A Yorkshire family with adult-onset cranio-cervical primary torsion dystonia.

Although a family history is described in approximately 20% of patients, large families with adult-onset craniocervical primary (idiopathic) torsion dystonia (PTD) are rare. We report a new British family with cranio-cervical dystonia. Seventeen members of the family were examined. Five cases were diagnosed as definite PTD and one as probable PTD. Mean age at onset was 29 years (range, 19-40 yrs). The phenotype was characterized by adult-onset cranio-cervical dystonia in all affected cases. A few cases had additional voice tremor and/or postural arm tremor. The GAG deletion in the DYT1 gene was excluded in the index case. Linkage analysis was performed between the disease and several marker loci spanning DYT6 and DYT7 regions, and haplotypes were reconstructed in all subjects. Although linkage analysis was not completely informative, reconstructed haplotypes excluded linkage between the disease and either DYT6 or DYT7. This report confirms that familial cranio-cervical dystonia is genetically heterogeneous, and further studies of other PTD families with similar clinical features are needed to identify other new genes.     

DYT13, a novel primary torsion dystonia locus, maps to chromosome 1p36.13--36.32 in an Italian family with cranial-cervical or upper limb onset

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion with reduced penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb-onset PTD. Two other PTD loci have been mapped to date. The DYT6 locus on chromosome 8 is associated with a mixed phenotype, whereas the DYT7 locus on chromosome 18p is associated with adult onset focal cervical dystonia Several families have been described in which linkage to the known PTD loci have been excluded. We identified a large Italian PTD family with 11 definitely affected members. Phenotype was characterized by prominent cranial-cervical and upper limb involvement and mild severity. A genome-wide search was performed in the family. Linkage analysis and haplotype construction allowed us to identify a novel PTD locus (DYT13) within a 22 cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 between the disease and marker D1S2667.     

Identification of a novel primary torsion dystonia locus (DYT13) on chromosome 1p36 in an Italian family with cranial-cervical or upper limb onset

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant fashion. Three PTD loci (DYT1, DYT6 and DYT7) have been identified to date. However, in several PTD families linkage to the known loci has been excluded. We identified an Italian PTD family with 11 definitely affected members. Phenotype was characterised by juvenile or early-adult onset, prominent cranial-cervical and upper limb involvement, mild course and occasional generalisation. A genome-wide search performed in the family identified a novel PTD locus (DYT13) within a 22-cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 (θ=0) between the disease and marker D1S2667.     

Novel Italian family supports clinical and genetic heterogeneity of primary adult-onset torsion dystonia.

We report on an Italian kindred with adult-onset primary torsion dystonia (PTD). A detailed clinical examination of the six definitely affected family members revealed a mild, purely focal phenotype. The disease involved only one body part (eyes, neck, or arm). PTD in this family was not linked to the known disease loci (DYT1, DYT6, DYT7, and DYT13), and the 3-bp deletion in the DYT1 gene was also excluded. These findings support genetic heterogeneity of PTD and indicate that a novel unassigned gene is responsible for focal dystonia in this family.     

Genetik der Dystonien

To date, at least 12 types of primary dystonia can be distinguished on a genetic basis. A 3-bp deletion in the DYT1 gene causes early onset, generalized torsion dystonia (TD), and mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes result in dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor in one large family (DYT11) has recently been implicated in myoclonus-dystonia. Furthermore, seven other loci for dystonia genes have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), three types of paroxysmal dystonia (DYT8-10), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia-parkinsonism (DYT12). No positive linkage results have yet been obtained for autosomal recessive TD (DYT2) and several other families of different types of dominantly inherited TD (DYT4). In addition, hereditary secondary dystonia may occur as part of familial diseases of the basal ganglia, metabolic and storage disorders, and various X-linked and other familial neurodegenerative syndromes affecting the basal ganglia. It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.     

