Background: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder. Aim: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland. Methods: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed. Results: On the prevalence date there were 592 individuals in Ireland with adult onset idiopathic isolated focal dystonia, a point prevalence of 17.8 per 100 000 (95% confidence interval 16.4-19.2). Phenotype numbers were cervical dystonia 410 (69.2%), blepharospasm 102 (17.2%), focal hand dystonia 39 (6.6%), spasmodic dysphonia 18 (3.0%), musician's dystonia 17 (2.9%) and oromandibular dystonia six (1.0%). Sixty-two (16.5%) of 375 consenting index cases had a relative with clinically confirmed adult onset idiopathic isolated focal dystonia (18 multiplex and 24 duplex families). Marked variations in the proportions of patients with tremor, segmental spread, sensory tricks, pain and psychiatric symptoms by phenotype were documented. Conclusions: The prevalence of adult onset idiopathic isolated focal dystonia in Ireland is higher than that recorded in many similar service-based epidemiological studies but is still likely to be an underestimate. The low proportion of individuals with blepharospasm may reflect reduced environmental exposure to sunlight in Ireland. This study will serve as a resource for international comparative studies of environmental and genetic factors in the pathogenesis of the disorder.

The temporal discrimination threshold (TDT) is the shortest time interval at which two sensory stimuli presented sequentially are detected as asynchronous by the observer. TDTs are known to increase with age. Having previously observed shorter thresholds in young women than in men, in this work we sought to systematically examine the effect of sex and age on temporal discrimination. The aims of this study were to examine, in a large group of men and women aged 20-65 years, the distribution of TDTs with an analysis of the individual participant's responses, assessing the "point of subjective equality" and the "just noticeable difference" (JND). These respectively assess sensitivity and accuracy of an individual's response. In 175 participants (88 women) aged 20-65 years, temporal discrimination was faster in women than in men under the age of 40 years by a mean of approximately 13 ms. However, age-related decline in temporal discrimination was three times faster in women so that, in the age group of 40-65 years, the female superiority was reversed. The point of subjective equality showed a similar advantage in younger women and more marked age-related decline in women than men, as the TDT. JND values declined equally in both sexes, showing no sexual dimorphism. This observed sexual dimorphism in temporal discrimination is important for both (a) future clinical research assessing disordered mid-brain covert attention in basal-ganglia disorders, and (b) understanding the biology of this sexual dimorphism which may be genetic or hormonal.

Background Adult-onset isolated focal dystonia may present with various phenotypes including blepharospasm and cervical dystonia. Although inherited in an autosomal dominant manner with a markedly reduced penetrance, environmental factors are considered important in disease penetrance and expression. We observed a marked variation by latitude in the reports of the frequency of patients with blepharospasm relative to those with cervical dystonia; we hypothesised that sun exposure is an environmental risk factor for the development of blepharospasm in genetically susceptible individuals. Methods From published clinic cohorts and epidemiological reports, the ratio of the number of cases of blepharospasm to cervical dystonia (phenotype case ratio) at each study site was analysed with regard to latitude and measures of annual insolation. Meta-regression analyses of the phenotype case ratio to these environmental factors were performed. Results The phenotype case ratio in 15 eligible study sites over 41° of latitude demonstrated a statistically significant inverse association with latitude (p=0.0004, R2=53.5%). There were significant positive associations between the phenotype case ratio and quarter-one (January–March) insolation (p=0.0005, R2=53%) and average annual insolation (p=0.003, R2=40%). Conclusion The increase in the blepharospasm: cervical dystonia case ratio with decreasing latitude and increasing insolation suggests that sunlight exposure is an environmental risk factor for the development of blepharospasm (rather than cervical dystonia) in individuals genetically susceptible to adult-onset dystonia.

Background The 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 approximately 50% of their unaffected relatives. Putaminal activation positively correlates with effective temporal discrimination in healthy subjects. We hypothesised that relatives of AOPTD patients with abnormal TDT thresholds would have hypoactivation of the putamen, vs relatives with normal TDT. Methods Eleven AOPTD patients (median age =48.4 years), 12 first-degree relatives with abnormal TDT (median age =46.9 years), 12 first-degree relatives with normal TDT (median age =40.8 years), and 12 healthy controls (median age =48.9 years) underwent fMRI scanning while judging if two stimuli were synchronous or asynchronous. The significance threshold was p<0.05, family-wise error corrected across the whole-brain. Results Relatives with abnormal TDTs had less activation than relatives with normal TDTs in the putamen (z=7.1) and in the middle frontal gyrus (z=6.83). Patients had less activation in the middle frontal gyrus (z=5.8) and in the medial frontal gyrus (z=5.45) than controls. Relatives with abnormal TDTs had less activation than patients in the middle frontal gyus (z=5.92) and the pre-SMA (z=5.90). Conclusions Temporal processing is abnormal in unaffected first-degree relatives of sporadic AOPTD patients and is due to disordered putaminal processing.

Introduction Adult-onset primary torsion dystonia (AOPTD) is an autosomal dominant disorder with markedly reduced penetrance; sporadic AOPTD patients are much more prevalent than familial. The temporal discrimination threshold (TDT) is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in AOPTD. Aim/Hypothesis The aim was to determine the frequency of abnormal TDTs in sporadic AOPTD patients and their first degree relatives. We hypothesised that abnormal TDT s in first degree relatives would be compatible with an autosomal dominant endophenotype. Methods TDTs were examined in 61 control subjects (39 under 50 years, 22 over 50 years), 32 sporadic AOPTD patients (30 cervical dystonia, 1 spasmodic dysphonia, one Meige9s Syndrome) 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-score >2.5 was considered abnormal. Results The mean TDT in controls under 50 was 24.54 ms and 31.11 ms in controls over 50. Abnormal TDTs (Z-score >2.5) were found in 1 of 61 (2%) control subjects, 27 of 32 (84%) AOPTD patients and 32 of 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 TDT. Conclusion The frequency of abnormal TDTs in first degree relatives of patients with sporadic AOPTD is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic AOPTD is genetic in origin.

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.

Objective To 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). Background AOPTD is an autosomal dominant condition with markedly reduced penetrance. The mean age of onset in cervical dystonia is 41 years. TDT is the shortest time interval at which two separate stimuli are detected to be asynchronous. An abnormal TDT is found in 50% of unaffected first-degree relatives of AOPTD patients and considered an endophenotype. Methods TDTs were examined in 61 healthy control subjects and 144 unaffected first-degree relatives of AOPTD patients, using visual and tactile stimuli. Standardised Z-scores were calculated for all subjects; a Z-score greater than 2.5 was considered abnormal. Results 65/144 (45%) of unaffected first-degree relatives had abnormal TDTs (Z-score >2.5). Abnormal TDTs were found in 19/69 (28%) of relatives 18–39 years, in 19/33 (58%) of relatives 40–49 years and in 12/20 (60%) of relatives 50–59 years of age. The frequency was significantly higher in relatives over 40 years (61%) than in those under 40 years (28%) (p=<0.0001). Conclusion Abnormal temporal discrimination shows age-related penetrance, becoming fully penetrant after the age of 40 years. Thus a normal TDT can only be determined as not indicating non-manifesting gene carriage in relatives older than 40 years of age. The age-related penetrance of the endophenotype is similar to that of the phenotype and suggests that it is mediational in nature.