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Aim: This exploratory study evaluates rating scale usage by experts from the European Reference Network for Rare Neurological Diseases (ERN-RND) for paediatric MD, considering factors like diagnosis, intellectual disability, age, and transition to adult care. The aim is to propose a preliminary framework for consistent application., Methods: A multicentre survey among 25 ERN-RND experts from 10 European countries examined rating scale usage in paediatric MD, categorizing MD into acute, non-progressive, and neurodegenerative types. Factors influencing scale choice and the transition to adult care practices were analysed. A comprehensive literature search was conducted to identify the earliest age of application of these scales in paediatric patients., Results: The study identifies various rating scales and establishes their usage frequencies for different MDs. Experts highlighted the need for standardized scales and proposed preliminary evaluation strategies based on clinical contexts. Challenges in applying scales to young, non-cooperative patients were acknowledged., Interpretation: The study recommends developing standardized rating scales for paediatric MDs to improve evaluations and data collection. It suggests potential scales for specific clinical scenarios to better evaluate disease progression. Comprehensive, patient-centred care remains crucial during the transition to adult care, despite the identified challenges. This exploratory approach aims to enhance patient outcomes and care., Competing Interests: Declaration of competing interest We hereby affirm that all authors involved in the preparation of this manuscript declare no conflicts of interest. This includes financial, personal, or professional relationships that could potentially influence the interpretation of the work presented herein., (Copyright © 2024 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: See appendix for declarations of interest.

Background: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea., Objective: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders., Methods: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded., Results: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively., Conclusion: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine., Objective: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia., Methods: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire., Results: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening., Conclusion: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

In humans, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NTN1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyze the morphological and functional consequences of floor plate Netrin-1 depletion in conditional knockout mice. We show that depletion of floor plate Netrin-1 in the brainstem critically disrupts CST midline crossing, whereas the other commissural systems are preserved. The only associated defect is an abnormal entry of CST axons within the inferior olive. Alteration of CST midline crossing results in functional ipsilateral projections and is associated with abnormal symmetric movements. Our study reveals the role of Netrin-1 in CST development and describes a mouse model recapitulating the characteristics of human congenital mirror movements., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes., Objective: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates., Methods: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with μ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold., Results: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (μ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower μ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower μ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022)., Conclusion: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.

Objective: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51., Methods: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server., Results: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC)., Conclusion: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered., (© 2014 American Academy of Neurology.)

Background: Management of psychogenic movement disorders (PMDs) is challenging for neurologists and, to date, there is no consensus about their treatment. Recent studies suggested a possible therapeutic effect of repeated transcranial magnetic stimulation (TMS) in psychogenic paralysis and tremor., Objective: To document the clinical impact of TMS in PMDs., Methods: We blindly video scored symptoms of consecutive patients with PMD who were recorded before and after TMS. TMS was delivered at low frequency (0.25 Hz) over the motor cortex contralateral to symptoms., Results: Twenty-four patients were included. They presented with dystonia, myoclonus, tremor, Parkinsonism or stereotypies. The median duration of symptoms before TMS was 2.8 years (6 months to 30 years). The overall score of 75% of patients improved by >50% and, furthermore, the clinical benefits were sustained upon protracted follow-up (median 19.8 months). There was no correlation between improvement and duration of symptoms before TMS., Conclusions: TMS is a therapeutic option for PMDs, including chronic PMDs.

The clinical evaluation of a patient with dystonia is a stepwise process, beginning with classification of the phenomenology of the movement disorder(s), then formulation of the dystonia syndrome, which, in turn, leads to a targeted etiological differential diagnosis. In recent years, there have been significant advances in our understanding of the etiological basis of dystonia, aided especially by discoveries in imaging and genetics. In this review, we provide an update on the assessment of a patient with dystonia, including the phenomenology of dystonia and highlighting how to integrate clinical, imaging, blood, and neurophysiological investigations in order to formulate a dystonia syndrome. Evolving or emerging dystonia syndromes are reviewed, and potential etiologies of these as well as established dystonia syndromes listed to guide diagnostic testing. © 2013 Movement Disorder Society., (© 2013 Movement Disorder Society.)

