Publications by authors named "Marina A J Tijssen"

181 Publications

Antiseizure Drugs and Movement Disorders.

CNS Drugs 2022 Aug 21;36(8):859-876. Epub 2022 Jul 21.

Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Division of Neurology, University of Toronto, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada.

The relationship between antiseizure drugs and movement disorders is complex and not adequately reviewed so far. Antiseizure drugs as a treatment for tremor and other entities such as myoclonus and restless leg syndrome is the most common scenario, although the scientific evidence supporting their use is variable. However, antiseizure drugs also represent a potential cause of iatrogenic movement disorders, with parkinsonism and tremor the most common disorders. Many other antiseizure drug-induced movement disorders are possible and not always correctly identified. This review was conducted by searching for all the possible combinations between 15 movement disorders (excluding ataxia) and 24 antiseizure drugs. The main objective was to describe the movement disorders treated and worsened or induced by antiseizure drugs. We also summarized the proposed mechanisms and risk factors involved in the complex interaction between antiseizure drugs and movement disorders. Antiseizure drugs mainly used to treat movement disorders are clonazepam, gabapentin, lacosamide, levetiracetam, oxcarbazepine, perampanel, phenobarbital, pregabalin, primidone, topiramate, and zonisamide. Antiseizure drugs that worsen or induce movement disorders are cenobamate, ethosuximide, felbamate, lamotrigine, phenytoin, tiagabine, and vigabatrin. Antiseizure drugs with a variable effect on movement disorders are carbamazepine and valproate while no effect on movement disorders has been reported for brivaracetam, eslicarbazepine, lacosamide, and stiripentol. Although little information is available on the adverse effects or benefits on movement disorders of newer antiseizure drugs (such as brivaracetam, cenobamate, eslicarbazepine, lacosamide, and rufinamide), the evidence collected in this review should guide the choice of antiseizure drugs in patients with concomitant epilepsy and movement disorders. Finally, these notions can lead to a better understanding of the mechanisms involved in the pathophysiology and treatments of movement disorders.
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http://dx.doi.org/10.1007/s40263-022-00937-xDOI Listing
August 2022

Eye movement disorders in inborn errors of metabolism: A quantitative analysis of 37 patients.

J Inherit Metab Dis 2022 Jun 27. Epub 2022 Jun 27.

Department of Neurology and Clinical Neurophysiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism.
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http://dx.doi.org/10.1002/jimd.12533DOI Listing
June 2022

Multi-centre classification of functional neurological disorders based on resting-state functional connectivity.

Neuroimage Clin 2022 Jun 17;35:103090. Epub 2022 Jun 17.

Psychosomatic Medicine, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Background: Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a "rule-in" procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting.

Methods: This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross-validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation).

Results: FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%).

Conclusions: The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms.
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http://dx.doi.org/10.1016/j.nicl.2022.103090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240866PMC
June 2022

A novel diagnostic approach for patients with adult-onset dystonia.

J Neurol Neurosurg Psychiatry 2022 Jun 10. Epub 2022 Jun 10.

Neurology, University Medical Centre Groningen, Groningen, The Netherlands

Adult-onset dystonia can be acquired, inherited or idiopathic. The dystonia is usually focal or segmental and for a limited number of cases causal treatment is available. In recent years, rapid developments in neuroimmunology have led to increased knowledge on autoantibody-related dystonias. At the same time, genetic diagnostics in sequencing technology have evolved and revealed several new genes associated with adult-onset dystonia. Furthermore, new phenotype-genotype correlations have been elucidated. Consequently, clinicians face the dilemma of which additional investigations should be performed and whether to perform genetic testing or not. To ensure early diagnosis and to prevent unnecessary investigations, integration of new diagnostic strategies is needed.We designed a new five-step diagnostic approach for adult-onset dystonia. The first four steps are based on a broad literature search and expert opinion, the fifth step, on when to perform genetic testing, is based on a detailed systematic literature review up to 1 December 2021.The basic principle of the algorithm is that genetic testing is unlikely to lead to changes in management in three groups: (1) patients with an acquired form of adult-onset dystonia; (2) patients with neurodegenerative disorders, presenting with a combined movement disorder including dystonic symptoms and (3) patients with adult-onset isolated focal or segmental dystonia. Throughout the approach, focus lies on early identification of treatable forms of dystonia, either acquired or genetic.This novel diagnostic approach for adult-onset dystonia can help clinicians to decide when to perform additional tests, including genetic testing and facilitates early aetiological diagnosis, to enable timely treatment.
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http://dx.doi.org/10.1136/jnnp-2021-328120DOI Listing
June 2022

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force - An Update.

