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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 -
Toxins Sep 2022The review is an introduction to medical, non-cosmetic treatments with botulinum neurotoxin (BoNT) in the orofacial region. It focuses on the current most common,... (Review)
Review
The review is an introduction to medical, non-cosmetic treatments with botulinum neurotoxin (BoNT) in the orofacial region. It focuses on the current most common, best-documented and safest indications of interest for dentists in terms of dystonia and sialorrhea. These conditions are recommended to start with and suitable to gain better skill and experience with BoNT. The introduction also stresses the importance of correct diagnostics based on interdisciplinary cooperation, precise targeting of the injections, measurements of treatment effect, and control of the oral health with regard to side effects.
Topics: Humans; Botulinum Toxins, Type A; Sialorrhea; Dystonic Disorders; Dystonia; Dentists
PubMed: 36287936
DOI: 10.3390/toxins14100667 -
Toxins Jun 2024Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The...
Deep Brain Stimulation (DBS) is a recognized treatment for different dystonia subtypes and has been approved by the Food and Drug Administration (FDA) since 2003. The European Federation of Neurological Societies (EFNS) and the International Parkinson and Movement Disorders Society (MDS) recommend DBS for dystonia after failure of botulinum toxin (BoNT) and other oral medications for dystonia treatment. In addition, several long-term studies have demonstrated the continuous efficacy of DBS on motor and quality of life (QoL) scores. However, there are only a few reports comparing the overall impact of surgical treatment in BoNT protocols (e.g., dosage and number of selected muscles before and after surgery). This retrospective multicenter chart-review study analyzed botulinum toxin total dosage and dosage per muscle in 23 dystonic patients before and after DBS surgery. The study's primary outcome was to analyze whether there was a reduction in BoNT dosage after DBS surgery. The mean BoNT dosages difference between baseline and post-surgery was 293.4 units for 6 months, 292.6 units for 12 months, and 295.2 units at the last visit. The median total dose of BoNT in the preoperative period was 800 units (N = 23). At the last visit, the median was 700 units ( = 0.05). This represents a 12.5% reduction in BoNT median dosage. In conclusion, despite the limitations of this retrospective study, there was a significant reduction in BoNT doses after DBS surgery in patients with generalized dystonia.
Topics: Humans; Deep Brain Stimulation; Retrospective Studies; Male; Female; Dystonia; Middle Aged; Adult; Botulinum Toxins; Aged; Treatment Outcome; Quality of Life
PubMed: 38922176
DOI: 10.3390/toxins16060282 -
Journal of Neural Transmission (Vienna,... Apr 2021Genetic testing through a variety of methods is a fundamental but underutilized approach for establishing the precise genetic diagnosis in patients with heritable forms... (Review)
Review
Genetic testing through a variety of methods is a fundamental but underutilized approach for establishing the precise genetic diagnosis in patients with heritable forms of dystonia. Our knowledge of numerous dystonia-related genes, variants that they may contain, associated clinical presentations, and molecular disease mechanism may have significant translational potential for patients with genetically confirmed dystonia or their family members. Importantly, genetic testing permits the assembly of patient cohorts pertinent for dystonia-related research and developing therapeutics. Here we review the genetic testing approaches relevant to dystonia patients, and summarize and illustrate the multifold benefits of establishing an accurate molecular diagnosis for patients imminently or for translational research in the long run.
Topics: Dystonia; Dystonic Disorders; Genetic Testing; Humans; Translational Research, Biomedical
PubMed: 33876307
DOI: 10.1007/s00702-021-02329-9 -
JPMA. the Journal of the Pakistan... Oct 2022Hypermanganesaemia with dystonia, polycythemia, and cirrhosis (HMDPC) is a rare genetic and autosomal recessive disorder that occurs due to mutation of the SLC3A10 gene,...