Genetics of dystonia

Dystonia is characterized by muscle contractions leading to abnormal postures with involuntary twisting and repetitive movements. Inherited dystonia designated by DYT locus symbols can be separated into three broad phenotypic categories: primary torsion dystonia (PTD), where dystonia is the only clinical sign (except for tremor) (DYT1, 2, 4, 6, 7, 13, 17, and 21); dystonia plus loci, where other phenotypes in addition to dystonia, including parkinsonism or myoclonus, are present (DYT3, 5/14, 11, 12, 15, and 16); and paroxysmal forms of dystonia/dyskinesia (DYT8, 9, 10, 18, 19, and 20). Currently, 19 loci including 10 genes have been identified for inherited dystonias. In this review, the phenotypes associated with these loci and the responsible genes will be discussed.     

Genetics of primary dystonia

Currently, at least 12 types of dystonia can be distinguished on a genetic basis. Advances in the molecular genetics of dystonia have led to the recent identification of a 3-bp deletion in the DYT1 gene, causing early-onset generalized torsion dystonia (TD), and to the detection of mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes causing dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor has been shown to be associated with myoclonus-dystonia in one family. In addition, six other dystonia gene loci have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), two types of paroxysmal dystonia (DYT8, DYT9), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia parkinsonism (DYT12). No positive linkage studies have as yet been reported for autosomal recessive TD (DYT2) and in several other large families with various types of dominantly inherited TD (DYT4). It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.     

Atypical phenotypes and clinical variability in a large Italian family with DYT1-primary torsion dystonia.

The GAG deletion in the DYT1 gene usually causes a typical form of primary torsion dystonia (PTD) with early onset in a limb, rapid generalization, and sparing of cranial-cervical muscles, but atypical phenotypes have often been reported. Here, we describe a large DYT1 Italian family with phenotypically heterogeneous PTD that recapitulates all the atypical features associated with the DYT1 mutation, including late age at onset, focal or segmental phenotypes, onset or spreading of dystonia to the cranial-cervical muscles. Of 38 healthy family members, 15 also carried the DYT1 mutation, with an estimated penetrance of 21%. A literature review of atypical familial cases of DYT1-PTD showed that late onset, cervical involvement, and limited progression of dystonia are features frequently seen in DYT1 families. However, nearly all of these atypical patients fall within at least one of the clinical categories that best predict the DYT1 carrier status, namely, early onset, onset in a limb, and family history positive for early-onset dystonia.     

Clinical and genetic evaluation in a French population presenting with primary focal dystonia.

Primary focal dystonia (PFD) is known to be a clinically and genetically heterogeneous group of movement disorders. To evaluate the frequency of familial focal dystonia in a French population presenting with PFD, we screened 197 patients (150 index cases and 47 affected family members) presenting focal primary dystonia for the GAG deletion in the DYT1 gene and analyzed linkage to the DYT6, DYT7, and DYT13 loci in those who presented a family history. Fourteen families could be recruited and, among them 47 new symptomatic individuals could be identified by clinical examination. A group of 104 patients were without family history and 46 patients (30.7%) were found to have at least one first-degree relative with dystonia. Mean age at onset was significantly later (55.4 +/- 14.0 years) in the blepharospasm group and earlier in patients with writer's cramp (35.8 +/- 14.0 years). The group of patients with family history showed a mean age at onset significantly earlier (39.2 +/- 18.0) than in patients without family history (47.4 +/- 14.4 years). Fourteen families demonstrated an autosomal mode of transmission and five families were studied further for genetic linkage analysis, but no significant linkage to one of the three loci could be observed. Our results illustrate the importance of genetic factors and the clinical heterogeneity of PFD. They indicate the existence of one or several as yet unmapped genes responsible for these diseases.     

Genetics of dystonia

Primary torsion dystonia (PTD) has a broad clinical spectrum, with earlier onset of symptoms associated with more generalized muscle involvement. The causes for most dystonia are unknown although several monogenic subtypes have been identified. One important genetic cause of PTD is DYT1; a three base pair deletion in this gene is a major cause for early-onset dystonia. Its identification has allowed the development of cellular and animal models; it has also permitted studies that identify both "manifesting" and "non-manifesting" DYT1 mutation carriers. These studies have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. These advances provide a widened platform for future research.     

