Publications by authors named "Emmanuel Roze"

212 Publications

A Multi-center Genome-wide Association Study of Cervical Dystonia.

Mov Disord 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Lübeck, Lübeck, Germany.

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility.

Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach.

Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal.

Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823).

Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28732DOI Listing
July 2021

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

Eur J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background And Purpose: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.

Methods: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.

Results: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.

Conclusions: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.
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http://dx.doi.org/10.1111/ene.15031DOI Listing
July 2021

A single-center series of 482 patients with functional motor disorders.

J Psychosom Res 2021 Sep 2;148:110565. Epub 2021 Jul 2.

Service de Neurologie, Hôpital Avicenne, Hôpitaux Universitaires de Paris - Seine Saint Denis, Sorbonne Paris Nord, AP-HP, Bobigny, France; Dynamics and Pathophysiology of Neuronal Networks Team, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR7241/INSERM U1050, Université PSL, 75005 Paris, France.

Functional motor disorders (FMD) are common and disabling. They are known to predominantly affect women and young to middle-aged patients, although they also occur during childhood or in the elderly. Demographic and clinical characteristics of patients with FMD are poorly known, since large series of consecutive patients are scarce.

Methods: In a chart review study, we retrospectively abstracted data from consecutive FMD patients who were referred to the Neurophysiology Department of the Salpêtrière University Hospital between 2008 and 2016 for treatment with repeated transcranial magnetic stimulation.

Results: 482 patients were included. Most patients were women (73.7%). Median age at symptoms onset was 35.5 years and symptoms were mostly characterized by acute (47.3%) or subacute (46%) onset. Only 23% of patients were active workers, while 58.3% were unemployed because of FMD. Half of the patients had functional motor weakness (n = 241) whereas the other half had movement disorders (n = 241), mainly with tremor (21.1%) or dystonia (20.5%). Among all patients, 66.4% had psychiatric comorbidity and 82.6% reported a history of trauma in the 6 months before symptoms onset. No difference was found in age or gender according to clinical phenotypes.

Conclusion: This large series will contribute to better characterize FMDs.
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http://dx.doi.org/10.1016/j.jpsychores.2021.110565DOI Listing
September 2021

Long-term effect of apomorphine infusion in advanced Parkinson's disease: a real-life study.

NPJ Parkinsons Dis 2021 Jun 11;7(1):50. Epub 2021 Jun 11.

Neurology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson's disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson's disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
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http://dx.doi.org/10.1038/s41531-021-00194-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196159PMC
June 2021

COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters.

Sci Transl Med 2021 06 3;13(596). Epub 2021 May 3.

Perception and Memory Unit, Institut Pasteur, CNRS UMR3571, 75015 Paris, France.

Whereas recent investigations have revealed viral, inflammatory, and vascular factors involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung pathogenesis, the pathophysiology of neurological disorders in coronavirus disease 2019 (COVID-19) remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium is a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Last, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.
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http://dx.doi.org/10.1126/scitranslmed.abf8396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158965PMC
June 2021

Teaching Video NeuroImage: Paroxysmal Nocturnal Dyskinesias: A Characteristic Feature of Mutation.

Neurology 2021 09 7;97(10):e1062. Epub 2021 Apr 7.

From the Department of Clinical Neurosciences (T.M.P., N.C.), University of Calgary, Canada; and Department of Neurology (E.R.), Pitié-Salpêtrière Hospital, Sorbonne University and the Assistance Publique-Hôpitaux de Paris, France.

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http://dx.doi.org/10.1212/WNL.0000000000011920DOI Listing
September 2021

Trans-Spinal Direct Current Stimulation for Managing Primary Orthostatic Tremor.

Mov Disord 2021 08 27;36(8):1835-1842. Epub 2021 Mar 27.

Institut du Cerveau / Paris Brain Institute, ICM, Hôpital de la Pitié-Salpêtrière, CNRS UMR 7225, Inserm U 1127, Sorbonne Université UM75, Paris, France.

Background: Primary orthostatic tremor (POT) is a rare disorder, characterized by 13 to 18 Hz tremor in the legs when standing and is often refractory to medical treatment. Epidural spinal cord stimulation has been proposed as an alternative treatment. However, this approach is invasive, which limits its application.

Objective: Trans-spinal direct current stimulation (tsDCS) is a non-invasive method to modulate spinal cord circuits. The aim of this proof-of-concept study was to investigate the potential beneficial effect of tsDCS in POT.

