficiency caused by 18p deletion syndrome. J Mov Disord. 2024;17:354-56. [PMC free article: PMC11300386] [PubMed: 38736233]
  • Cai X, Chen X, Wu S, Liu W, Zhang X, Zhang D, He S, Wang B, Zhang M, Zhang Y, Li Z, Luo K, Cai Z, Li W. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia. Sci Rep. 2016;6:25834. [PMC free article: PMC4865952] [PubMed: 27174565]
  • Calakos N, Caffall ZF. The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia. J Clin Invest. 2024;134:e177833. [PMC free article: PMC10977992] [PubMed: 38557486]
  • Camargos S, Scholz S, Simon-Sanchez J, Paisan-Ruiz C, Lewis P, Hernandez D, Ding J, Gibbs JR, Cookson MR, Bras J, Guerreiro R, Oliveira CR, Lees A, Hardy J, Cardoso F, Singleton AB. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 2008;7:207-15. [PubMed: 18243799]
  • Casagrande SCB, Listik C, Coelho DB, Limongi JCP, Teixeira LA, Teixeira MJ, Barbosa ER, Cury RG. Deep brain stimulation in patients with isolated generalized dystonia caused by PRKRA mutation. Mov Disord Clin Pract. 2019;6:616-8. [PMC free article: PMC6749865] [PubMed: 31538099]
  • Charlesworth G, Angelova PR, Bartolome-Robledo F, Ryten M, Trabzuni D, Stamelou M, Abramov AY, Bhatia KP, Wood NW. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am J Hum Genet. 2015;96:657-65. [PMC free article: PMC4385177] [PubMed: 25799108]
  • Charlesworth G, Plagnol V, Holmstrom KM, Bras J, Sheerin UM, Preza E, Rubio-Agusti I, Ryten M, Schneider SA, Stamelou M, Trabzuni D, Abramov AY, Bhatia KP, Wood NW. Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis. Am J Hum Genet. 2012;91:1041-50. [PMC free article: PMC3516598] [PubMed: 23200863]
  • Cherian A, Kalikavil Puthanveedu D, Sundaram S, et al. A case series of functional movement disorders in paediatric population-phenomenology and clinical characteristics. Acta Neurol Belg. 2025;125:1287-92. [PubMed: 40619500]
  • da Silva Carvalho GF, de Gusmão CM, Wolff BM, Vieira LL, de Oliveira YG, Costa MR, da Silva Mendes R, Castro MAA, Sakuma MT, Kok F, Sadikovic B, Kulikowski LD. Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool. Clin Epigenetics. 2024;16:169. [PMC free article: PMC11590325] [PubMed: 39587624]
  • Fuchs T, Gavarini S, Saunders-Pullman R, Raymond D, Ehrlich ME, Bressman SB, Ozelius LJ. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet. 2009;41:286-8. [PubMed: 19182804]
  • Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, Lang AE, Liang TW, Trosch RM, White S, Ainehsazan E, Herve D, Sharma N, Ehrlich ME, Martemyanov KA, Bressman SB, Ozelius LJ. Mutations in GNAL cause primary torsion dystonia. Nat Genet. 2013;45:88-92. [PMC free article: PMC3530620] [PubMed: 23222958]
  • Geroin C, Petracca M, Di Tella S, Marcuzzo E, Erro R, Cuoco S, Ceravolo R, Mazzucchi S, Pilotto A, Padovani A, Romito LM, Eleopra R, Zappia M, Nicoletti A, Dallocchio C, Arbasino C, Bono F, Laterza V, Demartini B, Gambini O, Modugno N, Olivola E, Bonanni L, Albanese A, Ferrazzano G, Tessitore A, Lopiano L, Calandra-Buonaura G, Morgante F, Esposito M, Pisani A, Manganotti P, Tesolin L, Teatini F, Camozzi S, Ercoli T, Stocchi F, Coletti Moja M, Defazio G, Tinazzi M. Elderly onset of functional motor disorders: clinical correlates from the Italian registry. Mov Disord Clin Pract. 2024;11:38-44. [PMC free article: PMC10828615] [PubMed: 38291844]
