'Dystonia' describes a neurologic condition characterized by involuntary, sustained muscle contractions affecting one or more sites of the body; 'torsion' refers to the twisting nature of body movements observed in dystonia. Dystonia has been classified as primary (dystonia ... 'Dystonia' describes a neurologic condition characterized by involuntary, sustained muscle contractions affecting one or more sites of the body; 'torsion' refers to the twisting nature of body movements observed in dystonia. Dystonia has been classified as primary (dystonia as the sole or major symptom) or secondary (a symptom of another disorder), and by age of onset, muscle groups affected, and mode of inheritance (Muller and Kupke, 1990; Nemeth, 2002). See also DYT2 (224500) for reports of a similar disorder that shows autosomal recessive inheritance.
Primary torsion dystonia (also known as 'idiopathic' torsion dystonia; ITD) usually begins in childhood or adolescence with involuntary posturing of the trunk, neck, or limbs (Marsden et al., 1976; Nemeth, 2002). Some patients have a myostatic picture, such ... Primary torsion dystonia (also known as 'idiopathic' torsion dystonia; ITD) usually begins in childhood or adolescence with involuntary posturing of the trunk, neck, or limbs (Marsden et al., 1976; Nemeth, 2002). Some patients have a myostatic picture, such as was described by Wechsler and Brock (1922). Johnson et al. (1962) described an extensively affected French-Canadian family. Age of onset of affected family members ranged from 6 to 42 years and severity of the disease varied considerably, with early-onset cases being severely affected. Minor manifestations interpreted as 'formes frustes' were found in some family members. In a large North American family of non-Jewish ancestry, Brin et al. (1989) found that age of onset ranged from 4 to 43 years (mean 14.4, median 10.0). Generalization occurred within a median time of 3 years and occurred earlier in cases with onset in the leg. One 6.5-year-old was unable to walk within 3 months of onset. Batshaw et al. (1985) described a patient with severe simulated torsion dystonia as the main feature of Munchausen syndrome. Bressman et al. (1994) analyzed the haplotype of 174 Ashkenazi Jewish individuals affected with torsion dystonia. In this group, there were 90 carriers of the haplotype and 70 noncarriers. The authors found very striking differences in the phenotype between carriers and noncarriers. The age of onset in carriers was 12.5 years versus 36.5 years in the noncarriers. In 94% of carriers, symptoms began in a limb but only rarely in the neck and larynx. In contrast, the neck, larynx, or other cranial muscles were the site of onset in 79% of noncarriers. Discriminant analysis of limb onset, leg involvement, and age at onset distinguished haplotype carriers from noncarriers with 90% accuracy. In 23 of the 70 noncarriers, the disease was familial and included brachial, cervical, laryngeal, and facial dystonia. Cheng et al. (1996) studied 49 probands with cervical or cranial dystonia with age of onset greater than 12 years and with a positive family history. They found that age of onset of clinical symptoms was earlier by an average of 21.25 years in the second generation than in the first, and suggested that an unstable trinucleotide repeat may be involved in adult-onset primary cranial or cervical dystonia. Grundmann et al. (2003) stated that most cases of early-onset generalized dystonia are caused by a 3-bp deletion in the DYT1 gene (605204.0001). They reported 6 patients with dystonia caused by the 3-bp deletion who exhibited wide phenotypic variability: 2 had classic early-onset primary generalized dystonia, 2 had multifocal dystonia (1 with cranial and cervical muscle involvement), and 2 had only writer's cramp with mild progression. Kostic et al. (2006) reported a large Serbian family in which 7 members carried the DYT1 mutation (605204.0001). However, only 2 were affected by dystonia, indicating a penetrance of 29%. One of the affected individuals had late-onset mild torticollis, and the other had generalized jerky dystonia. In addition, 3 family members with dystonia did not carry the DYT1 mutation, indicating genetic heterogeneity or possibly a psychogenic origin. Kostic et al. (2006) commented on the phenotypic variability in this family. - Neuroradiologic Studies In 12 nonmanifesting carriers of a DYT1 mutation (605204.0001), Ghilardi et al. (2003) found decreased learning of new motor sequence tasks, compared to controls. PET scans during the tasks showed some areas of brain overactivity in the carriers, including in the premotor and supplemental motor cortices. The authors concluded that