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.     

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.     

Agreement among neurologists on the clinical diagnosis of dystonia at different body sites

OBJECTIVE: To study the reliability of the diagnosis of blepharospasm, oromandibular dystonia, cervical dystonia, and writer's cramp among neurologists. METHODS: 12 patients with adult onset focal segmental dystonia were videotaped in a standardised way. The tape was sent to six neurologists who are involved in clinical practice without a specific interest in movement disorders (general neurologists), and to four neurologists expert in movement disorders. The observers had to recognise whether the patients were affected by dystonia and to distinguish among blepharospasm, oromandibular dystonia, cervical dystonia, and writer's cramp. Interobserver reliability was assessed by kappa statistics, and the degree of agreement was classified according to the Landis classification. RESULTS: The 10 neurologists reached slight to moderate agreement on the diagnosis of these four disorders. When the observers were subdivided according with their professional experience in the field, a moderate to perfect agreement on the diagnosis was achieved by specialists in movement disorders, and a fair to moderate agreement by the general neurologists. CONCLUSIONS: Neurologists may have different ability to recognise adult onset focal dystonia, depending on their experience and on the type of dystonia.     

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.     

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.     

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     

Phenotype of the DYT1 mutation in the TOR1A gene in a Polish population of patients with dystonia. A preliminary report

BACKGROUND AND PURPOSE: DYT1 dystonia is the most common form of inherited primary dystonia. The aim of the study was: 1) to evaluate the prevalence of the DYT1 mutation in a population of Polish patients with early-onset generalized dystonia and with other forms of familial dystonia, 2) to evaluate the frequency of the DYT1 mutation in patients with writer's cramp, 3) to characterize the phenotype of the DYT1 mutation in the Polish population, and 4) to define the group of patients in whom genetic testing is recommended. MATERIAL AND METHODS: The following groups of patients were included in the study: 1) patients with early-onset (<30 years) generalized dystonia and those patients with onset after age 30 years who have relatives with early-onset dystonia, 2) patients with writer's cramp (focal or as part of segmental dystonia) independently of age of onset, 3) asymptomatic (adult only) relatives of the diagnosed DYT1 carriers. Genetic tests were performed in 63 subjects---28 sporadic cases of dystonia, 20 patients with familial dystonia, and 15 asymptomatic relatives of patients with confirmed DYT1 mutation. RESULTS: The DYT1 mutation was found in 17 subjects--10 patients with dystonia and 7 asymptomatic relatives (from 6 families). In all mutation carriers dystonia occurred in one limb before age 26 years. In 8 patients, generalization of dystonia was observed and in 2 cases it remained in a focal form. CONCLUSIONS: 1. The prevalence of DYT1 mutation among patients with early-onset (相似文献   

Focal and segmental primary dystonia in north-western Germany--a clinico-genetic study

OBJECTIVES: To determine the frequency of familial focal and segmental dystonias in a large patient cohort with primary dystonia from north-western Germany. MATERIALS AND METHODS: In this study, 130 patients with focal or segmental dystonia were examined and a family history was obtained. Whenever possible, affected relatives were examined (a total of 789 first-degree relatives). Data on disease duration, age at disease onset and age of the patients were investigated by Student's t-test and a segregation analysis was performed by Weinberg's proband method. RESULTS: Age at onset of disease was significantly later in the blepharospasm group. Only in the writer's cramp group were women outnumbered by men. A positive family history was found in 15 of the 130 index patients (11.5%). None of 102 index patients tested carried the GAG deletion in the DYT1 gene. CONCLUSIONS: In accordance with previous series our study provides evidence that primary focal dystonia may have a genetic etiology, most probably caused by an autosomal dominant trait with reduced penetrance.     

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.     

The DYT1 GAG deletion is infrequent in sporadic and familial writer' s cramp.

A 3-base pair (GAG) deletion in the DYT1 gene has recently been found to be responsible for most cases of early-onset primary generalized dystonia. In some cases, this mutation has been associated with writer's cramp. To determine the frequency of this mutation in a larger series of patients, we examined 44 index patients with sporadic or familial (seven patients) writer's cramp for the presence of the DYT1 GAG deletion, including eight patients with segmental dystonia involving at least one upper limb. We found the mutation in none of these index patients, which confirms that isolated writer's cramp is only in rare cases a phenotypic manifestation of this mutation, even if a positive family history of writer's cramp is present.     

Phenotypic characterization of DYT13 primary torsion dystonia.

We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD.     

Unbalanced whole arm translocation resulting in loss of 18p in dystonia.

Dystonia represents a genetically and clinically heterogeneous disorder, characterized by abnormal and sustained muscle contractions and rigid postures. At least 15 different loci (DYT1-DYT15) have been identified in dystonia. Adult-onset idiopathic focal dystonia affecting specific parts of the body, such as the eye (blepharospasm), neck (cervical dystonia), and hand (writer's cramp), is mostly associated with the DYT7 locus, which was originally mapped to chromosome 18p by genomewide linkage analysis in a large family showing autosomal dominant inheritance. We have identified a family in which the mother is affected with dystonia and the son shows signs of dystonia. Using fluorescent BAC probes spanning 18p, we were able to identify a deletion in these two individuals, spanning the entire short arm of 18p. This deletion is accompanied by a centric fusion involving chromosome 14. The 18p deleted region spans 15 megabases of DNA, with a number of interesting DYT7 candidate genes, including genes involved in G-protein-coupled signaling (GNAL), cell death (CIDEA), muscle development (MYOM1 and MRLM), mitochondrial activity (NDUFV2), and neuronal function (ADYCAP1, TGIF, DAP-1, and AFG3L2).     