  • Goodchild RE, Kim CE, Dauer WT. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron. 2005;48:923-32. [PubMed: 16364897]
  • Harrer P, Skorvanek M, Kittke V, Dzinovic I, Borngraber F, Thomsen M, Mandel V, Svorenova T, Ostrozovicova M, Kulcsarova K, Berutti R, Busch H, Ott F, Kopajtich R, Prokisch H, Kumar KR, Mencacci NE, Kurian MA, Di Fonzo A, Boesch S, Kuhn AA, Blumlein U, Lohmann K, Haslinger B, Weise D, Jech R, Winkelmann J, Zech M. Dystonia linked to EIF4A2 haploinsufficiency: a disorder of protein translation dysfunction. Mov Disord. 2023;38:1914-24. [PubMed: 37485550]
  • Hersheson J, Mencacci NE, Davis M, MacDonald N, Trabzuni D, Ryten M, Pittman A, Paudel R, Kara E, Fawcett K, Plagnol V, Bhatia KP, Medlar AJ, Stanescu HC, Hardy J, Kleta R, Wood NW, Houlden H. Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia. Ann Neurol. 2013;73:546-53. [PMC free article: PMC3698699] [PubMed: 23424103]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
  • Keritam O, Badmann S, Jacob M, Harrer P, Klein C, Kurz A, Cetin H, Zech M. Rediscovery of the tubulin beta-4A p.Arg2Gly variant in whispering dysphonia: a report from Austria. Mov Disord. 2025;40:1725-6. [PMC free article: PMC12371619] [PubMed: 40415656]
  • Kim H, Kim E, Lee BC. Investigation of phosphatidylserine-transporting activity of human TMEM16C isoforms. Membranes (Basel). 2022;12:1005. [PMC free article: PMC9611045] [PubMed: 36295764]
  • Kuipers DJS, Mandemakers W, Lu CS, Olgiati S, Breedveld GJ, Fevga C, Tadic V, Carecchio M, Osterman B, Sagi-Dain L, Wu-Chou YH, Chen CC, Chang HC, Wu SL, Yeh TH, Weng YH, Elia AE, Panteghini C, Marotta N, Pauly MG, Kuhn AA, Volkmann J, Lace B, Meijer IA, Kandaswamy K, Quadri M, Garavaglia B, Lohmann K, Bauer P, Mencacci NE, Lubbe SJ, Klein C, Bertoli-Avella AM, Bonifati V. EIF2AK2 missense variants associated with early onset generalized dystonia. Ann Neurol. 2021;89:485-97. [PMC free article: PMC7986743] [PubMed: 33236446]
  • Lange LM, Gonzalez-Latapi P, Rajalingam R, Tijssen MAJ, Ebrahimi-Fakhari D, Gabbert C, Ganos C, Ghosh R, Kumar KR, Lang AE, Rossi M, van der Veen S, van de Warrenburg B, Warner T, Lohmann K, Klein C, Marras C, on behalf of the Task Force on Genetic Nomenclature in Movement D. Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - an update. Mov Disord. 2022;37:905-35. [PubMed: 35481685]
  • Lange LM, Junker J, Loens S, Baumann H, Olschewski L, Schaake S, Madoev H, Petkovic S, Kuhnke N, Kasten M, Westenberger A, Domingo A, Marras C, Konig IR, Camargos S, Ozelius LJ, Klein C, Lohmann K. Genotype-phenotype relations for isolated dystonia genes: MDSGene systematic review. Mov Disord. 2021;36:1086-103. [PubMed: 33502045]
  • Lasky L, Bliss L, Sidiropoulos C. Successful pallidal deep brain stimulation treatment in a case of generalized dystonia due to a novel ANO3 mutation. Case Rep Neurol Med. 2019;2019:3154653. [PMC free article: PMC6906865] [PubMed: 31871801]
