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Torsion Dystonias

  • Author: Priyantha Herath, MD, PhD; Chief Editor: Selim R Benbadis, MD  more...
 
Updated: Feb 15, 2016
 

Background

Dystonia is a syndrome of sustained muscle contractions of agonist and antagonist muscles, usually resulting in twisting, torsional, and repetitive movements or abnormal postures.[1]  It can either be primary or secondary. Primary torsion dystonia (PTD) is dystonia in isolation without brain degeneration and without an acquired cause. Secondary dystonia includes a heterogenous group of etiologies including inherited (with and without brain degeneration) and acquired neurologic disorders. The phenotypic spectrum associated with PTD is broad, from early-onset generalized to adult-onset focal dystonia.[3, 4]

The first description of what is now considered primary, or idiopathic, torsion dystonia was described by Schwalbe in 1908. In 1911, Oppenheim termed this same condition dystonia musculorum deformans (DMD) or dysbasia lordotica progressiva.[2] Initially believed to be a manifestation of hysteria, idiopathic torsion dystonia is now established as a specific neurologic entity with a well-established genetic basis. DMD and Oppenheim disease are terms now used for childhood- and adolescent-onset dystonia due to the DYT1 gene.

Classification of dystonia

At the present time there are 25 types of genetically determined dystonias. Several classification schemes have been used to categorize the various forms of dystonia. One common scheme is based on genetic features, including mode of inheritance and molecular genetic data. There is also a topographic classification where torsion dystonia may be described as focal, segmental, multifocal, or generalized, depending on which anatomic distribution of the symptoms (see Table 1).

Table 1. Anatomic Distribution of Primary Torsion Dystonia (Open Table in a new window)

Focal Body Site
Segmental two or more contiguous body regions
Multifocal two or more noncontiguous body regions
Generalized involving atleast one leg, the trunk and another body region
Hemidystonia involving one side of the body

In addition, depending on the clinical features, dystonias can be divided into two main groups: isolated dystonia or combined dystonia. Combined dystonia can be classified into three sub-types: those accompanied by parkinsonism, by myoclonus, or by a mixed pattern of various hyperkinetic movements.

Genetically defined isolated dystonias include TOR1A/DYT1, TUBB4/DYT4, THAP1/DYT6, PRKRA/DYT16, CIZ1/DYT23, ANO3/DYT24, and GNAL/DYT25. Combined dystonias, accompanied by parkinsonism with known genetic loci include TAF1/DYT3, GCH1/DYT5a, TH/DYT5b, and ATP1A3/DYT12. Genetically determined dystonias that are accompanied by myoclonus include SGCE/DYT11, whereas dystonias that accompany a mixed pattern of hyperkinetic disorders include MR-1/DYT8, PRRT2/DYT10, and SLC2A1/ DYT18.[51]  

Sometimes, combined dystonias are also classified depending on whether the symptoms are continually and continuously present or whether they are paroxysmal. Generic forms of common, persistent combined dystonias are GCH1/ DYT5a, TH/DYT5b, SGCE/DYT11, APT1A3/DYT12, and TAF1/ DYT3. Genetically defined paroxysmal combined dystonias include MR-1/DYT8, PRRT2/DYT10, and SLC2A1/DYT18.[51]  

DYT1 (early-onset generalized dystonia)

DYT1 are caused by a 3-base pair in-frame deletion within the coding region of the TOR1A (torsinA) gene located on chromosome 9q34. TorsinA is expressed at high levels in neuronal cytoplasm of specific neuronal populations in the adult human brain, including the SN, thalamus, cerebellum, hippocampus, and neostriatum.

DYT1 is the most common hereditary dystonia. Phenomenologically, it is an isolated dystonia. Some degree of genetic anticipation in regards to the age of onset and disease severity has been noted in DYT1. It is especially common among the Ashkenazi Jewish population.

In most instances, DYT1 symptoms often start with a focal dystonia as talipes equinovarus of one leg in early childhood, typically around 6 years of age. The dystonic posturing then gradually progresses with age to other extremities and trunk muscles by the early teens. There is obvious asymmetry to the dystonia, with involvement of the extremities on the dominant side along with the ipsilateral sternocleidomastoid muscle. In these patients, interlimb coordination and locomotive movements are not affected at all. Moreover, intellectual, mental, and psychological functions are completely intact in these patients.

