Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 https://doi.org/10.1186/s13023-020-01455-z RESEARCH Open Access Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry) Tomàs Pinós1, Antoni L. Andreu1, Claudio Bruno2, Georgios M. Hadjigeorgiou3, Ronald G. Haller4, Pascal Laforêt5,6, Alejandro Lucía7,8, Miguel A. Martín8, Andrea Martinuzzi9, Carmen Navarro10, Piraye Oflazer11, Jean Pouget12, Ros Quinlivan13, Sabrina Sacconi14, Renata S. Scalco13, Antonio Toscano15, John Vissing16, Matthias Vorgerd17, Andrew Wakelin18, Ramon Martí1* and EUROMAC Consortium Abstract Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders. Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients. Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level. Keywords: Myopathy, Rare diseases, International registry, McArdle disease, Metabolic diseases, Glycogen storage disease * Correspondence: ramon.marti@vhir.org 1 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, and Research Group on Neuromuscular and Mitochondrial Diseases, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d’Hebron 119, 08035 Barcelona, Catalonia, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 2 of 11 Background muscle glycogenoses (types 0, III, IV, VII, VIII, IX, X, XI, McArdle disease (glycogen storage disease type V, myopho- XII, XIII, XIV and XV). Glycogenosis type II (Pompe dis- sphorylase deficiency) is an autosomal recessive disorder of ease) was not included in EUROMAC because a global glycogen metabolism, originally described in 1951 [1]. It is registry for Pompe disease already exists (NCT00231400, the most frequent metabolic myopathy with an estimated https://clinicaltrials.gov/), which is planned to last at least prevalence of ~ 1 in 140,000 people [2]. The disease is until year 2034. To achieve this main goal, several specific caused by mutations in PYGM that encodes the muscle aims were proposed: a) to obtain epidemiology data on isoform of glycogen phosphorylase (GP-MM; 1,4-alpha-D- these diseases in Europe; b) to reach patients and medical glucan: phosphate alpha-D-glucosyltransferase). The muta- community to inform on these disorders; c) to assess clin- tions lead to loss of enzyme activity and thus inability to ical and cost effectiveness of standard and novel thera- break down muscle glycogen, making this source of energy peutic interventions; d) to assess quality of care provided unavailable to patients [3]. Clinically, McArdle Disease is by services; e) to gain insight on disease pathophysiology; characterized by exercise intolerance typified by acute crises and f) to provide an inventory of patients that can be con- of early fatigue and muscle contractures that in ~ 50% of tacted for clinical research. In pursuance of these objec- the cases are accompanied by rhabdomyolysis, hyper- tives, the EMR intended to recruit into the registry all creatine kinase (CK)-emia and myoglobinuria, which occa- individuals who had been diagnosed with McArdle Dis- sionally result in acute renal failure [3, 4]. In case of delayed ease and other rare muscle glycogenoses in Europe. Thus, diagnosis and incorrect medical advice, this could lead to the expected long-term impacts of the EMR are as risk of life-threatening crises necessitating admission to followed: 1) an improved access by patients to specialized critical care. There is phenotypic variability, ranging from care; 2) facilitation of the involvement of governments and rare cases of patients that are virtually asymptomatic to the regulatory agencies; 3) improved knowledge of the natural more common ones reporting recurrent exertional myoglo- history of these diseases; 4) shorter delay in diagnosis; 5) binuria, fixed muscle weakness and severe limitations of ex- reduced risk of incorrect advice leading to debilitating ercise and most daily life activities [2, 5]. symptoms and risk of life-threatening crises, and 6) ex- There are scarce data available on the McArdle Dis- tended use of the registry to all European countries. The ease epidemiology, as most of the studies have been lim- possibility to increase the expertise on these disorders in ited by small sample sizes, consistently < 100 cases [4, eastern European countries makes this goal especially 6–20]. The study of large cohorts of patients with rare valuable. disorders such as McArdle Disease is hampered by the low prevalence and heterogeneity of patient populations, Target groups as well as by the limited knowledge of their natural his- EUROMAC has promoted the involvement of a number tory. The largest cohort of McArdle Disease patients was of stakeholders, such as: reported in 2012, which described the features of 239 Spanish patients [5], updated 5 years later with 94 add- a) Patients and their relatives, as well as caregivers. itional patients [2]. Studies of larger cohorts are clinically b) Patients’ advocacy groups (e.g., patients’ important as they help to improve our knowledge about associations). the disease and of the main problems faced by patients, c) Clinicians and researchers, participating as data thereby allowing for targeted lifestyle intervention. Thus, contributors. the European Commission and the National Institutes of d) Biopharmaceutical industry. Health have set-up international patient registries for e) Governments and regulatory agencies. rare diseases to facilitate knowledge about them and to promote better standards of care and diagnosis. Implementation We aimed to implement a European Patient Registry EUROMAC was founded by joining 13 full partners for McArdle Disease and other rare muscle glycogenoses from seven EU member countries at the time of the con- (EUROMAC registry, EMR). The present paper de- sortium building (United Kingdom, Spain, Italy, France, scribes how the EMR was developed and implemented Germany, Denmark and Greece) plus five collaborative detailing its strengths and shortcomings with the aim of members from four countries (Spain, France, Turkey facilitating the creation of other rare disease patient and USA). The initial building of the consortium aimed registries. to apply for funding to the European Commission’s Consumers, Health, Agriculture and Food Executive Methods and results Agency (CHAFEA) to develop the EUROMAC project Aims of the EMR (see “Funding and Acknowledgements” section below) The main aim of the EMR was to promote awareness and so partners were divided into two categories accord- and understanding of McArdle Disease and other rare ing to the specificities of the CHAFEA call: full partners Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 3 of 11 were in charge of specific tasks, receiving funds bud- administrative managers. Additionally, EUROMAC geted for those tasks, while collaborative partners pro- benefited from the experience gained by the different vided expertise and valuable collaboration, but did not partners in obtaining their own patient cohorts and na- receive direct funding as they were not responsible of tional registries [2, 4–6, 12, 19, 20]. specific tasks. Travel expenses for EUROMAC meetings Initially, the registry was restricted to European coun- and events were covered for both full and collaborative tries, as the project was framed within a funding con- partners. The complete list of members is shown in tract with the CHAFEA agency of the European Table 1. The EUROMAC team constituted a multidis- Commission. However, the aim to expand the registry to ciplinary group in the field of neuromuscular disorders non-European countries in the future was also stated including neurologists, paediatricians, physiotherapists, since the beginning. EUROMAC is now open to accept exercise physiologists, clinical psychologists, biologists, new professionals from non-European countries, pro- patients’ representatives as well as project and vided they follow the same procedures already applied to Table 1 List of partners and collaborative members of the EUROMAC consortium Membership Organization name Acronym Department Type of partner City Country Full partner Vall d’Hebron Institut de VHIR Neuromuscular and Academic/Hospital Barcelona Spain Recerca Mitochondrial Research Full partner Servicio Madrileño de la SERMAS Mitochondrial and Academic/Hospital Madrid Spain Salud Neuromuscular Diseases group Full partner Fundación Biomédica del FBCHUVI Pathology and Neuropathology Academic/Hospital Vigo Spain Complejo Hospitalario Universitario de Vigo Full partner IRCCS Eugenio Medea- MEDEA Conegliano-Pieve di Soligo Academic/Hospital Conegliano Italy Associazione “La Nostra Research Centre Famiglia” Scientific Institute Full partner IRCSS Giannina Gaslini IGG Neuroscience Academic/Hospital Genova Italy Full partner University of Messina UMESSINA Neurology and Neuromuscular Academic/Hospital Messina Italy diseases Unit, Department of Clinical and Experimental Medicine. Full partner Assistance Publique- APHP Clinical Research and Academic/Hospital Paris France Hopitaux de Paris Development/Institut de Myologie Full partner Centre Hospitalo-Universitaire CUH-NICE Centre de Référence Maladies Academic/Hospital Nice France de Nice Neuromusculaires et SDA Full partner Institute of Neurology, UCL-MRC MRC Centre for Academic/Hospital London UK University College of London Neuromuscular Disease Full partner Association for Glycogen AGSD-UK Not applicable Patient organization Droxford UK Storage Disease (UK) Full partner Faculty of Medicine -School UTH Neurology Academic/Hospital Larissa Greece of Health Sciences-University of Thessaly Full partner Rigshospitalet, University RIGUC Neurology Academic/Hospital Copenhagen Denmark of Copenhagen Full partner Berufsgenossenschaftliches BGH Neuroscience Academic/Hospital Bochum Germany Universitätsklinikum Bergmannsheil