Hypermanganesaemia with dystonia, polycythemia, and cirrhosis (HMDPC) is a rare genetic and autosomal recessive disorder that occurs due to mutation of the SLC3A10 gene, which encodes the manganese (Mn) transporter in the body; as a result, Mn accumulates in the brain, liver and muscles. This accumulation leads to symptoms of generalized dystonia, polycythemia, and hypermanganesaemia. In this report, we present the case of a 2½-year-old baby girl (patient) with complaints of lower limb weakness and increased difficulty in walking for six months. Her laboratory test results showed deranged values with increased Mn levels in the body. The patient was put on six cycles of EDTA therapy, which showed an improvement in her condition. This case report is presented to create awareness about a rare genetic disorder with an effective treatment in some cases. Thus, more work and research is required to understand and develop better treatment options for this disease.
Topics: Humans; Female; Young Adult; Adult; Cation Transport Proteins; Dystonia; Metabolic Diseases; Polycythemia; Mutation; Manganese; Dystonic Disorders; Liver Cirrhosis
PubMed: 36661006
DOI: 10.47391/JPMA.1776 -
Seminars in Neurology Feb 2023Dystonia is the third most common movement disorder, characterized by abnormal, frequently twisting postures related to co-contraction of agonist and antagonist muscles....
Dystonia is the third most common movement disorder, characterized by abnormal, frequently twisting postures related to co-contraction of agonist and antagonist muscles. Diagnosis is challenging. We provide a comprehensive appraisal of the epidemiology and an approach to the phenomenology and classification of dystonia, based on the clinical characteristics and underlying etiology of dystonia syndromes. We discuss the features of common idiopathic and genetic forms of dystonia, diagnostic challenges, and dystonia mimics. Appropriate workup is based on the age of symptom onset, rate of progression, whether dystonia is isolated or combined with another movement disorder or complex neurological and other organ system features. Based on these features, we discuss when imaging and genetic should be considered. We discuss the multidisciplinary treatment of dystonia, including rehabilitation and treatment principles according to the etiology, including when pathogenesis-direct treatment is available, oral pharmacological therapy, chemodenervation with botulinum toxin injections, deep brain stimulation and other surgical therapies, and future directions.
Topics: Humans; Dystonia; Dystonic Disorders; Diagnostic Techniques and Procedures; Muscles
PubMed: 36972613
DOI: 10.1055/s-0043-1764292 -
Tremor and Other Hyperkinetic Movements... 2023This study aimed to determine the demographic and clinical characteristics of patients with oromandibular dystonia (OMD).
OBJECTIVE
This study aimed to determine the demographic and clinical characteristics of patients with oromandibular dystonia (OMD).
BACKGROUND
Dystonia is a movement disorder characterized by sustained involuntary muscle contractions that often cause abnormal postures. OMD is a rare focal dystonia that affects the tongue, jaw, and mouth. OMD, which is a rare public health problem, is often recognized as psychogenic and there are delays in its diagnosis and treatment.
METHODS
Patients with OMD, both isolated and combined, followed at our Movement Disorders Outpatient Clinic between 2004 and 2021 were enrolled in this study. Age, sex, age at onset, and disease duration were recorded. The type of OMD, affected muscles, etiologies of accompanying neurological disorders, and treatment were noted.
RESULTS
A total of 82 patients (44 women, 38 men) were included in this study. Among these, 39 patients had isolated OMD, and 43 patients had either segmental or generalized dystonia. Seven patients reported a family history of dystonia. Only nine patients reported a sensory trick. The average disease duration was 6.01 ± 3.73 (range, 1-29) years, and the average age at onset was 43.34 ± 18.24 (range, 1-78) years. The disease etiology was unknown (idiopathic) in most patients. Fifteen patients reported task-specific dystonia. The most common type of dystonia was jaw-opening dystonia.
