Dystonia 1, Torsion, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that torsion dystonia-1 (DYT1) is caused by heterozygous mutation in the TOR1A gene (605204), encoding the ATP-binding protein torsin-A, on chromosome 9q34.

Description

'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).

Clinical Features

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 (delE302/303; 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 delE302/303 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.

Zirn et al. (2008) reported an 18-year-old girl with a severe form of early-onset dystonia. She had mildly delayed early motor development with stalling of further development during the second year of life. She never learned to walk independently and became wheelchair-bound at age 5 years. At age 13, she could no longer eat or drink without assistance. At age 18, she had dysphagia, severe dysarthria, facial palsy with reduced tongue mobility, dystonic movements, multiple joint contractures, increased muscle tone, hyperreflexia, and extensor plantar responses. Cognition was normal.

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 that was 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 endoplasmic reticulum in about 44% of cells, suggesting impaired function.

Other Features

Heiman et al. (2004) administered a standard psychiatric interview to 96 manifesting carriers of the DYT1 deletion mutation (605204.0001), 60 nonmanifesting carriers of the mutation, and 65 noncarriers. The risk for early-onset (before 30 years) recurrent major depression (see 608516) was increased in both manifesting mutation carriers (relative risk of 3.62) and nonmanifesting mutation carriers (relative risk of 4.95) compared to noncarriers. The severity of dystonia in manifesting carriers was not associated with the likelihood of major depression, and mutation carriers did not have an increased risk for other affective disorders. Heiman et al. (2004) concluded that early-onset recurrent major depression is a clinical expression of the DYT1 gene mutation that is independent of dystonia.

Biochemical Features

Some groups have found elevation of plasma dopamine-beta-hydroxylase, the enzyme that converts dopamine to norepinephrine, in the dominant form of dystonia (Wooten et al., 1973; Ziegler et al., 1976; Askenasy et al., 1980).

Hornykiewicz et al. (1986) performed histologic and biochemical studies on the brains of 2 patients with a generalized childhood-onset form of dystonia. No important histologic change was found, but levels of norepinephrine and serotonin were decreased in some areas and elevated in others. The authors concluded that some of these changes may represent a basic abnormality of the disorder. They pointed to elevated norepinephrine levels found in an inherited dystonia of the Sprague-Dowley rat with no obvious neuropathologic changes (Lorden et al., 1984). In this model, the alpha-2-adrenergic receptor agonist clonidine has antidystonic effects.

Inheritance

Zeman et al. (1959, 1960) traced the disorder through 4 generations and Larsson and Sjogren (1963) traced it through 5 generations. Zilber et al. (1984) analyzed data from a nationwide survey of idiopathic torsion dystonia in Israel. Assuming that all cases fit the same genetic model, an X-linked or simple autosomal recessive model could be rejected. An autosomal dominant model with low penetrance could have accounted for the observations. Paternal age was increased (33.8 vs 30.1, p = 0.01) for isolated cases. Bundey et al. (1975) had also observed paternal age effect.

Risch et al. (1989, 1990) ascertained 43 Ashkenazi Jewish probands with idiopathic torsion dystonia with onset before age 28 years and studied all available first- and second-degree relatives. The findings were considered consistent with autosomal dominant inheritance with about 30% penetrance; recessive inheritance was strongly rejected. Risch et al. (1989, 1990) concluded that torsion dystonia in Ashkenazi Jews may be largely homogeneous. Bressman et al. (1989) studied 39 kindreds derived from 43 independently ascertained probands of Ashkenazi ancestry. The age-adjusted risk for all first-degree relatives was 15.5% and for all second-degree relatives 6.5%, with no significant sex differences; parent, offspring, and sib risks did not differ significantly. The risks were consistent with autosomal dominant inheritance with a penetrance estimated at 29.4% using definite cases only, and 32.2% using definite and probable cases. Assuming a disease frequency of 1 in 15,000, the gene frequency was estimated to be 1 in 9,000. Penetrance in this disorder is usually low (approximately 30%), but varies considerably between families; the particularly large French-Canadian family first described by Johnson et al. (1962) showed a penetrance greater than 90%.

Muller and Kupke (1990) reviewed the genetics of primary torsion dystonia and noted there are multiple forms of autosomal dominant torsion dystonia. They also listed genetic and nongenetic causes of secondary dystonia.

Heterogeneity

In 1 French and 26 British families with torsion dystonia, 3 of which were Ashkenazi Jewish, Warner et al. (1993) found that nearly half of the dystonia families may be of a variety unlinked to 9q34, supporting the existence of genetic heterogeneity.

Gasser et al. (1996) found no common haplotypes in the DYT1 region on chromosome 9q in 10 Ashkenazi Jewish patients with focal hand dystonia, indicating separate etiology for this disorder.

In a review of primary dystonias, Muller et al. (1998) indicated that at least 8 clinically distinct autosomal dominant and 2 X-linked recessive forms had been identified. In addition, pedigree analyses suggested the occurrence of an autosomal recessive variant. They tabulated the primary dystonias, numbered 1 through 12, and proposed that most of them can be distinguished by genetic criteria.