Symptomatic treatment of cerebral palsy (CP) is difficult, with variable beneficial effect. The choice of therapy is guided by the main clinical features (spasticity, dystonia/choreoathetosis), by the experience of experts, and by the results of open-label trials and a few controlled studies. Treatments of spasticity are not discussed in depth here. From open-label trials and a few controlled studies in dystonia/choreoathetosis CP, it appears that treatment should be started at a low dose and increased slowly, and that more beneficial effects are obtained on upper extremity function, face and jaw dystonia and drooling, and in children. L-Baclofen or antiepileptic drugs are rarely effective and poorly tolerated whereas benzodiazepines may be moderately helpful. Local injections of botulinum toxin help to reduce pain and limit the amplitude of some movements (violent neck movements with high risk of symptomatic radiculomyelopathy). In a rare subtype of dystonia-choreathetosis CP with little spasticity and MRI lesions, bilateral pallidal stimulation (GPi) has shown mild to moderate improvement of dystonia (in open-label small series and in one controlled study) with no cognitive or mood adverse effects. Optimal placement of the leads was a major (but not exclusive) factor for good outcome but results cannot be predicted on an individual basis and larger studies are needed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to determine if there was a common pattern in movements during REM sleep behavior disorder (RBD)., Methods: We blindly compared video-monitored movements during RBD (n = 136 clips) and wakefulness/arousal (n = 53 clips) in patients with Parkinson's disease (n = 29) and without parkinsonism (idiopathic RBD, n = 31; narcolepsy, n = 5)., Results: The scorers accurately guessed the sleep/wake stage of 94% of video clips. Compared with wake movements, RBD movements were faster and more often repeated, jerky, and pseudohallucinatory, not self-centered, never associated with tremor, and rarely involved the environment in an appropriate manner. A specific posture of the hand (limp wrist with flexed digits) during grasping movements was evidenced during RBD in 48% of patients, reminiscent of hand-babbling in babies., Conclusions: These characteristics of movements were found in the 3 conditions (Parkinson's disease, idiopathic RBD, and primary narcolepsy), delineating a common motor signature of RBD., (Copyright © 2011 Movement Disorder Society.)

Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Our knowledge of the clinical, neurophysiological, and genetic aspects of myoclonus-dystonia (M-D) has improved markedly in the recent years. Basic research has provided new insights into the complex dysfunctions involved in the pathogenesis of M-D. On the basis of a comprehensive literature search, this review summarizes current knowledge on M-D, with a focus on recent findings. We also propose modified diagnostic criteria and recommendations for clinical management., (2008 Movement Disorder Society)

Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder due to glutaryl CoA dehydrogenase deficiency. Comprehensive descriptions of GA1-associated movement disorders are rare. In order to refine the description of the motor phenotype, we prospectively studied 16 consecutive pediatric and adult GA1 patients, focusing on the movement disorders and their time course. In most patients, generalized dystonia, superimposed on baseline axial hypotonia, remained the predominant feature throughout the disease course. With aging, it tended to evolve from mobile to fixed dystonia and to be associated with akinetic-rigid parkinsonism. Prominent orofacial involvement was a consistent feature in GA1 patients with movement disorders, resulting in speech disorders with features of combined hyperkinetic dysarthria and speech apraxia. The types and outcome of movement disorders in this setting should be taken into consideration during rehabilitation and for patient selection and evaluation in therapeutic trials., ((c) 2008 Movement Disorder Society.)

Inborn errors of metabolism (IEMs) may present in adolescence or adulthood with various movement disorders including parkinsonism, dystonia, chorea, tics or myoclonus. Main diseases causing movement disorders are metal-storage diseases, neurotransmitter synthesis defects, energy metabolism disorders and lysosomal storage diseases. IEMs should not be missed as many are treatable. Here we briefly review IEMs causing movement disorders in adolescence and adults and propose a simple diagnostic approach to guide metabolic investigations based on the clinical course of symptoms, the type of abnormal movements, and brain MRI abnormalities.

Botulinum toxin has been a useful treatment in many movement disorders and more recently in other non-neurological motor dysfunctions for more than 15 years. Here, we review the various indications in neurology, mainly in the field of movement disorders. From 1973 to 2002, we searched the Medline database on this topic. We selected the most useful and relevant papers, with a special interest in dystonia. We summarized the results in the main indications (spasmodic torticollis, bleparospasm, hemifacial spasm) and in other manifestations such as writer's cramp, oromandibular dystonia, tremor, tics and myoclonus. We discuss the data of literature and compare them with the experience of the French movement disorders groups.

