Complex Movement Disorder Research Articles

Jerky dystonic tremor

Dystonia is a very complex movement disorder. Recently, the classification of dystonia has been updated by a group of experts to simplify the clinical approach to dystonia. As per this new classification, clinically we can divide dystonia into either isolated or combined dystonia. In the isolated group, dystonia is the only feature with or without tremor. In the isolated dystonia (DYT) group, DYT-TOR1A and DYT-THAP1 are the commoner entities worldwide. In DYT-THAP1 cases, apart from classic generalized dystonia phenotype, appendicular tremor has also been described. However, in some cases, it could be jerky and may create confusion with myoclonus. To prevent this confusion and subsequent investigations in the line of myoclonic dystonic syndromes, identification of this jerky tremor assumes great clinical significance. Hereby, we are describing a genetically confirmed DYT-THAP1 patient with a jerky dystonic tremor of upper limbs.

Psychiatric manifestations of anti-NMDAR encephalitis

IntroductionAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by neuropsychiatric symptoms before progressing to seizures, complex movement disorder, autonomic dysfunction and hypoventilation.ObjectivesPresenting a review of the psychiatric manifestations of anti-NMDAR encephalitis.MethodsSearch on Pubmed® and Medscape® databases with the following keywords: “psychiatric”, “anti-NMDA receptor encephalitis” and “anti-NMDAR encephalitis”. We focused on data from systematic reviews and meta-analyzes. The articles were selected by the authors according to their relevance.ResultsStudies show that 77% to 95% of patients with anti-NMDAR encephalitis initially present psychiatric manifestations. Age and sex distribution are young women, and the frequency of cases is lower after 40 years of age. The most common psychiatric symptoms are agitation (59%) and psychotic symptoms (54%). The psychotic symptoms more common are visual (64%), auditory (59%) hallucinations and persecutory delusions (73%). Catatonia is described in 42% of patients. Antipsychotic treatment induces an adverse drug reaction (33%), the neuroleptic malignant syndrome represents 22% of the cases. Delays in distinguishing this disease from a psychiatric disorder can have serious complications, with a mortality of up to 25% in patients receiving limited or delayed immunotherapy.ConclusionsIt’s important to consider anti-NMDAR encephalitis in the differential diagnosis of patients with an acute onset psychosis or unusual psychiatric symptoms. Antipsychotic treatment should be use with caution when suspected or confirmed anti-NMDAR encephalitis. Without appropriate treatment, patients may suffer a protracted course with significant long-term disability or death. A clinical index of suspicion is required to identify patients who would benefit from cerebrospinal fluid testing and immunotherapies.DisclosureNo significant relationships.

Tablet-based patient educational interventions in care and management of complex movement disorders

Background Patient education is an essential part of management of complex, disabling neurological disorders. Mobile web-based educational materials provide a novel and potentially valuable means to communicate clinical information that can aid in both medical management and rehabilitation. Aims We, therefore, evaluated an educational tablet-based intervention in three patient cohorts regarding the following topics: Parkinson’s disease (PD) medications, dystonia and botulinum toxin treatment. Methods A total of 50 subjects with PD, 32 with dystonia and 61 receiving botulinum toxin treatment for movement disorders or sialorrhoea were enrolled. Participants in each cohort completed a specific educational module at the time of their regularly scheduled clinic visit, comprising slides, in addition to pre- and post-module quizzes and a satisfaction survey. Additionally, participants in the dystonia and botulinum toxin modules were given a follow-up test at their 3- or 6-month clinical treatment visit. Results There were 143 participants with 50 completing the PD module, 32 completing the dystonia module and 61 completing the botulinum toxin module. All three groups demonstrated significant improvement in knowledge of module content between their pre- and post-module test scores (PD: p=.0001, dystonia: p<.0001 and botulinum toxin: p=.008), and those who took the dystonia module maintained significant improvement at either a 3- or 6-month follow up compared to pre-module (p <.0001). Conclusions Tablet-based teaching modules are an effective means of communicating key concepts to patients. This study supports their use for improving patient understanding that can support lifelong approaches to managing disabling, neurological conditions. Implication for Rehabilitation Tablet-based modules are relatively easy to use for enhancing education during clinic visits and can possibly help reduce and maintain disability with chronic conditions like Parkinson’s disease and dystonia. Improvements in post-test scores suggested that patient participants were able to retain information from the tablets about their complex and challenging conditions and treatments. Adding patients who are fluent in another language would have made this study more generalizable and future studies exploring educational interventions are warranted to help better tailor interventions to patients with chronic neurologic illnesses to help understand the complex aspects of their medical and rehabilitation therapy. The effect of cognitive changes in neurological conditions and understanding of educational information needs to be further tested. This positive result is especially meaningful during the COVID-19 pandemic when in-person access to both medical and rehabilitative care has been curtailed.

