Background
Dystonia is a syndrome of sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures.[1]
In 1908, Schwalbe first described primary, or idiopathic, torsion dystonia in a Jewish family, and in 1911, Oppenheim termed this dystonia musculorum deformans (DMD).[2] Initially believed to be a manifestation of hysteria, idiopathic torsion dystonia gradually became established as a neurologic entity with a genetic basis. DMD and Oppenheim disease are terms now used for childhood- and adolescent-onset dystonia due to the DYT1 gene.
With the recent mapping of genes for idiopathic torsion dystonia and identification of a gene for early onset dystonia, the description primary, or idiopathic, dystonia has evolved; it now may be viewed as secondary to or symptomatic of an identified cause. However, continuing to use primary torsion dystonia to classify a group of dystonias as a clinically and genetically heterogeneous group of movement disorders is justifiable because dystonia is the primary and sole abnormality attributable to the condition, and degeneration on pathologic examination is not clearly established.
Primary torsion dystonia may be focal, segmental, multifocal, or generalized, depending on which anatomic sites are involved (see Table 1).
Table 1. Anatomic Distribution of Primary Torsion Dystonia (Open Table in a new window)
| Focal | Single Body Site |
| Segmental | Contiguous body regions |
| Multifocal | Multiple, noncontiguous body sites |
| Generalized | Leg involvement with other body sites |
| Hemidystonia | Unilateral |
Pathophysiology
Although secondary forms of dystonia are frequently associated with structural lesions of the basal ganglia and thalamus, no consistent histologic or biochemical findings are noted in primary torsion dystonia. 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.[3]
No discernible abnormalities are seen on current 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.[4]
Besides motor control difficulties, defective sensory processing and sensory abnormalities are described.[5, 6]
Current models of basal ganglia circuitry have been adapted and suggest dysfunction at the basal ganglia level.[7] These aberrations involve the direct and indirect pathways and result in impaired inhibition at the cortical level with consequent loss of normal inhibitory reflexes at the level of the brainstem and spinal levels.
See the image below for a diagram of the basal ganglia circuitry dysfunction in dystonia.
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. Epidemiology
Frequency
United States
The relative frequencies of primary and secondary forms of dystonia are not known.
The prevalence of primary torsion dystonia is difficult to estimate because of the variation in its 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.[8] Late-onset focal primary dystonia was 10 times more common than early-onset generalized primary torsion dystonia.[8]
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.[9, 10]
International
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.[11]
Race
Childhood- and adolescent-onset primary dystonia is more common in Jews of Eastern European or Ashkenazi ancestry than in other groups.
- 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.[12]
- 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.[13]
Sex
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.[11]
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| Focal | Single Body Site |
| Segmental | Contiguous body regions |
| Multifocal | Multiple, noncontiguous body sites |
| Generalized | Leg involvement with other body sites |
| Hemidystonia | Unilateral |
| Characteristic | DYT1 | DYT6 | DYT7 | DYT13 |
| Age of onset | Early (< 26 y); rare cases of late onset | Childhood or adulthood | Adult | 5-40 y (mean, 15.6 y) |
| Site of involvement | Limb onset (>95% of patients have arm involvement), trunk, neck, cranial (< 15%) | Limb, neck, or cranial muscles; cranial involvement with dysarthria and dysphagia | Cervicocranial | Prominent cervicocranial and upper-limb involvement |
| Mode of transmission | Autosomal dominant with reduced penetrance (30-40%) | Autosomal dominant with reduced penetrance | Autosomal dominant with reduced penetrance (12-15%) | Autosomal dominant |
| Locus | 9q32 | 8p | 18p | 1p36.13-p36.32 |
| Pathophysiology | Mutation in gene TOR1A coding for an adenosine-triphosphate-binding protein, resulting from a GAG deletion | Various mutations in the THAP1 gene | No data | No data |
| Families described | Ashkenazi and on-Ashkenazi groups | Mennonite or Amish and others[17] | German | Italian |
| Gene | Locus | Features |
| DYT1* | 9q34 | Early, limb-onset primary torsion dystonia; autosomal dominant with 30% penetrance; gene encodes torsin A; all mutations except 1 are GAG deletions |
| DYT2 | None | Autosomal recessive in Gypsy populations; early onset |
| DYT3 | Xq13.1 | X-linked (ie, Lubag) dystonia parkinsonism; almost all due to a founder Filipino mutation; young adult-onset, cranial (including larynx and/or stridor) and limb dystonia, parkinsonism develops (or is present at onset) with shuffling, drooling |
| DYT4 | None | Whispering dysphonia in Australian family (autosomal dominant) |
| DYT5 | 14q22.1 | Childhood-onset dopa-responsive dystonia (DRD) and parkinsonism; autosomal dominant, sex influenced, reduced penetrance (higher in girls than in boys); gene encodes guanosine triphosphate cyclohydrolase I, with many different mutations |
| DYT6* | 8p | Adolescent and early-adult onset, mixed phenotype with limb, cervical, and cranial onset and limited and generalized spread; originally found in Amish-Mennonite families, but numerous variants have subsequently been found in families of European descent[11] ; autosomal dominant with reduced penetrance |
| DYT7* | 18p | Late-onset primary cervical dystonia in North German families; autosomal dominant with reduced penetrance |
| DYT8 | 2q33-35 | Paroxysmal nonkinesiogenic dyskinesia or chorea, autosomal dominant |
| DYT9 | 1p21 | Episodic choreoathetosis/spasticity (CSE), episodic choreoathetosis with spasticity, autosomal dominant |
| DYT10 | 16p11.2-q12.1 | Paroxysmal kinesiogenic dyskinesia or chorea, autosomal dominant |
| DYT11 | 7q21 | Myoclonus-dystonia, autosomal dominant, childhood-onset dystonia (especially limbs and neck) and myoclonus (especially neck, shoulders, face); often improves with alcohol |
| DYT12 | 19q13 | Rapid-onset dystonia parkinsonism |
| DYT13* | 1p36.13-35.32 | Prominent craniocervical and upper-limb involvement and mild severity in a large Italian family |
| DYT14 | Redefined as DYT5[20] | |
| DYT15 | 18p11 | Myoclonus dystonia; autosomal dominant[21] |
| DYT16 | 2q31 | Progressive, generalized, early-onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia, and sometimes parkinsonian features, unresponsive to levodopa therapy; autosomal recessive[22] |
| DYT17 | 20p11.22-q13.12 | Primary focal torsion dystonia in a large Lebanese family; autosomal recessive[23] |
| DYT18 | 1p35-p31.3 | Paroxysmal exertion-induced dystonia with hemolytic anemia; autosomal dominant |
| Note: Although the etiologies for these dystonic syndromes are attributed mainly to genetic causes and to no other secondary causes, only some of these conditions have dystonia as the sole clinical finding to fulfill the criteria for a diagnosis of primary torsion dystonia. *Adapted from Bressman et al.[24] | ||
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