Torsion Dystonia
Introduction
Background
Torsion dystonia refers to a group of neurological movement disorders characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and postures. [1] These involuntary movements can affect any part of the body, leading to twisting, repetitive motions or sustained, abnormal postures. [1] While "dystonia" is a broad term, torsion dystonia specifically describes forms where the twisting movements are prominent and often widespread, historically associated with severe, generalized forms of the disorder. Dystonia can be classified by its clinical features, including age at onset, body distribution (e.g., focal, segmental, generalized), and whether it occurs in isolation (isolated dystonia) or with other neurological signs (combined dystonia). [2]
Biological Basis
The biological underpinnings of torsion dystonia are complex, involving both genetic and environmental factors. Genetic contributions are significant, with approximately 25% of patients with various forms of isolated dystonia having a family history of the condition. [3] While several monogenic causes have been identified, these typically account for a minority of cases, primarily those with early onset and additional clinical features. [4] For the majority of patients, the specific genetic risk factors remain largely unknown. [3] Research indicates that dystonia likely has a high polygenicity, meaning many genetic variants, including rare ones, each contribute small effects to its development. [3] Genes such as ARSG have been implicated in task-specific dystonia [5] and variants in PDE10A have been linked to dystonic symptoms. [3] Other genes, like PDE6A and PRKAR2B, are being investigated for their potential roles, particularly in pathways related to cyclic adenosine monophosphate (cAMP) signaling, which influences striatocortical basal ganglia circuitry and movement control. [3] Genome-wide association studies (GWAS) are a primary method for identifying genetic risk variants, though their application to dystonia has been challenged by the disorder's relative rarity and the need for very large sample sizes. [3]
Clinical Relevance
Torsion dystonia manifests with a wide spectrum of clinical presentations, ranging from focal involvement (e.g., cervical dystonia affecting the neck) to generalized forms affecting multiple body parts. The age at onset can vary significantly, influencing the progression and severity of the condition. [3] Diagnosis is primarily clinical, based on observable symptoms and exclusion of secondary causes. The involuntary muscle contractions lead to pain, functional disability, and reduced quality of life for affected individuals. Understanding the genetic basis is crucial for improving diagnostic accuracy, predicting disease course, and developing targeted therapies.
Social Importance
Dystonia, including its torsion forms, represents a significant public health concern due to its impact on individuals and healthcare systems. It is considered a relatively rare disorder, with an estimated prevalence of idiopathic dystonia around 16.4 per 100,000 individuals. [6] The chronic and often progressive nature of torsion dystonia can severely limit daily activities, employment, and social participation. The substantial genetic contribution, combined with the current lack of definitive genetic markers for many cases, highlights the ongoing need for extensive research. Collaborative efforts, such as those by the Dystonia Coalition, involve large-scale studies to collect patient data and DNA samples to uncover the complex genetic architecture of these disorders. [7] These studies aim to identify risk factors, improve prognosis, and ultimately lead to better treatment and prevention strategies.
Methodological and Statistical Constraints
The genetic study of isolated dystonia faces significant methodological and statistical challenges, primarily stemming from the complex genetic architecture of the disorder. While the presented genome-wide association study (GWAS) represents the largest to date for isolated dystonia, it did not identify robust, replicable associations for overall case-control status, age at onset (AAO), or the clinical score. . Genetic factors are recognized as substantial contributors to dystonia, with a significant proportion of patients having relatives also affected by the condition. [3]
Several other variants have been identified in genome-wide association studies (GWAS) for their suggestive associations with dystonia, particularly concerning age at onset (AAO). For instance, rs77507424 on chromosome 5 is located within PDE6A, a gene encoding a phosphodiesterase. Phosphodiesterases play a vital role in regulating cyclic adenosine monophosphate (cAMP) signaling, a pathway fundamental for striatocortical basal ganglia circuitry and movement control. [3] Similarly, rs2536490 on chromosome 7 resides in PRKAR2B, another gene linked to cAMP signaling, and both variants have shown associations with the age at onset of dystonia. [3] Pathogenic variants in related genes, such as PDE10A, have also been directly associated with dystonic symptoms, highlighting the importance of cAMP signaling in dystonia's underlying mechanisms.
