DYT1 mutation in Korean primary dystonia patients

One hundred sixty-two patients with Korean primary dystonia patients were screened for DYT1 mutation. Five patients were positive for DYT1 mutation. Generalized dystonia patients have higher rate of DYT1 mutation (3/7). Their onset age is young (7-20; mean 13.4). Two patients were found to have segmental dystonia. Like Japanese patients with DYT1 mutation, axial muscle involvement is notable.     

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     

DYT1 mutation in Japanese patients with primary torsion dystonia

A GAG deletion at position 946 in the DYT1 gene has been identified as one of the gene mutations responsible for autosomal dominant primary torsion dystonia. We examined 178 Japanese patients with various forms of dystonia, and found the mutation in six patients (3.4%) from three families. Five of them had early clinical onset (before age 12) with initial involvement of a limb. To our knowledge, this is the first report of the frequency and the clinical features of DYT1 mutation in oriental patients, and the clinical presentation of the mutation in these patients was similar to that of Jewish or non-Jewish Caucasian patients.     

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.     

Striatal dopamine in early-onset primary torsion dystonia with the DYT1 mutation

Although nigrostriatal dopaminergic dysfunction has been suggested in early onset primary torsion dystonia (PTD) with the DYT1 mutation, the actual status of brain dopamine (DA) is unknown. In a DYT1 mutation-positive autopsy patient with PTD, we found that nigral cellularity was normal and that subregional striatal DA levels were within the control range, except for those in the rostral portions of the putamen and caudate nucleus (50% to 54% of control means). Our data suggest that the DYT1 mutation is not associated with significant damage to the nigrostriatal DA system, in keeping with the absence of parkinsonism and levodopa response in this disorder.     

Frequency of the DYT1 mutation in primary torsion dystonia without family history

BACKGROUND: Idiopathic torsion dystonia is a clinically and genetically heterogeneous movement disorder. A GAG deletion at position 946 of the DYT1 gene was the first mutation found, in early-onset dystonia, with an autosomal dominant transmission and reduced penetrance. OBJECTIVE: To evaluate the frequency of the DYT1 mutation in patients with idiopathic torsion dystonia but without a family history. DESIGN: Prospective cohort study. SETTING: Four botulinum toxin clinics in the Paris, France, area. PATIENTS: A French population of 100 patients with dystonia. MAIN OUTCOME: Frequency of the DYT1 mutation tested by polymerase chain reaction and enzyme restriction analysis for the 946 GAG deletion, and genotype-to-phenotype correlation. RESULTS: Only 5 mutation carriers were identified, 4 of whom were part of a group of 10 patients with generalized dystonia. Onset was between ages 5 and 12 years as in typical early-onset dystonia. All 4 patients had cranial muscle involvement, which is atypical for DYT1 mutation carriers. One had segmental dystonia. Molecular analysis of relatives in 2 families demonstrated that the lack of family history was due to reduced penetrance. CONCLUSIONS: For accurate diagnosis and genetic counseling, screening for the DYT1 deletion is of great interest in cases with generalized dystonia without a family history. In other cases, positive results are rare.     

Frequency of DYT1 mutation in early onset primary dystonia in Italian patients.

Thirty Italian patients with sporadic, early-onset, primary dystonia were screened for the DYT1 mutation. Five patients were positive (mean age at onset, 8 years); two had the typical phenotype, two a generalised dystonia also involving the cranial muscles, and one a segmental dystonia. In the other 25 patients (mean age at onset, 7.7 years), dystonia was generalised in 22 patients and remained segmental in three. Our results indicate the role of DYT1 mutation in Italian patients and confirm clinical and genetic heterogeneity of early-onset primary dystonia.     

Unusual phenotypic expression of the DYT1 mutation

Highly variable phenotype expression has long been recognized in DYT1 carrier patients. We report here an Ashkenazi-Jewish woman who carried a DYT1 mutation and developed a predominant unilateral myoclonic-dystonia (MD) displaying a fluctuating course. The present case is the second supporting the variability of DYT1 phenotype and further illustrates its ability to mimic the MD syndrome.     

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.     

