Adult-onset Primary Torsion Dystonia Research Articles

The endophenotype and the phenotype: Temporal discrimination and adult‐onset dystonia

The pathogenesis and the genetic basis of adult-onset primary torsion dystonia remain poorly understood. Because of markedly reduced penetrance in this disorder, a number of endophenotypes have been proposed; many of these may be epiphenomena secondary to disease manifestation. Mediational endophenotypes represent gene expression; the study of trait (endophenotypic) rather than state (phenotypic) characteristics avoids the misattribution of secondary adaptive cerebral changes to pathogenesis. We argue that abnormal temporal discrimination is a mediational endophenotype; its use facilitates examination of the effects of age, gender, and environment on disease penetrance in adult-onset dystonia. Using abnormal temporal discrimination in unaffected first-degree relatives as a marker for gene mutation carriage may inform exome sequencing techniques in families with few affected individuals. We further hypothesize that abnormal temporal discrimination reflects dysfunction in an evolutionarily conserved subcortical-basal ganglia circuit for the detection of salient novel environmental change. The mechanisms of dysfunction in this pathway should be a focus for future research in the pathogenesis of adult-onset primary torsion dystonia.

Advances in molecular genetic studies of primary dystonia

Dystonias are heterogeneous hyperkinetic movement disorders characterized by involuntary muscle contractions which result in twisting, repetitive movements and abnormal postures. In recent years, there was a great advance in molecular genetic studies of primary dystonia. This paper will review the clinical characteristics and molecular genetic studies of primary dystonia, including early-onset generalized torsion dystonia ( DYT1 ), whispering dysphonia ( DYT4 ), dopa⁃responsive dystonia ( DYT5 ), mixed-type dystonia ( DYT6 ), paroxysmal kinesigenic dyskinesia ( DYT10 ), myoclonus⁃dystonia syndrome ( DYT11 ), rapid-onset dystonia parkinsonism ( DYT12 ), adult-onset cervical dystonia ( DYT23 ), craniocervical dystonia ( DYT24 ) and primary torsion dystonia ( DYT25 ).

Is TOR1A a risk factor in adult‐onset primary torsion dystonia?

Studies of genetic association between TOR1A and adult-onset primary torsion dystonia have contradictory results. The authors genotyped TOR1A single nucleotide polymorphisms rs1801968, rs2296793, rs1182 and rs3842225 in a cohort of clinically well characterized cervical dystonia patients (n=367) and constructed haplotypes. The authors systematically reviewed the published case-control TOR1A association studies in adult-onset primary torsion dystonia. In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance. However, in a selection of familial cases the functional variant p.Asp216His (rs1801968) was associated with increased dystonia risk (odds ratio 1.43; 95%CI 1.01-2.02). Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases.

AGE-RELATED PENETRANCE OF ABNORMAL TEMPORAL DISCRIMINATION THRESHOLDS IN UNAFFECTED FIRST-DEGREE RELATIVES OF ADULT ONSET PRIMARY TORSION DYSTONIA PATIENTS

ObjectiveTo examine the age-related frequency of an abnormal temporal discrimination threshold (TDT) in unaffected first-degree relatives of patients with adult onset primary torsion dystonia (AOPTD).BackgroundAOPTD is an autosomal dominant condition...

Penetrance of Abnormal Temporal Discrimination Thresholds in Unaffected First-Degree Relatives of Adult Onset Primary Torsion Dystonia Patients (P01.218)

Penetrance of Abnormal Temporal Discrimination Thresholds in Unaffected First-Degree Relatives of Adult Onset Primary Torsion Dystonia Patients (P01.218)

Functional Correlates of Temporal Discrimination in Adult Onset Primary Torsion Dystonia Patients and Unaffected First-Degree Relatives (P01.220)

Functional Correlates of Temporal Discrimination in Adult Onset Primary Torsion Dystonia Patients and Unaffected First-Degree Relatives (P01.220)

122 Functional correlates of abnormal temporal discrimination in adult onset primary torsion dystonia patients and first-degree relatives

BackgroundThe Temporal Discrimination Threshold (TDT) is the shortest time interval at which a subject can detect that two stimuli are asynchronous. The TDT is abnormal in patients with AOPTD and...

Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test

Adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance; patients with sporadic adult-onset primary torsion dystonia are much more prevalent than familial. The temporal discrimination threshold is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in adult-onset primary torsion dystonia. The aim was to determine the frequency of abnormal temporal discrimination thresholds in patients with sporadic adult-onset primary torsion dystonia and their first-degree relatives. We hypothesized that abnormal temporal discrimination thresholds in first relatives would be compatible with an autosomal dominant endophenotype. Temporal discrimination thresholds were examined in 61 control subjects (39 subjects <50 years of age; 22 subjects >50 years of age), 32 patients with sporadic adult-onset primary torsion dystonia (cervical dystonia n = 30, spasmodic dysphonia n = 1 and Meige's syndrome n = 1) and 73 unaffected first-degree relatives (36 siblings, 36 offspring and one parent) using visual and tactile stimuli. Z-scores were calculated for all subjects; a Z > 2.5 was considered abnormal. Abnormal temporal discrimination thresholds were found in 1/61 (2%) control subjects, 27/32 (84%) patients with adult-onset primary torsion dystonia and 32/73 (44%) unaffected relatives [siblings (20/36; 56%), offspring (11/36; 31%) and one parent]. When two or more relatives were tested in any one family, 22 of 24 families had at least one first-degree relative with an abnormal temporal discrimination threshold. The frequency of abnormal temporal discrimination thresholds in first-degree relatives of patients with sporadic adult-onset primary torsion dystonia is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic adult-onset primary torsion dystonia is genetic in origin.

Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype

Adult-onset primary torsion dystonia (AOPTD) is an autosomal dominant disorder with markedly reduced penetrance. Sensory abnormalities are present in AOPTD and also in unaffected relatives, possibly indicating non-manifesting gene carriage (acting as an endophenotype). The temporal discrimination threshold (TDT) is the shortest time interval at which two stimuli are detected to be asynchronous. We aimed to compare the sensitivity and specificity of three different TDT tasks (visual, tactile and mixed/visual-tactile). We also aimed to examine the sensitivity of TDTs in different AOPTD phenotypes. To examine tasks, we tested TDT in 41 patients and 51 controls using visual (2 lights), tactile (non-painful electrical stimulation) and mixed (1 light, 1 electrical) stimuli. To investigate phenotypes, we examined 71 AOPTD patients (37 cervical dystonia, 14 writer's cramp, 9 blepharospasm, 11 spasmodic dysphonia) and 8 musician's dystonia patients. The upper limit of normal was defined as control mean +2.5 SD. In dystonia patients, the visual task detected abnormalities in 35/41 (85%), the tactile task in 35/41 (85%) and the mixed task in 26/41 (63%); the mixed task was less sensitive than the other two (p = 0.04). Specificity was 100% for the visual and tactile tasks. Abnormal TDTs were found in 36 of 37 (97.3%) cervical dystonia, 12 of 14 (85.7%) writer's cramp, 8 of 9 (88.8%) blepharospasm, 10 of 11 (90.1%) spasmodic dysphonia patients and 5 of 8 (62.5%) musicians. The visual and tactile tasks were found to be more sensitive than the mixed task. Temporal discrimination threshold results were comparable across common adult-onset primary torsion dystonia phenotypes, with lower sensitivity in the musicians.

POMD06 Utility of visual, tactile and mixed tasks in the determination of temporal discrimination thresholds in adult-onset primary torsion dystonia

Adult-onset primary torsion dystonia (AOPTD) is autosomal dominant with reduced penetrance. Sensory abnormalities in unaffected relatives may indicate nonmanifesting gene carriage—an ideal endophenotype being present in all patients and 50%...

POMD05 Temporal discrimination threshold in patients with sporadic adult-onset primary torsion dystonia and their first degree relatives

AOPTD is autosomal dominant; the frequency of apparently sporadic cases may reflect low penetrance (12–15%). Sensory abnormalities in unaffected relatives may indicate nonmanifesting gene carriage. An ideal endophenotype in an...

POMD04 Utility of temporal discrimination threshold testing in different adult-onset primary torsion dystonia phenotypes

AOPTD is autosomal dominant with significantly reduced penetrance. Sensory abnormalities are a marker of basal ganglia dysfunction in these patients and may be used as an endophenotype. The temporal discrimination...

Comparing endophenotypes in adult‐onset primary torsion dystonia

Adult-onset primary torsion dystonia (AOPTD) has an autosomal dominant pattern of inheritance with markedly reduced penetrance; the genetic causes of most forms of AOPTD remain unknown. Endophenotypes, markers of sub-clinical gene carriage, may be of use detecting non-manifesting gene carriers in relatives of AOPTD patients. The aim of this study was to compare the utility of the spatial discrimination threshold (SDT) and temporal discrimination threshold (TDT) as potential endophenotypes in AOPTD. Data on other published candidate endophenotypes are also considered. Both SDT and TDT testing were performed in 24 AOPTD patients and 34 of their unaffected first degree relatives; results were compared with normal values from a control population. Of the 24 AOPTD patients 5 (21%) had abnormal SDTs and 20 (83%) had abnormal TDTs. Of the 34 first degree relatives 17 (50%) had abnormal SDTs and 14 (41%) had abnormal TDTs. Discordant results on SDT and TDT testing were found in 16 (67%) AOPTD patients and 21 (62%) first degree relatives. TDT testing has superior sensitivity compared to SDT testing in AOPTD patients; although false positive TDTs are recognised, the specificity of TDT testing in unaffected relatives is not determinable. The high level of discordance between the two tests probably relates methodological difficulties with SDT testing. The SDT is an unreliable AOPTD endophenotype; TDT testing fulfils criteria for a reliable endophenotype with a high sensitivity.