Mov Disord 2022 05 28;37(5):905-935. Epub 2022 Apr 28.

The Edmond J. Safra Program in Parkinson's Disease and The Morton and Gloria Shulman Movement Disorder Clinic, Toronto Western Hospital, University of Toronto, Toronto, Canada.

In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion-based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease-causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging-based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28982DOI Listing
May 2022

Serotonergic system in vivo with [C]DASB PET scans in GTP-cyclohydrolase deficient dopa-responsive dystonia patients.

Sci Rep 2022 04 15;12(1):6292. Epub 2022 Apr 15.

Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms. Dynamic [C]DASB PET scans, a marker of serotonin transporter availability, were performed. Ten DRD, 14 cervical dystonia patients and 12 controls were included. Univariate- and network-analysis did not show differences in binding between DRD patients compared to controls. Sleep disturbances were correlated with binding in the dorsal raphe nucleus (all participants: r = 0.45, p = 0.04; patients: r = 0.64, p = 0.05) and participants with a psychiatric disorder had a lower binding in the hippocampus (all participants: p = 0.00; patients: p = 0.06). Post-hoc analysis with correction for psychiatric co-morbidity showed a significant difference in binding in the hippocampus between DRD patients and controls (p = 0.00). This suggests that psychiatric symptoms might mask the altered serotonergic metabolism in DRD patients, but definite conclusions are difficult as psychiatry is considered part of the phenotype. We hypothesize that an imbalance between different neurotransmitter systems is responsible for the non-motor symptoms, and further research investigating multiple neurotransmitters and psychiatry in DRD is necessary.
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http://dx.doi.org/10.1038/s41598-022-10067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012759PMC
April 2022

Electrophysiological testing aids the diagnosis of tremor and myoclonus in clinically challenging patients.

Clin Neurophysiol Pract 2022 29;7:51-58. Epub 2022 Jan 29.

Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands.

Objective: We investigated how clinical neurophysiological testing can help distinguish tremor and myoclonus and their subtypes.

Methods: We retrospectively analysed clinical and neurophysiological data from patients who had undergone polymyography (EMG + accelerometry) to diagnose suspected tremor or myoclonus. We show a systematic approach, which includes contraction pattern, rhythm regularity, burst duration and evidence of cortical drive.

Results: We detected 773 patients in our database, of which 556 patients were ultimately diagnosed with tremor (enhanced physiological tremor n = 169, functional tremor n = 140, essential tremor n = 90, parkinsonism associated tremor n = 64, cerebellar tremor n = 19, Holmes tremor n = 12, dystonic tremor n = 8, tremor not further specified n = 9), 140 with myoclonus and 23 with a combination of tremor and myoclonus. Polymyography confirmed the presumptive diagnosis in the majority of the patients and led to a change of diagnosis in 287 patients (37%). Conversions between diagnoses of tremor and myoclonus occurred most frequently between enhanced physiological tremor, essential tremor, functional tremor and cortical myoclonus.

Conclusions: Neurophysiology is a valuable additional tool in clinical practice to differentiate between tremor and myoclonus, and can guide towards a specific subtype.

Significance: We show how the stepwise neurophysiological approach used at our medical center aids the diagnosis of tremor versus myoclonus.
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http://dx.doi.org/10.1016/j.cnp.2021.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867002PMC
January 2022

[A patient with an acute neurological deficit: is it really an ischemic stroke?]

Ned Tijdschr Geneeskd 2021 12 2;165. Epub 2021 Dec 2.

UMCG, Groningen: Afd. Neurologie.

