Parsed document review

Submitting author: Katja Lohmann

Summary

The purpose of this overview is to:

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] :

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

Body distribution . See Table 1.

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

Onset indicates the first occurrence of symptoms or signs of dystonia until the first peak of severity. Whe n 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 course of dystonia may change with longer observation periods .

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 ) .

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 202 2 ] (see Table 2 ). This naming system eliminates previously listed loci that were erroneous, duplicated, or unconfirmed . D isorders that are not predominantly dystonic are not labeled with a DYT prefix . In addition, d istinguishing paroxysmal movement disorders by replacing DYT with PxMD is recommended [ Marras et al 2016 ] . Paroxysmal movement disorders are not discussed in this chapter.

Although d ystonia 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].

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 , 1 2 genes are confirmed to be primarily associated with isolated dystonia (see Table 2). Collectively, pathogenic variants in the 1 2 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 v e ry rare (<0.1%).

Number of affected individuals reported. To date, about 100 individuals have been reported. P athogenic 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 variabl y 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 infan tile-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 region s . 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 encode s 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] .

T he 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. T ests 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] .

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 : I ntrafamilial variability and interfamilial variability are considerable.

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

Mode of inheritance is a utosomal 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).

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. B oth upper limbs and lower limbs are involved with equal frequency [Thomsen et al 2023] .

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

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

Mode of inheritance is a utosomal dominant.

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

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 2024 a ] .

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 .

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 var ying severity can include tremor and jerky movements resembling myoclonus.

Other findings in a bout 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] .

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 : I ntrafamilial 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 a utosomal dominant . A utosomal 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 2024 a ] . 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] .

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 year s ( IQR : 1-8 years ; range : 0-20 years ) .

Clinical manifestations at onset and disease progression. Although d ystonia 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 a utosomal 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 .

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, m ore than 200 individuals heterozygous for a KMT2B pathogenic variant have been described .

Age at onset. The m edian 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 a utosomal 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 histon e 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 .

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 a utosomal 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 .

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 vari es and includ es 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: T here is considerable int er familial variability and intrafamilial variability [Lange et al 2021] .

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

S everal pathogenic variants were demonstrated to be de novo .

P enetrance 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 2024 a ] . The heterozygous variants causing autosomal dominant DYT- THAP1 include truncating and missense variants as well as a whole - gene deletion.

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 a utosomal 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 envelop e [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.

Not e: 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] .

Number of affected individuals. A TUBB4A pathogenic heterozygous missense variant was first reported in a clinically well-defined multigenerational U nited K ingdom / 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 i nvolvement 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 202 1 ] .

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 a utosomal 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 ] .

Number of affected individuals. VPS16 heterozygous variants were first reported as causal for dystonia by Steel et al [ 2020 ] . T o 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. O nset 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, suggest ing 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] suggest ed that homozygosity for a relatively frequent missense variant (supported by functional studies) in the Asian population w as the cause of dystonia in a Chinese family with four affected sibs. S everal 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 2024 a ] .

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

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

P athogenic 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 diagnos e s, 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 dystoni a ), and presence of additional features (lower in isolated dystonia than in combined dystonia) [ Thomsen et al 2025 ] .

The absence of a n identifiable genetic cause in most individuals with isolated dystonia suggest s 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 ] .

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 .

<?escape?> 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 diagnos i s . 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 dystonia s , 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 biomarker s [Thomsen et al 2025] .

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

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

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 scar c e, and the authors' personal experience managing individuals with these disorder s . 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.

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 .

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 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 ).

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

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.

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

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.

Parents of a proband

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 ; b ecause 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.

Parents of a proband

Sibs of a proband

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

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].

Once the monogenic isolated dystonia-related pathogenic variant (s) have been identified in a n 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.

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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: michael.zech@mri.tum.de ; w eb page: www.humangenetik.mri.tum.de

Dr Lara M Lange, Institute of Neurogenetics, University of Luebeck, Luebeck, Germany . E mail: la.lange@uni-luebeck.de

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 support ed 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.

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 M ü nchau , 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)