Adult-onset Primary Dystonia Research Articles

A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia

Brain-derived neurotrophic factor (BDNF) modulates neuroplasticity. A functional polymorphism [Val66Met (G196A)] in BDNF has been reported to modify cortical plasticity in humans. Physiologic investigations have revealed that dystonia might be a consequence of the pathologic plasticity of the sensorimotor cortex. We aimed to investigate the role of the Val66Met polymorphism in a cohort of Serbian patients with adult-onset primary focal and segmental dystonia (PTD). One hundred and forty-nine patients with primary adult-onset PTD, 194 patients with Parkinson's disease (PD), and 366 healthy control subjects were recruited for the study. Patients with PTD and PD, as well as healthy controls had a similar distribution of genotypes and allele frequencies. There was no any significant difference in the allelic distribution at the Val66Met SNP of the BDNF gene among patients with adult-onset PTD, PD, and healthy volunteers from the same geographic areas. In addition, the presence of the Met allele did not influence the clinical characteristics of PTD patients. Patients with the Met variant did not differ by age at onset, number of affected regions, and efficacy of a sensory trick. Met66Met is not associated with an increased risk of dystonia.

Tremor in primary adult-onset dystonia: prevalence and associated clinical features

ObjectiveTo investigate the frequency and the main clinical features of tremor in primary adult-onset dystonia (PAOD).MethodsThis cross-sectional study was conducted on 429 patients with PAOD from eight Italian movement disorder...

Age at onset and symptom spread in primary adult‐onset blepharospasm and cervical dystonia

The site of dystonia onset is known to affect the risk of spread in primary adult-onset focal dystonia, but other factors possibly influencing spread are unknown. This study explored the relationship between age and spread of dystonia in primary adult-onset focal dystonia. Two survival models analyzed spread of dystonia in a large cohort of patients with primary blepharospasm (BSP) and cervical dystonia. The first model was based on time interval between onset and spread of dystonia, and the second model was based on age at spread. Patients presenting with BSP had a 2-fold higher rate of spread than those presenting with cervical dystonia, regardless of the survival model used. However, survival analysis, based on age at spread, showed that spread develops at a similar age period in both groups, with most spread events occurring after the age of 50. The convergent age of spread in BSP and cervical dystonia is a novel finding indicating age as a factor modulating spread of dystonia. These findings may assist in informing prognostication for patients with primary adult-onset focal dystonia.

Prevalence, predictors, and perceived effectiveness of complementary, alternative and integrative medicine in adult-onset primary dystonia

BackgroundComplementary and Alternative Medicine (CAM) use is on the rise in both the US and Europe, despite questions about its safety and effectiveness, and lack of national standards. We aimed to determine the prevalence and predictors of CAM and integrative medicine use (CAM-I) and perceived effectiveness compared to the standard treatment of botulinum toxin injections in patients with adult-onset primary dystonia. MethodsThis was a retrospective questionnaire study of 389 dystonia patients examining the effects age, gender, education level and number of affected anatomical regions on botulinum toxin and CAM-I use and their perceived effectiveness. Results53% (208) of patients reported CAM-I use, while 90% (349) used the standard treatment (botulinum toxin), and 48% used both. Education was the only significant predictor of CAM-I use – individuals with bachelor's degrees were more likely to try CAM-I whereas those with high school diplomas were less likely. The mean effectiveness rate for botulinum toxin injections (59%) significantly exceeded that for CAM-I (28%, p < 0.0001). ConclusionsOur work highlights the need for scientifically sound studies to determine the safety, effectiveness and expense of CAM-I treatments for dystonia and other neurological disorders given that CAM-I use is steadily increasing, there is great variability in what is classified as CAM-I, and the effectiveness of some modalities may be significantly less than conventional medical treatments.

Phenotypic overlap in familial and sporadic primary adult-onset extracranial dystonia

We recently demonstrated that familial and sporadic blepharospasms share several phenotypic features (including age of dystonia onset, sex, and tendency to spread) believed to reflect the etiology of a blepharospasm. To investigate whether familial and sporadic forms of primary adult-onset dystonia other than the blepharospasm also share phenotypic features, we studied the families of 98 probands with primary adult-onset dystonia other than blepharospasms using a validated two-step procedure (questionnaire and clinical examination) that yields 95 % sensitivity and 100 % specificity when used to identify dystonia among relatives. The 98 probands provided a population of 402 living first-degree relatives aged 20 years or more, 336 of whom (83 %, 111 parents, 152 siblings, and 73 children) were screened for dystonia. The screening procedure identified 26 affected relatives (five parents, 16 siblings, and five children; 11 men/15 women; age at dystonia onset, 51 ± 11.7 years) from 24/98 families (25 %). No causes of secondary dystonia were found in the relatives who suffered from various forms of dystonia. When familial and sporadic patients were compared, no significant differences emerged in age, education, family size, sex distribution, age at dystonia onset, or tendency to spread. The phenotypic overlap we observed between the study groups suggests that familial and sporadic patients with primary adult-onset dystonia other than blepharospasm probably share a common etiological background.

