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Neurobiology of Disease Oct 2019Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions.... (Review)
Review
Dystonia is a movement disorder characterized by involuntary muscle contractions, twisting movements, and abnormal postures that may affect one or multiple body regions. Dystonia is the third most common movement disorder after Parkinson's disease and essential tremor. Despite its relative frequency, small molecule therapeutics for dystonia are limited. Development of new therapeutics is further hampered by the heterogeneity of both clinical symptoms and etiologies in dystonia. Recent advances in both animal and cell-based models have helped clarify divergent etiologies in dystonia and have facilitated the identification of new therapeutic targets. Advances in medicinal chemistry have also made available novel compounds for testing in biochemical, physiological, and behavioral models of dystonia. Here, we briefly review motor circuit anatomy and the anatomical and functional abnormalities in dystonia. We then discuss recently identified therapeutic targets in dystonia based on recent preclinical animal studies and clinical trials investigating novel therapeutics.
Topics: Animals; Basal Ganglia; Cerebellum; Disease Models, Animal; Drug Discovery; Dystonia; Dystonic Disorders; Humans
PubMed: 31279827
DOI: 10.1016/j.nbd.2019.104526 -
The Journal of Molecular Diagnostics :... Mar 2022Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this,...
Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this, we applied an integrated two-step approach that included gene dosage analysis and a next-generation sequencing panel containing 72 known genes causative for dystonia and related movement disorders to 318 Taiwanese patients with isolated or combined dystonia. Whole-genome sequencing was performed for one multiplex family with no known causative variant. The panel confirmed the genetic diagnosis in 40 probands (12.6%). A genetic diagnosis was more likely with juvenile onset compared with adult onset (24.2% vs 10.8%; P = 0.03) and those with combined features, especially with myoclonus, compared with isolated dystonia (35.3% vs 10.5%; P = 0.004). The most common causative genes were SGCE followed by GCH1, TH, CACNA1B, PRRT2, MR1, CIZ1, PLA2G6, and PRKN. Genetic causes were identified from single cases in TOR1A, TUBB4A, THAP1, ATP1A3, ANO3, GNAL, KMT2B, SLC6A3, ADCY5, CYP27A1, PANK2, C19orf12, and SPG11. The whole-genome sequencing analysis identified a novel intragenic deletion in OPHN1 in a multiplex family with X-linked dystonia and intellectual delay. Our findings delineate the genetic architecture and clinical spectrum of dystonia-causing pathogenic variants in an Asian population.
Topics: Adult; Anoctamins; Apoptosis Regulatory Proteins; DNA-Binding Proteins; Dystonia; Dystonic Disorders; Humans; Mitochondrial Proteins; Molecular Chaperones; Mutation; Nuclear Proteins; Proteins; Sodium-Potassium-Exchanging ATPase; Spastic Paraplegia, Hereditary; Taiwan; Tubulin; Whole Genome Sequencing
PubMed: 35041927
DOI: 10.1016/j.jmoldx.2021.12.003 -
Internal Medicine (Tokyo, Japan) Aug 2022KMT2B-related dystonia (DYT28, DYT-KMT2B) is an inherited dystonia that generally begins in the lower limbs during childhood and evolves into generalized dystonia. We...
KMT2B-related dystonia (DYT28, DYT-KMT2B) is an inherited dystonia that generally begins in the lower limbs during childhood and evolves into generalized dystonia. We herein report a case of adult-onset DYT28 with dystonic tremor. A 27-year-old woman initially displayed right upper limb and cervical tremors over the course of 1 year. A neurological examination also revealed cervical and lower limb dystonia. Although the disease generally develops during childhood, we diagnosed the woman with DYT28, as genetic testing revealed a mutation in KMT2B. Adult-onset patients with DYT28 might also show uncommon symptoms as well as DYT-TOR1A (DYT1).
Topics: Adult; Dystonia; Dystonic Disorders; Female; Histone-Lysine N-Methyltransferase; Humans; Molecular Chaperones; Mutation; Tremor
PubMed: 35022352
DOI: 10.2169/internalmedicine.8700-21 -
Brain and Behavior Jun 2023Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically... (Review)
Review
BACKGROUND
Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear.
OBJECTIVES
This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques.
METHODS
A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211).
RESULTS
All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers.
CONCLUSIONS
Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.
Topics: Humans; Dystonia; Dystonic Disorders; Molecular Chaperones; Neuroimaging
PubMed: 37165749
DOI: 10.1002/brb3.3023 -
Experimental Brain Research Aug 2020Dystonia is a movement disorder characterised by involuntary muscle contractions resulting in abnormal movements, postures and tremor. The pathophysiology of dystonia is... (Review)
Review
Dystonia is a movement disorder characterised by involuntary muscle contractions resulting in abnormal movements, postures and tremor. The pathophysiology of dystonia is not fully understood but loss of neuronal inhibition, excessive sensorimotor plasticity and defective sensory processing are thought to contribute to network dysfunction underlying the disorder. Neurophysiology studies have been important in furthering our understanding of dystonia and have provided insights into the mechanism of effective dystonia treatment with pallidal deep brain stimulation. In this article we review neurophysiology studies in dystonia and its treatment with Deep Brain Stimulation, including Transcranial magnetic stimulation studies, studies of reflexes and sensory processing, and oscillatory activity recordings including local field potentials, micro-recordings, EEG and evoked potentials.