Further investigations have revealed other noteworthy variants associated with specific dystonia phenotypes. In patients with craniocervical onset, rs3010282 on chromosome 6 was significantly associated with AAO and is found within a long noncoding RNA gene. [3] Additional candidates include rs9319387 on chromosome 13, near genes like POLR1D and NPM1P4, and rs3744730 on chromosome 17, located in VPS53, which encodes a vacuolar protein sorting protein crucial for recycling endocytic vesicles. [3] For dystonia with onset in the upper extremities, rs7907011 on chromosome 10, located within LOXL4 (a gene encoding a lysyl oxidase involved in extracellular matrix development), showed genome-wide significance for AAO. [3] Moreover, variants like rs3802288 in ASPH and rs77695916 in MFAP3 were associated with a clinical score reflecting genetic burden in craniocervical and upper extremity onset dystonia, respectively, with both ASPH and MFAP3 being expressed in the brain. [3]
Beyond these, the ARSG (arylsulfatase G) gene has been implicated in task-specific dystonias. The variant rs11655081 in ARSG shows a possible association with musician's dystonia (MD) and may also contribute to the risk of writer's dystonia (WD), a related form of dystonia often observed in relatives of MD patients. [8] Furthermore, there is evidence of an accumulation of rare variants in ARSG in task-specific dystonia, suggesting a role for this gene in the pathogenesis of these focal dystonias. [5] Another gene, COL6A3, a member of the collagen family, has also been reported to potentially cause dystonia through biallelic mutations, indicating diverse genetic mechanisms contributing to the disorder. [7]
Definition and Core Characteristics of Dystonia
Torsion dystonia refers to a neurological movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive, twisting movements and postures. [7] These involuntary movements can affect various parts of the body, leading to distorted postures and patterned, excessive muscle contractions. [7] The term "torsion" specifically highlights the rotational or twisting nature of these movements, which are a hallmark of dystonia. [7] The underlying mechanisms involve complex alterations in brain circuitry, influencing movement control.
Clinical Classification and Subtypes
Dystonia is classified based on several criteria, including its clinical presentation, age at onset, and etiology. [2] Clinically, dystonia can be categorized by the body regions affected, such as focal (affecting one part, like cervical dystonia), segmental (affecting contiguous parts), or generalized (affecting widespread body regions). [3] Cervical dystonia (CD), for instance, is a common adult-onset form specifically characterized by involuntary contractions of neck muscles, leading to abnormal head and neck movements or postures. [7] Dystonias are also broadly classified as "isolated" (formerly "primary") when dystonia is the sole neurological sign, or "combined" (formerly "dystonia-plus") when it occurs with other neurological features. [7]
Diagnostic and Measurement Criteria
Diagnosis of dystonia primarily relies on clinical assessment, observing the characteristic movements and postures. [1] Researchers employ specific criteria to characterize dystonia for studies, including age at onset (AAO), which can be a continuous variable for analysis, and the distribution of dystonic features (focal, segmental/multifocal, or generalized). [3] A clinical score has been developed to scale the degree of presumed genetic burden, incorporating factors such as family history, AAO (categorized into <21, 21-50, or >50 years), and the distribution of dystonic features. [3] This scoring system provides a quantitative measure for assessing potential genetic influence in patients with isolated dystonia. [3]
Terminology and Evolving Understanding
The terminology surrounding dystonia has evolved to ensure precise communication among clinicians and researchers. [9] Key terms include "isolated dystonia" for cases without other neurological signs [3] and specific subtypes like "cervical dystonia" or "musician's dystonia," which describe the affected body part or provoking activity . [3], [7] Historically, various terms were used, but a consensus update provided a standardized framework for phenomenology and classification. [1] Despite significant progress, the identification of genetic risk factors remains a complex challenge, with many monogenic causes accounting for only a minority of cases, particularly those with early onset and additional features . [3], [4] Research continues to refine the understanding of both genetic and environmental contributions to dystonia. [7]
Clinical Manifestations and Phenotypes
In isolated dystonia, patients typically present with involuntary, sustained or intermittent muscle contractions that cause twisting, repetitive movements, or abnormal postures. These dystonic features can manifest across various body regions, categorized by their distribution as focal, segmental, multifocal, or generalized. For example, cervical dystonia, a frequently studied subtype, primarily involves the neck region, though individuals may exhibit minor dystonic symptoms in other areas if the neck remains the main affected site [7] Some patients may also experience associated symptoms, such as tremor, further diversifying the clinical picture [7]
The severity and extent of dystonic features are crucial for both classification and assessment. A "generalized" distribution, affecting multiple body parts, represents a more widespread presentation and is often associated with a higher presumed genetic burden within clinical scoring systems [3] Conversely, "focal" dystonia is confined to a single body part, while "segmental" or "multifocal" dystonias involve two or more adjacent or non-adjacent body parts, respectively. These distinct clinical phenotypes are meticulously evaluated by movement disorder specialists using standardized protocols, often including videotaped verification, to ensure accurate characterization [7]
Assessment and Diagnostic Indicators
The clinical evaluation of dystonia relies on comprehensive assessment methods to precisely characterize the disorder. Diagnostic tools encompass a detailed patient history, thorough neurological examination, and the application of structured clinical scores. One such score, developed to estimate the presumed genetic burden, assigns points based on the presence of family history, the patient's age at onset (AAO), and the distribution of their dystonic features. For instance, a generalized distribution of dystonia receives more points than a focal presentation, and an AAO under 21 years is weighted more heavily than onset later in life [3] These combined objective and subjective measures contribute significantly to a holistic understanding of the patient's condition.