Methods: We conducted a double-blind, sham-controlled study in 16 patients with POT. In two separate visits, patients received sham tsDCS first followed by active (either cathodal or anodal) tsDCS. The primary outcome was the change in time in standing position. Secondary outcomes comprised quantitative assessment of tremor, measurement of corticospinal excitability including short-latency afferent inhibition, and clinical global impression-improvement (CGI-I). Measurements were made at baseline, after sham tsDCS, 0-30 min, and 30-60 min after active conditions.

Results: Cathodal-tsDCS reduced tremor amplitude and frequency and lowered corticospinal excitability whereas anodal-tsDCS reduced tremor frequency only. CGI-I scores positively correlated with the time in standing position after both active tsDCS conditions.

Conclusion: A single session of tsDCS can improve instability in POT. This opens a new vista for experimental treatment options using multiple sessions of spinal DC stimulation. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28581DOI Listing
August 2021

Quality of life in isolated dystonia: non-motor manifestations matter.

J Neurol Neurosurg Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

Department of Neurology, University of Luebeck, Luebeck, Germany

Objective: To evaluate the relationship between health-related quality of life (HR-QoL) and both physical and psychiatric factors in a large, international, multicentre cohort of patients with isolated dystonia, the Dystonia Coalition.

Methods: Natural history data from 603 patients with isolated dystonia (median age 57 years (IQR: 48 to 64 years), 67.0% women) were prospectively acquired and analysed. HR-QoL (RAND 36-Item Health Survey), severity of depressive symptoms, generalised anxiety (Hospital Anxiety and Depression Scale) and social anxiety (Liebowitz Social Anxiety Scale) were assessed. Dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale) and dystonic tremor were examined. Statistical predictors of HR-QoL were calculated using saturated path analysis.

Results: Reduced HR-QoL was strongly associated with the degree of depressive symptoms and generalised and social anxiety (8/8 RAND 36 subscales, p≤0.001). Increased dystonia severity was associated with worse physical functioning, physical and emotional role functioning and social functioning (all p≤0.001). The presence of tremor correlated with worse physical functioning and pain (all p≤0.006). Younger age was associated with reduced emotional well-being and vitality (all p≤0.006). There were no HR-QoL differences between sexes.

Conclusion: HR-QoL in isolated dystonia is strongly associated with psychiatric and physical features. While current standard of care focus on motor aspects of dystonia, comprehensive care should address both physical and mental aspects of health.
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http://dx.doi.org/10.1136/jnnp-2020-325193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356023PMC
February 2021

NeuroQ: A neurophobia screening tool assesses how roleplay challenges neurophobia.

J Neurol Sci 2021 Feb 20;421:117320. Epub 2021 Jan 20.

AP-HP, Hôpital Pitié-Salpêtrière, Département de Neurologie, Paris, France; Sorbonne Université, France; INSERM U1127, CNRS 7225, Institut du Cerveau, Paris, France.

Background: Neurophobia is a chronic disease of medical students and junior doctors. Early detection is needed to facilitate prevention and management as this fear can negatively impact patient care.

Methods: We conducted a two-part mono-centric study at the faculty of Medicine, Sorbonne University, in Paris. Part one: a cross-sectional study to validate a newly constructed neurophobia scale, NeuroQ. Part two: a prospective longitudinal study to assess the impact of The Move on student neurophobia using NeuroQ. A population-based sample of second-year medical students of the 2019 and 2020 class of the Faculty of Medicine of Sorbonne University were invited to participate.

Results: NeuroQ incorporates the main themes of the neurophobia definition and demonstrates uni-dimensionality. Three hundred and ninety-five medical students participated in the study (mean age was 20.0 years, SD: 2.1 years) assessing the effect of The Move teaching on neurophobia. Two hundred and eighty-eight (72.9%) students were female. After the Move teaching the mean NeuroQ score was significantly lower compared to the baseline NeuroQ score (mean [SD] variation, -1.1 [2.6], p < 0.001). There was a 22.3% relative reduction in the number of neurophobic students after The Move teaching.

Conclusion: Our results highlight the utility of NeuroQ in assessing (i) baseline neurophobia and (ii) the impact of pre-clinical educational interventions on neurophobia. Furthermore, we have shown the importance of pre-clinical educational interventions, such as The Move, in tackling neurophobia.
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http://dx.doi.org/10.1016/j.jns.2021.117320DOI Listing
February 2021

Acute cerebellar ataxia and myoclonus with or without opsoclonus: a para-infectious syndrome associated with COVID-19.