  • Laurie S, Steyaert W, de Boer E, Polavarapu K, Schuermans N, Sommer AK, Demidov G, Ellwanger K, Paramonov I, Thomas C, Aretz S, Baets J, Benetti E, Bullich G, Chinnery PF, Clayton-Smith J, Cohen E, Danis D, de Sainte Agathe JM, Denomme-Pichon AS, Diaz-Manera J, Efthymiou S, Faivre L, Fernandez-Callejo M, Freeberg M, Garcia-Pelaez J, Guillot-Noel L, Haack TB, Hanna M, Hengel H, Horvath R, Houlden H, Jackson A, Johansson L, Johari M, Kamsteeg EJ, Kellner M, Kleefstra T, Lacombe D, Lochmuller H, Lopez-Martin E, Macaya A, Marce-Grau A, Maver A, Morsy H, Muntoni F, Musacchia F, Nelson I, Nigro V, Olimpio C, Oliveira C, Paulasova Schwabova J, Pauly MG, Peterlin B, Peters S, Pfundt R, Piluso G, Piscia D, Posada M, Reich S, Renieri A, Ryba L, Sablauskas K, Savarese M, Schols L, Schutz L, Steinke-Lange V, Stevanin G, Straub V, Sturm M, Swertz MA, Tartaglia M, Te Paske I, Thompson R, Torella A, Trainor C, Udd B, Van de Vondel L, van de Warrenburg B, van Reeuwijk J, Vandrovcova J, Vitobello A, Vos J, Vyhnalkova E, Wijngaard R, Wilke C, William D, Xu J, Yaldiz B, Zalatnai L, Zurek B, Solve RD-G, Solve RD-I, Solve RD-E-N, Solve RD-R, Solve RDc, Brookes AJ, Evangelista T, Gilissen C, Graessner H, Hoogerbrugge N, Ossowski S, Riess O, Schule R, Synofzik M, Verloes A, Matalonga L, Brunner HG, Lohmann K, de Voer RM, Topf A, Vissers L, Beltran S, Hoischen A. Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses. Nat Med. 2025;31:478-89. [PMC free article: PMC11835725] [PubMed: 39825153]
  • Lohmann K, Wilcox RA, Winkler S, Ramirez A, Rakovic A, Park JS, Arns B, Lohnau T, Groen J, Kasten M, Bruggemann N, Hagenah J, Schmidt A, Kaiser FJ, Kumar KR, Zschiedrich K, Alvarez-Fischer D, Altenmuller E, Ferbert A, Lang AE, Munchau A, Kostic V, Simonyan K, Agzarian M, Ozelius LJ, Langeveld AP, Sue CM, Tijssen MA, Klein C. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann Neurol. 2013;73:537-45. [PMC free article: PMC6956988] [PubMed: 23595291]
  • Ma LY, Wang L, Yang YM, Feng T, Wan XH. Mutations in ANO3 and GNAL gene in thirty-three isolated dystonia families. Mov Disord. 2015;30:743-4. [PubMed: 25847575]
  • Magrinelli F, Bhatia KP, Beiraghi Toosi M, Arab F, Karimiani EG, Sedighzadeh S, Ansari B, Neshatdoust M, Rocca C, Houlden H, Maroofian R. Childhood-onset choreo-dystonia due to a recurrent novel homozygous nonsense HPCA variant: case series and literature review. Mov Disord Clin Pract. 2022;10:101-8. [PMC free article: PMC9847280] [PubMed: 36698997]
  • Mao D, Reuter CM, Ruzhnikov MRZ, Beck AE, Farrow EG, Emrick LT, Rosenfeld JA, Mackenzie KM, Robak L, Wheeler MT, Burrage LC, Jain M, Liu P, Calame D, Kury S, Sillesen M, Schmitz-Abe K, Tonduti D, Spaccini L, Iascone M, Genetti CA, Koenig MK, Graf M, Tran A, Alejandro M, Lee BH, Thiffault I, Agrawal PB, Bernstein JA, Bellen HJ, Chao HT, et al. De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation. Am J Hum Genet. 2020;106:570-83. [PMC free article: PMC7118694] [PubMed: 32197074]
  • Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, Mercimek-Mahmutoglu S, Ebrahimi-Fakhari D, Warner TT, Durr A, Assmann B, Lohmann K, Kostic V, Klein C. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord. 2016;31:436-57. [PubMed: 27079681]
