Dystonia 6, Torsion

A number sign (#) is used with this entry because this form of torsion dystonia (DYT6) is caused by a heterozygous mutation in the THAP1 gene (609520) on chromosome 8p11.

Description

Dystonia-6 is an autosomal dominant movement disorder characterized by early involvement of craniofacial muscles with secondary generalization often involving the arms, and laryngeal dystonia that causes speech difficulties (review by Djarmati et al., 2009).

Blanchard et al. (2011) provided a review of dystonia-6 and the THAP1 gene.

Clinical Features

Almasy et al. (1997) performed clinical and genetic analyses of idiopathic torsion dystonia (ITD) in 2 Mennonite families that were not obviously related. Of 220 family members, a total of 15 definitely affected individuals were identified. Some affected persons had a phenotype indistinguishable from that seen in patients with DYT1 (128100) due to mutation in the TOR1A gene (605204) on chromosome 9q34. However, the average age of onset in these patients was later (18.9 vs 13.6 years) and the distribution of affected body parts different from those with the DYT1 mutation. In patients with the DYT1 mutation, symptoms start in a limb and spread to other limbs and the axial musculature, with laryngeal muscles rarely affected. In contrast, about half of the patients from the Mennonite families presented with cranial or cervical involvement and those who presented with limb symptoms later developed cranial or cervical symptoms. In 2 cases, the symptoms remained localized. Muller et al. (1998) designated the type of dystonia observed in these 2 families as adult-onset ITD of mixed type, or dystonia-6 (DYT6).

Saunders-Pullman et al. (2007) reported follow-up of the families reported by Almasy et al. (1997) and identified a third affected Amish-Mennonite family. The mean age at onset was 16 years (range, 5 to 38), with more than half of patients developing symptoms before age 16 years. Dystonia was most likely to start in an arm, although many had first symptoms involving cranial muscles, such as the larynx, tongue, and facial muscles, or the neck. The leg was rarely affected first. Almost all patients had some degree of progression to other body regions, but final distribution varied widely and included focal dystonia, segmental dystonia, and generalized or multifocal dystonia. More than half of patients had severely affected speech. Penetrance was decreased (approximately 60%).

Fuchs et al. (2009) reported a family of partial German ancestry in which 4 individuals had autosomal dominant dystonia. Age at onset ranged from 9 to 14 years. Three affected individuals had generalized dystonia affecting the face, and jaw, tongue, neck, arms, legs, and trunk, whereas the fourth individual had segmental dystonia only affecting the lower face and jaw.

Bressman et al. (2009) reported 19 individuals from 9 unrelated North American families, mainly of mixed European origin, with DYT6 confirmed by genetic analysis. Most had childhood or adolescent onset of dystonia in the arm or simultaneous onset in the arm, leg, neck, or tongue. Three had onset in adulthood. Dystonia tended to become generalized, with 12 of 19 reporting multifocal distribution, particularly with cranial muscle and speech involvement. Women were more often affected than men. Inheritance was consistent with autosomal dominant with reduced penetrance.

Clot et al. (2011) identified heterozygous mutations in the THAP1 gene in 5 index patients (4.5%) of 113 subjects with primary dystonia from France, European countries, and North Africa. Two index cases had family members with the mutation; in one family, one of these relatives was affected and the other was asymptomatic. The median age at onset in mutation carriers was 12.5 years (range 9 to 20), and the most frequent site of dystonia at onset was the neck (4/6). During the course of the disease, 5 patients developed cranial muscle and upper limb involvement, and 4 had impaired speech. Four patients developed generalized dystonia after a median disease duration of 20 years, but 1 patient's dystonia remained segmental and another's remained focal. Two patients had myoclonic jerks that were superimposed on dystonia. The mutation frequency rose to 12% in patients in whom dystonia began in the neck or cranial muscles.