clinically unaffected DYT1 mutation carriers exhibit mild abnormalities in motor behavior and brain functioning, suggesting an innate compensation for mild striatal dysfunction. Using diffusion tensor magnetic resonance imaging (DTI) to assess axonal integrity and coherence in the brain, Carbon et al. (2004) found that 4 clinically affected DYT1 patients and 8 nonmanifesting DYT1 carriers had microstructural disturbances of the white matter pathways that carry afferents and efferents to the primary sensorimotor cortex compared to controls. The changes were more severe in the clinically affected patients. Using PET scans, Carbon et al. (2004) found that manifesting gene carriers of DYT1 and DYT6 (602629) had bilateral hypermetabolism in the presupplementary motor area and parietal association cortices compared to their respective nonmanifesting gene carriers. DYT1 carriers as a whole showed increased metabolism in the inferior cerebellum and putamen, with decreases in the anterior cingulate. In contrast, DYT6 carriers as a whole showed hypometabolism in the putamen and hypermetabolism in the temporal cortex. Carbon et al. (2004) concluded that dystonia in general is a disease of 'movement preparation' driven by a disruption of sensorimotor integration, but that unique metabolic abnormalities, particularly in subcortical structures, may represent genotype-specific differences. Using PET scans and radiolabeled raclopride, Asanuma et al. (2005) found that 9 nonmanifesting carriers of DYT1 mutations had significantly reduced striatal D2 receptor (DRD2; 126450)-binding compared to 13 control individuals. DYT1 carriers had a reduction in D2 binding in the caudate and ventral putamen. Although Asanuma et al. (2005) were not able to distinguish between D2 receptor loss and increased dopamine turnover, the findings implicated abnormal dopaminergic transmission in the pathogenesis of primary dystonia. Using PET scans and radiolabeled raclopride, Carbon et al. (2009) found significant reductions in caudate and putamen DRD2 availability in 21 individuals with DYT1, including 12 nonmanifesting and 9 manifesting carriers, and 12 individuals with DYT6, including 4 nonmanifesting and 8 manifesting carriers, compared to 13 controls. There was no significant difference between manifesting and nonmanifesting mutation carriers within either group, but those with DYT6 mutations had greater reductions than those with DYT1 mutations. Voxel-based analysis using stringent thresholds showed that the lateral putamen and right ventrolateral thalamus were most affected, with DYT6 carriers again more affected than DYT1 carriers. In addition, DYT6 carriers showed significantly greater reduction in the posterior putamen than DYT1 carriers. Carbon et al. (2009) emphasized that there was no difference between manifesting and nonmanifesting mutation carriers, suggesting that alterations in dopamine neurotransmission are susceptibility factors for the development of clinical symptoms, but that there likely needs to be an additional insult for manifestation. - Neuropathologic Features McNaught et al. (2004) found perinuclear inclusion bodies in cholinergic neurons of the midbrain reticular formation, particularly in the pedunculopontine nuclei (PPN), and periaqueductal gray matter in 4 clinically affected patients with genetically confirmed DYT1. The inclusions stained positively for ubiquitin (191339), torsin-A, and lamin A/C (LMNA; 150330). No inclusion bodies were identified in the substantia nigra, striatum, hippocampus, or selected regions of the cerebral cortex. McNaught et al. (2004) concluded that DYT1 dystonia is associated with impaired protein handling and possible disruption of the nuclear envelope, and that alterations in the brainstem may underlie the motor abnormalities in DYT1. - Clinical Variability Calakos et al. (2010) reported a man with late-onset focal torsion dystonia of the oromandibular region occurring in the fifth decade associated with a heterozygous mutation (F205I; 605204.0004) in the TOR1A gene. The dystonia was characterized by involuntary jaw movements and grimacing. Neurologic examination showed cogwheel tone without rigidity and mild action tremor in the upper limbs, as well as absent ankle reflexes. He had a history of bipolar disorder, treated with lithium, and remote history of treatment with a dopamine receptor blocking agent. There was a family history of tremor and depression, but no family history of dystonia. In vitro functional expression studies in cultured cells showed that the F205I-mutant protein produced TOR1A inclusion bodies that colocalized with the endoplastmic reticulum in about 44% of cells, suggesting impaired function.