Based on clinical characteristics, DYT1 can be classified into two types: the postural type with appendicular and truncal dystonias, or the action type, which is associated with violent dyskinetic movements in addition to dystonic posture.

DYT5 (dopa-responsive dystonia)

Hereditary progressive dystonia with marked diurnal fluctuation, or Segawa disease, is an autosomal dominantly inherited dopa-responsive dystonia (DRD) caused by heterozygous mutations of the GCH1 gene located on chromosome 14q22.1-q22.2. DYT5 shows a marked female predominance in the young. In contrast, adult-onset cases show a male predominance

Onset is around 6 years of age, mostly with rigid talipes equinovarus of one foot not dissimilar to DYT1. With age, it expands to other limbs and trunk muscles by the midteens with progressive rigidity. Starting around age 10 years, postural tremor of 8 to 10 Hz appears. These symptoms show marked diurnal fluctuations, worsening through the day and almost absent in the early morning. However, this fluctuation decreases with age in the late teens, and is no longer apparent in early adulthood, when symptoms become static. Clinically, DYT5 is also classified into two types: postural and action. Patients with the action type develop dystonic movements of one extremity or the neck (action retrocollis) in addition to dystonic, and show focal or segmental dystonia during the teenage years.

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Pathophysiology

In DYT1 and the other genetic dystonias, no consistent histologic or biochemical abnormalities have been identified. However, perinuclear inclusion bodies have been described in the midbrain reticular formation and in the periaqueductal gray matter in 4 patients in whom DYT1 was clinically documented and genetically confirmed.[5]  This is in contrast, however, to the secondary forms of dystonia that are frequently associated with macroscopic structural lesions of the basal ganglia and thalamus.

As such, in primary torsion dystonias and other genetic dystonias no discernible abnormalities are seen on structural neuroimaging studies. Abnormal brain networks have been described in different functional imaging studies; substantial evidence implicates dysfunction in dopaminergic pathways in the pathophysiology of primary torsion dystonia.[6, 7]

Besides motor control difficulties, defective sensory processing and sensory abnormalities are described,[8, 9]  but these findings are inconsistent.

While the exact pathogenesis of dystonia is unknown, based on the current models of basal ganglia circuitry, some form of electro-biochemical dysfunction at the basal ganglia level has been proposed as the underlying unifying mechanism behind various forms of dystonia.[10]  Such dysfunctions may involve direct and indirect pathways and result in impaired center-surround inhibition at the cortical level. 

See the image below for a diagram of the basal ganglia circuitry dysfunction in dystonia.

Idiopathic torsion dystonia. Major nuclear complex Idiopathic torsion dystonia. Major nuclear complex of the basal ganglia is the striatum, which is composed of the caudate and putamen. The striatum receives glutamatergic input from the cerebral cortex and dopaminergic input from the substantia nigra pars compacta (SNc). Two types of spiny projection neurons receive cortical and nigral inputs: those that project directly and those that project indirectly to the internal segment of the globus pallidus (GPI), which is the major output site of the basal ganglia. Complementary action of both of these pathways regulates the overall function of the GPI. The GPI, which, in turn, provides tonic inhibitory (ie, gamma-aminobutyric acid [GABA]–ergic) discharges downstream into the thalamic nuclei that project to the frontal cortical and other CNS areas. Direct pathway (D1) inhibits the substantia nigra pars reticulata (SNr) and the GPI, which are the major output sites, resulting in a net disinhibition and facilitation of thalamocortical circuits. Indirect pathway (D2), through serial connections with the globus pallidus pars externa (GPe) and the subthalamic nucleus (STN), is excitatory to the GPI, resulting in further inhibitory action on thalamocortical pathways. In this model, the mean discharge rate of the GPI is the key factor that determines a hypokinetic or hyperkinetic movement disorder. Increased inhibitory influences of the GPI on the thalamocortical circuitry result in hypokinetic disorders, such as Parkinson disease, whereas decreased GPI activity results in hyperkinetic disorders, such as hemiballismus. VL = ventrolateral thalamus.
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Epidemiology

Frequency

The exact relative frequencies of primary and secondary forms of dystonia remain unknown.