Familial blepharospasm is inherited as an autosomal dominant trait and relates to a novel unassigned gene.

Blepharospasm (BSP) is a common form of primary torsion dystonia (PTD). Although most cases are sporadic, an increased familial incidence of BSP has been reported. Precisely how blepharospasm is inherited remains unclear. We report on two Italian families with adult-onset focal BSP inherited as an autosomal dominant trait with reduced penetrance. None of the affected family members had the 3-bp (GAG) or the 18-bp deletion in the DYT1 gene. In one family, linkage analysis allowed us to exclude segregation of the disease with the known PTD loci (DYT1, DYT6, DYT7, and DYT13). These findings suggest that primary familial adult-onset BSP is a distinct entity among inherited PTD and is caused by a novel, unmapped gene. Copyright Movement Disorder Society     

Italian family with cranial cervical dystonia: clinical and genetic study.

A white Italian family affected by primary torsion dystonia (PTD) is described. The family phenotype most commonly presented with adult onset, cranial cervical involvement, and focal or segmental distribution without progression to generalization. Thirty-nine family members and nine spouses were studied. Five subjects received a diagnosis of definite PTD, three of probable PTD. Age at onset was in adulthood for all. In four definitely affected subjects, dystonia started in the cranial or cervical districts; in one it presented as writer's cramp. Familial writer's cramp also occurred in the family of the unrelated parent of the latter patient. The mean age at time of examination was 61.8 years in the individuals with a definite diagnosis; 60 in those with a probable diagnosis. At the time of examination, in most of the affected subjects, dystonia was focal; in three cases (two definitely and one probably affected), it was segmental. DNA linkage analysis, although limited by the size of the family, suggested exclusion of linkage between the disease and known PTD loci (DYT6 and DYT7). The GAG deletion in the DYT1 gene was excluded in the proband and in the family member affected by writer's cramp.     

Clinical and genetic characterization of a large Dutch family with primary focal dystonia

We describe a large family with a primary focal dystonia from a small Dutch village on a former island. Twenty‐four individuals spanning three generations were examined by two movement‐disorder neurologists. Two other movement‐disorder neurologists evaluated the videos independently. Subjects were classified as “affected,” “possibly affected,” or “not affected.” A diagnosis was defined if all the neurologists agreed on the definition. Eight definitely affected and four possibly affected subjects were detected. Clinical presentation consisted of mild cranio‐cervical‐brachial dystonia. Mean age at onset was 45.5 years (range, 39–56). Mean BFMDRS motor score was 4.4 (range, 1–8). Mean TWSTRS score (part I) was 11.3 (range, 8–23). Mutations in DYT1 gene and in the ε‐sarcoglycan (SGCE) genes were not detected. We could not find linkage to the dominant DYT6, DYT7, DYT13, or the recessive DYT16 loci. The identification and accurate clinical evaluation of large dystonia families not linked to known genes is crucial for further advancement in molecular genetic characterization of focal dystonia. © 2008 Movement Disorder Society     

Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal

The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.     

Overview of primary monogenic dystonia

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.     

DYT1 mutation in primary torsion dystonia in a Serbian population

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. A GAG deletion at position 946 in the DYT1 gene is responsible for most cases of autosomal dominant early-onset PTD. We analysed the DYT1 mutation in 50 patients from a Serbian population, selected according to the proposed guidelines for diagnostic testing: (a) 38 patients with PTD onset < 26 years, and (b) 12 patients with the disease onset ± 26 years, but with at least one affected family member with early-onset dystonia. Only three apparently sporadic patients among the 50 individuals tested were positive for the GAG deletion in the DYT1 gene: one with typical, generalized, one with long-lasting, non-progressive segmental, and one with multifocal dystonia. Molecular analysis of relatives in 2 families revealed that the lack of family history was due to reduced penetrance. Received: 29 December 2000, Received in revised form: 23 March 2001, Accepted: 10 April 2001     