Topics: Deep Brain Stimulation; Dystonia; Dystonic Disorders; Globus Pallidus; Humans; Neurophysiology
PubMed: 32638036
DOI: 10.1007/s00221-020-05833-8 -
European Journal of Neurology Nov 2022HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and...
BACKGROUND AND PURPOSE
HIBCH and ECHS1 genes encode two enzymes implicated in the critical steps of valine catabolism, 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase (HIBCH) and short-chainenoyl-CoA hydratase (ECHS1), respectively. HIBCH deficiency (HIBCHD) and ECHS1 deficiency (ECHS1D) generate rare metabolic dysfunctions, often revealed by neurological symptoms. The aim of this study was to describe movement disorders spectrum in patients with pathogenic variants in ECHS1 and HIBC.
METHODS
We reviewed a series of 18 patients (HIBCHD: 5; ECHS1D: 13) as well as 105 patients from the literature. We analysed the detailed phenotype of HIBCHD (38 patients) and ECHS1D (85 patients), focusing on MDs.
RESULTS
The two diseases have a very similar neurological phenotype, with an early onset before 10 years of age for three clinical presentations: neonatal onset, Leigh-like syndrome (progressive onset or acute neurological decompensation), and isolated paroxysmal dyskinesia. Permanent or paroxysmal MDs were recorded in 61% of HIBCHD patients and 72% of ECHS1D patients. Patients had a variable combination of either isolated or combined MD, and dystonia was the main MD. These continuous MDs included dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Patients with paroxysmal dyskinesia (HIBCHD: 4; ECHS1D: 9) usually had pure paroxysmal dystonia with normal clinical examination and no major impairment in psychomotor development. No correlation could be identified between clinical pattern (especially MD) and genetic pathogenic variants.
CONCLUSIONS
Movement disorders, including abnormal ocular movements, are a hallmark of HIBCHD and ECHS1D. MDs are not uniform; dystonia is the most frequent, and various types of MD are combined in single patient.
Topics: Abnormalities, Multiple; Amino Acid Metabolism, Inborn Errors; Chorea; Coenzyme A; Dystonia; Dystonic Disorders; Enoyl-CoA Hydratase; Humans; Leigh Disease; Movement Disorders; Thiolester Hydrolases; Valine
PubMed: 36200804
DOI: 10.1111/ene.15515 -
NeuroImage. Clinical 2023Hyperkinetic movement disorders (HMD) manifest as abnormal and uncontrollable movements. Despite reported involvement of several neural circuits, exact connectivity... (Review)
Review
BACKGROUND
Hyperkinetic movement disorders (HMD) manifest as abnormal and uncontrollable movements. Despite reported involvement of several neural circuits, exact connectivity profiles remain elusive.
OBJECTIVES
Providing a comprehensive literature review of resting-state brain connectivity alterations using resting-state fMRI (rs-fMRI). We additionally discuss alterations from the perspective of brain networks, as well as correlations between connectivity and clinical measures.
METHODS
A systematic review was performed according to PRISMA guidelines and searching PubMed until October 2022. Rs-fMRI studies addressing ataxia, chorea, dystonia, myoclonus, tics, tremor, and functional movement disorders (FMD) were included. The standardized mean difference was used to summarize findings per region in the Automated Anatomical Labeling atlas for each phenotype. Furthermore, the activation likelihood estimation meta-analytic method was used to analyze convergence of significant between-group differences per phenotype. Finally, we conducted hierarchical cluster analysis to provide additional insights into commonalities and differences across HMD phenotypes.
RESULTS
Most articles concerned tremor (51), followed by dystonia (46), tics (19), chorea (12), myoclonus (11), FMD (11), and ataxia (8). Altered resting-state connectivity was found in several brain regions: in ataxia mainly cerebellar areas; for chorea, the caudate nucleus; for dystonia, sensorimotor and basal ganglia regions; for myoclonus, the thalamus and cingulate cortex; in tics, the basal ganglia, cerebellum, insula, and frontal cortex; for tremor, the cerebello-thalamo-cortical circuit; finally, in FMD, frontal, parietal, and cerebellar regions. Both decreased and increased connectivity were found for all HMD. Significant spatial convergence was found for dystonia, FMD, myoclonus, and tremor. Correlations between clinical measures and resting-state connectivity were frequently described.
CONCLUSION
Key brain regions contributing to functional connectivity changes across HMD often overlap. Possible increases and decreases of functional connections of a specific region emphasize that HMD should be viewed as a network disorder. Despite the complex interplay of physiological and methodological factors, this review serves to gain insight in brain connectivity profiles across HMD phenotypes.
