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Additional file 1. Tables S1–S7.

Additional file 2. Figures S1–S5.

ObjectiveDystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities.MethodsThe NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations.ResultsThe heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia.ConclusionOverall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.

Background: Dystonia is characterized by sustained or intermittent muscle contractions resulting in abnormal, often repetitive, movements, postures, or both. Neuropathologic research has been essential in understanding the etiology and disease progression of other movement disorders, including Parkinson’s disease and cerebellar ataxias. In the field of dystonia, however, research is stymied by the paucity of post-mortem tissue available and the phenotypic heterogeneity found in those with dystonia. Methods: A PubMed search was conducted using the term “neuropathology of dystonia”. The resulting list of references was limited to English-language human neuropathology articles. A total of 20 publications were retrieved and reviewed. Results: Historically, based on study of acquired forms of dystonia, lesions of the putamen and globus pallidus have been identified as causing dystonia. After the identification of genetic causes of dystonia and the study of limited tissue available from those cases, as well as findings from cases of isolated focal and segmental dystonia, there is evidence that brainstem cholinergic neurons and specific cell populations within the cerebellum also play a role in the pathophysiology of dystonia. Discussion: Based on limited available brain tissue, there is evidence that the pathophysiology of dystonia may involve a combination of dysfunction within neurons of the brainstem, cerebellum, putamen, and globus pallidus. In order to gain a better understanding of the pathophysiology of dystonia, a prospective, quantitative study in well-phenotyped subjects with different types of genetic and isolated dystonia is required., Tremor and Other Hyperkinetic Movements, Tremor and Other Hyperkinetic Movements

Summary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment in patients with the disease. Methods In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. Findings 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase ( GBA ) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4–36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. Funding National Institutes of Health, US Department of Defense.

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.

Polymorphisms in the TOR1A/TOR1B region have been implicated as being associated with primary focal and segmental dystonia. In a cohort of subjects with either focal or segmental dystonia affecting the face, larynx, neck, or arm, we report a strong association of a single nucleotide polymorphism (SNP), the deletion allele at the Mtdel SNP (rs3842225), and protection from focal dystonia. In contrast, we did not find an association of either allele at the D216H SNP (rs1801968) with focal or segmental dystonia in the same cohort.

Calotropin isolated and characterized from the roots of Calotropis procera when administered to gerbils (25mg/kg b.wt) and rabbits (25mg; kg b.wt) each day for a period of 30 days inhibited the process of spermatogenesis. The population of spermatids was depleted by 65% and 94% in gerbils and rabbits. The seminiferous tubules and the Leydig cell nuclei diameters were reduced in both the species.The production of mature Leydig cells were decreased by 51.2% and 33.9% in gerbils and rabbits. The number of fibroblast like cells remain unchanged. Reduced protein, sialic acid, and glycogen contents of tests indicate dimished androgenesis. Abortifacient activity was also notived in female rats on the 12(th) day of pregnancy. In conclusion, Calotropin was found to inhibit spermatogenesis in male and induced abortion in pregnant females.