Screening of Brazilian families with primary dystonia reveals a novel THAP1 mutation and a de novo TOR1A GAG deletion

The TOR1A and THAP1 genes were screened for mutations in a cohort of 21 Brazilian patients with Primary torsion dystonia (PTD). We identified a de novo delGAG mutation in the TOR1A gene in a patient with a typical DYT1 phenotype and a novel c.1A > G (p.Met1?) mutation in THAP1 in a patient with early onset generalized dystonia with speech involvement. Mutations in these two known PTD genes, TOR1A and THAP1, are responsible for about 10% of the PTD cases in our Brazilian cohort suggesting genetic heterogeneity and supporting the role of other genes in PTD. © 2010 Movement Disorder Society     

Genetics of Primary Torsion Dystonia

Advances in the genetics of dystonia have further elucidated the pathophysiology of this clinically and etiologically heterogeneous group of movement disorders. Currently, 20 monogenic forms of dystonia, designated by the acronym DYT, are grouped as 1) pure dystonias, 2) dystonia-plus syndromes, and 3) paroxysmal dystonias/dyskinesias. We summarize recently discovered genes and loci, including the 1) detection of two primary dystonia genes (DYT6, DYT16), 2) identification of the DYT17 locus, 3) association of a dystonia/dyskinesia phenotype with a gene previously linked to GLUT1 (glucose transporter of the blood–brain barrier) deficiency syndrome (DYT18), 4) designation of paroxysmal kinesigenic and nonkinesigenic dyskinesia as DYT19 and DYT20, and 5) redefinition of DYT14 as DYT5. Further, we review current knowledge regarding genetic modifiers and susceptibility factors. Because recognizing and diagnosing monogenic dystonias have important implications for patients and their families with regard to counseling, prognosis, and treatment, we highlight clinical “red flags” of individual subtypes and review guidelines for genetic testing.     

Phenotypic variability of DYT1‐PTD: Does the clinical spectrum include psychogenic dystonia?

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous group of movement disorders, usually inherited in an autosomal dominant manner with reduced (30-40%) penetrance. The DYT1 gene on chromosome 9q34 is responsible for most cases of early limb-onset PTD. DYT1-PTD clinical spectrum is broad, as the disease may present with several degrees of body involvement and severity. We identified an Italian family with 4 members definitely affected by PTD, genetically diagnosed as carriers of the GAG mutation at DYT1 gene. Phenotype was homogeneous when considering the presentation at onset (limb involvement and early onset), the disease progression was variable; in the subjects of the last generation, the disease progressed to a severe, generalized PTD; in the remaining 2 subjects, dystonia presented with writer's cramp or upper body segmental dystonia of mild severity. One family member, carrier of the GAG mutation on DYT1 gene and mother of the most severely affected individual, presented with a clinically established psychogenic movement disorder resembling dystonia initially diagnosed as a severe generalized PTD. Psychogenic movement disorders are among the most controversial and challenging diseases to diagnose, in particular when the affected individual belongs to a family with an inherited movement disorder.     

Phenotypic Differences in Dyt1 Between Ethnic Groups

A DYT1 mutation is the most common genetic cause of early-onset primary torsion dystonia. Herein we present the phenotypes of 25 Korean dystonia patients with DYT1 mutations. We further compare the clinical features of the Asian patients with those of the Western DYT 1 mutation patients. In Korean patients, upper extremity was the most common site of symptom onset while there were a few patients with axial-onset dystonia. Generalized dystonia was the most common subtype followed by segmental dystonia. A few patients from the same families had their symptoms at the same age. The clinical features of Korean patients were similar to those of other Asian patients. The Asian patients were differentiated from Western patients by more frequent axial onset, no cranial involvement at onset, and more common segmental dystonia. The variable clinical manifestation in different ethnic groups may suggest that ethnicity is a significant modifier of DYT1 dystonia.