Eur J Neurol 2021 Oct;28(10):3533-3536

Assistance Publique-Hôpitaux de Paris, Service de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France.

Background And Purpose: Patients with COVID-19 can have central or peripheral neurological manifestations.

Methods: The cases of two patients with acute cerebellar ataxia and myoclonus associated with COVID-19 are reported (with Video S1) and five previously reported patients are discussed.

Results: Acute cerebellar ataxia and myoclonus started between 10 days and 6 weeks after the first manifestations of COVID-19. Opsoclonus or ocular flutter was present in four patients. Patients were treated with intravenous immunoglobulins and/or steroids except for one patient, resulting in a striking improvement within a week.

Conclusion: Acute cerebellar ataxia and myoclonus with or without opsoclonus belongs to the wide spectrum of neurological manifestations associated with COVID-19. It is important to recognize this possible manifestation since early treatment allows for rapid recovery.
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http://dx.doi.org/10.1111/ene.14726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013847PMC
October 2021

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements.

Cell Rep 2021 01;34(3):108654

Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris-Seine (IBPS), Neuroscience Paris-Seine (NPS), 75005 Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.celrep.2020.108654DOI Listing
January 2021

A Reliable and Rapid Language Tool for the Diagnosis, Classification, and Follow-Up of Primary Progressive Aphasia Variants.

Front Neurol 2020 5;11:571657. Epub 2021 Jan 5.

Department of Neurology, National Reference Center for "PPA and rare dementias", Institute for Memory and Alzheimer's Disease, Pitié Salpêtrière Hospital, AP-HP, Paris, France.

Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking. We developed and evaluated a rapid language test for PPA ("PARIS") assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients ( = 36), typical amnesic Alzheimer's disease (AD) patients ( = 24) and healthy controls ( = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia ("LAST", "ART"). The application duration of the "PARIS" was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the "PARIS" reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the "LAST" and "ART," the "PARIS" also had the highest sensitivity for detecting language decline. The "PARIS" is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing.
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http://dx.doi.org/10.3389/fneur.2020.571657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813774PMC
January 2021

Transitional Care for Young People with Neurological Disorders: A Scoping Review with A Focus on Patients with Movement Disorders.

Mov Disord 2021 06 17;36(6):1316-1324. Epub 2020 Nov 17.

Department of Neurology, Salpêtrière Hospital, Sorbonne University and Assistance Publique - Hôpitaux de Paris, Paris, France.

Childhood-onset movement disorders represent a heterogenous group of conditions. Given the complexity of these disorders, the transition of care from pediatric to adult medicine is an important consideration. We performed a scoping review of the literature on transitional care in chronic neurological disease, exploring key transitional issues and proposed transitional care models. Our aim was to describe the current knowledge and gaps about the transition process of young adults with chronic neurological disorders, paying special attention to childhood onset movement disorders. A total of 64 articles were included in the qualitative synthesis; 56 articles reported on transitional care issues, and 8 articles reported on transitional care models. Only 2 articles included patients with movement disorders. The following 4 main transitional issues were identified following synthesis of the available literature: (1) inadequate preparation for the transition process, (2) inappropriate and inconsistent transition practices, (3) inadequate adult services, and (4) heightened emotional response surrounding transition. Of the reported transitional care models, multidisciplinary ambulatory care was the most common approach. In studies evaluating patient-related outcomes, positive health, educational, and vocational outcomes were found. The available literature provides insights on issues that can arise during transition that should be addressed to improve patient and caregiver comfort and satisfaction with care. Further research is needed to evaluate how transitional care programs affect outcomes and their cost effectiveness. More studies are required to determine the needs and outcomes specific to patients with childhood onset movement disorders. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28381DOI Listing
June 2021

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

Mov Disord 2021 06 16;36(6):1342-1352. Epub 2020 Nov 16.

Research and Development, Retrophin, Inc., San Diego, California, USA.

Background: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments.

Objectives: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression.

Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL.

Results: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups.

Conclusions: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 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.28392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246547PMC
June 2021

Dystonia: genetics, phenomenology, and pathophysiology.