GmbH Collaborative partner Neuromuscular Center, IEEM Neuromuscular Disorders Academic/Hospital Dallas USA Institute for Exercise and Environmental Medicine Collaborative partner Istanbul University IU Neurology Academic/Hospital Istambul Turkey Collaborative partner Assistance Publique- AP-HM Centre de Référence Academic/Hospital Marseille France Hopitaux de Marseille Maladies Neuromusculaires Collaborative partner Universidad Europea de UEM Not applicable Academic Madrid Spain Madrid Collaborative partner Instituto de Salud Carlos III ISCIII Not applicable Health Research Agency Madrid Spain Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 4 of 11 the existing centres (namely, translation of the patient Data collection, storage, and access policy information and consent form to the local language, and The EMR complies with the confidentiality policies of approval by the local Ethics committee of centre to the EU and with national directives and regulations on which the new participant form an external country ethical aspects of patients’ data processing. belongs). The EUROMAC project has a public website (http:// All EUROMAC actions were supported and funded by www.euromacregistry.eu, see below), aimed to promote the agencies quoted at the “Funding and Acknowledge- the knowledge and dissemination of the project. The ments” section, at the end of this article. The implemen- registry website (https://www.registryeuromac.eu) is tation of the EUROMAC project was divided into eight hosted separate from the public website, as a secure net- work packages (WP) as detailed in Table 2. A Steering work. Local databases are the entry points where data is Committee (constituted by the eight WP leaders) was collected, encrypted, pseudo-anonymized, and then established to provide guidance on the development, im- transferred to a central registry, which currently stores plementation and management of the project. Addition- all the data in a secure and inexpensive system. To re- ally, the Steering Committee facilitated the design, assure the safety of the instrument, a back-up registry is content and structure of the registry utilizing the varied maintained in a participating country (Italy). skill sets of individual members. All decisions were taken The applicative of the EMR has been designed, devel- during 10 different meetings (five exclusively for the oped and periodically updated by the Italian GARR Con- Steering Committee and the remainder with the partici- sortium (www.garr.it/b/eng/garr-en/about-us). It includes pation of members of the whole consortium) that took a public area, in which the informed consent form can be place in Luxembourg, London, Brighton, Conegliano, downloaded, and a section for professional registration, Roma, Madrid, Villaviciosa de Odón and Barcelona, be- which provides a user account to clinicians that enables tween May 2013 (kick-off meeting, Luxembourg) and them to have access to the private area, accessed through July 2016 (final project meeting, Barcelona). Other work a personal username and a password previously provided, meetings to discuss and manage specific tasks related where registered clinicians can enter, edit and modify data with the implementation of the registry took place as from their patients. As indicated above, patients’ data are needed. encrypted and pseudo-anonymized for research purposes, but linked to their patient sources through an encrypted algorithm. Following informed consent, data from each Structure of the registry patient can be uploaded onto the encrypted web-based The data obtained from patients and included in the registry with a unique code in the database record. The registry were divided in eight different items: 1) demo- link between the code of a patient and his/her identity can graphic data; 2) diagnostic data; 3) clinical data; 4) data only be known by the physician who got the informed on concomitant diseases; 5) genetic data; 6) self-reported consent from the patient. This identity can be revealed by functional data; 7) previous and/or ongoing treatments this physician only under specific conditions clearly indi- and 8) services provided. The full list of variables intro- cated in the consent form. The coordinator of the registry duced in the registry is shown in Table 3. has the means to de-anonymize the patients’ codes too, but is only allowed to do it if the specific physician is miss- ing or not able to be contacted. Registered patients are able to log in with a personal Table 2 List of work packages and their corresponding leading password, review their own information and complete centre in the EUROMAC consortium selected sections with their personal experiences. None Leading Centre of the recruited participants or participating doctors is Horizontal Work Packages allowed to see data from other parties. WP1 Coordination VHIR As mentioned above, the EUROMAC project also has WP2 Dissemination AGSD-UK its own public webpage that provides news, updates and basic information on the disease and the EMR. It also in- WP3 Evaluation MEDEA cludes a link to the applicative of the EMR destined to Core Work Packages medical doctors and patients. This public webpage has WP4 Methodology and registering activity SERMAS been translated into nine languages (English, German, WP5 Quality assessment and management UTH Spanish, French, Italian, Greek, Danish, Catalan and WP6 Data analysis RIGUC Turkish), but the registry platform is in English only. WP7 Training and education UCL-MRC WP8 Ethical and legal issues APHP Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 5 of 11 Table 3 List of variables included in the EUROMAC registry applicativea Type of field Optional/Required field Field accessible by patients Personal datab Firs name To fill Required Yes Last name To fill Required Yes Email address To fill Optional Yes Date of birth Date Required Yes Phone number To fill Optional Yes City of birth To fill Required Yes Country of birth Dropdown menu Required Yes City of residence To fill Optional Yes Country of residence Dropdown menu Optional Yes Sex Male/Female choice Required Yes Height (cm) To fill Optional Yes Weight (kg) To fill Optional Yes 1.Demographic datac Case code Automatically generated Required No Age Generated from personal data Required Yes Country of birth Generated from personal data Required Yes Sex Generated from personal data Required Yes Height Generated from personal data Optional Yes Weight Generated from personal data Optional Yes Body mass index Generated from personal data Optional Yes 2.Diagnosis First diagnostic centre Dropdown menu Required No Diagnosing age To fill Required No Diagnosed disease Dropdown menu Required No Diagnosing through biopsy Yes/No choice Required No Diagnosing through genetic testing Yes/No choice Required No Genetic mutations Allele 1 Dropdown menu Required No Allele 2 Dropdown menu Required No Reference sequence used To fill Optional No 3.Clinical data Second wind Yes/No/NA choice Required Yes Myoglobinuria Yes/No/NA choice Required Yes Systems with disease (affected organs) Dropdown menu Required No Difficulties in maintaining physical activities Yes/No choice Required No Weakness Yes/No choice Required No Muscle wasting Yes/No choice Required No Disease severity Dropdown menu Optional No Lab data Forearm test Performed/Not performed Required No Basal serum CK levels To fill Optional No Other tests (specify) To fill Optional No Exercise testing VO2 peak To fill Optional No Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 6 of 11 Table 3 List of variables included in the EUROMAC registry applicativea (Continued) Type of field Optional/Required field Field accessible by patients %HRmax predicted To fill Optional No VO2 peak power output To fill Optional No Lab demonstrated second wind To fill Optional No Other tests (specify) To fill Optional No 4.Concomitant diseases Diabetes Yes/No/NA choice Optional No Coronary Artery Disease Yes/No/NA choice Optional No Hypertension Yes/No/NA choice Optional No Cancer Yes/No/NA choice Optional No COPD Yes/No/NA choice Optional No Acute renal failure Yes/No/NA choice Optional No Chronic renal failure Yes/No/NA choice Optional No Hyperuricemia or Gout Yes/No/NA choice Optional No Anemia or Hyperbilirubinemia Yes/No/NA choice Optional No Other comorbidity To fill Optional No 5.Other genetic factors ACE Genotype I/I, I/D, D/D or N/D choice Optional No ACTN3 Genotype R/R, R/X, X/X or N/D choice Optional No AMPD1 Genotype Q/Q, Q/X, X/X or N/D choice Optional No PGC Genotype G/G, G/S, S/S or N/D choice Optional No Other Genotype To fill Optional No 6.Self-reported functional data Limitations Yes/No/NA choice Optional Yes WHO DAS 2.0 To fill (Score) Optional Yes QOL SF 36 To fill (Score) Optional Yes QOL Bouchard To fill (Score) Optional Yes IPAQ To fill (Score) Optional Yes FSS To fill (Score) Optional Yes Other (specify) To fill Optional Yes 7.Previous/ongoing treatments Drugs Pain Relief Yes/No/NA choice Optional Yes ACE Inhibitors Yes/No/NA choice Optional Yes Diuretics Yes/No/NA choice Optional Yes Cardiovascular Drugs Yes/No/NA choice Optional Yes Insulin or Antidiabetics Yes/No/NA choice Optional Yes Muscle Relaxants Yes/No/NA choice Optional Yes Psychoactive Drugs Yes/No/NA choice Optional Yes Allopurinol: Yes/No/NA choice Optional Yes Other (specify) To fill Optional Yes Special diet Sucrose Yes/No/NA choice Optional Yes Carbohydrate rich Yes/No/NA choice Optional Yes Protein rich Yes/No/NA choice Optional Yes Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 7 of 11 Table 3 List of variables included in the EUROMAC registry applicativea (Continued) Type of field Optional/Required field Field accessible by patients Lipid rich Yes/No/NA