The prevalence of primary torsion dystonia is difficult to estimate because of the variation in its phenotypic expression and the tendency for mild cases to go undiagnosed. In Rochester, Minnesota, the prevalence was calculated to be approximately 34 per million persons for generalized dystonia and 295 per million persons for all focal dystonia from a study conducted in 1980s.[11] Late-onset focal primary dystonia was 10 times more common than early-onset generalized primary torsion dystonia.[11]

Several large studies have shown that early-onset primary torsion dystonia is 5-10 times more common in Ashkenazi Jews than in people who were not Jewish or in Jewish individuals not of Ashkenazi heritage. Subsequent studies have found a wide range in the prevalence of dystonia from 6-7,320 persons per million population.[12, 13]

In a European collaborative study (the Epidemiological Study of Dystonia in Europe [ESDE]), investigators found a crude annual prevalence of 15.2 cases per 100,000 individuals, the majority of whom had focal dystonia at a rate of 11.7 cases per 100,000 individuals.[14]

Race

Childhood- and adolescent-onset primary dystonia is more common in Jews of Eastern European or Ashkenazi ancestry than in other groups and seemingly rare in Far Eastern populations.

  • Many cases of early primary torsion dystonia, especially those among non-Jewish populations, are not due to the TOR1A GAG deletion in DYT1. The DYT6 locus was identified by means of linkage analysis in 15 affected members from 2 Swiss Mennonite families. [15]
  • A genome-wide search for primary torsion dystonia in a large family from central Italy in whom 11 members were definitely affected revealed a novel locus, namely, DYT13. [16]

Gender

In a large study of 957 cases of primary dystonia from Europe, segmental and focal dystonias had notable female predilections. This finding suggested that patients with focal dystonia should not be treated as a homogeneous group and that sex-linked factors may play a role.[14]

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Contributor Information and Disclosures
Author

Priyantha Herath, MD, PhD Director of Movement Disorders Clinic, Attenting Neurologist, Department of Neurology, University of South Carolina School of Medicine at Columbia

Priyantha Herath, MD, PhD is a member of the following medical societies: American Academy of Neurology, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Coauthor(s)

Souvik Sen, MD, MPH, MS, FAHA Professor and Chair, Department of Neurology, University of South Carolina School of Medicine

Souvik Sen, MD, MPH, MS, FAHA is a member of the following medical societies: American Academy of Neurology, Association for Patient-Oriented Research, American Heart Association

Disclosure: Nothing to disclose.

Sonal Mehta, MD Clinical Assistant Professor, Department of Neurology, University of South Carolina School of Medicine

Sonal Mehta, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Stroke Association, Neurocritical Care Society, Society of Vascular and Interventional Neurology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nestor Galvez-Jimenez, MD, MSc, MHA The Pauline M Braathen Endowed Chair in Neurology, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cyberonics; Eisai; Lundbeck; Sunovion; UCB; Upsher-Smith<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cyberonics; Eisai; Glaxo Smith Kline; Lundbeck; Sunovion; UCB<br/>Received research grant from: Cyberonics; Lundbeck; Sepracor; Sunovion; UCB; Upsher-Smith.

Additional Contributors

Stephen T Gancher, MD Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University

Stephen T Gancher, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Vijaya K Patil, MD Assistant Professor, Department of Neurology, Edward Hines Jr Veterans Affairs Medical Center, Loyola University, Chicago Stritch School of Medicine

Vijaya K Patil, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Medical Council of India

Disclosure: Nothing to disclose.