When a patient presents with acute neurological deficit, ischemic stroke is often assumed. However, a functional neurological disorder (FND) can also present with stroke-like symptoms. FND is a multifactorial condition to which biological, psychological and social factors predispose. The distinction between FND and acute ischemic stroke can be challenging, but is very important because fast reperfusion treatment is indicated for ischemic stroke. We show the specific features of FND in history and neurologic examination to pay attention to. Furthermore, we discuss the use of additional investigation to support the diagnosis. We describe two patients with an acute neurological deficit: a 34-year-old male with hemiparesis and speech disturbances due to FND, and a 51-year-old male with hemiparesis and hemi-ataxia due to ischemic stroke. These 2 patients demonstrate how challenging the distinction between FND and stroke may be.
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December 2021

Developmental neurobiology of cerebellar and Basal Ganglia connections.

Eur J Paediatr Neurol 2022 Jan 7;36:123-129. Epub 2021 Dec 7.

Genetics University Medical Center, University of Groningen, Groningen, the Netherlands.

Background: The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network.

Methods: In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia.

Results: In a clinical EOA cohort, the prevalence of dystonia was over 60%. Both human and animal studies converge on the underlying role for the cortico-basal-ganglia-ponto-cerebellar network. Genetic -clinical and -in silico network studies reveal underlying biological pathways for energy production and neural signal transduction.

Conclusions: EOA-dystonia phenotypes are attributable to the cortico-basal-ganglia-ponto-cerebellar network, instead of to the cerebellum, alone. The underlying anatomic and pathogenetic pathways have clinical implications for our understanding of the heterogeneous phenotype, neuro-metabolic and genetic testing and potentially also for new treatment strategies, including neuro-modulation.
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http://dx.doi.org/10.1016/j.ejpn.2021.12.001DOI Listing
January 2022

Next move in movement disorders (NEMO): developing a computer-aided classification tool for hyperkinetic movement disorders.

BMJ Open 2021 10 11;11(10):e055068. Epub 2021 Oct 11.

Department of Neurology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

Introduction: Our aim is to develop a novel approach to hyperkinetic movement disorder classification, that combines clinical information, electromyography, accelerometry and video in a computer-aided classification tool. We see this as the next step towards rapid and accurate phenotype classification, the cornerstone of both the diagnostic and treatment process.

Methods And Analysis: The Next Move in Movement Disorders (NEMO) study is a cross-sectional study at Expertise Centre Movement Disorders Groningen, University Medical Centre Groningen. It comprises patients with single and mixed phenotype movement disorders. Single phenotype groups will first include dystonia, myoclonus and tremor, and then chorea, tics, ataxia and spasticity. Mixed phenotypes are myoclonus-dystonia, dystonic tremor, myoclonus ataxia and jerky/tremulous functional movement disorders. Groups will contain 20 patients, or 40 healthy participants. The gold standard for inclusion consists of interobserver agreement on the phenotype among three independent clinical experts. Electromyography, accelerometry and three-dimensional video data will be recorded during performance of a set of movement tasks, chosen by a team of specialists to elicit movement disorders. These data will serve as input for the machine learning algorithm. Labels for supervised learning are provided by the expert-based classification, allowing the algorithm to learn to predict what the output label should be when given new input data. Methods using manually engineered features based on existing clinical knowledge will be used, as well as deep learning methods which can detect relevant and possibly new features. Finally, we will employ visual analytics to visualise how the classification algorithm arrives at its decision.

Ethics And Dissemination: Ethical approval has been obtained from the relevant local ethics committee. The NEMO study is designed to pioneer the application of machine learning of movement disorders. We expect to publish articles in multiple related fields of research and patients will be informed of important results via patient associations and press releases.
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http://dx.doi.org/10.1136/bmjopen-2021-055068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506849PMC
October 2021

Daily fluctuations of negative affect are only weakly associated with tremor symptoms in functional and organic tremor patients.

J Psychosom Res 2021 11 23;150:110627. Epub 2021 Sep 23.