Neuroradiologic Studies

Using PET scans, Carbon et al. (2004) found that manifesting gene carriers of DYT1 and DYT6 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, suggested genotype-specific differences.

Using PET scans and radiolabeled raclopride, Carbon et al. (2009) found significant reductions in caudate and putamen DRD2 (126450) 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.

Mapping

By linkage analysis in the Mennonite families, Almasy et al. (1997) mapped the DYT6 gene to 8p21-q22 with a maximum lod score of 3.69 at theta = 0.0 for marker D8S1797 in family 'M' and 2.11 in family 'C,' giving a combined lod score of 5.80 at D8S1797. Inferred haplotypes across the candidate region were identical in affected members of the 2 families, suggesting a founder effect and common mutation.

Saunders-Pullman et al. (2007) found additional affected members in the DYT6 families reported by Almasy et al. (1997) and reported another Amish family with the disorder. Linkage analysis refined the locus to a 23-cM candidate region between markers D8S2323 and D8S2317 surrounding the centromere of chromosome 8. Genealogic sources indicated 5 common ancestral pairs between 2 of the families, 4 of whom were also shared by the third family, suggesting a founder effect. The most recent common ancestral pair that was unique to all families was an Amish couple, of whom the husband was born in 1791. Molecular analysis excluded mutations in 7 candidate genes within the region.

Heterogeneity

Saunders-Pullman et al. (2007) identified 2 Amish-Mennonite families with primary torsion dystonia that did not map to the DYT6 locus on chromosome 8p. The phenotype differed from those with DYT6 by later age at onset (46.9 years versus 16 years in DYT6), and by a greater incidence of focal dystonia beginning in the cervical muscles. The findings suggested that there is another locus for autosomal dominant dystonia in this population.

Molecular Genetics

In affected members of 3 Amish families with DYT6 (Almasy et al., 1997; Saunders-Pullman et al., 2007), Fuchs et al. (2009) identified a heterozygous truncating mutation in the THAP1 gene (609520.0001). An additional Amish family with the disorder also carried the same mutation. Fuchs et al. (2009) identified another heterozygous mutation in the THAP1 gene (609520.0002) in affected members of a German family with DYT6.

In 9 (25%) of 36 unrelated families with primary dystonia, Bressman et al. (2009) identified 9 different heterozygous mutations in the THAP1 gene (see, e.g., 609520.0003 and 609520.0004), including 1 family of mixed European ancestry that had the Amish founder mutation (609520.0001). Most of the mutations were in the DNA-binding domain, and 1 was predicted to disrupt the nuclear-localization signal. There were no genotype/phenotype correlations.

Djarmati et al. (2009) identified 2 different heterozygous mutations in the THAP1 gene (609520.0005 and 609520.0006) in 2 (1%) of 160 German patients with dystonia. Both mutation carriers had laryngeal dystonia beginning in childhood that progressed to generalized dystonia. One of the patients had 2 family members with very subtle findings of dystonia.

Xiao et al. (2010) identified 9 different sequence variants in the THAP1 gene in 16 (1.4%) of 1,114 individuals with various forms of dystonia. Six of the variants were predicted to result in missense mutations (see, e.g., G9C; 609520.0007). Functional studies were not performed.

Houlden et al. (2010) identified 9 different novel mutations in the THAP1 gene in 9 (2.5%) of 362 British patients with dystonia. One individual had a homozygous missense mutation and no family history of dystonia, but functional studies of the mutation were not performed.

Lohmann et al. (2012) identified 6 different heterozygous pathogenic mutations in the THAP1 gene in 6 (1.1%) of 567 patients with dystonia. Five of the mutations (see, e.g., 609520.0008 and 609520.0009) were located in the DNA-binding domain and shown to cause decreased THAP1 activity (20-80% of controls) using a luciferase assay.

In a review, Blanchard et al. (2011) noted that 53 different THAP1 mutations had been identified in 56 families with DYT6; there were no apparent genotype/phenotype correlations.