Lancet Neurol 2020 11;19(11):881-882

Department of Neurology, Sorbonne Université, Paris, France; Institut du Cerveau et de la Moëlle épinière-Inserm U1127, Groupe Hospitalier Pitié-Salpêtrière, France; Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, France.

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http://dx.doi.org/10.1016/S1474-4422(20)30366-5DOI Listing
November 2020

Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders.

Expert Rev Neurother 2021 Jan 8;21(1):81-97. Epub 2020 Nov 8.

Département de Neurologie, AP-HP, Hôpital Pitié-Salpêtrière , Paris, France.

Introduction: Paroxysmal movement disorders mostly comprise paroxysmal dyskinesia and episodic ataxia, and can be the consequence of a genetic disorder or symptomatic of an acquired disease.

Areas Covered: In this review, the authors focused on certain hot-topic issues in the field: the respective contribution of the cerebellum and striatum to the generation of paroxysmal dyskinesia, the importance of striatal cAMP turnover in the pathogenesis of paroxysmal dyskinesia, the treatable causes of paroxysmal movement disorders not to be missed, with a special emphasis on the treatment strategy to bypass the glucose transport defect in paroxysmal movement disorders due to GLUT1 deficiency, and functional paroxysmal movement disorders.

Expert Opinion: Treatment of genetic causes of paroxysmal movement disorders is evolving towards precision medicine with targeted gene-specific therapy. Alteration of the cerebellar output and modulation of the striatal cAMP turnover offer new perspectives for experimental therapeutics, at least for paroxysmal movement disorders due to selected causes. Further characterization of cell-specific molecular pathways or network dysfunctions that are critically involved in the pathogenesis of paroxysmal movement disorders will likely result in the identification of new biomarkers and testing of innovative-targeted therapeutics.
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http://dx.doi.org/10.1080/14737175.2021.1840978DOI Listing
January 2021

Whispering dysphonia in TUBB4A-related disorders responsive to bipallidal deep brain stimulation.

Eur J Neurol 2021 03;28(3):1082-1083

Département de Neurologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.

Background: Mutations in TUBB4A are associated with a wide phenotypic spectrum including generalized dystonia with whispering dysphonia (DYT-TUBB4A).

Methods: We report the case of a 44-year-old patient with DYT-TUBB4A with a clinical presentation of disabling progressive dystonia, with a prominent laryngeal, cervical and facial involvement.

Results: Bipallidal deep brain stimulation (DBS) resulted in a 55% reduction of dystonia severity assessed by the Burke-Fahn-Marsden scale score 6 months after surgery. The effect was obvious on the cervical and facial components of dystonia.

Conclusion: We suggest that bipallidal DBS should be considered in patients with disabling dystonia related to TUBB4A variants.
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http://dx.doi.org/10.1111/ene.14602DOI Listing
March 2021

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

Neurology 2021 01 12;96(4):e563-e574. Epub 2020 Oct 12.

From the Departments of Biomedical Engineering (A.G.S., S.B.B.) and Neurology (A.G.S.), Case Western University School of Medicine; Neurological Institute (A.G.S.), University Hospitals Cleveland; Neurology Service (A.G.S.), Louis Stokes Cleveland VA Medical Center, OH; Department of Neurology (L.S., G.K.-B., A.F., S. Factor, H.A.J.), Human Genetics (H.A.J.), and Pediatrics (H.A.J.), Emory University School of Medicine, Atlanta, GA; Institute of Neurogenetics (C.K., J.J., S.L., N.B., A.M., T.B.), University of Lübeck, Germany; Department of Neurology (M.V., E.R., C.B.), Pitié-Salpêtrière Hospital, Paris, France; Department of Neurology (J.J.), Baylor College of Medicine, Houston, TX; Neurology and Neurosurgery (J.J.-S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neurology (N.P.), Henry Ford Health System, West Bloomfield, MI; Department of Psychiatry and Neurology (L.M.), Baylor College of Medicine, Houston, TX; Department of Neurological Sciences (C.C.), Rush University Medical Center, Chicago, IL; Department of Neurology (R.L.B.), University of Rochester, NY; Department of Neurology (B.D.B.), University of Colorado School of Medicine, Aurora; Department of Neurology (I.M., A.W.S.), Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville; Department of Neurology (S.G.R.), University of Maryland School of Medicine, Baltimore; University of Tennessee Health Science Center (M.S.L.), Memphis; Department of Neurosciences (A.B.), Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome; IRCCS Neuromed (G.F.), Pozzilli, Italy; The University of Alabama at Birmingham (N.S.); Methodist Neurological Institute (W.O.), Houston, TX; Department of Neurology (S.P.R.), University of New Mexico Health Sciences Center, Albuquerque; Department of Neurology (R.S.-P.), Mount Sinai Beth Israel, New York, NY; Lou Ruvo Center for Brain Health (Z.M.), Cleveland Clinic, Las Vegas, NV; Booth Gardner Parkinson's Care Center (P.A.), Kirkland, WA; Mayo Clinic (C.A.), Scottsdale, AZ; Andre Barbeau Movement Disorders Unit (S.C.), Montreal University Hospital Center (CHUM); Movement Disorder Clinic (S.H.F.), Toronto Western Hospital, Division of Neurology University of Toronto, Canada; UC Davis School of Medicine (A.B.), Sacramento; The Parkinson's and Movement Disorder Institute (D.T.), Orange Coast Memorial Medical Center, Fountain Valley, CA; Department of Medicine (O.S.), Medical Genetics, and Pediatrics, University of Alberta, Canada; Department of Neurology (S. Frank), Beth Israel Deaconess Medical Center, Boston, MA; and Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy (J.P.), Washington University School of Medicine, St Louis, MO.

Objective: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia.

Methods: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition.

Results: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics.

Conclusion: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.
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http://dx.doi.org/10.1212/WNL.0000000000011049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905789PMC
January 2021

Characterization of Recessive Parkinson Disease in a Large Multicenter Study.

Ann Neurol 2020 10 28;88(4):843-850. Epub 2020 Jul 28.

Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.
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http://dx.doi.org/10.1002/ana.25787DOI Listing
October 2020

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort.

Front Neurol 2020 28;11:682. Epub 2020 Jul 28.

Sorbonne Université, Unité Mixte de Recherche (UMR) 1127, Paris, France.

, and are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of , and mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with point mutations or genomic rearrangements (1.1%), and three with the Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], = 0.001). PD patients with variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], = 0.03), whereas those with mutations tended to have earlier age at onset disease (≤ 50 years, = 0.06). The clinical features of carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.
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http://dx.doi.org/10.3389/fneur.2020.00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399219PMC
July 2020

Clinical and Demographic Characteristics of Upper Limb Dystonia.

Mov Disord 2020 11 26;35(11):2086-2090. Epub 2020 Aug 26.

Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.

Background: Knowledge of characteristics in upper limb dystonia remains limited, derived primarily from small, single-site studies.

Objective: The objective of this study was to characterize demographic and clinical characteristics of upper limb dystonia from the Dystonia Coalition data set, a large, international, multicenter resource.

Methods: We evaluated clinical and demographic characteristics of 367 participants with upper limb dystonia from onset, comparing across subcategories of focal (with and without dystonia spread) versus nonfocal onset.

Results: Focal onset occurred in 80%; 67% remained focal without spread. Task specificity was most frequent in this subgroup, most often writer's cramp and affecting the dominant limb (83%). Focal onset with spread was more frequent in young onset (<21 years). Focal onset occurred equally in women and men; nonfocal onset affected women disproportionately.

Conclusions: Upper limb dystonia distribution, focality, and task specificity relate to onset age and likelihood of regional spread. Observations may inform clinical counseling and design, execution, and interpretation of future studies. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350751PMC
November 2020

Dissociation in reactive and proactive inhibitory control in Myoclonus dystonia.

Sci Rep 2020 08 18;10(1):13933. Epub 2020 Aug 18.

Sorbonne University, 75005, Paris, France.

Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive-compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.
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http://dx.doi.org/10.1038/s41598-020-70926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434767PMC
August 2020

MRI of neurodegeneration with brain iron accumulation.

Curr Opin Neurol 2020 08;33(4):462-473

Paris Brain Institute, Institut du Cerveau et de la Moelle épinière - ICM, INSERM U 1127, CNRS UMR 7225, Sorbonne Université, Team 'Movement Investigations and Therapeutics' (MOV'IT).

Purpose Of Review: The diagnosis of neurodegeneration with brain iron accumulation (NBIA) typically associates various extrapyramidal and pyramidal features, cognitive and psychiatric symptoms with bilateral hypointensities in the globus pallidus on iron-sensitive magnetic resonance images, reflecting the alteration of iron homeostasis in this area. This article details the contribution of MRI in the diagnosis by summarizing and comparing MRI patterns of the various NBIA subtypes.

Recent Findings: MRI almost always shows characteristic changes combining iron accumulation and additional neuroimaging abnormalities. Iron-sensitive MRI shows iron deposition in the basal ganglia, particularly in bilateral globus pallidus and substantia nigra. Other regions may be affected depending on the NBIA subtypes including the cerebellum and dentate nucleus, the midbrain, the striatum, the thalamus, and the cortex. Atrophy of the cerebellum, brainstem, corpus callosum and cortex, and white matter changes may be associated and worsen with disease duration. Iron deposition can be quantified using R2 or quantitative susceptibility mapping.

Summary: Recent MRI advances allow depicting differences between the various subtypes of NBIA, providing a useful analytical framework for clinicians. Standardization of protocols for image acquisition and analysis may help improving the detection of imaging changes associated with NBIA and the quantification of iron deposition.
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http://dx.doi.org/10.1097/WCO.0000000000000844DOI Listing
August 2020

Characterization of recessive Parkinson's disease in a large multicenter study.

Ann Neurol 2020 May 30. Epub 2020 May 30.

Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson's disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1587 cases. Mutations were found in 14.1% of patients: 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.25787DOI Listing
May 2020

Increased diagnostic yield in complex dystonia through exome sequencing.

Parkinsonism Relat Disord 2020 05 20;74:50-56. Epub 2020 Apr 20.

Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Introduction: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing.

Material And Methods: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature.

Results: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002).

Conclusion: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.
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http://dx.doi.org/10.1016/j.parkreldis.2020.04.003DOI Listing
May 2020

Structural and functional abnormalities within sensori-motor and limbic networks underpin intermittent explosive symptoms in Tourette disorder.

J Psychiatr Res 2020 06 4;125:1-6. Epub 2020 Mar 4.

Sorbonne University, 75005, Paris, France; Inserm U1127, CNRS UMR7225, UM75, ICM, Paris, France; Movement Investigation and Therapeutics Team, F-75013, Paris, France; National Reference Center for Tourette Syndrome, Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, F-75013, Paris, France; Department of Neurophysiology, Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris, France. Electronic address:

Background: Intermittent explosive outbursts (IEO), manifesting as sudden episodes of verbal or physical aggression, are frequently present in patients with Tourette disorder (TD) and considered as one of the most disabling symptoms by patients and families. The neuronal correlates of these behaviours are poorly understood, and this was the primary objective of the present study.

Methods: We assessed the presence of IEO in 55 patients with TD and then compared the subgroup of the patients with IEO to those without these manifestations using a multimodal neuroimaging approach.

Results: 47% of TD patients presented IEO, which was frequently associated with attention deficit hyperactivity disorder (ADHD). TD patients (without ADHD) with IEO compared to TD without IEO, showed structural changes in the right supplementary motor area as well as in the right hippocampus (increased fractional anisotropy), and in the left orbitofrontal cortex (decreased mean diffusivity). Using these three nodes as seeds for resting state functional connectivity, we showed a lower connectivity within the sensori-motor cortico-basal ganglia network, and an altered connectivity pattern among the orbito-frontal cortex, amygdala and hippocampus.

Conclusions: Overall, our results indicate that TD with IEO is associated with brain dysfunction related to a less efficient top-down control on action selection, and impairments related to emotional regulation, impulse control and aggressive behaviours.
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http://dx.doi.org/10.1016/j.jpsychires.2020.02.033DOI Listing
June 2020

Subcortical Myoclonus and Associated Dystonia in 22q11.2 Deletion Syndrome.

Tremor Other Hyperkinet Mov (N Y) 2019 24;10. Epub 2020 Jan 24.

Neurology Unit, Avicenne University Hospital, Hôpitaux Universitaires de Paris-Seine Saint Denis, Bobigny, FR.

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http://dx.doi.org/10.7916/tohm.v0.729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982424PMC
January 2020

Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism.

Mov Disord 2020 05 10;35(5):880-885. Epub 2020 Jan 10.

Sorbonne Université, Institut du Cerveau et de la Moelle épinière, Inserm U 1127, CNRS UMR 7225, F-75013, Paris, France.

Background: The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown.

Objective: To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2.

Methods: Phenotypic characterization and exome sequencing were carried out in 2 families.

Results: The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second.

Conclusions: NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27982DOI Listing
May 2020
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