  • Marras C, Lohmann K, Lang A, Klein C. Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. Neurology. 2012;78:1016-24. [PMC free article: PMC3310311] [PubMed: 22454269]
  • Menden B, Gutschalk A, Wunderlich G, Haack TB. Expanded genetic spectrum and variable disease onset in AOPEP-associated dystonia. Mov Disord. 2022;37:1113-5. [PubMed: 35587627]
  • Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJ, Morrogh D; UK10K Consortium; Deciphering Developmental Disorders Study; NIHR BioResource Rare Diseases Consortium; Pittman A, Carr LJ, Perez-Dueñas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49:223-37. [PubMed: 27992417]
  • Mirza-Schreiber N, Zech M, Wilson R, Brunet T, Wagner M, Jech R, Boesch S, Škorvánek M, Necpál J, Weise D, Weber S, Mollenhauer B, Trenkwalder C, Maier EM, Borggraefe I, Vill K, Hackenberg A, Pilshofer V, Kotzaeridou U, Schwaibold EMC, Hoefele J, Waldenberger M, Gieger C, Peters A, Meitinger T, Schormair B, Winkelmann J, Oexle K. Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset. Brain. 2022;145:644-54. [PubMed: 34590685]
  • Musacchio T, Zech M, Reich MM, Winkelmann J, Volkmann J. A recurrent EIF2AK2 missense variant causes autosomal-dominant isolated dystonia. Ann Neurol. 2021;89:1257-8. [PubMed: 33866603]
  • Olschewski L, Jesus S, Kim HJ, Tunc S, Lons S, Junker J, Zeuner KE, Kühn AA, Kuhlenbäumer G, Schaffer E, Berg D, Kasten M, Ferbert A, Altenmüller E, Brüggemann N, Bauer P, Rolfs A, Jeon B, Bäumer T, Mir P, Klein C, Lohmann K. Role of ANO3 mutations in dystonia: a large-scale mutational screening study. Parkinsonism Relat Disord. 2019;62:196-200. [PubMed: 30712998]
  • Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, Fahn S, Risch NJ, Buckler AJ, Gusella JF, Breakefield XO. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet. 1997;17:40-8. [PubMed: 9288096]
  • Paul MS, Duncan AR, Genetti CA, Pan H, Jackson A, Grant PE, Shi J, Pinelli M, Brunetti-Pierri N, Garza-Flores A, Shahani D, Saneto RP, Zampino G, Leoni C, Agolini E, Novelli A, Blumlein Tobias BHU, Heinritz W, Matzker E, Alhaddad B, Jamra RA, Bartolomaeus T, AlHamdan S, Carapito R, Isidor B, Bahram S, Ritter A, Izumi K, Shakked BP, Barel O, Ben Zeev B, Begtrup A, Carere DA, Mullegama SV, Palculict TB, Calame DG, Schwan K, Aycinena ARP, Traberg R, Genomics England Research C, Douzgou S, Pirt H, Ismayilova N, Banka S, Chao HT, Agrawal PB. Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. Am J Hum Genet. 2023;110:548. [PMC free article: PMC10027494] [PubMed: 36868207]
  • Poulen G, Chan-Seng E, Sanrey E, Coubes P. A case of successful pallidal deep brain stimulation in ANO3 dystonia. Mov Disord. 2024;39:746-7. [PubMed: 38341631]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rajan R, Garg K, Saini A, Radhakrishnan DM, Carecchio M, Bk B, Singh M, Srivastava AK. GPi-DBS for KMT2B-associated dystonia: systematic review and meta-analysis. Mov Disord Clin Pract. 2021;9:31-37. [PMC free article: PMC8721835] [PubMed: 35005062]
  • Risch NJ, Bressman SB, Senthil G, Ozelius LJ. Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia. Am J Hum Genet. 2007;80:1188-93. [PMC free article: PMC1867106] [PubMed: 17503336]