Primary torsion dystonia: the search for genes is not over

A GAG deletion in the DYT1 gene accounts for most early, limb onset primary torsion dystonia (PTD). The genetic bases for the more common adult onset and focal PTD are less well delineated. Genetic loci for an "intermediate dystonia" phenotype and for torticollis, named DYT6 and DYT7 respectively, have recently been mapped in single families. To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions. There was no evidence of linkage to either locus in any family. These findings illustrate the genetic heterogeneity of the dystonias and indicate the existence of one or more as yet unmapped genes for dystonia. Large collaborative efforts will be required to identify these, and additional genes, causing PTD.     

Two phenotypes and anticipation observed in Japanese cases with early onset torsion dystonia (DYT1) - pathophysiological consideration

Early onset torsion dystonia (DYT1) is a dominantly inherited dystonia caused by a deletion of three bases, GAG, coding glutamic acid, in chromosome 9q34. The protein coded by this gene was named as torsin A. DYT1 is common among the Ashkenazi Jewish population, but has been thought to be rare among Japanese. Among the idiopathic torsion dystonias being followed in this clinic, we found five families with DYT1 by gene analysis. This is the first report of genetically proven Japanese DYT1.The clinical features of five proband cases were divided into two types. One type is postural dystonia with marked trunkal torsion, and the other is action dystonia associated with violent dyskinetic movements. The affected family members in the upper generations presented with focal or segmental dystonia; it was postural dystonia of the legs in the former, and writer's cramp or tremor of the arms in the latter families. There was an asymptomatic carrier in the upper generation. Anticipation in the age of onset and severity of the disease was observed in all families. Medical treatment, including anticholinergics and levodopa, did not show apparent effects, while stereotactic thalamotomy to the nucleus ventralis lateralis (VL) or ventralis intermedius (Vim), with or without posterior ventral pallidotomy, were effective with action dystonia, but not postural dystonia. This study suggests the existence of at least two phenotypes in DYT1, in which different pathways of the basal ganglia are involved.     

Sex-related influences on the frequency and age of onset of primary dystonia. Epidemiologic Study of Dystonia in Europe (ESDE) Collaborative Group

We studied 957 cases of primary (idiopathic) dystonia and found a significant excess of female patients for segmental and focal dystonia. A novel observation was a significantly earlier age at onset in males as opposed to females for primary segmental (mean age, 44.6 versus 53.3) and focal dystonia (43.8 versus 47.8). This trend was also apparent in cervical dystonia, blepharospasm, and laryngeal dystonia. For writer's cramp and focal limb dystonia, this trend was reversed with an earlier age at onset in females. These results suggest that focal dystonia should not be treated as an homogenous group, and sex-linked factors may play a role.     

Non-DYT1 dystonia in a large Italian family.

A large non-Jewish Italian family affected by idiopathic torsion dystonia with autosomal dominant transmission and almost complete penetrance is reported. The prevalent phenotype was characterised by early onset with cranial-cervical involvement and progression to a segmental distribution; progression to generalisation was also found. Among 45 people examined, 14 were considered definitely or probably affected by idiopathic torsion dystonia. Eight definitely affected members had mean age (SD) at onset of 15.6 (12.5); idiopathic torsion dystonia started in the cranial-cervical region in six of them, in the upper limbs in two; in four cases dystonia progressed to other body regions, in two cases a generalisation was seen. Linkage analysis with 9q34 markers excluded the region containing the DYT1 locus in this family; linkage to the dopa-responsive dystonia markers was also excluded. A comparison of the phenotype in the present family and other non-DYT1 families shows striking overlapping features differing from those of DYT1 idiopathic torsion dystonia.     

Adult onset idiopathic torsion dystonia is excluded from the DYT 1 region (9q34) in a Swedish family.

A gene (DYT1) for early onset idiopathic torsion dystonia was mapped to chromosome 9q34 in non-Jewish and Jewish families. The DYT1 gene region has been excluded in other families with adult onset and cervical or cranial onset idiopathic torsion dystonia from the United States, Great Britain, and France. The role of DYT1 in a Swedish family with adult onset idiopathic torsion dystonia in four generations was examined. The disease seems to be inherited in an autosomal dominant mode with reduced penetrance in this family. There were 10 affected family members, with a mean age of onset of 27 (range 18 to 50) years. The disease showed variable expression, with focal, multifocal, and generalised forms of dystonia in different family members. Genetic analysis excluded the chromosomal region containing the DYT1 locus as being responsible for dystonia in this family.     

Phenotypic variability of the DYT1 mutation in German dystonia patients

Primary dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained involuntary muscle contractions causing repetitive movements and/or abnormal postures. Recently, the gene locus (DYT1) and mutation responsible for a substantial number of cases suffering from early-onset primary dystonia was described. Here we report 2 German families and 1 sporadic patient with early-onset dystonia due to the DYT1 mutation in order to illustrate the variability of clinical manifestation within this molecularly defined entity. We demonstrate that writer's cramp or focal cervical dystonia is a clinical presentation of DYT1 as well as generalized dystonia.