University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation, Groningen, the Netherlands. Electronic address:

Background: There is a long-standing research history on the presumed psychological origin of functional movement disorders. Most studies do not address the heterogeneity in functional movement disorders and do not distinguish between risk factors, causes and consequences. We studied the associations between negative affect and objective as well as subjective symptom levels in patients with functional and organic tremor.

Methods: Thirty-three patients with a functional (14) or organic tremor (19) completed a web-based diary on subjective symptom burden and negative affect, five times a day for 30 days (total number of observations = 4759). During the same period, the participants wore an accelerometer to objectively record tremor. Vector autoregressive modelling was used to determine the time-lagged and contemporaneous associations between negative affect and objective/subjective tremor symptoms, both on an individual and a group level.

Results: In contrast to previous literature, patients with a functional or organic tremor showed a weak contemporaneous association between negative affect and objective/subjective tremor symptoms (on average r = 0.038 and 0.174 respectively). Time-lagged associations between negative affect and objective/subjective tremor symptoms were mixed in effect and direction and only present in a subset of patients, with no differences between patients with functional or organic tremor.

Conclusions: Negative affect is only weakly associated with objective/subjective tremor symptoms, both on the contemporaneous and time-lagged associations, and these associations were mainly similar between patients with functional or organic tremor. These results argue against a strong influence of daily stress on tremor symptoms in patients with a functional or organic tremor.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110627DOI Listing
November 2021

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients.

Parkinsonism Relat Disord 2021 10 2;91:48-54. Epub 2021 Sep 2.

Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB, Groningen, the Netherlands; Department of Clinical Sciences, Lund University, Box 117, 221 00, Lund, Sweden. Electronic address:

Introduction: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations.

Methods: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites.

Results: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (r = -0.3, p < 0.01), depression (r = -0.3, p < 0.01) and fatigue (r = -0.2, p = 0.04).

Conclusion: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.
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http://dx.doi.org/10.1016/j.parkreldis.2021.08.019DOI Listing
October 2021

Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda.

Neuroimage Clin 2021 11;30:102623. Epub 2021 Mar 11.

Neurology Department, Psychosomatic Medicine Unit, Bern University Hospital Inselspital, University of Bern, Bern, Switzerland.

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart - leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using "rule-in" examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.
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http://dx.doi.org/10.1016/j.nicl.2021.102623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111317PMC
July 2021

Dystonia Management: What to Expect From the Future? The Perspectives of Patients and Clinicians Within DystoniaNet Europe.

Front Neurol 2021 3;12:646841. Epub 2021 Jun 3.

Expertise Centre Movement Disorders Groningen, Department of Neurology, University Medical Centre Groningen, Groningen, Netherlands.

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the , the which however only existed for a limited time), and the Dutch project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.
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http://dx.doi.org/10.3389/fneur.2021.646841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211212PMC
June 2021

Reply to: "Childhood Onset Chorea Caused by a Recurrent De Novo DRD2 Variant".

Mov Disord 2021 06;36(6):1473-1474

Expertise Center Movement Disorders Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1002/mds.28635DOI Listing
June 2021

Three Days of Measurement Provide Reliable Estimates of Daily Tremor Characteristics: A Pilot Study in Organic and Functional Tremor Patients.

Tremor Other Hyperkinet Mov (N Y) 2021 04 21;11:13. Epub 2021 Apr 21.

University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, The Netherlands.

Background: Long-term tremor recording is particularly useful for the assessment of overall severity and therapeutic interventions in tremor patients. The purpose of this paper is to investigate the optimal number of days needed to obtain reliable estimates of tremor percentage, tremor frequency variability and tremor intensity in tremor patients using long-term tremor recordings.

Methods: Participants were 18 years or older and were diagnosed with tremor by a movement disorders specialist. Participants wore an accelerometer on the wrist of the most affected arm during 30 consecutive days. Tremor presence, frequency variability and intensity were calculated per day. We used reliability analysis to determine the minimum number of days needed to obtain reliable estimates of these tremor characteristics.

Results: Data from 36 adult organic (OrgT) and functional tremor (FT) patients (24 males; mean age 63.9 ± 11.9 years; 15 FT) were analyzed. Using five hours per day, one day of measurement is enough, except for tremor frequency variability in the OrgT group, where three days are needed and for tremor intensity where two days are always needed.