  • Samanci B, Sahin E, Samanci Y, Bilgic B, Atasu B, Lohmann E, Peker S, Hanagasi HA. Pallidal deep brain stimulation improves HPCA-linked (DYT 2) dystonia. Mov Disord Clin Pract. 2024;11:184-7. [PMC free article: PMC10883396] [PubMed: 38386491]
  • Sarva H, Trosch R, Kiss ZHT, Furtado S, Luciano MS, Glickman A, Raymond D, Ozelius LJ, Bressman SB, Saunders-Pullman R. Deep brain stimulation in isolated dystonia with a GNAL mutation. Mov Disord. 2019;34:301-3. [PMC free article: PMC6659994] [PubMed: 30536916]
  • Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007;25:1-14. [PubMed: 17218267]
  • Shilatifard A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr Opin Cell Biol. 2008;20:341-8. [PMC free article: PMC2504688] [PubMed: 18508253]
  • Sorrentino U, Pavlov M, Mirza-Schreiber N, Brugger M, Brunet T, Tsoma E, Saparov A, Dzinovic I, Harrer P, Stehr AM, Wagner M, Tilch E, Wallacher B, Alhasan S, Koy A, Di Fonzo A, Kolnikova M, Kusikova K, Havrankova P, Tautanova R, Lösecke S, Eck S, Boesch S, Necpal J, Skorvanek M, Jech R, Prokisch H, Winkelmann J, Oexle K, Graf E, Zech M. Integrating long-read nanopore sequencing for precision resolution of genomic variants in dystonia. Mov Disord. 2025. Epub ahead of print. [PubMed: 41028987]
  • Steel D, Zech M, Zhao C, Barwick KES, Burke D, Demailly D, Kumar KR, Zorzi G, Nardocci N, Kaiyrzhanov R, Wagner M, Iuso A, Berutti R, Skorvanek M, Necpal J, Davis R, Wiethoff S, Mankad K, Sudhakar S, Ferrini A, Sharma S, Kamsteeg EJ, Tijssen MA, Verschuuren C, van Egmond ME, Flowers JM, McEntagart M, Tucci A, Coubes P, Bustos BI, Gonzalez-Latapi P, Tisch S, Darveniza P, Gorman KM, Peall KJ, Botzel K, Koch JC, Kmiec T, Plecko B, Boesch S, Haslinger B, Jech R, Garavaglia B, Wood N, Houlden H, Gissen P, Lubbe SJ, Sue CM, Cif L, Mencacci NE, Anderson G, Kurian MA, Winkelmann J, Genomics England Research C. Loss-of-function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities. Ann Neurol. 2020;88:867-77. [PubMed: 32808683]
  • Svorenova T, Romito LM, Kaymak A, Mulroy E, Cif L, Moro E, Zeuner KE, Zittel S, Petry-Schmelzer JN, Gruber D, Centen L, Albanese A, Ostrozovicova M, Han V, Magocova V, Knorovsky K, Kollova A, Garavaglia B, Golfre-Andreasi N, Reale C, Mazzoni A, Zorzi G, Eleopra R, Levi V, Foltynie T, Limousin P, Akram H, Zrinzo L, Magrinelli F, Murphy D, Houlden H, Kurian MA, Baiata C, Paschen S, Lohmann K, Volkmann J, Hamel W, Barbe MT, van Egmond ME, Tijssen M, Ambro L, Jurkova V, Jech R, Havrankova P, Winkelmann J, Zech M, Skorvanek M. Deep brain stimulation for VPS16-related dystonia: a multicenter study. Ann Neurol. 2025;98:711-25. [PMC free article: PMC12542321] [PubMed: 40539388]
  • Thomsen M, Lange LM, Klein C, Lohmann K. MDSGene: Extending the list of isolated dystonia genes by VPS16, EIF2AK2, and AOPEP. Mov Disord. 2023;38:507-8. [PubMed: 36670070]
  • Thomsen M, Lange LM, Zech M, Lohmann K. Genetics and pathogenesis of dystonia. Annu Rev Pathol. 2024a;19:99-131. [PubMed: 37738511]