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Idiopathic torsion dystonia. Major nuclear complex of the basal ganglia is the striatum, which is composed of the caudate and putamen. The striatum receives glutamatergic input from the cerebral cortex and dopaminergic input from the substantia nigra pars compacta (SNc). Two types of spiny projection neurons receive cortical and nigral inputs: those that project directly and those that project indirectly to the internal segment of the globus pallidus (GPI), which is the major output site of the basal ganglia. Complementary action of both of these pathways regulates the overall function of the GPI. The GPI, which, in turn, provides tonic inhibitory (ie, gamma-aminobutyric acid [GABA]–ergic) discharges downstream into the thalamic nuclei that project to the frontal cortical and other CNS areas. Direct pathway (D1) inhibits the substantia nigra pars reticulata (SNr) and the GPI, which are the major output sites, resulting in a net disinhibition and facilitation of thalamocortical circuits. Indirect pathway (D2), through serial connections with the globus pallidus pars externa (GPe) and the subthalamic nucleus (STN), is excitatory to the GPI, resulting in further inhibitory action on thalamocortical pathways. In this model, the mean discharge rate of the GPI is the key factor that determines a hypokinetic or hyperkinetic movement disorder. Increased inhibitory influences of the GPI on the thalamocortical circuitry result in hypokinetic disorders, such as Parkinson disease, whereas decreased GPI activity results in hyperkinetic disorders, such as hemiballismus. VL = ventrolateral thalamus.
Table 1. Anatomic Distribution of Primary Torsion Dystonia
Focal Body Site
Segmental two or more contiguous body regions
Multifocal two or more noncontiguous body regions
Generalized involving atleast one leg, the trunk and another body region
Hemidystonia involving one side of the body
Table.
Type Designation Mode of Inheritance Gene Gene Locus OMIM#
DYT1 Early-onset generalized Autosomal dominant TOR1A 9q.34.11 128100
DYT2 Early-onset generalized Autosomal recessive Uknown Uknown 224500
DYT3 X-linked dystonia parkinsonism (Lubag syndrome) X-chromosomal recessive TAF1 Xq13.1 314250
DYT4 Torsion dystonia (Whispering dysphonia) Autosomal dominant TUBB4A 19p13.3 128101
DYT5a Dopa-responsive dystonia (Segawa disease) Autosomal dominant GCH1 14q22.1–22.2 128230
DYT5b Dopa-responsive dystonia Autosomal recessive TH 11p15.5 605407
DYT6 Adolescent-onset mixed phenotype Autosomal dominant THAP1 8p11.21 602629
DYT7 Paroxysmal dystonic choreoathetosis Autosomal dominant Unknown 18p 602124
DYT8 Paroxysmal kinesigenic, nonkinesigenic dyskinesia Autosomal dominant MR-1 2q33–35 118800
DYT9 Paroxysmal choreoathetosis with spasticity Autosomal dominant CSE 1p 601042
DYT10 Paroxysmal kinesigenic dystonia Autosomal dominant PRRT2 16q11.2–12.1 128200
DYT11 Myoclonus dystonia Autosomal dominant SGCE 7q21.3 159900
DYT11 Myoclonus dystonia Autosomal dominant DRD2 11q23.2 159900
DYT12 Rapid-onset dystonia parkinsonism (syndrome) Autosomal dominant ATP1A3 19q12–13.2 128235
DYT13 Early- and late-onset focal or craniocervical dystonia Autosomal dominant Unknown 1p36.32-p36.13 607671
DYT14 Dopa-responsive generalized dystonia        
DYT15 Myoclonus-dystonia Autosomal dominant Unknown 18p11 607488
DYT16 Dystonia-parkinsonism syndrome Autosomal recessive PRKRA 2q31.2 612067
DYT17 Adolescent onset Autosomal recessive Unknown 20p11.2-q13.12 612406
DYT18 Paroxysmal exertion-induced dyskinesia Autosomal dominant SLC2A1 1p34.2 612126
DYT19 Paroxysmal kinesigenic dyskinesia 2 Autosomal dominant Unknown 16q13-q22.1 611031
DYT20 Paroxysmal nonkinesigenic dyskinesia 2 Autosomal dominant Unknown 2q31 611147
DYT21 Late-onset torsion dystonia Autosomal dominant Unknown 2q14.3-q21.3 614588
DYT22     Unknown Unknown Not listed
DYT23 Adult-onset cervical dystonia Autosomal dominant CIZ1 9q34 614860
DYT24 Focal dystonia Autosomal dominant ANO3 11p14.2 615034
DYT25 Adult-onset focal dystonia Autosomal dominant GNAL 18p11.21 615073
Table.
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