The Phenomenon of Exquisite Motor Control in Tic Disorders and its Pathophysiological Implications.

The unifying characteristic of movement disorders is the phenotypic presentation of abnormal motor outputs, either as isolated phenomena or in association with further clinical, often neuropsychiatric, features. However, the possibility of a movement disorder also characterized by supranormal or enhanced volitional motor control has not received attention. Based on clinical observations and cases collected over a number of years, we here describe the intriguing clinical phenomenon that people with tic disorders are often able to control specific muscle contractions as part of their tic behaviors to a degree that most humans typically cannot. Examples are given in accompanying video documentation. We explore medical literature on this topic and draw analogies with early research of fine motor control physiology in healthy humans. By systematically analyzing the probable sources of this unusual capacity, and focusing on neuroscientific accounts of voluntary motor control, sensory feedback, and the role of motor learning in tic disorders, we provide a novel pathophysiological account explaining both the presence of exquisite control over motor output and that of overall tic behaviors. We finally comment on key questions for future research on the topic and provide concluding remarks on the complex movement disorder of tic behaviors. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches.

Study of paediatric patients with the clinical and biochemical phenotype of glucose transporter type 1 deficiency syndrome

IntroductionGlucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. AimsWe describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. Material and methodsThe study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. ResultsSix patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7%, vs 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs 46mg/dL, P=.04) and CSF/serum glucose ratio (0.4 vs 0.48, P<.05). ConclusionsGLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose level, and good response to the ketogenic diet.

Two cases with postural axial tremor: Consider a genetic origin

We present two cases with postural axial tremor predominantly involving the head, trunk, and shoulders. In the first patient, the postural tremor occurred in multiple attacks a day lasting approximately 10 min. The second patient developed a progressive tremor of his head and arms, worsened during sitting and standing. Electrophysiological supported the postural axial tremor in both patients with a varying 3–10 Hz tremor frequency between different muscles and within the same muscles at different times.Postural axial tremor is a rare and complex movement disorder. The majority of cases are caused by acquired cerebellar pathology. However, isolated cases with underlying genetic disorders are described in literature.Here, we illustrate how to differentiate paroxysmal axial tremor from other axial hyperkinetic movement disorders and extend the genetic heterogeneity of this intriguing movement disorder phenotype.

Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction.

Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.

Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series

Mutations in the ADCY5 gene can cause a complex hyperkinetic movement disorder. Episodic exacerbations of dyskinesia are a particularly disturbing symptom as they occur predominantly during night and interrupt sleep. We present the clinical short- and long-term effects of pallidal deep brain stimulation (DBS) in three patients with a confirmed pathogenic ADCY5 mutation. Patients were implanted with bilateral pallidal DBS at the age of 34, 20 and 13 years. Medical records were reviewed for clinical history. Pre- and postoperative video files were assessed using the “Abnormal Involuntary Movement Scale” (AIMS) as well as the motor part of the “Burke Fahn Marsden Dystonia Rating Scale” (BFMDRS). All patients reported subjective general improvement ranging from 40 to 60%, especially the reduction of nocturnal episodic dyskinesias (80–90%). Objective scales revealed only a mild decrease of involuntary movements in all and reduced dystonia in one patient. DBS-induced effects were sustained up to 13 years after implantation. We demonstrate that treatment with pallidal DBS was effective in reducing nocturnal dyskinetic exacerbations in patients with ADCY5-related movement disorder, which was sustained over the long term.