Brainstem pathology in DYT1 primary torsion dystonia

DYT1 dystonia is a severe form of young-onset dystonia caused by a mutation in the gene that encodes for the protein torsinA, which is thought to play a role in protein transport and degradation. We describe, for the first time to our knowledge, perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray in four clinically documented and genetically confirmed DYT1 patients but not in controls. The inclusions were located within cholinergic and other neurons in the pedunculopontine nucleus, cuneiform nucleus, and griseum centrale mesencephali and stained positively for ubiquitin, torsinA, and the nuclear envelope protein lamin A/C. No evidence of inclusion body formation was detected in the substantia nigra pars compacta, striatum, hippocampus, or selected regions of the cerebral cortex. We also noted tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and locus coeruleus in all four DYT1 dystonia cases, but not in controls. This study supports the notion that DYT1 dystonia is associated with impaired protein handling and the nuclear envelope. The role of the pedunculopontine and cuneiform nuclei, and related brainstem brainstem structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia [corrected]     

Stiff child syndrome with mutation of DYT1 gene

The authors report a Chinese boy with a DYT1 gene mutation having muscle stiffness, severe painful muscle spasm, myoclonus, and dystonia compatible with stiff child syndrome. Autoantibodies to glutamic acid decarboxylase (anti-GAD) were absent. His asymptomatic mother had a DYT1 mutation. His asymptomatic sister has diabetes mellitus and antibodies to glutamic acid decarboxylase but no DYT1 mutation.     

Impaired sequence learning in carriers of the DYT1 dystonia mutation

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age-matched controls. Regional differences in brain function during task performance were assessed with simultaneous H(2) (15)O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning.     

PINK1 mutation in Taiwanese early-onset parkinsonism

Abstract The PINK1 gene mutation is probably the second most common genetic cause of early-onset Parkinson's disease (EOPD). The frequency and the characteristics of the PINK1 mutation in the Taiwanese population are unknown. This study was designed to investigate the genotype, phenotype and dopaminergic function of PINK1 in a cohort of EOPD patients. The genetic settings were to detect the PINK1 gene mutations in 138 EOPD patients and in 191 controls. Using the ^99mTc-TRODAT-1 (TRODAT) scan, we investigated the differences in the dopamine transporter (DAT) activities between the PINK1 patients, late-onset Parkinson's disease (LOPD) patients and healthy controls. Four EOPD patients with 3 genotypic mutations in the PINK1 gene were found: a compound heterozygous mutation (Q239X/R492X) in 2 sisters, a novel homozygous mutation (R492X) in a woman, and a novel heterozygous mutation (G193R) in a man. The three PINK1 patients had typical phenotype with juvenile onset, benign course, and frequently with dyskinesias. The TRODAT scan showed a rather even and symmetrical reduction of uptake in PINK1 patients, unlike the dominant decline in the putamen in the LOPD patients. The annual reduction rate of uptake in the striatum was much slower in PINK1 patients than that in the LOPD patients (1.7 % vs. 4.1%; p<0.005). In the patient with a heterozygous mutation in the PINK1 gene, the reduction ratio in the striatum, as well as the annual reduction rate, were closer to those in the LOPD group. We conclude that the incidence of carrying PINK1 mutations in the present cohort of Taiwanese EOPD patients was low, accounting for 2/39 (5.1 %) in familial cases, and 2/99 (2 %) in sporadic cases. The slower annual reduction of DAT activity might indicate the insidious degeneration of dopamine neurons and a benign prognosis.     

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     

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.     

Microstructural white matter changes in carriers of the DYT1 gene mutation

We tested the hypothesis that the DYT1 genotype is associated with a disorder of anatomical connectivity involving primarily the sensorimotor cortex. We used diffusion tensor magnetic resonance imaging (DTI) to assess the microstructure of white matter pathways in mutation carriers and control subjects. Fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced (p < 0.005) in the subgyral white matter of the sensorimotor cortex of DYT1 carriers. Abnormal anatomical connectivity of the supplementary motor area may contribute to the susceptibility of DYT1 carriers to develop clinical manifestations of dystonia.