Certain clinical characteristics possess substantial diagnostic significance and can serve as prognostic indicators. A family history of dystonia suggests a considerable genetic predisposition, observed in approximately 25% of patients with isolated dystonia [3] An early age at onset, particularly before 21 years, is considered a red flag, often correlating with an increased likelihood of monogenic causes or a higher overall genetic burden, though such specific genetic causes are identified in only a minority of patients [3] Accurate diagnosis of isolated dystonia also necessitates the careful exclusion of acquired forms of the condition or dystonia occurring alongside other movement disorders, such as parkinsonism [7]
Variability and Heterogeneity
Dystonia manifests with considerable inter-individual variation and phenotypic diversity across affected populations. The age at onset can span a wide range, from early childhood to late adulthood, profoundly influencing the clinical presentation and the potential underlying genetic factors. Patients are frequently categorized by their AAO, such as <21 years, 21–50 years, or >50 years, which can impact prognostic outlook and guide therapeutic strategies [3] Furthermore, the initial site of onset, whether craniocervical or in the upper extremities, contributes to the overall heterogeneity observed in presentations [3]
Despite ongoing efforts to classify dystonia based on observable clinical features, the diverse underlying biological mechanisms present challenges in defining distinct molecular-based subgroups. The current absence of reliable biomarkers hinders the effective stratification of patients according to these molecular distinctions [3] This inherent heterogeneity suggests that the genetic risk factors for isolated dystonia are intricate, likely involving rare variants or low-frequency variants with subtle effects, which necessitates innovative approaches beyond conventional genome-wide association studies for their comprehensive identification [3]
Complex Genetic Architecture and Heritability
Torsion dystonia is understood to have a significant genetic component, with approximately 25% of affected individuals having relatives who also experience dystonia, indicating a familial predisposition .
Genetic Architecture and Candidate Loci
The genetic landscape of dystonia is being actively investigated, with GWAS serving as a promising approach for identifying candidate genes and loci. Studies have revealed several genes potentially associated with specific forms of dystonia. For instance, a recent GWAS identified DENND1A as significantly associated with cervical dystonia (CD), along with other genes such as ATP11A, ST7-OT4, PPP1R16B, and SLC39A12 showing nominal associations. [7] Prior research also suggested associations with genes like ANO3, CIZ1, COL6A3, GNAL, THAP1, and TOR1A, although these have not always been consistently replicated in all studies or across different dystonia subtypes. [7] The identification of a significant association in a locus of the ARSG gene was also noted in musician's dystonia, though this finding awaits independent replication. [7] These findings highlight the challenge of identifying common genome-wide significant loci for isolated dystonia, suggesting that the effects of individual variants might be very small, and comprehensive analyses of low-frequency variants may be necessary. [3]
Gene Expression and Neurological Relevance
Genetic variations identified through GWAS can influence gene expression patterns, providing insights into the specific tissues and cells affected in dystonia. Gene expression quantitative trait locus (eQTL) analysis, which links genetic variants to their impact on gene expression levels, has shown that eQTLs associated with cervical dystonia are most enriched for brain tissue. [7] This enrichment extends to specific sub-regions of the brain, underscoring the central nervous system's crucial role in the development and manifestation of the disorder. [7] Understanding these tissue-specific gene expression changes is vital for connecting genetic predispositions to the molecular and cellular dysfunctions that ultimately lead to dystonic symptoms.