Objective: To determine which thalamic subnuclei are involved in symptomatic unilateral movement disorders due to localized thalamic infarction, and the clinical characteristics of these abnormal movements., Methods: The authors studied 22 patients with thalamic infarcts for their clinical presentation and the topography of the lesions, using three-dimensional T1-weighted MRI sequencing and stereotaxic analysis of the lesions., Results: Patients were divided into four groups: 1) absence of abnormal involuntary movements (AIM) (nine patients); 2) isolated dystonic posture (two patients); 3) myoclonic dystonia (five patients); and 4) tremor or myoclonus (six patients). In patients with AIM, thalamic lesions were contralateral to the abnormal movements, involving the thalamogeniculate territory, centered on the ventral intermediate (Vim) and ventral caudal (Vc) nuclei. No significant difference in the volumes or center of mass of the lesions was found between patients with tremor and myoclonus and patients with dystonia, although the central nucleus and the internal part of the Vim nucleus were more consistently damaged in dystonic patients., Conclusion: Movement disorders related to thalamic lesions included: 1) myoclonic dystonia with predominating myoclonus and "thalamic" hand associating dystonic posture and slow, pseudo-athetoid movements, both related to lesions in the Vim and Vc nuclei of the thalamus; and 2) postural and action tremor, also related to lesions in the Vim, similar to tremor associated with midbrain lesions, as a result of abnormal functioning of the cerebello-thalamic pathways.

Paroxysmal dyskinesias are genetically and clinically heterogeneous. Paroxysmal kinesigenic choreoathetosis is frequently familial, with autosomal-dominant transmission. Benign infantile convulsions can be observed in these families and both diseases as linked to the pericentromeric region of chromosome 16. Two different forms of paroxysmal dystonic choreoathetosis are distinguished on clinical grounds, by the presence or absence of spasticity, and genetically, as they are linked with loci on different chromosomes. Among the paroxysmal disorders, these diseases may belong to the group of channelopathies.

The severity of parkinsonian motor disability and dyskinesias was evaluated in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist apomorphine, before and after low-dose clozapine (50 mg) for 18 +/- 2 days. There was a significant 59% improvement (p < 0.05) of apomorphine-induced dyskinesias without aggravation of parkinsonian motor disability following clozapine treatment. The results suggest that low-dose clozapine, already shown to improve psychotic symptoms, may help to reduce severe levodopa-induced dyskinesias in parkinsonian patients.

Seven patients suffering from Parkinson's disease (PD) with severely disabling dyskinesia received low-dose propranolol as an adjunct to the currently used medical treatment. There was a significant 40% improvement in the dyskinesia score without increase of parkinsonian motor disability. Ballistic and choreic dyskinesia were markedly ameliorated, whereas dystonia was not. This study suggests that administration of low doses of beta-blockers may improve levodopa-induced ballistic and choreic dyskinesia in PD.

The cerebral activity preceding voluntary, self-paced ankle dorsiflexion movements while seated was compared with that before a stepping movement of the same foot while standing in four patients with isolated gait ignition failure. Results within the patients group were variable, but all exhibited some increase in the Bereitschaftspotential (BP) amplitude when stepping as compared with sitting, similar to that seen in normal subjects. This differs from previous results in patients with Parkinson's disease in which stepping was not accompanied by a normal increase in BP amplitude. This difference suggests that the mechanisms responsible for the start hesitation that is common to both Parkinson's disease and gait ignition failure may differ in the two conditions.

We describe the case of a human immunodeficiency virus-infected 34-year-old man with progressive multifocal leukoencephalopathy (PML). His case displayed unusual features, including a bizarre movement disorder, predominant involvement of the subcortical U fibers on neuropathologic examination, and the absence of MRI abnormalities suggestive of PML. Anatomic-clinical correlations are discussed.

Cerebral energy metabolism was studied by positron emission tomography and [18F]fluorodeoxyglucose in five patients with clinical diagnoses of probable corticobasal degeneration. A reduction in glucose consumption was observed in most cortical and subcortical structures compared to age-matched controls. The reduction was greatest on the side of the brain contralateral to the most affected limbs, as shown by the significantly lower ratios of contralateral to homolateral metabolic rates, in the temporal and sensorimotor cortex of patients compared to controls. A distinct asymmetry between the two hemispheres could be observed in a patient who was examined twice in the course of his illness. Detection of this asymmetrical decrease in brain cortical and subcortical glucose metabolism may prove useful as additional evidence supporting clinical diagnoses of the disease.