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     

Developments in the molecular biology of DYT1 dystonia.

The identification of a mutation of the DYT1 gene as a cause of inherited dystonia has led to many insights regarding the genetics of this disorder. In addition, there is a rapidly expanding list of inherited dystonia syndromes, the genes for some of which have been identified or localized. The DYT1 mutation has been found in a variety of ethnic groups, and it may result in a range of phenotypes. To date, studies of torsinA, the protein product of the DYT1 gene, have not revealed its function, although its widespread distribution throughout the central nervous system suggests a universal role. TorsinA has structural homology to heat shock and chaperone proteins. Evidence from studies in cell cultures and Caenorhabditis elegans, and the presence of torsinA in inclusion bodies in several neurodegenerative diseases may be indicative of a function of this nature. Preliminary studies in humans with DYT1 dystonia and in DYT1 transgenic mice suggest disruption of the dopaminergic nigrostriatal system. A functional interference with neuronal signal processing induced by mutation of torsinA is consistent with current hypotheses regarding impairment of the center-surround mechanism in the striatum.     

Prevalence of THAP1 sequence variants in German patients with primary dystonia

Primary dystonias are a clinically and genetically heterogeneous group of movement disorders, but only for two of them, i.e., dystonia 1 and dystonia 6, the disease causing gene has been identified. Dystonia 1 is characterized by an early onset and is caused by a mutation in the TOR1A gene. Only recently, mutations in THAP1 have been shown to be the cause of DYT6 dystonia. We analyzed 610 patients with various forms of dystonia for sequence variants in the THAP1 gene by means of high resolution melting to delineate the prevalence of sequence variants and phenotypic variability. We identified seven sequence variants in patients and one sequence variant in a control. The sequence variants were not detected in 537 healthy controls. Four patients present with generalized dystonia with speech involvement of early onset, another three patients suffered exclusively from cervical dystonia of adult onset. These findings suggest that THAP1 sequence variations seem to be associated with different ages of onset and distribution of symptoms. Consequently, the phenotypic spectrum might be broader than previously assumed. © 2010 Movement Disorder Society     

Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients

OBJECTIVES: Dystonia is a common movement disorder. The purpose of this study is to examine the relative distribution of the primary dystonia subtypes and identify mutation (s) in the DYT1 gene in Indian patients. MATERIALS AND METHODS: Primary dystonia patients (n = 178) and controls (n = 63), lacking any symptoms of the disease, were recruited for the study from eastern India. The nucleotide variants in the DYT1 gene were identified by carrying out polymerase chain reaction, single stranded conformation polymorphism, and DNA sequencing. RESULTS: Unlike other reports, pain and/or tremor was more common in our sporadic patients than in familial cases. Three reported and two novel changes were identified in this gene. The homozygous genotype (G,G) for a missense variant (c.646G > C; Asp216His) was significantly over-represented in the patients compared with controls (P < 0.05). However, the commonly reported 3 bp deletion (904-906delGAG) was not detected. CONCLUSION: Our results suggest that the DYT1 gene might have a limited role in causation of dystonia in the Indian population.     

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     

Onset and progression of primary torsion dystonia in sporadic and familial cases

Four hundred and sixty records of patients with primary torsion dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 ± 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 ± 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 ± 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.     

Clinical and molecular genetic evaluation of patients with primary dystonia

Primary dystonia is a movement disorder characterized by involuntary and sustained muscle contractions causing twisting or abnormal postures and mutations in several genes have been identified. Our goal was to investigate, whether the clinical presentation would differ between patients with a positive family history, and patients without. Furthermore, we have performed mutation analysis in the subgroup of patients with a positive family history. A total of 175 patients with primary dystonia were evaluated. Data on gender, presence and frequency of pain and tremor, age of onset, and the distribution of affected body parts were compared between patients with positive and negative family history. All exons of the torsion dystonia 1, GTP cyclohydrolase 1 and epsilon-sarcoglycan genes were examined in 40 patients by SSCP analysis of PCR products followed by sequencing of variant conformers. Dystonia patients with a positive family history of dystonia had an earlier age of onset and those with a positive family history of tremor more often associated tremor than those with a negative family history. Four new polymorphisms in the epsilon-sarcoglycan gene were found and others confirmed, but no known or new mutations could be detected. Our study supports the notion that primary dystonia is a genetically heterogeneous disease.     

Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China

Background: Dystonia is defined as the presence of sustained involuntary muscle contractions, often leading to abnormal posture and movement. DYT1 is caused by a mutation in the TOR1A gene, whilst mutations in THAP1 gene have been identified as responsible for DYT6. The relative frequency and phenotype differences between DYT1 and DYT6 amongst Chinese primary dystonia patients have not been well‐characterized. Patients and methods: One hundred eleven unrelated Chinese patients with primary dystonia were screened for mutations in TOR1A and THAP1 genes, and correlate this with clinical presentation. Exon 5 of TOR1A and all three exons and exon‐intron conjunctions in THAP1 were screened by direct sequencing. Results: Three subjects were found to have the GAG deletion in the TOR1A gene, and two patients were detected with THAP1 gene mutations/variations (c.224A>T, c.449A>C). The overall mutation frequency was 4.5% in this cohort with TOR1A mutations found in 2.7% and THAP1 mutations found in 1.8%. No mutations were detected in the controls composed of 100 normal Chinese subjects. The clinical presentations of the DYT1 cases included onset in the limbs that could progress to the generalized dystonia within several years but without cranial involvement. Whilst in the DYT6 cases, the onset was cranial or cervical and progresses very slowly. Conclusion: The major clinical differences between DYT1 and DYT6 dystonia in China were the cranial involvement in DYT6 and progress to general dystonia within several years in DYT1.     

Intrafamilial phenotypic and genetic heterogeneity of dystonia

Most cases of early-onset primary torsion dystonia are caused by the same 3-bp (GAG) deletion in the DYT1 gene. We describe a large Serbian family with significant intrafamilial variability of the DYT1 phenotype, from asymptomatic carrier status to late-onset focal, and generalized jerky dystonia. Seven mutation carriers (six proven by direct analysis and one by inferred haplotype) were identified, but only two of them were affected by dystonia (penetrance reduced to 29%). In addition, three GAG-deletion-negative family members also developed dystonia (two multifocal dystonia and one torticollis), suggesting that their involuntary movements are due to some other etiological factor(s) (i.e., another dystonia gene), or may be psychogenic.     

Opioid binding in DYT1 primary torsion dystonia: an 11C-diprenorphine PET study.

The opioid transmitters enkephalin and dynorphin are known to regulate pallidal output and consequently cortical excitability. Indeed, abnormal basal ganglia opioid transmission has been reported in several involuntary movement disorders, including levodopa-induced dyskinesias in Parkinson's disease (PD), tardive dyskinesias/dystonia, Huntington's disease, and Tourette's syndrome. Moreover, a previous 11C-diprenorphine PET study investigating levodopa-induced dyskinesias found reduced opioid receptor availability in PD with but not without dyskinesias. We wished to investigate if a similar alteration in basal ganglia opioid binding was present in DYT1 primary torsion dystonia (PTD). Regional cerebral 11C-diprenorphine binding was investigated in 7 manifesting carriers of the DYT1 gene and 15 age-matched normal controls using a region-of-interest (ROI) approach and statistical parametric mapping (SPM). No difference in regional mean 11C-diprenorphine binding was found between DYT1-PTD and controls, and no correlation between the severity of dystonia and opioid binding was seen. We conclude that aberrant opioid transmission is unlikely to be present in DYT1-PTD and altered opioid transmission is not a common mechanism underlying all disorders of involuntary movement.     

Atypical presentations of DYT1 dystonia with acute craniocervical onset

DYT1 gene mutations lead to early-onset dystonia that begins with focal limb onset and spreads to other body regions within 5 years, with typical sparing of the oromandibular muscles. In the present study, we describe two patients with an unusual presentation of the disease.     

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.     

Assessment of D216H DYT1 polymorphism in a Chinese primary dystonia patient cohort

Background: The D216H single‐nucleotide polymorphism (SNP) (rs1801968) in DYT1 exon 4 has been suggested to be a genetic modifier in primary dystonia. Methods: To further explore this question, we assessed rs1801968 variations in a cohort of 210 Chinese patients with primary dystonia devoid of DYT1 mutations. Results: We found that focal dystonia, specifically cervical dystonia, was the most common form of dystonia, with 8.1% of all the patients having a positive family history of dystonia. No association of the D216H SNP with primary dystonia was identified. In a subsequent subgroup analysis, the 216H allele was found to occur more frequently in patients with writer’s cramp, but no correlation was found between the allele and other forms of dystonia or age of onset. Conclusions: Our findings do not confirm that the allele contributes to the risk of D216H SNP primary dystonia.     