choice Optional Yes Other (specify) To fill Optional Yes Supplements B6 Yes/No/NA choice Optional Yes Creatine Yes/No/NA choice Optional Yes CoQ or Idebenone Yes/No/NA choice Optional Yes Other vitamins Yes/No/NA choice Optional Yes BCAA Yes/No/NA choice Optional Yes Carnitine Yes/No/NA choice Optional Yes Other (specify) Yes/No/NA choice Optional Yes Rehabilitation program Yes/No/NA choice Optional Yes Other treatments (specify) To fill Optional Yes 8.Services provided Currently working Yes/No/NA choice Optional Yes Benefited from specific healthcare Yes/No/NA choice Optional Yes Changed job because disease Yes/No/NA choice Optional Yes Employer modified environment because disease Yes/No/NA choice Optional Yes Abbreviations: ACE Angiotensin-converting enzyme, ACTN3 Alpha-actinin-3, AMPD1 Adenosine monophosphate deaminase 1, BCAA Branched chain amino acids, CK Creatine kinase, CoQ Coenzyme Q, COPD Chronic obstructive pulmonary disease, FSS Fatigue severity scale, HR Heart rate, IPAQ International physical activity questionnaire, PGC Progastricsin, QOL SF36 The 36-Item Short Form Health Survey questionnaire, VO2 peak Peak oxygen uptake, WHO DAS 2.0 World Health Organization Disability Assessment Schedule 2.0 a For most variables with “Yes/No (NA) choice”, if answer is “Yes”, new field(s) with additional related questions open (e.g., if “Myoglobinuria = yes”, then an additional field: “Frequency” opens; if “Muscle weakness = yes”, then new fields open asking for affected muscles and severity; if the answer for a specific treatment is “Yes”, new fields open asking for frequency of use and whether it was beneficial or not) b All data introduced in “Personal Data” section is encrypted and not available for anybody, except for the physician who registered this particular patient c Demographic data is automatically generated from the data introduced in the section of personal data Expected outcomes countries to which EUROMAC partners belong. Among Generation of a database aimed at improving access of the elements contained in the Ethics Report, the follow- patients to specialized care, improving knowledge of the ing items can be mentioned: natural history of these disorders and generation of treatment guidelines. The database will facilitate the in- 1) Review of the existing legislations in all the volvement of the biopharmaceutical industry and gov- countries involved in the registry. ernments. Additional outcomes include the dissemination 2) Description of the process flow and criteria to of the EUROMAC website at neurology and neuromuscu- determine it. lar meetings, the publication on the EUROMAC website 3) List of the reference EUROMAC investigators for contact details of all European diagnostic labs, together every country (country managers). with specialist clinics, and the implementation of training 4) Patient information and consent form, explaining courses and patient support groups meetings. the registry, data collection, and option to opt-out at any time. Ethics One of the core WP was dedicated to the ethical and One of the main ethical issues to be considered in pa- legal issues of the project. Among other elements, this tient registries is that data protection is an obvious pre- WP included the establishment of an Ethics Committee, requisite, including transparency of the procedures of nominated at the kick-off meeting, and the generation of data collection and data analyses. Therefore, this was a an Ethics Report before the Registry was active. The core part of the Ethics Report, as well as one of the main generation of the Ethics Report constituted a mandatory subjects to be addressed in the WP dedicated to the eth- milestone during the development of the project. This ical and legal issues. document establishes all internal rules and procedures The project was approved by the Institutional Review designed to ensure that the project and the Registry Board of the Coordinating Center (Vall d’Hebron meet the mandatory regulations of the EU and all Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 8 of 11 Research Institute, Barcelona), and by review boards of Serbia) and EUROMAC teaching course (May each institution recruiting participants. 2016, Warsaw, Poland). 