The prevalence of depression in adult onset idiopathic dystonia: Systematic review and metaanalysis.
Medina Escobar Alex,Pringsheim Tamara,Goodarzi Zahra,Martino Davide
Neuroscience and biobehavioral reviews
Adult onset idiopathic dystonia (AOID) is the third most common movement disorder in adults. Co-existing depressive symptoms and disorders represent major contributors of disability and quality of life in these patients, but their prevalence remains unclear. We investigated the point prevalence of supra-clinical threshold depressive symptoms/depressive disorders in AOID in a systematic review with qualitative synthesis and meta-analysis. Our search identified 60 articles suitable for qualitative synthesis and 54 for meta-analysis. The overall pooled prevalence of either supra-clinical threshold depressive symptoms or depressive disorders was 31.5 % for cervical dystonia, 29.2 % for cranial dystonia, and 33.6 % for clinical samples with mixed forms of AOID. Major depressive disorder was more prevalent than dysthymia in cervical dystonia, whereas dysthymia was more prevalent in cranial dystonia. In cervical dystonia, the prevalence of supra-clinical threshold depressive symptoms screened by rating scales was higher than that of depressive disorders diagnosed with structured interviews. Prevalence studies using rating scales yielded higher heterogeneity. More research is warranted to standardize screening methodology and characterization of mood disorders in AOID.
10.1016/j.neubiorev.2021.02.036
Monogenic variants in dystonia: an exome-wide sequencing study.
Zech Michael,Jech Robert,Boesch Sylvia,Škorvánek Matej,Weber Sandrina,Wagner Matias,Zhao Chen,Jochim Angela,Necpál Ján,Dincer Yasemin,Vill Katharina,Distelmaier Felix,Stoklosa Malgorzata,Krenn Martin,Grunwald Stephan,Bock-Bierbaum Tobias,Fečíková Anna,Havránková Petra,Roth Jan,Příhodová Iva,Adamovičová Miriam,Ulmanová Olga,Bechyně Karel,Danhofer Pavlína,Veselý Branislav,Haň Vladimír,Pavelekova Petra,Gdovinová Zuzana,Mantel Tobias,Meindl Tobias,Sitzberger Alexandra,Schröder Sebastian,Blaschek Astrid,Roser Timo,Bonfert Michaela V,Haberlandt Edda,Plecko Barbara,Leineweber Birgit,Berweck Steffen,Herberhold Thomas,Langguth Berthold,Švantnerová Jana,Minár Michal,Ramos-Rivera Gonzalo Alonso,Wojcik Monica H,Pajusalu Sander,Õunap Katrin,Schatz Ulrich A,Pölsler Laura,Milenkovic Ivan,Laccone Franco,Pilshofer Veronika,Colombo Roberto,Patzer Steffi,Iuso Arcangela,Vera Julia,Troncoso Monica,Fang Fang,Prokisch Holger,Wilbert Friederike,Eckenweiler Matthias,Graf Elisabeth,Westphal Dominik S,Riedhammer Korbinian M,Brunet Theresa,Alhaddad Bader,Berutti Riccardo,Strom Tim M,Hecht Martin,Baumann Matthias,Wolf Marc,Telegrafi Aida,Person Richard E,Zamora Francisca Millan,Henderson Lindsay B,Weise David,Musacchio Thomas,Volkmann Jens,Szuto Anna,Becker Jessica,Cremer Kirsten,Sycha Thomas,Zimprich Fritz,Kraus Verena,Makowski Christine,Gonzalez-Alegre Pedro,Bardakjian Tanya M,Ozelius Laurie J,Vetro Annalisa,Guerrini Renzo,Maier Esther,Borggraefe Ingo,Kuster Alice,Wortmann Saskia B,Hackenberg Annette,Steinfeld Robert,Assmann Birgit,Staufner Christian,Opladen Thomas,Růžička Evžen,Cohn Ronald D,Dyment David,Chung Wendy K,Engels Hartmut,Ceballos-Baumann Andres,Ploski Rafal,Daumke Oliver,Haslinger Bernhard,Mall Volker,Oexle Konrad,Winkelmann Juliane
The Lancet. Neurology
BACKGROUND:Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS:For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS:We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION:In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING:Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.
10.1016/S1474-4422(20)30312-4
Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders.