  • Thomsen M, Marth K, Loens S, Everding J, Junker J, Borngräber F, Ott F, Jesús S, Gelderblom M, Odorfer T, Kuhlenbäumer G, Kim HJ, Schaeffer E, Becktepe J, Kasten M, Brüggemann N, Pfister R, Kollewe K, Krauss JK, Lohmann E, Hinrichs F, Berg D, Jeon B, Busch H, Altenmüller E, Mir P, Kamm C, Volkmann J, Zittel S, Ferbert A, Zeuner KE, Rolfs A, Bauer P, Kühn AA, Bäumer T, Klein C, Lohmann K. Large-scale screening: phenotypic and mutational spectrum in isolated and combined dystonia genes. Mov Disord. 2024b;39:526-538. [PubMed: 38214203]
  • Thomsen M, Ott F, Loens S, Kilic-Berkmen G, Tan AH, Lim SY, Lohmann E, Schroder KM, Ipsen L, Nothacker LA, Welzel L, Rudnik AS, Hinrichs F, Odorfer T, Zeuner KE, Schumann F, Kuhn AA, Zittel S, Moeller M, Pfister R, Kamm C, Lang AE, Tay YW, de Almeida Marcelino AL, Vidailhet M, Roze E, Perlmutter JS, Feuerstein JS, Fung VSC, Chang F, Barbano RL, Bellows S, Wagle Shukla AA, Espay AJ, LeDoux MS, Berman BD, Reich S, Deik A, Franke A, Wittig M, Franzenburg S, Volkmann J, Bruggemann N, Jinnah HA, Baumer T, Klein C, Busch H, Lohmann K. Genetic diversity and expanded phenotypes in dystonia: insights from large-scale exome sequencing. Ann Clin Transl Neurol. 2025;12:1648-59. [PMC free article: PMC12343315] [PubMed: 40533913]
  • Tunc S, Denecke J, Olschewski L, Baumer T, Munchau A, Lessel D, Lohmann K. A recurrent de-novo ANO3 mutation causes early-onset generalized dystonia. J Neurol Sci. 2019;396:199-201. [PubMed: 30502610]
  • Vemula SR, Puschmann A, Xiao J, Zhao Y, Rudzińska M, Frei KP, Truong DD, Wszolek ZK, LeDoux MS. Role of Gα(olf) in familial and sporadic adult-onset primary dystonia. Hum Mol Genet. 2013;22:2510-9. [PMC free article: PMC3658169] [PubMed: 23449625]
  • Vulinovic F, Krajka V, Hausrat TJ, Seibler P, Alvarez-Fischer D, Madoev H, Park JS, Kumar KR, Sue CM, Lohmann K, Kneussel M, Klein C, Rakovic A. Motor protein binding and mitochondrial transport are altered by pathogenic TUBB4A variants. Hum Mutat. 2018;39:1901-15. [PubMed: 30079973]
  • Weissbach A, Saranza G, Domingo A. Combined dystonias: clinical and genetic updates. J Neural Transm (Vienna). 2021;128:417-29. [PubMed: 33099685]
  • Wilcox RA, Winkler S, Lohmann K, Klein C. Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal. Mov Disord. 2011;26:2404-8. [PubMed: 21956287]
  • Wirth T, Kumar KR, Zech M. Long-read sequencing: the third generation of diagnostic testing for dystonia. Mov Disord. 2025;40:1009-19. [PMC free article: PMC12160967] [PubMed: 40265723]
  • Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, Wieland T, Lunetta C, Sansone V, Messner M, Mueller J, Ceballos-Baumann A, Strom TM, Colombo R, Poewe W, Haslinger B, Winkelmann J. Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up. Mov Disord. 2017;32:549-59. [PubMed: 27666935]
  • Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, Pilshofer V, Ceballos-Baumann A, Alhaddad B, Berutti R, Poewe W, Haack TB, Haslinger B, Strom TM, Winkelmann J. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet. 2016;99:1377-87. [PMC free article: PMC5142117] [PubMed: 27839873]