Molecular and Cellular Pathways Implied by Genetic Findings
The genes identified through genetic studies, such as DENND1A, ARSG, ATP11A, ST7-OT4, PPP1R16B, and SLC39A12, are presumed to encode proteins that contribute to various fundamental cellular functions. These proteins, as products of specific genes, would participate in complex regulatory networks and metabolic processes essential for cell viability and specialized functions, particularly within the nervous system where eQTLs are enriched. [7] While the specific signaling pathways or structural components these particular genes directly influence are not detailed in current findings, their genetic association with dystonia suggests their involvement in maintaining cellular homeostasis crucial for neurological health. [7] Further research into these key biomolecules and their roles in molecular and cellular pathways will be essential to elucidate the precise mechanisms by which genetic variations contribute to dystonia.
Pathophysiological Mechanisms and Clinical Heterogeneity
Dystonia encompasses a spectrum of conditions, and understanding its pathophysiology involves examining distinct clinical manifestations. Cervical dystonia (CD), for example, is a common adult-onset isolated dystonia that has been the focus of extensive genetic investigation. [7] Other forms, such as musician's dystonia, affect specific body regions and are also under genetic scrutiny. [7] The studies also investigate potential genetic determinants of phenotypic variations within dystonia, such as age-at-onset and the presence of tremor, indicating that genetic factors may not only predispose individuals to the disorder but also influence its clinical presentation and progression. [7] The observed moderate single-nucleotide polymorphism (SNP)-based heritability implies that, while common variants may not individually contribute large effects, the cumulative impact of many small genetic variations or the involvement of low-frequency variants plays a role in the overall susceptibility to isolated dystonia. [3]
Genetic Contributions and Enzymatic Pathways
Torsion dystonia involves genetic factors that influence crucial enzymatic and structural pathways. Rare variants in the ARSG gene, which encodes arylsulfatase G, have been observed to accumulate in individuals with task-specific dystonia and are considered a risk variant for musician's dystonia. [5] Arylsulfatases are enzymes critical for the catabolism of sulfate esters, suggesting that dysregulation in this metabolic pathway could lead to the accumulation of specific substrates or altered cellular processes. This genetic predisposition points towards a disruption in the normal metabolic regulation and flux control essential for neuronal health.
Furthermore, biallelic mutations in COL6A3, a member of the collagen family, have been implicated as a potential cause of dystonia. [7] Collagen proteins like COL6A3 are fundamental for maintaining the structural integrity of tissues, including those in the nervous system. Alterations in these structural components could affect cellular architecture, cell-matrix interactions, and overall tissue function, highlighting a pathway where genetic defects lead to physical and functional deficits through compromised biosynthesis and assembly of extracellular matrix components.
Cyclic Nucleotide Signaling and Basal Ganglia Function
Aberrations in cyclic nucleotide signaling pathways represent a significant mechanistic avenue in dystonia. Genetic analysis has identified noteworthy variants such as rs77507424 on chromosome 5, which harbors PDE6A, a gene encoding a phosphodiesterase. [3] Phosphodiesterases are crucial enzymes that hydrolyze cyclic adenosine monophosphate (cAMP), thereby regulating its intracellular levels and subsequent downstream signaling cascades. This regulation is essential for the proper functioning of striatocortical basal ganglia circuitry and the precise control of movement. [3]
Further supporting the role of cAMP signaling, rs2536490 on chromosome 7 is located in PRKAR2B, a gene also linked to cAMP signaling. [3] PRKAR2B encodes a regulatory subunit of protein kinase A (PKA), a key effector of cAMP, indicating that dysregulation in either cAMP synthesis/degradation or its effector proteins can disrupt critical intracellular signaling cascades. Additionally, pathogenic variants in PDE10A, another phosphodiesterase, have been directly associated with dystonic symptoms, underscoring the profound impact of cyclic nucleotide metabolism on neurological function and motor control. [3] These findings collectively highlight how fine-tuned regulation of cAMP signaling is vital, and its disruption through genetic variants can lead to pathway dysregulation characteristic of dystonia.