Temporal Discrimination Threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia

Familial adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance. Most adult-onset primary torsion dystonia patients are sporadic cases. Disordered sensory processing is found in adult-onset primary torsion dystonia patients; if also present in their unaffected relatives this abnormality may indicate non-manifesting gene carriage. Temporal discrimination thresholds (TDTs) are abnormal in adult-onset primary torsion dystonia, but their utility as a possible endophenotype has not been examined. We examined 35 adult-onset primary torsion dystonia patients (17 familial, 18 sporadic), 42 unaffected first-degree relatives of both familial and sporadic adult-onset primary torsion dystonia patients, 32 unaffected second-degree relatives of familial adult-onset primary torsion dystonia (AOPTD) patients and 43 control subjects. TDT was measured using visual and tactile stimuli. In 33 unaffected relatives, voxel-based morphometry was used to compare putaminal volumes between relatives with abnormal and normal TDTs. The mean TDT in 26 control subjects under 50 years of age was 22.85 ms (SD 8.00; 95% CI: 19.62-26.09 ms). The mean TDT in 17 control subjects over 50 years was 30.87 ms (SD 5.48; 95% CI: 28.05-33.69 ms). The upper limit of normal, defined as control mean + 2.5 SD, was 42.86 ms in the under 50 years group and 44.58 ms in the over 50 years group. Thirty out of thirty-five (86%) AOPTD patients had abnormal TDTs with similar frequencies of abnormalities in sporadic and familial patients. Twenty-two out of forty-two (52%) unaffected first-degree relatives had abnormal TDTs with similar frequencies in relatives of sporadic and familial AOPTD patients. Abnormal TDTs were found in 16/32 (50%) of second-degree relatives. Voxel-based morphometry analysis comparing 13 unaffected relatives with abnormal TDTs and 20 with normal TDTs demonstrated a bilateral increase in putaminal grey matter in unaffected relatives with abnormal TDTs. The prevalence of abnormal TDTs in sporadic and familial AOPTD patients and their first-degree relatives follows the rules for a useful endophenotype. A structural correlate of abnormal TDTs in unaffected first-degree relatives was demonstrated using voxel-based morphometry. Voxel-based morphometry findings indicate that putaminal enlargement in AOPTD is a primary phenomenon. TDTs may be an effective tool in AOPTD research with particular relevance to genetic studies of the disorder.

Striatal morphology correlates with sensory abnormalities in unaffected relatives of cervical dystonia patients

Structural grey matter abnormalities have been described in adult-onset primary torsion dystonia (AOPTD). Altered spatial discrimination thresholds are found in familial and sporadic AOPTD and in some unaffected relatives who may be non-manifesting gene carriers. Our hypothesis was that a subset of unaffected relatives with abnormal spatial acuity would have associated structural abnormalities. Twenty-eight unaffected relatives of patients with familial cervical dystonia, 24 relatives of patients with sporadic cervical dystonia and 27 control subjects were recruited. Spatial discrimination thresholds (SDTs) were determined using a grating orientation task. High-resolution magnetic resonance imaging (MRI) images (1.5 T) were analysed using voxel-based morphometry. Unaffected familial relatives with abnormal SDTs had reduced caudate grey matter volume (GMV) bilaterally relative to those with normal SDTs (right Z = 3.45, left Z = 3.81), where there was a negative correlation between SDTs and GMV (r = -0.76, r(2) = 0.58, p < 0.0001). Familial relatives also had bilateral sensory cortical expansion relative to unrelated controls (right Z = 4.02, left Z = 3.79). Unaffected relatives of patients with sporadic cervical dystonia who had abnormal SDTs had reduced putaminal GMV bilaterally compared with those with normal SDTs (right Z = 3.96, left Z = 3.45). Sensory abnormalities in some unaffected relatives correlate with a striatal substrate and may be a marker of genetic susceptibility in these individuals. Further investigation of grey matter changes as a candidate endophenotype may assist future genetic studies of dystonia.