CONCLUSION
OMD is focal dystonia that significantly affects the quality of life. This study adds more data to the literature by defining the clinical features of this rare disorder and draws attention to this neglected type of dystonia.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Young Adult; Dystonia; Dystonic Disorders; Movement Disorders; Neuromuscular Agents; Quality of Life
PubMed: 36789171
DOI: 10.5334/tohm.730 -
Medicine Jul 2023Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract... (Randomized Controlled Trial)
Randomized Controlled Trial
Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract and cause abnormal postures and movements of the head, neck, and shoulders. Treatment of CD prior to botulinum toxin was unsatisfactory, as existing therapies often did not improve symptoms. The use of botulinum toxin for CD grew out of its success in treating blepharospasm, another type of focal dystonia. On the basis of results from a double-blind, placebo-controlled trial, onabotulinumtoxinA was approved in 2000 in the US for the treatment of CD in adults in order to alleviate abnormal head position and neck pain. A subsequent large observational trial further demonstrated the effectiveness of onabotulinumtoxinA for CD, showing improvements in various rating scales, physician-reported measures, and profound positive effects on patient quality of life, including in amelioration of pain and improvements in work productivity. In addition, onabotulinumtoxinA treatment also reduced the complications of CD, as patients no longer develop contractures (permanent muscle and tendon shortening from prolonged untreated dystonia), which markedly limited the range of neck motion. The onset of onabotulinumtoxinA treatment also accompanied advances in understanding the functional anatomy of neck muscles, basal ganglia physiology, and video and other recording technology. Following the success of onabotulinumtoxinA in the treatment of CD, its use has been expanded into numerous other therapeutic indications, and these advances stimulated educational and training programs by various neurologic and other medical societies.
Topics: Adult; Humans; Botulinum Toxins, Type A; Torticollis; Quality of Life; Dystonic Disorders; Neck Pain; Treatment Outcome
PubMed: 37499081
DOI: 10.1097/MD.0000000000032403 -
Journal of Neurology Dec 2022The prevalence of dystonia has been studied since the 1980s. Due to different methodologies and due to varying degrees of awareness, resulting figures have been...
The prevalence of dystonia has been studied since the 1980s. Due to different methodologies and due to varying degrees of awareness, resulting figures have been extremely different. We wanted to determine the prevalence of dystonia according to its current definition, using quality-approved registries and based on its relevance for patients, their therapy and the health care system. We applied a service-based chart review design with the City of Hannover as reference area and a population of 525,731. Barrier-free comprehensive dystonia treatment in few highly specialised centres for the last 30 years should have generated maximal dystonia awareness, a minimum of unreported cases and a high degree of data homogeneity. Prevalence [n/1mio] and relative frequency is 601.1 (100%) for all forms of dystonia, 251.1 (42%) for cervical dystonia, 87.5 (15%) for blepharospasm, 55.2 (9%) for writer's cramp, 38.0 (6%) for tardive dystonia, 32.3 (5%) for musician's dystonia, 28.5 (5%) for psychogenic dystonia, 26.6 (4%) for generalised dystonia, 24.7 (4%) for spasmodic dysphonia, 20.9 (3%) for segmental dystonia, 15.2 (3%) for arm dystonia and 13.3 (2%) for oromandibular dystonia. Leg dystonia, hemidystonia and complex regional pain syndrome-associated dystonia are very rare. Compared to previous meta-analytical data, primary or isolated dystonia is 3.3 times more frequent in our study. When all forms of dystonia including psychogenic, generalised, tardive and other symptomatic dystonias are considered, our dystonia prevalence is 3.7 times higher than believed before. The real prevalence is likely to be even higher. Having based our study on treatment necessity, our data will allow better allocation of resources for comprehensive dystonia treatment.
Topics: Humans; Dystonic Disorders; Blepharospasm; Torticollis; Prevalence
PubMed: 35948800
DOI: 10.1007/s00415-022-11310-9 -
Cerebellum (London, England) Oct 2023The cerebellum plays an important role in movement disorders, specifically in symptoms of ataxia, tremor, and dystonia. Understanding the physiological signals of the... (Review)
Review
The cerebellum plays an important role in movement disorders, specifically in symptoms of ataxia, tremor, and dystonia. Understanding the physiological signals of the cerebellum contributes to insights into the pathophysiology of these movement disorders and holds promise in advancing therapeutic development. Non-invasive techniques such as electroencephalogram and magnetoencephalogram can record neural signals with high temporal resolution at the millisecond level, which is uniquely suitable to interrogate cerebellar physiology. These techniques have recently been implemented to study cerebellar physiology in healthy subjects as well as individuals with movement disorders. In the present review, we focus on the current understanding of cerebellar physiology using these techniques to study movement disorders.
Topics: Humans; Movement Disorders; Cerebellum; Tremor; Cerebellar Ataxia; Dystonic Disorders
PubMed: 36070135
DOI: 10.1007/s12311-022-01473-6