Discussion: Visual analysis suggested that reliability can be increased considerably by using data from three days instead of one day even when using six hours of data per day. Three days with at least three hours of tremor data provide estimates of tremor percentage, frequency variability and intensity with good to excellent reliability, both for organic and functional tremor.
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http://dx.doi.org/10.5334/tohm.603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103847PMC
April 2021

Signaling-Biased and Constitutively Active Dopamine D2 Receptor Variant.

ACS Chem Neurosci 2021 06 11;12(11):1873-1884. Epub 2021 May 11.

Research Service, VA Portland Health Care System, and Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon 97239, United States.

A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. Compared to the wild type D2 receptor, the novel allelic variant D2-IF activates a Gαβγ heterotrimer with higher potency and modestly enhanced basal activity in human embryonic kidney (HEK) 293 cells and has decreased capacity to recruit arrestin3. We now report that omitting overexpressed G protein-coupled receptor kinase-2 (GRK2) decreased the potency and efficacy of quinpirole for arrestin recruitment. The relative efficacy of quinpirole for arrestin recruitment to D2-IF compared to D2-WT was considerably lower without overexpressed GRK2 than with added GRK2. D2-IF exhibited higher basal activation of Gα than Gα but little or no increase in the potency of quinpirole relative to D2-WT. Other signs of D2-IF constitutive activity for G protein-mediated signaling, in addition to basal activation of Gα, were enhanced basal inhibition of forskolin-stimulated cyclic AMP accumulation that was reversed by the inverse agonists sulpiride and spiperone and a ∼4-fold increase in the apparent affinity of D2-IF for quinpirole, determined from competition binding assays. In mouse midbrain slices, inhibition of tonic current by the inverse agonist sulpiride in dopamine neurons expressing D2-IF was consistent with our hypothesis of enhanced constitutive activity and sensitivity to dopamine relative to D2-WT. Molecular dynamics simulations with D2 receptor models suggested that an ionic lock between the cytoplasmic ends of the third and sixth α-helices that constrains many G protein-coupled receptors in an inactive conformation spontaneously breaks in D2-IF. Overall, these results confirm that D2-IF is a constitutively active and signaling-biased D2 receptor mutant and also suggest that the effect of the likely pathogenic variant in a given brain region will depend on the nature of G protein and GRK expression.
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http://dx.doi.org/10.1021/acschemneuro.0c00712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528033PMC
June 2021

, one gene associated with multiple neurodevelopmental disorders.

Autophagy 2021 12 12;17(12):3908-3923. Epub 2021 Apr 12.

Department of Biomedical Sciences of Cells & Systems, Molecular Cell Biology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

The gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders. ATG/Atg: autophagy related; BPAN: ß-propeller protein associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; EEG: electroencephalograph; ENO2/neuron-specific enolase, enolase 2; EOEE: early-onset epileptic encephalopathy; ER: endoplasmic reticulum; ID: intellectual disability; IDR: intrinsically disordered region; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NCOA4: nuclear receptor coactivator 4; PtdIns3P: phosphatidylinositol-3-phosphate; RLS: Rett-like syndrome; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.
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http://dx.doi.org/10.1080/15548627.2021.1899669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726670PMC
December 2021

Challenges in Clinicogenetic Correlations: One Phenotype - Many Genes.

Mov Disord Clin Pract 2021 Apr 2;8(3):311-321. Epub 2021 Mar 2.

Department of Neurology University of Groningen, University Medical Centre Groningen Groningen The Netherlands.

Background: In the field of movement disorders, what you see (phenotype) is seldom what you get (genotype). Whereas 1 phenotype was previously associated to 1 gene, the advent of next-generation sequencing (NGS) has facilitated an exponential increase in disease-causing genes and genotype-phenotype correlations, and the "one-phenotype-many-genes" paradigm has become prominent.

Objectives: To highlight the "one-phenotype-many-genes" paradigm by discussing the main challenges, perspectives on how to address them, and future directions.

Methods: We performed a scoping review of the various aspects involved in identifying the underlying molecular cause of a movement disorder phenotype.