Contarino et al. (2008) reported a large consanguineous family with adult-onset primary focal dystonia from a small Dutch village on a former island. There were 8 affected and 4 possibly affected individuals, with a mean age at onset of 45.5 years. Common clinical features included cervical dystonia, blepharospasm, writer's cramp, and mild arm tremor. The symptoms overall were quite mild in all patients. Contarino et al. (2008) noted that the transmission pattern could be consistent with autosomal recessive inheritance, given the consanguinity, or with autosomal dominant inheritance with reduced penetrance, because there was an instance of father-to-son transmission. Genetic analysis excluded mutations in the TOR1A and SGCE (604149) genes, and linkage analysis excluded several DYT loci.

Mapping

In the large non-Jewish kindred studied by Kramer et al. (1987), Ozelius et al. (1989) found tight linkage with the gene encoding gelsolin (137350); maximum lod score = 3.51 at theta = 0.0 cM. Ozelius et al. (1989) concluded from multipoint linkage analysis that the DYT1 locus lies in the 9q32-q34 region between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase, a possible candidate gene. In a study of 12 multiplex Ashkenazi Jewish families, Kramer et al. (1989, 1990) confirmed the assignment to 9q32-q34. Kramer et al. (1990) demonstrated close linkage with the gene encoding argininosuccinate synthetase (ASS; 603470). This suggests that the mutation causing the Ashkenazi Jewish disease is in the same gene as that causing dystonia in the non-Jewish kindred in which linkage to gelsolin was demonstrated. In a large non-Jewish family and in a group of Ashkenazi Jewish families, Kwiatkowski et al. (1991) used GT repeat polymorphisms from the 9q32-q34 region to demonstrate that the causative gene in both groups was in this region, in an 11-cM interval between AK1 (103000) and D9S10. Using (GT)n and RFLP markers from the region 9q32-q34, Ozelius et al. (1992) delineated the area containing the DYT1 gene to a 6-cM region bounded by loci AK1 and ASS.

Warner et al. (1993) determined that association observed between ABL/ASS and idiopathic torsion dystonia in Ashkenazi families in the U.S. was also present in some British Jewish kindreds. Kramer et al. (1994) studied 7 non-Jewish families of northern European and French-Canadian descent and found evidence for linkage to the DYT1 region in 5 of these families. Estimates of penetrance in the non-Jewish families ranged from 0.40 to 0.75. None of these families carried the Ashkenazi Jewish haplotype, suggesting that in these populations there was a different mutation in the DYT1 gene.

Ozelius et al. (1997) used a YAC contig spanning 600 kb of chromosome 9q34 and several new polymorphic loci to expand the linkage disequilibrium analysis of the torsion dystonia mutation in Ashkenazi Jewish families. They concluded that the most likely location of the DYT1 gene is within a 150-kb region between D9S2161 and D9S63.

Exclusion Studies

Kramer et al. (1985) used the 'candidate gene' approach to show that the proopiomelanocortin gene (POMC; 176830) is not linked to torsion dystonia in a kindred with the autosomal dominant form reported by Johnson et al. (1962). Using the same approach, Breakefield et al. (1986) excluded the POMC and glutamate decarboxylase (GAD; see 605363) genes as the site of the mutation. Kramer et al. (1987) excluded 11p, 13q, and 21q as the location of the mutation in a single non-Jewish pedigree with torsion dystonia.

Molecular Genetics

Ozelius et al. (1997) identified a heterozygous 3-bp deletion in the DYT1 gene (delE302/303; 605204.0001) in all affected and obligate carrier individuals with chromosome 9-linked primary dystonia, regardless of ethnic background and surrounding haplotype.

In a man with focal torsion dystonia of the oromandibular region occurring in the fifth decade, Calakos et al. (2010) identified a heterozygous mutation (F205I; 605204.0004) in the TOR1A gene.

In an 18-year-old girl with severe early-onset torsion dystonia, Zirn et al. (2008) identified a heterozygous missense mutation in the DYT1 gene (R288Q; 605204.0005). The mutation was inherited from the patient's unaffected mother, but was not found in 500 German control individuals. Transfection of the mutation into HEK293 cells resulted in a focally enlarged perinuclear space filled with membrane remnants; these abnormal findings were also observed in cells transfected with the common delE302/303 mutation, but were not observed in cells transfected with wildtype DYT1. The presence of the mutation in the unaffected mother was consistent with incomplete penetrance, which has been observed in DYT1.

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.

Associations Pending Confirmation

For discussion of a possible association between primary cervical focal dystonia and variation in the DRD5 gene, see 126453.0001.

Genotype/Phenotype Correlations

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.

Population Genetics

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.

Animal Model

Shashidharan et al. (2005) generated 4 independent lines of transgenic mice by overexpressing human delE-torsin-A using a neuron-specific enolase promoter. Approximately 40% of the transgenic mice developed abnormal involuntary movements with dystonic-appearing self-clasping of limbs, hyperkinesia, and rapid bidirectional circling. Neurochemical analyses revealed decreased striatal dopamine in affected transgenic mice, and immunohistochemical studies demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin (UBB; 191339), torsin-A, and lamin (LMNA; 150330). Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to that described in DYT1 patients.