Unilateral pallidal stimulation in a patient with truncal dystonia

Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can be present as well. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1. Mutations in THAP1 and CIZ1 have been associated with sporadic and familial adult-onset dystonia. Although significant recent progress had been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.

Mutations in CIZ1 cause adult onset primary cervical dystonia

Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia. Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult onset cervical dystonia and matching controls for sequence variants in this mutant gene. Exome sequencing led to the identification of an exonic splicing enhancer mutation in exon 7 of CIZ1 (c.790A>G, p.S264G), which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified 2 additional CIZ1 missense mutations (p.P47S and p.R672M). Mutations in CIZ1 may cause adult onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.

Delayed-onset focal dystonia of the leg secondary to traumatic brain injury

A 42-year-old man presented with action-induced, stereotyped posturing of the left leg with task specificity following major traumatic brain injury less than a year earlier. Although adult onset primary leg dystonia is a recognised entity, our patient is unusual in that dystonia was an isolated abnormality without associated spasticity, was not preceded by ipsilateral hemiparesis and remained focal without progression to involve other body regions. MRI brain showed a small area of gliosis in the left frontal subcortical white matter but with no lesions in the basal ganglia or thalamus. The dystonia in our patient almost completely resolved with botulinum toxin therapy.

Eye symptoms in relatives of patients with primary adult‐onset dystonia

Using a validated questionnaire, we screened eye symptoms (burning sensation, grittiness, dry eye) in 333 first-degree relatives of 140 probands with different forms of primary adult-onset dystonia, 208 healthy subjects, and 293 patients with primary blepharospasm. The rate of eye symptoms was similar in the relatives of focal dystonia patients and in healthy subjects (adjusted HR, 1.1; 95% CI, 0.7-1.7; P = .69), thus suggesting a common origin of eye symptoms in both groups. A higher rate was observed in blepharospasm patients (adjusted HR, 2; 95% CI, 1.4-2.9; P < .0001). Relatives of focal dystonia patients who developed blepharospasm were more likely to have preceding eye symptoms than were relatives who developed focal dystonia other than blepharospasm (BSP) or relatives who did not develop dystonia. Eye symptoms reported by relatives of patients with focal dystonia probably result from eye diseases and are not part of the clinical spectrum of blepharospasm.

The c.‐237_236GA&gt;TT THAP1 sequence variant does not increase risk for primary dystonia

Sequence variants in coding and noncoding regions of THAP1 have been associated with primary dystonia. In this study, 1,446 Caucasian subjects with mainly adult-onset primary dystonia and 1,520 controls were genotyped for a variant located in the 5'-untranslated region of THAP1 (c.-237_236GA>TT). Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P=0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein. Our findings indicate that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians.

The phenomenology of the geste antagoniste in primary blepharospasm and cervical dystonia

The geste antagoniste (GA), a relatively common feature of adult-onset primary dystonia, has been systematically evaluated only in cervical dystonia, but it is still unclear whether its frequency and phenomenology differ among the various forms of focal dystonia. We analysed the frequency, phenomenology, effectiveness, and relationship of the GA with demographic/clinical features of dystonia in a representative clinical series of patients with the two most common forms of adult-onset primary dystonia, blepharospasm (BSP) and cervical dystonia (CD). Clinical data were gathered using a standardized questionnaire, which showed substantial test-retest reliability (kappa = 0.79, P < 0.00001). The frequency of GA was similar among patients with BSP (42/59, 71.2%) and patients with CD (27/32, 84.4%), and in both groups GA showed similar effectiveness in reducing dystonia. The repertoire of GA was heterogenous in both BSP and CD patients, in whom seven BSP-related and five CD-related types of GA were recorded, and a "forcible" type of GA was present in 69% of BSP patients and in 48.1% of CD patients. In our whole patient population, age at dystonia onset was significantly lower among patients reporting a GA compared to those without GA (P = 0.01). GA features shared by BSP and CD predominate over differences, suggesting common mechanisms underlying this phenomenon in the two forms of primary adult-onset dystonia.

Novel THAP1 sequence variants in primary dystonia

THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.

Lower limb involvement in adult‐onset primary dystonia: frequency and clinical features

Despite the growing number of reports describing adult-onset primary lower limb dystonia (LLD) this entity has never been systematically evaluated in the general population of patients with primary adult-onset dystonia. From outpatients with adult-onset primary dystonia attending nine Italian University centres for movement disorders we consecutively recruited 579 patients to undergo a standardized clinical evaluation. Of the 579 patients assessed, 11 (1.9%) (8 women, 3 men) had LLD, either alone (n = 4, 0.7%) or as part of a segmental/multifocal dystonia (n = 7, 1.2%). The age at onset of LLD (47.9 +/- 17 years) was significantly lower than the age at onset of cranial dystonias (57.9 +/- 10.7 years for blepharospasm, and 58.9 +/- 11.8 years for oromandibular dystonia) but similar to that of all the other adult-onset primary dystonias. The lower limb was either the site of dystonia onset (36.4%) or the site of dystonia spread (63.6%). In patients in whom LLD was a site of spread, dystonia seemed to spread following a somatotopic distribution. Only one patient reported a recent trauma involving the lower limb whereas 36.4% of the patients reported pain at the site of LLD. Only 64% of our patients needed treatment for LLD, and similarly to previously reported cases, the most frequently tried treatments was botulinum toxin and trihexyphenidyl. The lower limb is an uncommon but possible topographical site of dystonia in adulthood that should be kept in consideration during clinical evaluation.