A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly

Mitochondrial ribosomal protein large 24 (MRPL24) is 1 of the 82 protein components of mitochondrial ribosomes, playing an essential role in the mitochondrial translation process.We report here on a baby girl with cerebellar atrophy, choreoathetosis of limbs and face, intellectual disability and a combined defect of complexes I and IV in muscle biopsy, caused by a homozygous missense mutation identified in MRPL24. The variant predicts a Leu91Pro substitution at an evolutionarily conserved site. Using human mutant cells and the zebrafish model, we demonstrated the pathological role of the identified variant. In fact, in fibroblasts we observed a significant reduction of MRPL24 protein and of mitochondrial respiratory chain complex I and IV subunits, as well a markedly reduced synthesis of the mtDNA-encoded peptides. In zebrafish we demonstrated that the orthologue gene is expressed in metabolically active tissues, and that gene knockdown induced locomotion impairment, structural defects and low ATP production. The motor phenotype was complemented by human WT but not mutant cRNA. Moreover, sucrose density gradient fractionation showed perturbed assembly of large subunit mitoribosomal proteins, suggesting that the mutation leads to a conformational change in MRPL24, which is expected to cause an aberrant interaction of the protein with other components of the 39S mitoribosomal subunit.

Neuromodulation in Childhood Onset Dystonia: Evolving Role of Deep Brain Stimulation

This review will provide an update on the current status of deep brain stimulation in pediatric onset dystonias. Dystonia is a complex movement disorder that may occur in isolation or in combination with other abnormalities of tone and posture. The dystonias represent a heterogeneous group of movement disorders that can be progressive, painful, and severely disabling. Genetic and extrinsic factors may influence the treatment response. Pharmacologic treatment often has limited effectiveness and unacceptable, unwanted effects. Neuromodulation by deep brain stimulation (DBS) is a targeted therapy that continues to evolve as a treatment option for children with medically refractory dystonia due to a variety of etiologies. We share some insights from our surgical experience with 124 children with dystonia treated by DBS and review the current literature on the use of DBS in pediatric onset dystonia. Advances in surgical options make the surgery more tolerable for young children. Secondary dystonia, in particular cerebral palsy, is more common than primary genetic etiologies. Both may respond to DBS, which may be considered once medical management has failed. Data sharing through registry platforms such as PEDiDBS is a vital component for expanding our knowledge base.

Defining research priorities in dystonia

Dystonia 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. The 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. The 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. Overall 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.

Cervical dystonia: ways to improve the effectiveness of botulinum therapy

Cervical dystonia is one of the most complex movement disorders, in which type A botulinum toxin (BTA) preparations are used. A significant number of types of dystonic installation of the head and neck determines a large number of different muscle patterns, sometimes with outwardly similar manifestations. Objective difficulties in choosing the actual pathological muscle pattern for subsequent injection in some cases determine the low effectiveness of botulinum therapy. Given this situation, it is necessary to adapt the anatomical approach to the correct choice of dystonic muscles in order to improve the results of botulinum therapy of cervical dystonia.

Development of a Data Logger for Capturing Human-Machine Interaction in Wheelchair Head-Foot Steering Sensor System in Dyskinetic Cerebral Palsy.

The use of data logging systems for capturing wheelchair and user behavior has increased rapidly over the past few years. Wheelchairs ensure more independent mobility and better quality of life for people with motor disabilities. Especially, for people with complex movement disorders, such as dyskinetic cerebral palsy (DCP) who lack the ability to walk or to handle objects, wheelchairs offer a means of integration into daily life. The mobility of DCP patients is based on a head-foot wheelchair steering system. In this work, a data logging system is proposed to capture data from human-wheelchair interaction for the head-foot steering system. Additionally, the data logger provides an interface to multiple Inertial Measurement Units (IMUs) placed on the body of the wheelchair user. The system provides accurate and real-time information from head-foot navigation system pressure sensors on the wheelchair during driving. This system was used as a tool to obtain further insights into wheelchair control and steering behavior of people diagnosed with DCP in comparison with a healthy subject.

Persistent complex movement disorders in NMDA encehalitis: A case report in a child

A wide variety of movement disorders, often in combination, can be observed in children with anti-NMDAR encephalitis. A case of a 8 year old boy presenting as movement disorder, faciobrachial movements and seizures was diagnosed as NMDA encephalitis 3 years ago. CSF and serum NMDA antibodies were positive early in the course and early diagnosis could be made. The child deteriorated in spite of IVIGand methylprednisolone, needing ICU care and recovered gradually in 3-4 weeks after addition of Azathioprine. Prednisolone tapering doses and Azathioprine were continued as maintenance therapy and is still ongoing after three years There was gradual speech deterioration with loss of speech and the child developed a complex movement disorder, having multiple movement types, difficult to classify into the standard classification of movement disorders. The movements wax and wane with therapy but have not completely responded to maintenance Azathiprine and low dose steroids even after 3 years of therapy suggesting long term affection and disability due to complex movement disorders in NMDA encephalitis.