Ion Channel Modulation and Neuronal Excitability
The precise control of neuronal excitability, mediated by ion channels, is another critical pathway implicated in dystonia. A genome-wide association study in cervical dystonia suggested a possible association with a sodium leak channel. [10] Sodium leak channels play a fundamental role in setting the resting membrane potential and regulating the intrinsic excitability of neurons, influencing their firing patterns and overall network activity. Dysregulation of these channels can lead to altered neuronal excitability, potentially contributing to the abnormal motor commands observed in dystonia by disrupting the delicate balance of inhibitory and excitatory signaling within motor circuits.
Integrated Network Dysregulation and Motor Control
The various molecular and genetic pathways implicated in torsion dystonia do not operate in isolation but rather form an intricate network whose dysregulation culminates in the characteristic motor phenotype. Alterations in cyclic nucleotide signaling, as seen with PDE6A, PDE10A, and PRKAR2B variants, can crosstalk with ion channel function, where, for instance, cAMP-dependent phosphorylation can modulate channel activity and neuronal excitability. [3] Similarly, compromised structural integrity due to COL6A3 mutations or altered metabolic processing by ARSG variants can indirectly impact neuronal signaling and connectivity, demonstrating a complex hierarchical regulation where defects at one level propagate across multiple pathways.
This systems-level integration highlights how subtle molecular perturbations can lead to emergent properties, manifesting as the involuntary muscle contractions and sustained postures of dystonia. The identified pathway dysregulations point to potential compensatory mechanisms that the brain might employ to counteract initial deficits, which could themselves become maladaptive over time. Understanding this intricate pathway crosstalk and network interactions is crucial for identifying specific therapeutic targets, moving beyond symptomatic treatment to address the underlying molecular and cellular mechanisms driving the disease.
Current Understanding of Genetic Risk and Diagnostic Utility
Identifying common genetic risk factors for torsion dystonia, particularly in its isolated forms, remains a significant challenge. Despite the execution of the largest genome-wide association study (GWAS) to date for isolated dystonia, no robust, replicable associations for common variants have been found for overall case-control status, age at onset (AAO), or a composite clinical score. [3] This indicates that current genetic diagnostic utility for common variant screening in a broad population of individuals with torsion dystonia is limited. Heritability analyses suggest that less than 25% of the variance in traits such as case-control status (14%), AAO (24%), and the clinical score (19%) can be explained by the genotyped and imputed single nucleotide polymorphisms (SNPs). [3] While several monogenic causes are known, they account for the molecular pathogenesis in only a minority of patients, typically those with early onset and additional clinical features. [3] This highlights the complex genetic landscape of torsion dystonia, where common variants with substantial effects are yet to be discovered, making broad genetic prognostication and diagnosis challenging based on current knowledge.
Phenotypic Variability, Clinical Assessment, and Risk Indicators
The genetic contribution to torsion dystonia is evident, with approximately 25% of patients having a family history of the disorder. [3] To help quantify the presumed genetic burden, a clinical score has been developed, incorporating factors such as family history, AAO (categorized as <21, 21-50, or >50 years), and the distribution of dystonic features (generalized, segmental/multifocal, or focal). [3] Although this score aims to reflect genetic influence, its association with common genetic variants has not yet been robustly established in large GWAS. For specific forms of torsion dystonia, such as cervical dystonia, multi-center GWAS have identified genome-wide significant SNPs, suggesting that more focused studies can yield actionable genetic insights for particular subtypes. [7] While a personalized medicine approach based on common genetic markers is still nascent for broad torsion dystonia, clinical indicators like a positive family history and early age at onset remain crucial for identifying individuals with a higher likelihood of a genetic etiology, informing clinical decision-making and risk discussions.
Future Directions for Prognosis and Treatment
The current research suggests that the genetic architecture of isolated dystonia, including torsion dystonia, is highly polygenic, involving numerous risk variants, potentially including many rare variants, each with small effects. [3] To overcome the limitations of current GWAS, future research will require significantly larger sample sizes and the application of advanced sequencing technologies, such as whole-genome sequencing. This would enable the detection of rarer variants and other types of genetic variations, like copy number variants, that are not captured by standard SNP genotyping. [3] The identification of these underlying genetic factors holds promise for improving the prognostic value of genetic testing, guiding personalized treatment selection, and developing more effective monitoring strategies. Ultimately, a deeper understanding of the genetic landscape could pave the way for novel, targeted prevention strategies for specific forms of torsion dystonia. [7]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs11904276 | TPO | torsion dystonia |
Frequently Asked Questions About Torsion Dystonia
These questions address the most important and specific aspects of torsion dystonia based on current genetic research.