Mencacci Niccolò E,Reynolds Regina,Ruiz Sonia Garcia,Vandrovcova Jana,Forabosco Paola,Sánchez-Ferrer Alvaro,Volpato Viola, , ,Weale Michael E,Bhatia Kailash P,Webber Caleb,Hardy John,Botía Juan A,Ryten Mina
Brain : a journal of neurology
Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in patients with dystonia. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships among dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from 10 human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson's disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, 4 of 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrate significant enrichments of the heritability of major depressive disorder, obsessive-compulsive disorder and schizophrenia within the putamen and white matter modules, and a significant enrichment of the heritability of Parkinson's disease within the substantia nigra module. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology.
10.1093/brain/awaa217
Brain Structural Changes in Focal Dystonia-What About Task Specificity? A Multimodal MRI Study.
Tomić Aleksandra,Agosta Federica,Sarasso Elisabetta,Svetel Marina,Kresojević Nikola,Fontana Andrea,Canu Elisa,Petrović Igor,Kostić Vladimir S,Filippi Massimo
Movement disorders : official journal of the Movement Disorder Society
BACKGROUND:The neural basis of task specificity in dystonia is still poorly understood. This study investigated gray and white matter (WM) brain alterations in patients with task-specific dystonia (TSD) and non-task-specific dystonia (NTSD). METHODS:Thirty-six patients with TSD (spasmodic dysphonia, writer's cramp), 61 patients with NTSD (blepharospasm, cervical dystonia), and 83 healthy controls underwent 3D T1-weighted and diffusion tensor magnetic resonance imaging (MRI). Whole brain cortical thickness and voxel-based morphometry; volumes of basal ganglia, thalamus, nucleus accumbens, amygdala, and hippocampus; and WM damage were assessed. Analysis of variance models were used to compare MRI measures between groups, adjusting for age and botulinum toxin (BoNT) treatment. RESULTS:The comparison between focal dystonia patients showed cortical thickness and gray matter (GM) volume differences (ie, decreased in NTSD, increased in TSD) in frontal, parietal, temporal, and occipital cortical regions; basal ganglia; thalamus; hippocampus; and amygdala. Cerebellar atrophy was found in NTSD patients relative to controls. WM damage was more severe and widespread in task-specific relative to NTSD patients. TSD patients receiving BoNT, relative to nontreated patients, had cortical thickening and increased GM volume in frontoparietal, temporal, and occipital regions. NTSD patients experiencing pain showed cortical thickening of areas involved in pain-inhibitory mechanisms. CONCLUSIONS:TSD and NTSD are characterized by opposite alterations of the main cortical and subcortical sensorimotor and cognitive-controlling brain structures, suggesting the possible presence of different pathophysiological and/or compensatory mechanisms underlying the complexity of the two clinical phenotypes of focal dystonia. © 2020 International Parkinson and Movement Disorder Society.
10.1002/mds.28304
Task-specific dystonia: pathophysiology and management.
Sadnicka Anna,Kassavetis Panagiotis,Pareés Isabel,Meppelink Anne Marthe,Butler Katherine,Edwards Mark
Journal of neurology, neurosurgery, and psychiatry
Task-specific dystonia is a form of isolated focal dystonia with the peculiarity of being displayed only during performance of a specific skilled motor task. This distinctive feature makes task-specific dystonia a particularly mysterious and fascinating neurological condition. In this review, we cover phenomenology and its increasingly broad-spectrum risk factors for the disease, critically review pathophysiological theories and evaluate current therapeutic options. We conclude by highlighting the unique features of task-specific dystonia within the wider concept of dystonia. We emphasise the central contribution of environmental risk factors, and propose a model by which these triggers may impact on the motor control of skilled movement. By viewing task-specific dystonia through this new lens which considers the disorder a modifiable disorder of motor control, we are optimistic that research will yield novel therapeutic avenues for this highly motivated group of patients.
10.1136/jnnp-2015-311298
A unifying motor control framework for task-specific dystonia.
Nature reviews. Neurology
Task-specific dystonia is a movement disorder characterized by a painless loss of dexterity specific to a particular motor skill. This disorder is prevalent among writers, musicians, dancers and athletes. No current treatment is predictably effective, and the disorder generally ends the careers of affected individuals. Traditional disease models of dystonia have a number of limitations with regard to task-specific dystonia. We therefore discuss emerging evidence that the disorder has its origins within normal compensatory mechanisms of a healthy motor system in which the representation and reproduction of motor skill are disrupted. We describe how risk factors for task-specific dystonia can be stratified and translated into mechanisms of dysfunctional motor control. The proposed model aims to define new directions for experimental research and stimulate therapeutic advances for this highly disabling disorder.
10.1038/nrneurol.2017.146