3. The registry has been implemented and registering activity started in September 2015. Results At present (November 2019), 313 patients have The main outcome of the registry is the scientific infor- been registered, which accomplishes the mation derived from the patient database analysis, and proposed objective for this project to register for this we refer to the companion article in this issue to 250 patients. These 313 patients represent evaluate how the registry can be useful to expand our approximately 10% of the total number of knowledge about the disorders [21]. However, the gener- patients in the participating countries, based ation of the first European registry dedicated to rare on prevalence estimates, which constitutes muscle glycogenoses can be considered a result in itself. an excellent percentage of entries 4 years The following summary of achievements may be useful after the implementation of the operative to suggest procedures and tips to be considered when registry. dealing with other similar registries: 4. EUROMAC has contributed so far to the implementation of at least two clinical trials 1. A dynamic clinical and research network focused (ClinicalTrials.gov: NCT03112889 and on muscle glycogenoses has been established at the NCT02432768) [24]. European level, allowing better communication and 5. Many patients were very happy to hear that the sharing of available information for designing and diagnosis made, in most cases, years ago, developing large-scale clinical trials. obtained new research interest, and they were 2. EUROMAC has significantly contributed to the satisfied to be able to contribute to the body of effective dissemination and raising the awareness of knowledge on their rare disease, and the registry the diseases not only in those countries with encouraged them to contact and participate in EUROMAC partners, but also in countries not patients organizations. initially represented (e.g., Netherlands or Poland). The EUROMAC project website (http://www. Discussion euromacregistry.eu) accumulates 9200 visits EMR is an entirely public and secure database de- (December 2019), which is a good indicator of the signed to contain the medical data from patients with awareness of the project. McArdle Disease and related conditions. The EURO- In the process of the project development, the MAC network collaboration was initiated in 2012 Dissemination Plan promoted the organization of with the main objective of improving diagnosis and events, publications and dissemination material care for people living with these rare disorders, to re- (leaflets, brochures, books) in different languages duce serious complications and social care costs and generated and distributed in the frame of to provide a research platform for future clinical trials EUROMAC. by raising awareness and increase knowledge with re- Specifically, some of the activities conducted in the spect to the natural history of these disorders. In pa- frame of the Dissemination Plan were: (i) creation tients with these disorders, delayed diagnosis and of a EUROMAC project video (https://www. incorrect medical advice leads to debilitating symp- youtube.com/watch?v=NXvmRGLcIy8&list= toms and increased risk of life-threatening crises ne- PLECPX8EZXgfMflBqX4hWLYc4n_4bieuwV), as cessitating admission to critical care, all of which can well as a video about McArdle patients’ experiences be prevented by correct medical care. The EURO- (https://www.youtube.com/watch?v=F4 MAC was a complex undertaking that involved multi- 9Vy8LTkjg&t=11s), both subtitled in several disciplinary teams of 18 partners from nine countries. languages (1919 and 1433 visits in all languages Owing to the low number of patients with rare respectively, November 2019); (ii) translation of muscle glycogenolytic disorders at national level, the several information booklets on McArdle Disease in EUROMAC registry was created at European level es- several languages; (iii) events and formative tablishing collaborative efforts to ensure data collec- meetings (McArdle exercise testing workshop (July tion and its maintenance. 2014, Madrid, Spain) [22], 211th European To date, the project fulfilled the expectations for an Neuromuscular Centre International Workshop accessible and readily visible e-platform where the scien- (April 2015, Naarden, Netherlands) [23], tific community can count and properly describe most EUROMAC symposium (April 2016, London, UK), patients with rare muscle glycogenoses. Registration of McArdle study day (February 2016, Belgrade, the patients proceeded steadily once the registry Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 9 of 11 functions were in place, reaching the number of 313 by aforementioned bottleneck (informed consent) and November 2019. The choice of enriching the registry helped to engage the participation of more patients. with a wealth of clinical and functional information – Most patients are diagnosed based on a molecular makes the registry, in its present form, a good starting genetic confirmatory test, clearly reflecting the shift point for a dynamic specialized e-health record, but is in diagnostics toward a molecular genetic approach. also the main reason for its underperformance in num- – The quality of recorded data is generally good, but ber of registered patients. Although the initial expecta- certain variables are not reported in most of the tions for registering rate were higher than those actually patients frequently enough. This drawback will be achieved (the initial target was having 500 registered pa- overcome in the future by the re-entry of those pa- tients at the end of the CHAFEA-funded period), this tients’ information in a retrospective manner. number had to be lowered to a more realistic value (250 – The data set offers a unique platform for the patients) in one of the interim amendments of the pro- EUROMAC consortium and collaborators to work ject. Indeed, when the consortium started registering pa- on in the future. The registry is a valuable asset not tients, it was soon detected that efficiency in loading the only for the members of the current EUROMAC patients’ data was below initial expectations because of consortium, but also for new collaborators that are the need to obtain a signed consent form from each sub- already contributing and other colleagues who are in ject, which was the main rate-limiting factor. Moreover, the process of arranging their capability to the richness of the clinical information required, which participate. demanded for direct patient re-examination for most of the requested measures, also added to the delay in regis- Additionally, the expected long-term impacts of the tration, which is still on going. This element is con- EUROMAC project at an international level are: a) im- firmed by the unequal speed and number of data entry proved access of patients to specialised care; b) facilitated by the various partners: those who have routine sched- involvement of national governments and regulatory agen- uled visits of the patients could easily retrieve the needed cies; c) improved knowledge of the natural history of data, those performing diagnostic workout but no clin- McArdle Disease and other rare muscle glycogenoses; d) ical follow-up could not keep up. Taken together, we as- reduced average delay in diagnosis; e) reduced risk of in- sumed that lowering the initial registering activity rate correct advice leading to debilitating symptoms and in- expectations was fully justified if that allowed that the creased risk of life-threatening crises; and f) extended use quality of the data (and so the usefulness of the registry) of the registry to all other European countries. All these is more robustly ensured. long-term expected impacts will need further analyses In addition to the scientific observations and conclu- after extended time of registering patients. sions derived from data analysis, presented in the com- The project has also contributed to the establishment panion paper [21], when we look to what we learned of a communicative channel with the biopharmaceutical from the registering activity from a methodological and industry, because the registry will improve the under- procedural point of view, we can raise the following standing of the natural history of these diseases, and the conclusions: available data enables designing better clinical trials and evaluating potential relevant clinical endpoints. – Countries providing centralized care focused on A positive aspect of the project is the dissemination muscle glycogenoses, such as the UK, have shown and the raised awareness about this neglected group of better rates of registering activity than those rare diseases. The power of a dedicated multilingual web countries where management and expertise of these site and the possibility for patients to directly contribute disorders is fragmented across multiple centres. was hailed by most patients as a very positive novelty. Although this does not make any judgment about The distribution of multilingual information material on whether centralization is a better strategy, it does McArdle Disease is a concrete achievement that will open the question to find strategies to engage other continue beyond the project life. Over 90% of the pa- professionals to participate in EUROMAC, serving tients contacted for first data collections were happy to as a pan-European reference organization to coord- be contacted again for follow-up. Participation by con- inate and manage these activities. sortium partners to all meetings forged a strong sense of – The rate-limiting step for the registering activity is belonging among the partners, which functioned as ac- obtaining signed informed consent from patients. cretion nucleus, leading other European partners to join – The active role of patients’ organizations is of the the consortium (Netherland and Poland). Actually, in- utmost importance to maximize the chances to corporation of new active EUROMAC partners has been recruit patients for the registry. Countries with more encouraged and welcome by the initial EUROMAC con- active patients’ organizations minimized the sortium, among those participants that have joint as Pinós et al. Orphanet Journal of Rare Diseases (2020) 15:187 Page 10 of 11 registering professionals following the mechanism de- Availability of data and materials scribed in the Methods and Results section above (Data Not applicable. collection, storage, and access policy), when they show interest to become active participating partners. The Ethics approval and consent to participate The project was approved by the Institutional Review Board of the training sessions held in London and Madrid, as well as Coordinating Center (Vall d’Hebron Research Institute, Barcelona), and by the workshop held in Naarden [23], achieved the double review boards of each institution recruiting participants. goal of standardizing assessment procedures and in- crease knowledge on specific functional and clinical as- Consent for publication pects of the diseases. They were attended by a large Not applicable. number of professionals and were rated by participants as very useful and qualitatively excellent. In addition, Competing interests The authors declare that they have no competing interests. special efforts dedicated to disseminate our project in Eastern countries, with meetings held in Warsaw and Author details 1 Belgrade, have contributed to increase knowledge and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, and Research Group on Neuromuscular and Mitochondrial awareness about these disorders in Eastern Europe. We Diseases, Vall d’Hebron Research Institute, Universitat Autònoma de expect that these dissemination strategies will contribute Barcelona, Pg. Vall d’Hebron 119, 08035 Barcelona, Catalonia, Spain. 2Center to improve diagnosis of these diseases in this region, of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 3Department of Neurology, Laboratory of Neurogenetics, where underdiagnose of these diseases seems to be of University of Thessaly, Volos, Greece. 4Neuromuscular Center, Institute for special concern. Exercise and Environmental Medicine of Texas Health Presbyterian Hospital, Dallas, TX, USA. 5Nord/Est/Ile de France Neuromuscular Reference Center, Neurology Department, Raymond-Poincaré Teaching Hospital, AP-HP, Conclusions Garches, France. 6INSERM U1179, END-ICAP, Paris Saclay University, Paris, France. 7Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, In conclusion, EMR represents a major step forward in Spain. 8Biomedical Network Research Centre on Rare Diseases (CIBERER), the knowledge of muscle glycogenoses with relevant Instituto de Salud Carlos III, and 12 de Octubre University Hospital Research clinical outcomes at the diagnostic, epidemiologic, clin- Institute, (‘imas12’), Madrid, Spain. 9Department of Conegliano-Pieve di Soligo, IRCCS Eugenio Medea-Associazione “La Nostra Famiglia” Scientific ical and research levels. Institute, Bosisio Parini, Italy. 10Institute of Biomedical Research of Vigo, Vigo, Spain. 11Department of Neurology, Neuromuscular Unit, Istanbul University, Abbreviations Istanbul, Turkey. 12Centre de Référence Maladies Neuromusculaires, AGSD-UK: Association for Glycogen Storage Disease (UK); CK: Creatine kinase; Assistance Publique-Hopitaux de Marseille, Marseille, France. 13MRC Centre EMR: EUROMAC registry; WP: Work package for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital, London, UK. 14University of Nice, Nice, France. 15Neurology and Neuromuscular Diseases Unit, Department of Clinical and Experimental Acknowledgements Medicine, University of Messina, Messina, Italy. 16Rigshospitalet, University of EUROMAC was supported by several patients’ associations and large Copenhagen, Copenhagen, Denmark. 17Heimer Institute for Muscle Research, networks of patient registries, such as the Association for Glycogen Storage University Hospital Bergmannsheil Bochum, Bochum, Germany. 18Association Disease (https://agsd.org.uk/) and the EPIRARE Group on Rare Disease for Glycogen storage Disease, Bristol, UK. Registries (https://www.eurordis.org/content/epirare). The European Neuromuscular Centre (https://www.enmc.org/) also supported the project Received: 21 April 2020 Accepted: 29 June 2020 by contributing to the organization and funding of a dedicated workshop. EUROMAC Consortium: Antoni L. Andreu, Ramon Martí, Tomàs Pinós, Noemi Baruch, Francisco J. Ortega, Miguel A. Martín, Carmen Navarro, Beatriz San-Millán, Irene Vieitez, Andrea Martinuzzi, Marinela Vavla, Claudio Bruno, References Antonio Toscano, Olimpia Musumeci, Pascal Laforêt, Sabrina Sacconi, Ros 1. McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clin Quinlivan, Renata Scalco, Andrew Wakelin, Georgios Hadjgeorgiou, Elias Sci. 1951;10(1):13–35. Zintzaras, John Vissing, Matthias Vorgerd, Enrico Zülow, Ronald Haller, 2. Santalla A, Nogales-Gadea G, Encinar AB, Vieitez I, Gonzalez-Quintana A, Piraye Oflazer, Hacer Durmus, Jean Pouget, Alejandro Lucía, Alfredo Santalla. Serrano-Lorenzo P, et al. 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Ann Clin Transl Neurol. 2019;6(10):1949–60. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.