Effect of thalamotomy on focal hand dystonia in a family with DYT1 mutation

We report the clinical and molecular features of a family with focal hand dystonia caused by DYT1 mutation. Four members of a family who underwent thalamotomy showed a marked and sustained therapeutic benefit that lasted for up to 12 years without recurrence of dystonia or any significant surgical complication. The hand dystonia caused by DYT1 mutation may be successfully managed by thalamotomy. © 2008 Movement Disorder Society     

Clinical characteristics of carriers of a GAG deletion in the DYT1 gene amongst Polish patients with primary dystonia

DYT1 primary torsion dystonia is an autosomal dominant disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. A significant proportion of individuals with early-onset generalized dystonia is believed to be DYT1 mutation carriers. We assessed the frequency of the GAG deletion in the DYT1 gene in a group of 61 Polish probands with clinical diagnosis of primary dystonia. The deletion was identified in four probands presenting with early-onset generalized disease (7%). Further studies in probands' families revealed two symptomatic and nine asymptomatic mutation carriers. We tested all mutation-positive individuals for the presence of some common polymorphisms within the DYT1 gene. Two of the 15 mutation-positive individuals additionally carried polymorphisms in 3'-UTR of the gene. Early onset in a limb and progression toward a generalized form, but not family history of dystonia, are indicative of DYT1 dystonia in Polish dystonic individuals.     

Non-DYT1 early-onset primary torsion dystonia: comparison with DYT1 phenotype and review of the literature.

To investigate the clinical features of early-onset primary torsion dystonia (EO-PTD), 57 consecutive genetically characterized patients with onset before 21 years were studied. Sex, ethnic origin, family history of dystonia, age at onset, disease duration, site of dystonia onset and distribution at latest examination, dystonia progression, time to generalization, and motor disability were noted. The 14 patients (25%) with GAG deletion (904_906/907_909delGAG) in the DYT1 gene were compared with the remaining non-DYT1 patients. Cranial involvement was present in 49% of non-DYT1 cases, but only 14% of DYT1 cases; non-DYT1 patients were younger at time of generalization. DYT1 cases had features similar to sporadic non-DYT1 cases but differed markedly from familial non-DYT1 cases, the latter having later age at onset, less common limb onset, more frequent cervical involvement, and slower progression than DYT1 PTD. These findings indicate that non-DYT1 forms of EO-PTD differ clinically from those of DYT1 forms. Cranial involvement before 21 years of age is the strongest predictor of non-DYT1 status. Positive family history and cervical involvement are associated with less severe progression in non-DYT1 forms.     

Atypical phenotypes of DYT1 dystonia in three children

DYT-1 dystonia is the most common primary dystonia seen in childhood. It is an autosomal dominantly inherited disorder caused by deletion of a GAG triplet in exon 5 of the DYT1 gene. It characteristically starts in a distal limb during late childhood, subsequently spreads to involve other body regions sparing oromandibular muscles. However, clinical presentation can vary remarkably with respect to age, site of onset and progression. In this study we present three early-onset DYT-1 dystonia patients who are atypical according to age of onset and localization. Dystonia has started at 2, 3 and 7 years of age and generalized to involve other limbs in all patients and also oromandibular muscles in one patient. None of them have benefited from medical treatments including L-dopa. All had normal brain MRI scan, a history of normal birth without significant perinatal asphyxia, infection or trauma and all are neurodevelopmentally otherwise normal. Conclusion: In children with dystonia; if brain imaging is unremarkable and when there is no history of CNS disorders such as perinatal asphyxia, infections, drug exposure or trauma; genetic analysis for GAG deletion of DYT-1 gene may be performed even if dystonia starts at a very young age or it spreads to involve oromandibular muscles.     

Unusual phenotypes in DYT1 dystonia: a report of five cases and a review of the literature.

Since the advent of widespread testing for the presence of the DYT1 gene mutation, the range of phenotypes that have been associated with this genetic abnormality has expanded. We report on 5 DYT1 gene-positive patients with unusual phenotypes. Two of them had late presentation, one of these after peripheral injury. Three additional patients had late progression of symptoms, onset after exposure to haloperidol, and severe bulbar involvement, respectively. The clinical heterogeneity of this condition raises problems for clinicians in selecting appropriate patients for diagnostic testing. Also, because of the low phenotypic penetrance of DYT1 dystonia, the discovery of the DYT1 mutation in a patient with an atypical clinical syndrome may not necessarily suggest a causal relationship. We have, therefore, analysed all published clinical studies of DYT1 dystonia to guide clinical decision making concerning DYT1 gene testing based on current information.