Results: The notable challenges are (1) the lack of gold standards, overlap in clinical spectrum of different movement disorders, and variability in the interpretation of classification systems; (2) selecting which patients benefit from genetic tests and the choice of genetic testing; (3) problems in the variant interpretation guidelines; (4) the filtering of variants associated with disease; and (5) the lack of standardized, complete, and up-to-date gene lists. Perspectives to address these include (1) deep phenotyping and genotype-phenotype integration, (2) adherence to phenotype-specific diagnostic algorithms, (3) implementation of current and complementary bioinformatic tools, (4) a clinical-molecular diagnosis through close collaboration between clinicians and genetic laboratories, and (5) ongoing curation of gene lists and periodic reanalysis of genetic sequencing data.

Conclusions: Despite the rapidly emerging possibilities of NGS, there are still many steps to take to improve the genetic diagnostic yield. Future directions, including post-NGS phenotyping and cohort analyses enriched by genotype-phenotype integration and gene networks, ought to be pursued to accelerate identification of disease-causing genes and further improve our understanding of disease biology.
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http://dx.doi.org/10.1002/mdc3.13163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015914PMC
April 2021

How to detect late-onset inborn errors of metabolism in patients with movement disorders - A modern diagnostic approach.

Parkinsonism Relat Disord 2021 04 2;85:124-132. Epub 2021 Mar 2.

Department of Neurology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands; Expertise Center Movement Disorders Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands. Electronic address:

We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement disorder. IEMs presenting in adults are still largely unexplored. These disorders receive little attention in neurological training and daily practice, and are considered complicated by many neurologists. Adult-onset presentations of IEMs differ from childhood-onset phenotypes, which may lead to considerable diagnostic delay. The identification of adult-onset phenotypes at the earliest stage of the disease is important, since early treatment may prevent or lessen further brain damage. Our approach is based on a systematic review of all papers that concerned movement disorders due to an IEM in patients of 16 years or older. Detailed clinical phenotyping is the diagnostic cornerstone of the approach. An underlying IEM should be suspected in particular in patients with more than one movement disorder, or in patients with additional neurological, psychiatric, or systemic manifestations. As IEMs are all genetic disorders, we recommend next-generation sequencing (NGS) as the first diagnostic approach to confirm an IEM. Biochemical tests remain the first choice in acute-onset or treatable IEMs that require rapid diagnosis, or to confirm the metabolic diagnosis after NGS results. With the use of careful and systematic clinical phenotyping combined with novel diagnostic approaches such as NGS, the diagnostic yield of late-onset IEMs will increase, in particular in patients with mild or unusual phenotypes.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.029DOI Listing
April 2021

Altered Posterior Midline Activity in Patients with Jerky and Tremulous Functional Movement Disorders.

Brain Connect 2021 09 7;11(7):584-593. Epub 2021 May 7.

Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.

To explore changes in resting-state networks in patients with jerky and tremulous functional movement disorders (JT-FMD). Resting-state functional magnetic resonance imaging data from seventeen patients with JT-FMD and seventeen age-, sex-, and education-matched healthy controls (HC) were investigated. Independent component analysis was used to examine the central executive network (CEN), salience network, and default mode network (DMN). Frequency distribution of network signal fluctuations and intra- and internetwork functional connectivity were investigated. Symptom severity was measured using the Clinical Global Impression-Severity scale. Beck Depression Inventory and Beck Anxiety Inventory scores were collected to measure depression and anxiety in FMD, respectively. Compared with HC, patients with JT-FMD had significantly decreased power of lower range (0.01-0.10 Hz) frequency fluctuations in a precuneus and posterior cingulate cortex component of the DMN and in the dorsal attention network (DAN) component of the CEN (false discovery rate-corrected  < 0.05). No significant group differences were found for intra- and internetwork functional connectivity. In patients with JT-FMD, symptom severity was not significantly correlated with network measures. Depression scores were weakly correlated with intranetwork functional connectivity in the medial prefrontal cortex, while anxiety was not found to be related to network connectivity. Given the changes in the posterodorsal components of the DMN and DAN, we postulate that the JT-FMD-related functional alterations found in these regions could provide support for the concept that particularly attentional dysregulation is a fundamental disturbance in these patients. Impact statement In this study, we explored static brain network functional connectivity in patients with jerky and tremulous functional movement disorders (JT-FMD) and healthy controls. We studied network functioning by analyzing functional connectivity measures, and also time course frequency spectra, which is novel compared with previous studies. We discovered aberrations in the frequency distribution of a posterior component of the default mode network (precuneus/posterior cingulate) and the dorsal attention network in patients with JT-FMD relative to controls. Conclusively, our findings could provide support for impaired attentional control as a fundamental disturbance in JT-FMD and contribute to the growing conceptualization of this disorder.
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http://dx.doi.org/10.1089/brain.2020.0779DOI Listing
September 2021

