Cervical dystonia incidence and diagnostic delay in a multiethnic population.

BackgroundCurrent cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized.ObjectivesTo determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization.MethodsWe identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration.ResultsCD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68).ConclusionsCD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society

The G2019S LRRK2 Mutation is Rare in Korean Patients with Parkinson's Disease and Multiple System Atrophy

Background and Purpose The LRRK2 (PARK8; OMIM607060)substitution was recently identified as a causative mutation for Parkinson`s disease (PD). The pathologic heterogeneity of LRRK2-positive patients Suggests that mutation of the LRRK2 gene is associated with the pathogenesis of PD and Parkinson-plus disorders, such as multiple system atrophy (MSA). We previously reported that the G2019S LRRK2 mutation-which is the most common LRRK-2 mutation-was not found in a sample of 453 Korean PD patients. In the present study, we extended the screening for the G2019S Mutation to a larger group of PD and MSA patients. Methods We performed a genetic analysis of the G2019S mutation ill 877 patients with PD and 199 patients with MSA using a standard PCR and restriction digestion method. Results None of the subjects carried the G2019S mutation. Conclusions The results of the present study support that the G2019S Mutation is extremely rare in PD and is unlikely to be associated with MSA in the Korean population. J Clin Neurol 2009;5:29-32This study was in part supported by a grant of the Korea Health 21 R & D Project. Ministry of Health & Welfare, Republic of Korea (03-PJ10- PG13-GD01-0002).Lin CH, 2008, J BIOMED SCI, V15, P661, DOI 10.1007/s11373-008-9260-0Healy DG, 2008, LANCET NEUROL, V7, P583, DOI 10.1016/S1474-4422(08)70117-0CHO JW, 2008, J CLIN NEUROL, V4, P23Ozelius LJ, 2007, MOVEMENT DISORD, V22, P546, DOI 10.1002/mds.21343Cho JW, 2007, CAN J NEUROL SCI, V34, P53Punia S, 2006, NEUROSCI LETT, V409, P83, DOI 10.1016/j.neulet.2006.04.052Hardy J, 2006, ANN NEUROL, V60, P389, DOI 10.1002/ana.21022Zabetian CP, 2006, NEUROLOGY, V67, P697Tomiyama H, 2006, MOVEMENT DISORD, V21, P1102, DOI 10.1002/mds.20886Tan EK, 2006, MOVEMENT DISORD, V21, P997, DOI 10.1002/mds.20875Fung HC, 2006, MOVEMENT DISORD, V21, P880, DOI 10.1002/mds.20814Schapira AHV, 2006, NEUROLOGY, V66, pS10Infante J, 2006, NEUROSCI LETT, V395, P224, DOI 10.1016/j.neulet.2005.10.083Giasson BI, 2006, ANN NEUROL, V59, P315, DOI 10.1002/ana.20791Taylor JP, 2006, TRENDS MOL MED, V12, P76, DOI 10.1016/j.molmed.2005.12.004Ross OA, 2006, ANN NEUROL, V59, P388, DOI 10.1002/ana.20731Lesage S, 2006, NEW ENGL J MED, V354, P422Ozelius LJ, 2006, NEW ENGL J MED, V354, P424Goldwurm S, 2006, PARKINSONISM RELAT D, V12, P410, DOI 10.1016/j.parkreldis.2006.04.001Hernandez D, 2005, NEUROSCI LETT, V389, P137, DOI 10.1016/j.neulet.2005.07.044Farrer M, 2005, NEUROLOGY, V65, P738Tan EK, 2005, NEUROSCI LETT, V384, P327, DOI 10.1016/j.neulet.2005.04.103Gasser T, 2005, CURR OPIN NEUROL, V18, P363Funayama M, 2005, ANN NEUROL, V57, P918, DOI 10.1002/ana.20484Kachergus J, 2005, AM J HUM GENET, V76, P672Gilks WP, 2005, LANCET, V365, P415Lu CS, 2005, PARKINSONISM RELAT D, V11, P521, DOI 10.1016/j.parkreldis.2005.09.003Nichols WC, 2005, LANCET, V365, P410Paisan-Ruiz C, 2004, NEURON, V44, P595Zimprich A, 2004, NEURON, V44, P601Wszolek ZK, 2004, NEUROLOGY, V62, P1619Funayama M, 2002, ANN NEUROL, V51, P296, DOI 10.1002/ana.10113Autere JM, 2000, J NEUROL NEUROSUR PS, V69, P107Gilman S, 1999, J NEUROL SCI, V163, P94HUGHES AJ, 1992, J NEUROL NEUROSUR PS, V55, P181

Dystonia Type 6 Gene Product Thap1: Identification Of a 50 kDa DNA-binding Species In Neuronal Nuclear Fractions

Mutations in THAP1 result in dystonia type 6, with partial penetrance and variable phenotype. The goal of this study was to examine the nature and expression pattern of the protein product(s) of the Thap1 transcription factor (DYT6 gene) in mouse neurons, and to study the regional and developmental distribution, and subcellular localization of Thap1 protein. The goal was accomplished via overexpression and knock-down of Thap1 in the HEK293T cell line and in mouse striatal primary cultures and western blotting of embryonic Thap1-null tissue. The endogenous and transduced Thap1 isoforms were characterized using three different commercially available anti-Thap1 antibodies and validated by immunoprecipitation and DNA oligonucleotide affinity chromatography. We identified multiple, novel Thap1 species of apparent Mr 32 kDa, 47 kDa, and 50–52 kDa in vitro and in vivo, and verified the previously identified species at 29–30 kDa in neurons. The Thap1 species at the 50 kDa size range was exclusively detected in murine brain and testes and were located in the nuclear compartment. Thus, in addition to the predicted 25 kDa apparent Mr, we identified Thap1 species with greater apparent Mr that we speculate may be a result of posttranslational modifications. The neural localization of the 50 kDa species and its nuclear compartmentalization suggests that these may be key Thap1 species controlling neuronal gene transcription. Dysfunction of the neuronal 50 kDa species may therefore be implicated in the pathogenesis of DYT6

Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 x 10(-56)), MAPT (OR = 0.62, P = 1.78 x 10(-11)) and GBA (multiple distinct haplotypes, OR \u3e 8.28, P = 1.13 x 10(-11) and OR = 2.50, P = 1.22 x 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 x 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts

Neural correlates of abnormal sensory discrimination in laryngeal dystonia

AbstractAberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder

Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia Parkinsonism

AbstractRapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+-ATPase α3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism

Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings

Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1279-x) contains supplementary material, which is available to authorized users

Rapid-onset dystonia-Parkinsonism phenotype consistency for a novel variant of ATP1A3 in patients across 3 global populations

info:eu-repo/semantics/publishedVersio

Plasticity and dystonia: a hypothesis shrouded in variability.

Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia

Dystonia and paroxysmal dyskinesias: under-recognized movement disorders in domestic animals? A comparison with human dystonia/paroxysmal dyskinesias.

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals