REVIEW published: 14 January 2021 doi: 10.3389/fneur.2020.616569 The European Reference Network for Rare Neurological Diseases Carola Reinhard 1,2 , Anne-Catherine Bachoud-Lévi 3,4,5 , Tobias Bäumer 6,7 , Enrico Bertini 8 , Alicia Brunelle 1,2 , Annemieke I. Buizer 9 , Antonio Federico 10 , Thomas Gasser 11,12 , Samuel Groeschel 13 , Sanja Hermanns 1,2 , Thomas Klockgether 14 , Ingeborg Krägeloh-Mann 13 , G. Bernhard Landwehrmeyer 15 , Isabelle Leber 16,17 , Alfons Macaya 18 , Caterina Mariotti 19 , Wassilios G. Meissner 20,21 , Maria Judit Molnar 22 , Jorik Nonnekes 23 , Juan Dario Ortigoza Escobar 24 , Belen Pérez Dueñas 25 , Lori Renna Linton 26 , Ludger Schöls 27 , Rebecca Schuele 12,28 , Marina A. J. Tijssen 29 , Rik Vandenberghe 30,31 , Anna Volkmer 32,33 , Nicole I. Wolf 34 and Holm Graessner 1,2* 1 Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany, 2 Centre for Rare Diseases, University Hospital Tübingen, Tübingen, Germany, 3 Assistance Publique-Hôpitaux de Paris, National Reference Center for Huntington’s Disease, Neurology Department, Henri Mondor-Albert Chenevier Hospital, Créteil, France, Edited by: 4 Département d’Etudes Cognitives, École normale supérieure, PSL University, Paris, France, 5 Inserm U955, Institut Mondor Huifang Shang, de Recherche Biomédicale, Equipe E01 NeuroPsychologie Interventionnelle, Créteil, France, 6 Institute of Systems Motor Sichuan University, China Science, University of Lübeck, Lübeck, Germany, 7 Centre for Rare Diseases, University of Lübeck, Lübeck, Germany, 8 Unit Reviewed by: of Neuromuscular and Neurodegenerative Disorders and Genetics and Rare Diseases Research Division, Bambino Gesù Filippo M. Santorelli, Children’s Research Hospital, Instituto de Ricovero e Cura a Carattere Scientifico, Rome, Italy, 9 Department of Rehabilitation Fondazione Stella Maris (IRCCS), Italy Medicine, Amsterdam Movement Sciences and Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Marcondes C. França Jr., Universiteit Amsterdam, Amsterdam, Netherlands, 10 Department of Medicine, Neurology, and Neurosciences, Medical Campinas State University, Brazil School, University of Siena, Siena, Italy, 11 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, 12 German Center for Neurodegenerative Diseases, Tübingen, *Correspondence: Germany, 13 Department of Paediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Holm Graessner Germany, 14 Department of Neurology, University Hospital Bonn, Bonn, Germany, 15 University of Ulm, Department of holm.graessner@med. Neurology, Ulm, Germany, 16 Sorbonne Universités, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS uni-tuebingen.de UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France, 17 Reference Centre for Rare or Early Dementias, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France, 18 Pediatric Neurology Department, Vall Specialty section: d’Hebron Research Institute and Neuroscience Institute, Autonomous University Barcelona, Barcelona, Spain, 19 Unit of This article was submitted to Medical Genetics and Neurogenetics, Fondazione Instituto de Ricovero e Cura a Carattere Scientifico Istituto Neurologico Movement Disorders, Carlo Besta, Milan, Italy, 20 CRMR AMS, Service de Neurologie des Maladies Neurodégénératives, CHU Bordeaux, France a section of the journal and Univ. Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France, 21 Department of Medicine, University of Otago, New Frontiers in Neurology Zealand Brain Research Institute, Christchurch, New Zealand, 22 Institute of Genomic Medicine and Rare Disorders, Received: 12 October 2020 Semmelweis University, Budapest, Hungary, 23 Department of Rehabilitation, Centre of Expertise for Parkinson and Movement Accepted: 30 November 2020 Disorders, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands, Published: 14 January 2021 24 Movement Disorders Unit, Institut de Recerca Sant Joan de Déu, and Centro de Investigación Biomédica en Red de Enfermedades Raras Instituto de Salud Carlos III (CIBERER-ISCIII), Barcelona, Spain, 25 Department of Pediatric Neurology, Citation: Hospital Vall d’Hebrón, Pediatric Neurology Research Group at Vall d’Hebrón Research Institute, Universitat Autonoma de Reinhard C, Bachoud-Lévi A-C, Barcelona, Barcelona, Spain, 26 EuroHSP, Plateforme Maladies Rares, Paris, France, 27 Department of Neurology, Hertie Bäumer T, Bertini E, Brunelle A, Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, 28 Department of Neurodegenerative Buizer AI, Federico A, Gasser T, Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany, Groeschel S, Hermanns S, 29 Expertise Center Movement Disorders Groningen, University Medical Center Groningen, University of Groningen, Klockgether T, Krägeloh-Mann I, Groningen, Netherlands, 30 Neurology Service, University Hospitals Leuven, Leuven, Belgium, 31 Laboratory for Cognitive Landwehrmeyer GB, Leber I, Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Belgium, 32 Division of Psychology and Macaya A, Mariotti C, Meissner WG, Language Sciences, University College London, London, United Kingdom, 33 Department of Therapy Services, University Molnar MJ, Nonnekes J, Ortigoza College London Hospitals National Health System Foundation Trust National Hospital for Neurology and Neurosurgery, Escobar JD, Pérez Dueñas B, Renna London, United Kingdom, 34 Department of Child Neurology, Amsterdam Leukodystrophy Centre, Emma Children’s Hospital, Linton L, Schöls L, Schuele R, Amsterdam University Medical Centres, Vrije Universiteit, and Amsterdam Neuroscience, Amsterdam, Netherlands Tijssen MAJ, Vandenberghe R, Volkmer A, Wolf NI and Graessner H (2021) The European Reference While rare diseases (RDs) are by definition of low prevalence, the total number of Network for Rare Neurological Diseases. Front. Neurol. 11:616569. patients suffering from an RD is high, and the majority of them have neurologic doi: 10.3389/fneur.2020.616569 manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Frontiers in Neurology | www.frontiersin.org 1 January 2021 | Volume 11 | Article 616569 Reinhard et al. ERN Rare Neurological Diseases 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. Keywords: rare neurological diseases, standards of care, training and education, virtual healthcare, European reference network INTRODUCTION European Reference Networks for Rare Rare Diseases in Europe—The Current Diseases As response to this challenge, European Reference Networks Situation and Challenges (ERNs) were launched in 2017 by the European Union Board In Europe, a disease is considered as “rare” if it affects <1 person of Member States as a pan-European initiative to facilitate in 2000 (1). Although rare diseases (RDs) have–per definition–a access to highly specialized healthcare for patients with rare or low prevalence, the total number of patients with an RD is high, low-prevalence complex diseases. It also aims to reinforce the concerning about 3.5–5.9% of the population that equates to 263– cooperation of Healthcare Providers in the field of RDs at the 446 million persons affected globally at any point in time (2). European level. The majority of RD have neurological manifestations, involving ERNs are legally based on the European Directive 2011/24/EU central, peripheral nerve and muscle (3). Most RDs are associated on patients’ rights in cross-border healthcare. with high unmet needs due to the lack of available and effective This worldwide-unique initiative resulted in 24 ERNs being diagnosis and treatment measures as well as the relative lack formed, involving more than 900 specialized healthcare units of research to develop such measures, at least partly due to the from over 300 hospitals in 26 Member States (4). There are low number of medical experts available for each condition and three ERNs with a neurological focus: ERN EpiCARE1 on rare limited financial resources. A current analysis of Orphanet has epilepsies, Euro-NMD2 on rare neuromuscular diseases, and shown that of the 5,304 diseases defined by point prevalence, European Reference Network for Rare Neurological Diseases 84.5% of those analyzed have a point prevalence of <1/1,000,000 (ERN-RND) that will be described in more detail below. (2) and can thus be characterized as ultra-rare diseases. This means that no single European Union (EU) member state can provide access to the best possible healthcare to its citizens in all 1 https://epi-care.eu/ 2 https://ern-euro-nmd.eu/ areas of highly specialized healthcare for RD patients on its own. Frontiers in Neurology | www.frontiersin.org 2 January 2021 | Volume 11 | Article 616569 Reinhard et al. ERN Rare Neurological Diseases Each ERN had to fulfill a number of criteria for of RNDs has, moreover, been facilitating the development of implementation, evaluation, and knowledge sharing, while targeted molecular therapies for RND, such as viral vector-based the respective national authorities endorsed the individual gene therapy and antisense oligonucleotides. healthcare providers to become an ERN member. For a detailed The huge heterogeneity of RND and healthcare systems in description of the conceptual framework, see Heon-Klin (5). Europe, as well as the still limited clinical expert workforce base The central political aim of the ERNs is that medical expertise for RND at a time of rapid clinical innovation, means that there “travels,” and that only in a few cases (e.g., for highly specialized is a very real risk that significant parts of estimated more than interventions and for diagnostic and therapeutic measures that 500,000 RND patients across Europe might not benefit from are not available in the country the respective person lives in) improved diagnosis, care, and treatment opportunities. the patient has to travel. This marks a significant step toward Consequently, the objectives of the ERN-RND are improving healthcare quality, harmonizing medical (diagnosis) as follows: procedures, reducing access inequalities, and increasing overall i. To significantly increase the overall percentage of RND medical experience and knowledge in the whole of Europe. patients with a confirmed (molecular) diagnosis In addition, the ERNs open the possibility to get sizable ii. To improve and harmonize care including neurorehabilitation cohorts of patients in the perspective of therapeutic trials and the and transition of RND patients across the EU development of research collaborations. iii. To develop, share, and implement care pathways and guidelines for all RND groups represented in ERN-RND Travel of Knowledge Put Into iv. To create, develop, and enhance the capacity to design, Practice—The Clinical Patient implement, and supervise RND training, education, and Management System capacity building activities at the level of member states and To improve the diagnosis and treatment of RDs in practical of the network terms, the European Commission has set up the Clinical v. To develop comprehensive and data-based European RND Patient Management System (CPMS3 ), a web-based clinical cohorts to be able to deploy digital solutions, including software application, enabling secure remote multi-national and artificial intelligence-based tools, for diagnosis and patient- multidisciplinary case discussions. centered integrated care, in order to better understand these The CPMS can be used by healthcare professionals of all ERNs, conditions and thus improve their management and help who can upload patient data in a structured manner following developing and testing treatments an informed consent procedure. Clinicians from outside the vi. To define the minimum quality and interoperability criteria ERNs can request CPMS-based advice from ERNs on specific for RND registries allowing the exchange of data between patients through referring them to the nearest national ERN existing registries and the ERN-RND registry. healthcare provider. So far, over 40 CPMS case discussions have Building on existing mature RND European disease networks, been performed by ERN-RND members. such as the European Huntington’s Disease Network4 , the Ataxia Study Group5 , and DystoniaNet6 , which have already strong The European Reference Network for Rare clinical collaborations, ERN-RND focuses on the following Neurological Diseases disease groups at the moment: The ERN-RND is a network of the European RND expertise centers. At present, it has 32 full members and 10 affiliated 1) Cerebellar Ataxias and Hereditary Spastic Paraplegias partners from 21 countries (a list of the actual ERN- (Coordinators: Enrico Bertini, Alfons Macaya, Caterina RND full members and affiliated partners, their countries, Mariotti, Rebecca Schuele) and their respective areas of expertise are provided as 2) Huntington’s disease and Other Choreas (Coordinators: Supplementary Material); however, through a currently ongoing Anne-Catherine Bachoud-Lévi, Bernhard Landwehrmeyer, expansion process, the ERN-RND will be including the vast Juan Dario Ortigoza Escobar) majority of EU countries by mid-2021. Thus, ERN-RND will 3) Frontotemporal dementia (Coordinators: Isabelle Leber, be the first truly pan-European rare neurological disease (RND) Markus Otto, Rik Vandenberghe) network that brings together all respective European expertise 4) Dystonia, (non-epileptic) paroxysmal disorders, and centers. Governance and activities of ERN-RND are patient Neurodegeneration with Brain Iron Accumulation centered that is reflected by the active involvement of European (Coordinators: Tobias Bäumer, Belen Pérez Dueñas, Patient Advocacy Groups (ePAGs) representatives. Giovanna Zorzi) The formation of ERN-RND is timely since RNDs present 5) Leukoencephalopathies (Coordinators: Odile Boespflug- a topic of continuously growing importance in neurology. Tanguy, Ingeborg Krägeloh-Mann, Samuel Groeschel, Nicole Rapid advances in clinical knowledge in recent years have been I. Wolf). facilitated by the emergence of genetic and other diagnostic technologies, helping us to develop a deeper understanding of RDs and their causes. The defined genetic etiology of the majority 4 http://www.ehdn.org 5 http://www.ataxia-study-group.net 3 https://cpms.ern-net.eu/login/ 6 https://dystonia.net/ Frontiers in Neurology | www.frontiersin.org 3 January 2021 | Volume 11 | Article 616569 Reinhard et al. ERN Rare Neurological Diseases FIGURE 1 | Network and governance structure of ERN-RND. 6) Atypical Parkinsonian Syndromes (Coordinators: Thomas the ERN-RND expertise centers has been improved through Gasser, Wassilios Meissner). collaboration with Orphanet, by providing contact information on a newly created website7 and by rolling out a comprehensive ERN-RND is coordinated at the University Hospital Tübingen, multi-channel information campaign. Secondly, disease Germany, with Holm Graessner being the coordinator and knowledge documents have been created and are being provided Ludger Schöls the clinical lead. An overview about the network to the different stakeholder groups. In particular, disease expert and governance structure of ERN-RND is given in Figure 1. groups developed and consented on RND diagnostic flowcharts, Activities of ERN-RND are coordinated based on the covered as well as on disease scales to assess the different aspects of RND. disease groups as well as the following cross-cutting lines of work ERN-RND recommends the use of these flowcharts and disease that address the objectives: scales and actively disseminates them to clinicians, national 1) RND diagnostic pathways (Coordinator: Alexandra Durr) and European professional societies, and patient organizations8 . 2) Expert RND Care Coordination (Coordinator: Marina Thirdly, ERN-RND has started to discuss patients without a de Koning-Tijssen) definitive diagnosis in the CPMS. Fourthly, ERN-RND has 3) Training, education, and capacity building (Coordinator: been collaborating with the EU rare disease diagnostic research Maria Judit Molnar) flagship project Solve-RD (Solving the unsolved Rare Diseases9 ); 4) Information sharing and disease resources (Coordinator: ERN-RND is one of four ERNs that serve as foundation Holm Graessner) of Solve-RD. 5) Guidelines, pathways, and best practice (Coordinator: Antonio Federico) 6) Registries and Research (Coordinator: Thomas Klockgether) EXPERT RND CARE COORDINATION 7) Pediatric issues (Coordinators: Juan Dario Ortigoza Escobar, RND care needs and situations differ between disease groups Caroline Sevin, Nicole I. Wolf) as well as between countries. In order to capture and assess 8) Neurorehabilitation (Coordinators: Annemieke I. Buizer, care needs ERN-RND can address, a care need survey has been Antonio Federico, Maria Judit Molnar, Jorik Nonnekes, Lori performed for all disease groups covered by ERN-RND across all Renna Linton). EU countries (6). The survey is based on a respective publication for dystonia (7). Main measures to improve the management RND DIAGNOSTIC PATHWAYS 7 www.ern-rnd.eu To improve the diagnosis of RND patients, ERN-RND has 8 http://www.ern-rnd.eu/disease-knowledge-hub/. been implementing four activities. Firstly, the visibility of 9 www.solve-rd.eu. Frontiers in Neurology | www.frontiersin.org 4 January 2021 | Volume 11 | Article 616569 Reinhard et al. ERN Rare Neurological Diseases of RND patients that have been identified include the (i) website11 . Efforts are provided to multiply document access to development of multidisciplinary teams, (ii) implementation of patients from different languages. educational activities to enhance recognition of RND among healthcare professionals and in the general population, (iii) improvement of the accessibility to standard and advanced GUIDELINES, PATHWAYS, AND BEST genetic testing and to clinical geneticists, and (iv) development PRACTICE of more dedicated tertiary centers meaning more expertise in the field. Clinical practice guidelines for RD are scarce and difficult to In addition, treatment algorithms and the composition of find (8). Therefore, ERN-RND will use the expertise of its the multidisciplinary care team for all covered RND will be partners to adopt and develop clinical practice guidelines for the developed and consented on. By this process and the activities diseases covered by the network. GRADE methodology12 will regarding diagnostic flowchart and assessment scales, ERN-RND be used, following the recommendations by the EAN (9, 10). will help to develop a comprehensive knowledge body of RND The work on European guidelines for diagnosis and treatment care standards within ERN-RND. of Metachromatic Leukodystrophies has recently started. Furthermore, ERN-RND endorses or affirms the value of existing guidelines, depending on whether an EAN equivalent TRAINING, EDUCATION, AND CAPACITY methodology was used or not. Examples are: Management of the BUILDING ataxias toward best clinical practice (11) and the International Guidelines for the Treatment of Huntington’s Disease (12). ERN-RND has implemented an RND training and education As a matter of fact, guideline development in RND often program10 based on the following pillars: struggles with the lack of systematic reviews and strong evidence. 1) Educational webinar series in collaboration with the European ERN-RND actively contributes to the project of the EAN Academy of Neurology (EAN) and the European Reference on guidance for developing and reporting guidelines in the Network for Neuromuscular Disorders (Euro-NMD). field of RNDs, as well as the critical appraisal of all existing 2) Hands-on training winter and summer schools for young RND guidelines. neurologists past topics ranging from “Diagnostic of rare Furthermore, in the context of the Value of Treatment movement disorders” to “Hereditary white matter diseases— project13 , ERN-RND has set up a collaboration with the clinics, genetics, therapy”. European Brain Council to assess the benefits of expertise centers 3) Short-term mobility fellowships for RND for rare neurological disorders in consideration of the quality of healthcare professionals. care being provided and cost-effectiveness. In particular, the webinar series has attracted a high number of attendees both across Europe and globally and has been expanded REGISTRIES AND RESEARCH from topics based on disease knowledge to neurorehabilitation. With the foundation of ERN-RND, a large network of potential trial sites for RND has been formed. As the ERN-RND expertise INFORMATION SHARING AND DISEASE centers are very likely those centers that are performing and RESOURCES will perform RND treatment trials in Europe, the network will facilitate trial readiness through three activities. Firstly, it is about ERN-RND aims to become the information hub for all available to establish an ERN-RND registry that is going to comprise information for the diseases covered by the network. Therefore, minimal data of all patients seen at the ERN-RND centers. ERN-RND collects and edits available information as well as This registry will thus provide a unique overview of existing produces new information and knowledge. Disease knowledge, genotype-based cohorts. The minimal data set being used is to be included in ERN-RND disease knowledge pages, needs based on the “Set of common data elements for Rare Diseases to undergo an affirmation process that includes patients’ Registration” as recommended by the European Platform on representatives as well as expert clinicians from the network. Rare Disease Registration14 . Secondly, ERN-RND has organized ERN-RND reached out to 27 European national neurological and will be organizing multi-stakeholder workshops focusing on societies with regard to setting up an RND webpage on their the different aspects of trial readiness. Thirdly, ERN-RND will respective society website to increase the visibility of RNDs across strive to support trial readiness platforms, such as ARCA and the European community of neurologists. Although this has not SCA Global15 , in order to help in addressing major knowledge yet been implemented, it is an important part of our awareness gaps that preclude further progress toward the development of strategy. In addition to this, the ERN-RND monthly newsletter effective therapies in RNDs. is sent to a varied audience including patients, patient advocates, clinicians, and researchers in Europe to inform them about the 11 www.ern-rnd.eu latest developments within the network and in the RND field in 12 http://www.gradeworkinggroup.org/ general. All disease information is compiled on the ERN-RND 13 https://www.braincouncil.eu/activities/projects/the-value-of-treatment 14 https://eu-rd-platform.jrc.ec.europa.eu/_en. 10 http://www.ern-rnd.eu/education-training/ 15 http://ataxia-global-initiatives.net/. Frontiers in Neurology | www.frontiersin.org 5 January 2021 | Volume 11 | Article 616569 Reinhard et al. ERN Rare Neurological Diseases PEDIATRIC ISSUES improvement, accountability, and identification of needs for strategy adjustments and promotion of patient empowerment. The working group on pediatric issues has been formed recently to specifically address the different needs of pediatric DISCUSSION AND CONCLUSIONS RND. The cross-cutting pediatric issues should be addressed (i) within ERN-RND, (ii) in collaboration with other ERNs, ERN-RND provides an expertise-based infrastructure for sharing and (iii) linked with the European Pediatric Neurological knowledge and coordinating care for patients affected by RNDs. Society (EPNS). The evolving network presents a new unique organization able As a first step, a mapping exercise is being performed to create, take up, and implement emerging diagnostic, care, and on the specific neuropediatric expertise of the ERN-RND treatment innovations. centers as well as on existing pediatric scales that are used Built as a virtual network, ERN-RND provides–besides across the disease groups to identify potential gaps. Patient the flagship CPMS–also e-solutions for all other areas of information leaflets with a focus on pediatric issues as well as cooperation of the different project bodies and stakeholders, information about clinical trials should be collected and made including webinars, cloud-based document-repositories, and available on the ERN-RND website. In addition, collaboration web conferences. with the EPNS, e.g., focusing on joint training activities, has Future challenges include equity of quality of care being been implemented. provided across the EU as well as the systematic integration of ERN into the national healthcare systems. NEUROREHABILITATION AUTHOR CONTRIBUTIONS As causal treatments are only scarcely available for RND, neurorehabilitation is an important aspect in the management of HG and CR are the coordinator and project manager, these diseases. To address this need, a specific working group has respectively, of the European Reference Network for Rare been formed with the following goals: (i) organization of teaching Neurological Diseases and wrote the publication. LS is the clinical courses on neurorehabilitation of the different RNDs. As a first lead of ERN-RND. SH and AB are members of the coordination step, online training webinars focusing on neurorehabilitation of office. RS, CM, EB, AM, RV, IL, SG, IK-M, NW, A-CB-L, BL, RND have been organized. (ii) Organization of national/regional JO, TG, WM, BP, and TB are disease group coordinators. AF, networks for RND neurorehabilitation. (iii) Guidelines MT, MM, TK, JO, AIB, JN, LR, and AV are working group production in collaboration with EAN panels and the European coordinators. All authors are responsible for the work described Federation for Neurorehabilitation. in their respective project roles and critically reviewed the As a first step, a mapping of the locally used manuscript. neurorehabilitation protocols including the evidence on which they are based and the possibility of transfer to other ACKNOWLEDGMENTS centers is underway. This work is generated within the European Reference Network MONITORING AND EVALUATION OF for Rare Neurological Diseases—Project ID No. 739510. We ERN-RND acknowledge support by the Open Access Publishing Fund of the University of Tübingen. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based SUPPLEMENTARY MATERIAL on this objective, ERNs are monitored on a regular basis by the European Commission to guarantee transparency and The Supplementary Material for this article can be found provide reassurance of both the RD community and the online at: https://www.frontiersin.org/articles/10.3389/fneur. general public. Additional reasons for monitoring include quality 2020.616569/full#supplementary-material REFERENCES 4. Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the Application of Patients’ Rights in Cross-Border Healthcare. 1. What is a rare disease? Available online at: https://www.eurordis.org/content/ Available online at: http://data.europa.eu/eli/dir/2011/24/oj what-rare-disease (accessed December 23, 2020). 5. Heon-Klin V. European Reference networks for rare diseases: what 2. 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GL receives/has received research support from 22:1505–10. doi: 10.1111/ene.12818 Bundesministerium für Bildung und Forschung (BMBF), CHDI Foundation, 11. de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou Deutsche Forschungsgemeinschaft (DFG), the European HD Network (EHDN), M. Diagnosis and management of progressive ataxia in adults. Pract Neurol. and the European Union (EU - Horizon2020, JPND), GL serves/served at (2019) 19:196–207. doi: 10.1136/practneurol-2018-002096 Scientific Advisory Boards of Hoffmann-LaRoche, Novartis, PTC Therapeutics, 12. Bachoud-Levi AC, Ferreira J, Massart R, Youssov K, Rosser A, Busse TEVA, Triplet Therapeutics & Takeda and provided scientific advice to Acadia M, et al. International guidelines for the treatment of Huntington’s Pharm, AOP Orphan, Boehringer-lngelhe1m, CHDI Foundation, lonis Pharma, disease. Front Neurol. (2019) 10:710. doi: 10.3389/fneur.2019. Lundbeck, NeuraMetrix, Prilenia, and Wave. MM received research support 00710 from the National Research, Development and Innovation Office for the National Brain Research and the National Bionics Projects. She has received consulting Conflict of Interest: TG has received research support from the Deutsche fees from Richter Gedeon Plc, Novartis, Sanofi-Genzyme, PTC Therapeutics, Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Stealth Biotherapeutics, Amicus, Takeda, and Biogen. She has received a speaker Forschung (BMBF), the European Union (EU), and the National Institutes honorarium from Johnson and Johnson and AOP Orphan. of Health (NIH). He has received speakers honoraria from, Roche, Teva and UBC. SG received institutional research support from Shire plc, outside of the The remaining authors declare that the research was conducted in the absence of submitted work. He is advisor and co-investigator for trials in Metachromatic any commercial or financial relationships that could be construed as a potential Leukodystrophy (Shire/Takeda, Orchard), but receives no personal payment conflict of interest. related to this role. TK has received research support from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Copyright © 2021 Reinhard, Bachoud-Lévi, Bäumer, Bertini, Brunelle, Forschung (BMBF), the Bundesministerium für Gesundheit (BMG), the Robert Buizer, Federico, Gasser, Groeschel, Hermanns, Klockgether, Krägeloh-Mann, Bosch Foundation, the European Union (EU), and the National Institutes of Landwehrmeyer, Leber, Macaya, Mariotti, Meissner, Molnar, Nonnekes, Ortigoza Health (NIH). He has received consulting fees from Biohaven, Roche and UBC. Escobar, Pérez Dueñas, Renna Linton, Schöls, Schuele, Tijssen, Vandenberghe, He has received a speaker honorarium from Novartis and Bayer. IL served as a Volkmer, Wolf and Graessner. This is an open-access article distributed under the member of advisory boards for Prevail Therapeutic and received research grants terms of the Creative Commons Attribution License (CC BY). The use, distribution from ANR, DGOS, Vaincre Alzheimer Association, ARSla Association, Fondation or reproduction in other forums is permitted, provided the original author(s) and Plan Alzheimer outside of the present work. Unrelated to the present work, WM the copyright owner(s) are credited and that the original publication in this journal has received fees for editorial activities with Springer and Elsevier, has served is cited, in accordance with accepted academic practice. No use, distribution or as advisor for Lundbeck and Biohaven, and has received teaching honoraria reproduction is permitted which does not comply with these terms. Frontiers in Neurology | www.frontiersin.org 7 January 2021 | Volume 11 | Article 616569