The European Reference Network for Rare Neurological Diseases.

Front Neurol 2020 14;11:616569. Epub 2021 Jan 14.

Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have "the knowledge travel instead of the patient," which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.
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http://dx.doi.org/10.3389/fneur.2020.616569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840612PMC
January 2021

Rare functional missense variants in CACNA1H: What can we learn from Writer's cramp?

Mol Brain 2021 01 21;14(1):18. Epub 2021 Jan 21.

Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. box 30 001, 9700 RB, Groningen, The Netherlands.

Writer's cramp (WC) is a task-specific focal dystonia that occurs selectively in the hand and arm during writing. Previous studies have shown a role for genetics in the pathology of task-specific focal dystonia. However, to date, no causal gene has been reported for task-specific focal dystonia, including WC. In this study, we investigated the genetic background of a large Dutch family with autosomal dominant‒inherited WC that was negative for mutations in known dystonia genes. Whole exome sequencing identified 4 rare variants of unknown significance that segregated in the family. One candidate gene was selected for follow-up, Calcium Voltage-Gated Channel Subunit Alpha1 H, CACNA1H, due to its links with the known dystonia gene Potassium Channel Tetramerization Domain Containing 17, KCTD17, and with paroxysmal movement disorders. Targeted resequencing of CACNA1H in 82 WC cases identified another rare, putative damaging variant in a familial WC case that did not segregate. Using structural modelling and functional studies in vitro, we show that both the segregating p.Arg481Cys variant and the non-segregating p.Glu1881Lys variant very likely cause structural changes to the Cav3.2 protein and lead to similar gains of function, as seen in an accelerated recovery from inactivation. Both mutant channels are thus available for re-activation earlier, which may lead to an increase in intracellular calcium and increased neuronal excitability. Overall, we conclude that rare functional variants in CACNA1H need to be interpreted very carefully, and additional studies are needed to prove that the p.Arg481Cys variant is the cause of WC in the large Dutch family.
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http://dx.doi.org/10.1186/s13041-021-00736-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819179PMC
January 2021

Myoclonus-Ataxia Syndromes: A Diagnostic Approach.

Mov Disord Clin Pract 2021 Jan 3;8(1):9-24. Epub 2020 Nov 3.

Department of Neurology, Donders Institute for Brain, Cognition & Behaviour Radboud University Medical Center Nijmegen The Netherlands.

Background: A myriad of disorders combine myoclonus and ataxia. Most causes are genetic and an increasing number of genes are being associated with myoclonus-ataxia syndromes (MAS), due to recent advances in genetic techniques. A proper etiologic diagnosis of MAS is clinically relevant, given the consequences for genetic counseling, treatment, and prognosis.

Objectives: To review the causes of MAS and to propose a diagnostic algorithm.

Methods: A comprehensive and structured literature search following PRISMA criteria was conducted to identify those disorders that may combine myoclonus with ataxia.

Results: A total of 135 causes of combined myoclonus and ataxia were identified, of which 30 were charted as the main causes of MAS. These include four acquired entities: opsoclonus-myoclonus-ataxia syndrome, celiac disease, multiple system atrophy, and sporadic prion diseases. The distinction between progressive myoclonus epilepsy and progressive myoclonus ataxia poses one of the main diagnostic dilemmas.