P.378A complex movement disorder associated with myasthenic features: a novel phenotype caused by a homozygous NGLY1 mutation

P.378A complex movement disorder associated with myasthenic features: a novel phenotype caused by a homozygous NGLY1 mutation

KIF1C Variants Are Associated with Hypomyelination, Ataxia, Tremor, and Dystonia in Fraternal Twins.

BackgroundKIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia.Case reportWe report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients.DiscussionKIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.

KIF1C Variants Are Associated with Hypomyelination, Ataxia, Tremor, and Dystonia in Fraternal Twins

<strong>Background:</strong> <em>KIF1C</em> (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. <strong>Case report:</strong> We report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous <em>KIF1C</em> variant in both patients. <strong>Discussion:</strong> <em>KIF1C</em> variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. <em>KIF1C</em> variants may also cause a hypomyelinating leukoencephalopathy.

Estudio de pacientes pediátricos con fenotipo clínico y bioquímico de síndrome de déficit de transportador de glucosa cerebral (GLUT-1)

IntroductionGlucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. AimsWe describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. Material and methodsThe study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. ResultsSix patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7% vs. 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs. 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs. 46mg/dL, P=.04) and CSF/serum glucose ratio (0.4 vs. 0.48, P<.05). ConclusionsGLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose level, and good response to the ketogenic diet.

Construction of Parkinson's disease marker-based weighted protein-protein interaction network for prioritization of co-expressed genes

Background: Parkinson's disease (PD) is a complex neurodegenerative movement disorder that primarily results due to the loss of dopaminergic neurons in the substantia nigra region. Studying gene expression in the substantia nigra region would potentially unravel disease-relevant protein-protein interactions. MethodsIn this study we have used network science approach to prioritize candidate genes by focussing on differentially expressed genes (DEGs) that interact with established PD associated-genes (PDAG). Prioritizing genes that interact with already established PDAG would reduce the probability of spurious protein-protein associations. The dataset GSE54282 with Parkinson's disease affected substantia nigra samples was extracted from Gene Expression Omnibus (GEO) database. Protein-Protein Interaction Network (PPIN) was constructed by retrieving all possible interactions between DEGs from high-throughput experiments and literature data using Bisogenet. This complex PPIN was decomposed to construct a subnetwork of Parkinson's Disease-Protein Interaction Map (PD-PIM) by including PDAG and following well-established concepts of network biology such as degree and betweenness centrality. We then implemented a “two-way analysis” where we selected genes belonging to PDPIM subnetwork with their primary interacting partners and highly coexpressed genes on the basis of Pearson score. ResultsA complex PPIN comprised of 5340 nodes (genes) and 39,199 edges (interactions) was obtained. A list of 205 genes (123 PDAGs, 69 hub genes and 13 bottleneck genes) with their respective first level interacting partners were extracted from PPIN interactome to build a PD-specific subnetwork, PD-PIM. This subnetwork PD-PIM comprised of 5078 nodes and 38,357 edges. We then employed a “two-way” gene prioritization method that delineated 267 genes of which 16 genes were found to intersect in the two networks of the “two-way analysis”. Of the 16 genes, we narrowed down to 7 novel candidate genes (VCAM1, BACH1, CALM3, EGR1, IKBKE, MYC and YWHAG) displaying significant changes in their network interactions between control and disease samples. Interestingly, these genes were associated with neuroinflammation signaling pathway, MAPK signaling apoptosis pathway, movement disorders and development of neurons that are linked with development of PD. ConclusionWe propose that VCAM1, BACH1, CALM3, EGR1, IKBKE, MYC and YWHAG genes might play important roles in PD pathogenesis, as well as facilitate the development of effective targeted therapies. Our integrative and network based approach for finding therapeutic targets in genomic data could accelerate the identification of novel drug targets for Parkinson's disease.