Speech-induced blepharospasm

Primary blepharospasm is an adult-onset dystonia typically present at rest and exacerbated by bright light, stress and voluntary movements of eyes and eyelids. Inconsistency or inducibility by activities involving muscles other than orbicularis oculi muscles are considered incongruous with typical primary blepharospasm, heralding the suspicion of psychogenicity. We report the clinical vignette of two patients manifesting an unusual presentation of primary blepharospasm, specifically triggered by voiced speech and associated with an otherwise 'typical' presentation of primary adult-onset dystonia in the lower face, larynx or upper limb. Speech-induced primary blepharospasm seems a rare occurrence, representing 1.3% of our clinic-based series of 149 patients with primary adult-onset primary blepharospasm. In these atypical patients, the feature of speech inducibility suggests that the abnormal surrounding inhibition between cortical subregions representing laryngeal and orbicularis oculi muscles might underlie dystonic overflow to the orbicularis oculi muscles following the voiced speech.

Brain‐derived neurotrophic factor and risk for primary adult‐onset cranial‐cervical dystonia

Adult-onset dystonia may be related, amongst other factors, to abnormal neuronal plasticity in cortical and subcortical structures. Brain-derived neurotrophic factor is a major modulator of synaptic efficiency and neuronal plasticity. Recent works documented that a single nucleotide polymorphism (SNP) of the BDNF gene, the Val66Met SNP, modulates short-term plastic changes within motor cortical circuits. In this study we aimed at exploring the effect of this SNP upon the risk of developing common forms of primary adult-onset dystonia. We explored the influence of the Val66Met SNP of the BDNF gene on the risk of cranial and cervical dystonia in a cohort of 156 Italian patients and 170 age- and gender-matched healthy control subjects drawn from the same population. The presence of the rare Met allele was not significantly associated with the diagnosis of dystonia (age- and gender-adjusted odds ratios of 1.22, P = 0.38). The study had a >90% power to detect a 50% change in the risk of developing cranial-cervical dystonia associated with the presence of the Met allele. Moreover, there was no relationship between Val66Met SNP and age at dystonia onset or type of dystonia. Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor shared by the various forms of primary adult-onset dystonia.

Successful GPi deep brain stimulation in a patient with adult onset primary axial dystonia

Axial dystonia is a rare manifestation of adult onset primary segmental dystonia. Typically, patients present with cranio-cervical dystonia spreading to the trunk but not to the extremities. Affected patients are...

Genotype–phenotype interactions in primary dystonias revealed by differential changes in brain structure

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia.This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles.By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers.We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Neurophysiological evidence for cerebellar dysfunction in primary focal dystonia

Recent studies have suggested that there may be functional and structural changes in the cerebellum of patients with adult onset primary focal dystonia. The aim of this study was to...

Quality of life in patients with focal dystonia

Objectives The aims of this study were to identify the clinical and demographic factors influencing health-related quality of life (HR-QoL) and to compare HR-QoL measures between various types of focal dystonia (cervical dystonia, blepharospasm, and writer’s cramp). Methods We examined 157 consecutive patients with adult-onset primary focal dystonia, and HR-QoL was assessed by using the SF-36 questionnaire. Univariate and multivariate regression analyses were performed. Results Patients with writer’s cramp scored better in all SF-36 domains, except role functioning physical (RP), while these differences were statistically significant for physical functioning (PF) ( p = 0.020), bodily pain (BP) ( p = 0.001), and general health (GH) ( p = 0.004). Patients with writer’s cramp and blepharospasm scored significantly better for BP ( p = 0.001) than patients with cervical dystonia. We found that each of the eight dimensions of SF-36 proved to be significantly correlated to the Hamilton depression rating scale score in patients with torticollis and blepharospsm, while vitality (VT), social functioning (SF), and mental health (MH) scales showed statistically significant correlations in patients with hand dystonia. Similar relationships were observed between anxiety and SF-36 domains. Conclusion Depression and anxiety are the most important predictors of poorer HR-QoL in patients with all three types of focal dystonia.

Arm swing is reduced in idiopathic cervical dystonia

Arm swing is typically reduced in people with Parkinsonism, and also in those with pyramidal dysfunction. We have previously observed that patients with focal arm dystonia can also have reduced arm swing. However, arm swing has not been formally studied in adult-onset primary cervical dystonia (AOPCD). We assessed arm swing in 100 consecutive patients diagnosed with AOPCD and 50 healthy controls. Reduced arm swing was more common in patients with AOPCD compared with healthy controls (55% vs. 6%, P < 0.001) and was more often abnormal on the same side as the direction of head turning (P < 0.05). Women with AOPCD had more often reduced arm swing compared with men (P = 0.002). Reduced arm swing is common in AOPCD. It may indicate segmental spread of subtle motor dysfunction or it may be a feature of dystonia per se.