Conclusions: Diagnostic algorithms for pediatric and adult patients, based on clinical manifestations including epilepsy, are proposed to guide the differential diagnosis and corresponding work-up of the most important and frequent causes of MAS. A list of genes associated with MAS to guide genetic testing strategies is provided. Priority should be given to diagnose or exclude acquired or treatable disorders.
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http://dx.doi.org/10.1002/mdc3.13106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780951PMC
January 2021

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology.

Diagnostics (Basel) 2020 Nov 24;10(12). Epub 2020 Nov 24.

Department of Genetics, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD), are still unclear. In 80 EOA-patients, we determined the EOAD-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus ( = 0.001)). Genetic network and functional enrichment analysis in EOAD-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.
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http://dx.doi.org/10.3390/diagnostics10120997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760948PMC
November 2020

Bilateral Pallidotomy for Dystonia: A Systematic Review.

Mov Disord 2021 03 20;36(3):547-557. Epub 2020 Nov 20.

Department of Neurosurgery, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication-refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre-and postoperative Burke-Fahn-Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty-five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median-reported follow-up was 12 months (n = 83; range: 2-180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication-refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048649PMC
March 2021

A Gain-of-Function Variant in Dopamine D2 Receptor and Progressive Chorea and Dystonia Phenotype.

Mov Disord 2021 03 16;36(3):729-739. Epub 2020 Nov 16.

Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.

Background: We describe a 4-generation Dutch pedigree with a unique dominantly inherited clinical phenotype of a combined progressive chorea and cervical dystonia carrying a novel heterozygous dopamine D2 receptor (DRD2) variant.

Objectives: The objective of this study was to identify the genetic cause of the disease and to further investigate the functional consequences of the genetic variant.

Methods: After detailed clinical and neurological examination, whole-exome sequencing was performed. Because a novel variant in the DRD2 gene was found as the likely causative gene defect in our pedigree, we sequenced the DRD2 gene in a cohort of 121 Huntington-like cases with unknown genetic cause (Germany). Moreover, functional characterization of the DRD2 variant included arrestin recruitment, G protein activation, and G protein-mediated inhibition of adenylyl cyclase determined in a cell model, and G protein-regulated inward-rectifying potassium channels measured in midbrain slices of mice.

Result: We identified a novel heterozygous variant c.634A > T, p.Ile212Phe in exon 5 of DRD2 that cosegregated with the clinical phenotype. Screening of the German cohort did not reveal additional putative disease-causing variants. We demonstrated that the D2 -I F receptor exhibited increased agonist potency and constitutive activation of G proteins in human embryonic kidney 239 cells as well as significantly reduced arrestin3 recruitment. We further showed that the D2 -I F receptor exhibited aberrant receptor function in mouse midbrain slices.

Conclusions: Our results support an association between the novel p.Ile212Phe variant in DRD2, its modified D2 receptor activity, and the hyperkinetic movement disorder reported in the 4-generation pedigree. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049080PMC
March 2021

Diagnostic approach to paediatric movement disorders: a clinical practice guide.

Dev Med Child Neurol 2021 03 5;63(3):252-258. Epub 2020 Nov 5.

Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Paediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This can make the diagnostic process time-consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next-generation sequencing, post-sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs. WHAT THIS PAPER ADDS: An up-to-date description and diagnostic framework for testing of paediatric movement disorders is presented. The framework helps to determine which patients will benefit from next-generation sequencing.
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http://dx.doi.org/10.1111/dmcn.14721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894329PMC
March 2021

Inborn Errors of Metabolism in Adults: Two Patients with Movement Disorders Caused by Glutaric Aciduria Type 1.

Mov Disord Clin Pract 2020 Sep 29;7(Suppl 3):S85-S88. Epub 2020 Sep 29.

Department of Neurology University of Groningen, University Medical Center Groningen Groningen The Netherlands.

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http://dx.doi.org/10.1002/mdc3.13054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525196PMC
September 2020

Pentameric repeat expansions: cortical myoclonus or cortical tremor?

Brain 2020 10;143(10):e86

Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1093/brain/awaa259DOI Listing
October 2020
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