Among 147 DYT1 deletion (605204.0001) carriers and 113 blood-related noncarriers from 43 families, Bressman et al. (2002) assessed the validity of the diagnostic categories of 'definite,' 'probable,' and 'possible' dystonia often used in genetic research studies. The category ... Among 147 DYT1 deletion (605204.0001) carriers and 113 blood-related noncarriers from 43 families, Bressman et al. (2002) assessed the validity of the diagnostic categories of 'definite,' 'probable,' and 'possible' dystonia often used in genetic research studies. The category of 'definite' dystonia, defined as characteristic overt twisting or directional movements and postures that are consistently present, was 100% specific: all patients classified as 'definite' carried the deletion mutation. 'Probable' dystonia was significantly increased in carriers compared with noncarriers, and 'possible' dystonia was not significantly different. Bressman et al. (2002) recommended that only patients with definite signs of dystonia be considered affected in linkage and other genetic studies.
Ozelius et al. (1997) identified a 3-bp deletion in the DYT1 gene (605204.0001) in all affected and obligate carrier individuals with chromosome 9-linked primary dystonia, regardless of ethnic background and surrounding haplotype.
- Modifier Alleles ... Ozelius et al. (1997) identified a 3-bp deletion in the DYT1 gene (605204.0001) in all affected and obligate carrier individuals with chromosome 9-linked primary dystonia, regardless of ethnic background and surrounding haplotype. - Modifier Alleles Although a GAG deletion in the DYT1 gene (605204.0001) is the major cause of early-onset dystonia, expression as clinical disease occurs in only 30% of mutation carriers. To gain insight into genetic factors that may influence penetrance, Risch et al. (2007) evaluated 3 DYT1 SNPs including D216H (605204.0003), a coding-sequence variation that moderates the effects of the DYT1 GAG deletion in cellular models. The D216H polymorphism encodes aspartic acid (D) in 88% and histidine (H) in 12% of control-population alleles (Ozelius et al., 1997: Leung et al., 2001). Risch et al. (2007) tested 119 DYT1 GAG-deletion carriers with clinical signs of dystonia and 113 mutation carriers without signs of dystonia as well as 197 control individuals; they found a frequency of the his216 allele to be increased in GAG-deletion carriers without dystonia and to be decreased in carriers with dystonia, compared with the control individuals. Analysis of haplotypes demonstrated a highly protective effect of the H allele in trans with the GAG deletion; there was also suggestive evidence that the asp216 allele in cis is required for the disease to be penetrant. The findings established, for the first time, a clinically relevant gene modifier of DYT1. Kamm et al. (2008) found that none of 42 symptomatic patients from 35 European families with dystonia carried the D216H variant, whereas 6 (12.5%) of 48 chromosomes from 24 asymptomatic mutation carriers had the D216H SNP. The findings indicated that deletion carriers with the his216 allele have a greatly reduced risk of developing symptoms of dystonia: the disease penetrance of those with the his216 allele is about 3% compared to about 35% in deletion carriers with the asp216 allele. The authors noted that although the his216 allele is generally rare, with a maximum frequency of 19% in Europeans, it should be included in molecular genetic testing for the disorder.