Neuropathology of primary adult-onset dystonia

Idiopathic adult-onset primary dystonia usually affects the upper body and remains focal. Underlying mechanisms are unknown, and there are only limited neuropathologic studies in the literature. Recently, ubiquitinated perinuclear inclusion bodies were found in the brainstem of patients with DYT1-related dystonia. In X-linked recessive dystonia-parkinsonism, neuronal loss in the striosome compartment of the striatum has been described. However, it was unclear whether these changes are characteristic of these particular disorders or an epiphenomenon of dystonic conditions in general. Six cases of adult-onset dystonia and four controls were studied using immunohistochemistry to determine the presence of inclusion bodies immunoreactive for torsinA, ubiquitin, and laminA/C in the brainstem. The distribution of calcineurin expressing neurons in the striatum was also determined to ascertain whether there is loss of neurons in the striosome compartment. In contrast to early-onset dystonia, neuronal inclusions immunoreactive for torsinA, ubiquitin, and laminA/C were not present in the brainstem nuclei. There was no apparent loss of the striatal striosome compartment. Our findings suggest that the underlying mechanism in the adult-onset primary torsion dystonia is different from that of early-onset DYT1-related dystonia and also DYT3 X-linked recessive dystonia-parkinsonism. Alternative mechanisms may underpin the pathophysiology of adult-onset primary dystonia.

Molding the sensory cortex: Spatial acuity improves after botulinum toxin treatment for cervical dystonia

Disorganization of sensory cortical somatotopy has been described in adult onset primary torsion dystonia (AOPTD). Although botulinum toxin type A (BTX-A) acts peripherally, some studies have suggested a central effect. Our primary hypothesis was that sensory cortical reorganization occurs after BTX-A treatment of AOPTD. Twenty patients with cervical dystonia and 18 healthy age-matched control patients had spatial discrimination thresholds (SDTs) measured at baseline and monthly for 3 months. Mean baseline SDT (+/-SD) was 1.75 +/-0.76 mm in the dystonia group, greater than the control group mean of 1.323 +/- 0.45 mm (P = 0.05). Mean control group SDT did not vary significantly over time. A transient improvement of 23% from baseline (P = 0.005) occurred in the dystonia group 1 month after injection, which did not positively correlate with changes in physician and patient ratings of torticollis severity. The presumed mechanism of SDT improvement is a modulation of afferent cortical inputs from muscle spindles. Society.

Relative risk of spread of symptoms among the focal onset primary dystonias

Adult-onset primary torsion dystonia (PTD) may spread to multiple body parts, but the relative risk of spread by site of onset of dystonia has not been well characterized. We retrospectively identified 602 patients with PTD out of 1,500 dystonia patients in our electronic database and extracted age at onset, site of onset, family history, and spread. Survival analyses were performed for groups based on site of onset, and hazard ratios compared relative risk of spread across groups. Patients with adult-onset blepharospasm were more likely to spread (31% past the head) than those with dystonia starting in the neck (9%), larynx (12%), or upper extremities (16%). Hazard ratios proved that the blepharospasm group had the greatest relative risk of spread. The rate of spread after onset varied significantly between the different groups. Most spread occurred in the first 1 to 2 years after onset of blepharospasm, whereas the risk of spread was relatively constant over time in cervical and laryngeal dystonia. Different sites of onset of PTD confer different risks of spread, important for clinical prognosis. Different risks of spread may provide clues about underlying pathogenesis of adult-onset primary dystonias.

Sensory abnormalities in unaffected relatives in familial adult-onset dystonia

Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.

Age at onset as a factor in determining the phenotype of primary torsion dystonia

The genetic basis of most forms of primary torsion dystonia (PTD) is unknown; multiplex families are uncommon due to low penetrance. Intrafamilial, age-related, phenotypic heterogeneity was noted in 14 PTD families. The authors hypothesized that the clinical presentation of PTD was modulated by the age at onset of the dystonia, irrespective of the genotype. This hypothesis was addressed in a study of 14 PTD families and a meta-analysis of 83 published series of PTD. In 12 families with adult-onset PTD, the index cases presented with cervical dystonia (CD); of the 22 affected relatives, 17 had CD, 2 had writer's cramp, 1 had blepharospasm, and 2 had spasmodic dysphonia. In the two other PTD families, the probands and all 10 symptomatic relatives had limb-onset dystonia at <20 years of age. There were differences between the median ages at onset of the different phenotypes (p = 0.0037). Analysis of 83 published series including 5,057 patients indicated significant differences in the mean age at onset of five phenotypes of PTD (mean age at onset; 95% CI): DYT1 dystonia (11.3 years; 10.3 to 12.2), writer's cramp (38.4; 36.9 to 39.9), CD (40.8; 40.3 to 41.3), spasmodic dysphonia (43.0; 42.2 to 43.9), and blepharospasm-oromandibular dystonia (55.7; 55.1 to 56.4). Phenotypic variation in PTD presentation is due to the effect of age at onset modulating the expression of a genetic disorder with a caudal-to-rostral change in the site of onset.