1. My family has this; will my kids inherit it?
There's a significant genetic component to torsion dystonia, with about 25% of patients having a family history of the condition. While some specific monogenic (single gene) causes are known, they are rare. For most cases, many different genetic variants, each contributing a small effect, are involved, so inheritance patterns can be complex and not always straightforward.
2. Why do I have this, but no one else in my family does?
Torsion dystonia's biological basis is complex, involving both genetic and environmental factors. For many people, the specific genetic risk factors remain unknown, and it's thought to be highly polygenic, meaning many genes contribute small effects. This complexity, combined with environmental influences, can lead to individual cases even without a clear family history.
3. Is a genetic test worth it for my twisting movements?
While genetic testing can identify specific monogenic causes for a minority of patients, especially those with early onset or additional symptoms, for the majority, the specific genetic risk factors are still largely unknown. Dystonia often involves many genetic variants, each with small effects, so a genetic test may not provide a definitive answer for most people at this time.
4. Does my age when it started affect how bad my dystonia gets?
Yes, the age at which your dystonia symptoms begin can significantly influence how the condition progresses and its overall severity. Early onset forms of dystonia are often linked to specific monogenic causes and can sometimes have a different disease course compared to those that develop later in life.
5. Why are my twisting movements different from other people's?
Torsion dystonia has a wide spectrum of clinical presentations. It can manifest as focal involvement, affecting just one body part like your neck, or as generalized forms affecting multiple areas. This significant variability means that different sets of genetic and environmental factors might be at play, leading to unique symptoms and affected body regions for each person.
6. Why haven't I heard much about this condition before?
Torsion dystonia is considered a relatively rare disorder. The estimated prevalence of idiopathic dystonia is around 16.4 per 100,000 individuals, which means it's not as commonly discussed or recognized as more prevalent neurological conditions. Its rarity also makes genetic research more challenging, requiring very large sample sizes.
7. My sibling has it, but I don't; how is that possible?
Even with a genetic component, torsion dystonia is often highly polygenic, meaning many different genetic variants contribute small effects. This, combined with potential environmental factors, means that even among siblings with shared genetics, the manifestation of the disorder can differ. You might have some genetic risk factors, but not enough to develop the condition, or different environmental exposures.
8. Are scientists finding ways to help people like me?
Yes, extensive research is ongoing to understand the complex genetic architecture of torsion dystonia. Collaborative efforts, such as those by the Dystonia Coalition, involve large-scale studies to collect patient data and DNA samples. The goal is to identify genetic risk factors, improve diagnostic accuracy, predict disease course, and ultimately develop better, more targeted treatments.
9. Can my twisting movements affect my job or daily life?
Yes, the chronic and often progressive nature of torsion dystonia can significantly impact daily activities, employment, and social participation. The involuntary muscle contractions can lead to pain, functional disability, and a reduced quality of life for affected individuals, making everyday tasks challenging.
10. Is there one main gene that causes my dystonia?
For the majority of people with torsion dystonia, there isn't one single main gene identified as the cause. While some specific monogenic causes (like variants in ARSG or PDE10A) have been found, they account for a minority of cases. Most often, it's believed to be highly polygenic, meaning many different genetic variants, each with small effects, contribute to its development.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
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[2] Grütz K, Klein C. Dystonia updates: definition, nomenclature, clinical classification, and etiology. J Neural Transm (Vienna) 2021;128:395–404.
[3] Laabs BH et al. Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies. Mov Disord. PMID: 39287592.
[4] Zech M, Jech R, Boesch S, et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol 2020;19:908–918.
[5] Nibbeling E, et al. Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia. J Neurol. PMID: 25825126
[6] Steeves, T. D., et al. "The prevalence of primary dystonia: a systematic review and meta-analysis." Mov Disord, vol. 27, 2012, pp. 1789–1796. PMID: 23114997.
[7] Sun YV et al. A Multi-center Genome-wide Association Study of Cervical Dystonia. Mov Disord. PMID: 34320236.
[8] Lohmann K, et al. Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus? Mov Disord. PMID: 24375517
[9] Lange, L. M., Junker, J., Loens, S., et al. "Genotype-phenotype relations for isolated dystonia genes: MDSGene systematic review." Mov Disord, vol. 36, 2021, pp. 1086-1103.
[10] Mok, K. Y., et al. "Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel." Mov Disord, vol. 29, 2014, pp. 245–251.