  • Zech M, Dzinovic I, Skorvanek M, Harrer P, Necpal J, Kopajtich R, Kittke V, Tilch E, Zhao C, Tsoma E, Sorrentino U, Indelicato E, Stehr A, Saparov A, Abela L, Adamovicova M, Afenjar A, Assmann B, Baloghova J, Baumann M, Berutti R, Brezna Z, Brugger M, Brunet T, Cogne B, Colangelo I, Conboy E, Distelmaier F, Eckenweiler M, Garavaglia B, Geerlof A, Graf E, Hackenberg A, Harvanova D, Haslinger B, Havrankova P, Hoffmann GF, Janzarik WG, Keren B, Kolnikova M, Kolokotronis K, Kosutzka Z, Koy A, Krenn M, Krygier M, Kusikova K, Maier O, Meitinger T, Mertes C, Milenkovic I, Monfrini E, Mourao ASD, Musacchio T, Nizon M, Ostrozovicova M, Pavlov M, Prihodova I, Rektorova I, Romito LM, Rybanska B, Sadr-Nabavi A, Schwenger S, Shoeibi A, Sitzberger A, Smirnov D, Svantnerova J, Tautanova R, Toelle SP, Ulmanova O, Vetrini F, Vill K, Wagner M, Weise D, Zorzi G, Di Fonzo A, Oexle K, Berweck S, Mall V, Boesch S, Schormair B, Prokisch H, Jech R, Winkelmann J. Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia. Brain. 2025;148:2827-46. [PMC free article: PMC12316014] [PubMed: 39937650]
  • Zech M, Jech R, Boesch S, Skorvanek M, Weber S, Wagner M, Zhao C, Jochim A, Necpal J, Dincer Y, Vill K, Distelmaier F, Stoklosa M, Krenn M, Grunwald S, Bock-Bierbaum T, Fecikova A, Havrankova P, Roth J, Prihodova I, Adamovicova M, Ulmanova O, Bechyne K, Danhofer P, Vesely B, Han V, Pavelekova P, Gdovinova Z, Mantel T, Meindl T, Sitzberger A, Schroder S, Blaschek A, Roser T, Bonfert MV, Haberlandt E, Plecko B, Leineweber B, Berweck S, Herberhold T, Langguth B, Svantnerova J, Minar M, Ramos-Rivera GA, Wojcik MH, Pajusalu S, Ounap K, Schatz UA, Polsler L, Milenkovic I, Laccone F, Pilshofer V, Colombo R, Patzer S, Iuso A, Vera J, Troncoso M, Fang F, Prokisch H, Wilbert F, Eckenweiler M, Graf E, Westphal DS, Riedhammer KM, Brunet T, Alhaddad B, Berutti R, Strom TM, Hecht M, Baumann M, Wolf M, Telegrafi A, Person RE, Zamora FM, Henderson LB, Weise D, Musacchio T, Volkmann J, Szuto A, Becker J, Cremer K, Sycha T, Zimprich F, Kraus V, Makowski C, Gonzalez-Alegre P, Bardakjian TM, Ozelius LJ, Vetro A, Guerrini R, Maier E, Borggraefe I, Kuster A, Wortmann SB, Hackenberg A, Steinfeld R, Assmann B, Staufner C, Opladen T, Ruzicka E, Cohn RD, Dyment D, Chung WK, Engels H, Ceballos-Baumann A, Ploski R, Daumke O, Haslinger B, Mall V, Oexle K, Winkelmann J. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol. 2020;19:908-18. [PMC free article: PMC8246240] [PubMed: 33098801]
  • Zech M, Kumar KR, Reining S, Reunert J, Tchan M, Riley LG, Drew AP, Adam RJ, Berutti R, Biskup S, Derive N, Bakhtiari S, Jin SC, Kruer MC, Bardakjian T, Gonzalez-Alegre P, Keller Sarmiento IJ, Mencacci NE, Lubbe SJ, Kurian MA, Clot F, Meneret A, de Sainte Agathe JM, Fung VSC, Vidailhet M, Baumann M, Marquardt T, Winkelmann J, Boesch S. Biallelic AOPEP loss-of-function variants cause progressive dystonia with prominent limb involvement. Mov Disord. 2022;37:137-47. [PubMed: 34596301]
Copyright © 1993-2026, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2026 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1155PMID: 20301334
GeneReviews by Title

Views

In this GeneReview

Bulk Download

GeneReviews Links

Tests in GTR by Gene

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

ClearTurn OffTurn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...