Topics: Humans; Tremor; Myoclonus; Tics; Dystonia; Magnetic Resonance Imaging; Chorea; Hyperkinesis; Brain; Brain Mapping; Dystonic Disorders; Ataxia; Neural Pathways
PubMed: 36669351
DOI: 10.1016/j.nicl.2022.103302 -
Brain and Behavior Feb 2022Japanese encephalitis (JE) is a potentially fatal viral infection with a wide range of manifestations and can also present with a variety of movement disorders (MD)... (Review)
Review
BACKGROUND
Japanese encephalitis (JE) is a potentially fatal viral infection with a wide range of manifestations and can also present with a variety of movement disorders (MD) including dystonia. Dystonic features in JE are uncommon. Here, we have tried to summarize the clinical features and management of dystonia among JE patients with a comprehensive literature search.
METHODS
Various databases, including PubMed, Embase, and Google Scholar, were searched against the predefined criteria using suitable keywords combination and boolean operations. Relevant information from observational and case studies was extracted according to the author, dystonic features, radiological changes in the brain scans, treatment options, and outcome wherever provided.
RESULT
We identified 19 studies with a total of 1547 JE patients, the diagnosis of which was confirmed by IgM detection in serum and/or cerebrospinal fluid in the majority of the patients (88.62%). 234 (15.13%) of JE patients had dystonia with several types of focal dystonia being present in 131 (55.98%) either alone or in combination. Neuroimaging showed predominant involvement of thalami, basal ganglia, and brainstem. Oral medications including anticholinergics, GABA agonists, and benzodiazepines followed by botulinum toxin were the most common treatment modalities.
CONCLUSION
Dystonia can be a disabling consequence of JE, and various available medical therapies can significantly improve the quality of life. Owing to insufficient studies on the assessment of dystonia associated with JE, longitudinal studies with a larger number of patients are warranted to further clarify the clinical course, treatment, and outcome of dystonia.
Topics: Dystonia; Dystonic Disorders; Encephalitis, Japanese; Humans; Movement Disorders; Quality of Life
PubMed: 35025122
DOI: 10.1002/brb3.2496 -
Advances in Neurobiology 2023Isolated dystonia is a neurological disorder of diverse etiology, multifactorial pathophysiology, and wide spectrum of clinical presentations. We review the recent... (Review)
Review
Isolated dystonia is a neurological disorder of diverse etiology, multifactorial pathophysiology, and wide spectrum of clinical presentations. We review the recent neuroimaging advances that led to the conceptualization of dystonia as a neural network disorder and discuss how current knowledge is shaping the identification of biomarkers of dystonia and the development of novel pharmacological therapies.
Topics: Humans; Brain; Dystonia; Connectome; Magnetic Resonance Imaging; Dystonic Disorders
PubMed: 37338705
DOI: 10.1007/978-3-031-26220-3_13 -
American Journal of Human Genetics Nov 2021Dystonia is a neurologic disorder associated with an increasingly large number of genetic variants in many genes, resulting in characteristic disturbances in volitional...
Dystonia is a neurologic disorder associated with an increasingly large number of genetic variants in many genes, resulting in characteristic disturbances in volitional movement. Dissecting the relationships between these mutations and their functional outcomes is critical in understanding the pathways that drive dystonia pathogenesis. Here we established a pipeline for characterizing an allelic series of dystonia-specific mutations. We used this strategy to investigate the molecular consequences of genetic variation in THAP1, which encodes a transcription factor linked to neural differentiation. Multiple pathogenic mutations associated with dystonia cluster within distinct THAP1 functional domains and are predicted to alter DNA-binding properties and/or protein interactions differently, yet the relative impact of these varied changes on molecular signatures and neural deficits is unclear. To determine the effects of these mutations on THAP1 transcriptional activity, we engineered an allelic series of eight alterations in a common induced pluripotent stem cell background and differentiated these lines into a panel of near-isogenic neural stem cells (n = 94 lines). Transcriptome profiling followed by joint analysis of the most robust signatures across mutations identified a convergent pattern of dysregulated genes functionally related to neurodevelopment, lysosomal lipid metabolism, and myelin. On the basis of these observations, we examined mice bearing Thap1-disruptive alleles and detected significant changes in myelin gene expression and reduction of myelin structural integrity relative to control mice. These results suggest that deficits in neurodevelopment and myelination are common consequences of dystonia-associated THAP1 mutations and highlight the potential role of neuron-glial interactions in the pathogenesis of dystonia.
Topics: Alleles; Animals; Apoptosis Regulatory Proteins; Clustered Regularly Interspaced Short Palindromic Repeats; DNA-Binding Proteins; Dystonia; Dystonic Disorders; Humans; Mice; Mutation; Myelin Sheath
PubMed: 34672987
DOI: 10.1016/j.ajhg.2021.09.017