Zilber et al. (1984) found that the frequency of the disease in European Jews was about 1:23,000 live births or about 5 times greater than in Jews of Afro-Asian origin. Risch et al. (1989), (1990) reported a high ... Zilber et al. (1984) found that the frequency of the disease in European Jews was about 1:23,000 live births or about 5 times greater than in Jews of Afro-Asian origin. Risch et al. (1989), (1990) reported a high incidence of the disease among Ashkenazi Jews. In 52 unrelated, affected Ashkenazi Jewish persons, Ozelius et al. (1992) found highly significant linkage disequilibrium between a particular extended haplotype at the ABL-ASS loci and the DYT1 gene. Most affected individuals were heterozygous for the particular haplotype, a finding supporting autosomal dominant inheritance of the DYT1 gene. Of the 53 definitely affected individuals typed, 13 appeared to be sporadic, with no family history of dystonia. Ozelius et al. (1992) concluded that many sporadic cases are in fact hereditary, that the disease gene frequency is greater than 1 in 15,000, and that the penetrance is lower than 30% (the previously estimated value for this population). Risch et al. (1995) examined data on 6 closely linked microsatellite loci on 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia. The data indicated that more than 90% of early-onset cases in the Ashkenazi population are due to a single founder mutation, which the authors estimated first appeared approximately 350 years ago. They showed that carriers preferentially originated from the northern part of the historic Jewish Pale, Lithuania and Byelorussia. The recent origin of this dominant mutation and its current high frequency, between 1 in 6,000 and 1 in 2,000, suggested that the Ashkenazi population descended from a limited number of founders and emphasized the importance of genetic drift in determining disease allele frequencies in this population. Zoossmann-Diskin (1995) challenged the significance of genetic drift in determining the high frequency of the DYT1 gene in Ashkenazim. He questioned the accuracy of the small population numbers before 1600 and the rapid expansion thereafter and favored heterozygote advantage as the explanation for the high gene frequency. In a long reply, Risch et al. (1995) defended the population statistics and cited a number of reasons that the claim of heterozygote advantage for this dominant disorder is untenable. They suggested that genetic drift provides a general explanation for the high frequency of at least a dozen genetic diseases that occur at high frequency uniquely to the Ashkenazi population. None of these mutations is common among the non-Jews living in proximity to the Jews. Founder effect of recent mutations in a rapidly expanding population from a limited number of founders offers a simple, parsimonious solution, in their view. Motulsky (1995) gave a useful review of 10 'Ashkenazi Jewish diseases,' including torsion dystonia. Valente et al. (1999) analyzed the haplotypes surrounding the DYT1 gene in 9 Ashkenazi Jewish and 15 non-Jewish British patients carrying the GAG deletion. They found that all Ashkenazi-Jewish British patients carried the same haplotype as the North American Jews, sustaining the theory that the current British Ashkenazi community descends from the same small group of individuals as the North American Jewry. Furthermore, in the non-Jewish British patients, only a limited number of distinct founder mutations were observed. This supported the hypothesis that the GAG deletion in the DYT1 gene (605204.0001) is not a very frequent mutation, and that it has arisen only a limited number of times throughout the centuries. Ikeuchi et al. (1999) noted that Yanagisawa et al. (1972) had described families with the clinical diagnosis of dystonia musculorum deformans. Because of the high frequency in Japanese of hereditary progressive dystonia with marked diurnal fluctuations (128230), which has symptoms similar to those of primary torsion dystonia, Ikeuchi et al. (1999) concluded that it is important to document the GAG deletion in the DYT1 gene (605204.0001) in the Japanese population. Hjermind et al. (2002) examined 107 unrelated Danish probands with primary torsion dystonia. The clinical examinations showed that 22 probands had generalized dystonia (20 of whom had early limb-onset), 2 had hemidystonia, 5 had multifocal dystonia, 15 had segmental dystonia, and 63 had focal dystonia. Among the 107 probands investigated, the GAG deletion (605204.0001) in the DYT1 gene was detected in 3 (2.8%). This corresponded to 15% of the 20 probands with early limb-onset generalized dystonia. Of the 3 probands with the GAG deletion, only 1 had familial dystonia, with the mutation detected in the affected father and in 6 asymptomatic adult relatives. In the second proband the DYT1 mutation was also encountered in the asymptomatic mother, while in the third case none of the parents had the GAG deletion and therefore represented a de novo mutation. Hjermind et al. (2002) pointed out that the difficulties in genetic counseling concerning dystonia are due to the low penetrance of many of the hereditary forms of dystonia, the variable phenotype within the same type of dystonia, and the occurrence of de novo DYT1 mutations. Frederic et al. (2008) found that DYT1 was rare in France, with an estimated disease frequency of 0.13 in 100,000 and an estimated mutation frequency of 0.17 in 100,000. Eleven (20.7%) of 53 families carried the Ashkenazi Jewish haplotype, suggesting that independent mutational events occurred in the other families.