157th ENMC International Workshop: Patient registries for rare, inherited muscular disorders 25–27 January 2008 Naarden, The Netherlands

1. Introduction 

Twenty participants, including bioinformatics experts, geneticists, neurologists, paediatricians and representatives of patient advocacy organizations, from eight countries, met in Naarden from 25th to 27th January 2008 to review patients’ registries for rare, inherited neuromuscular disorders (NMDs). Inherited NMDs form a large group of diseases each of which is individually rare (prevalence<5/10,000), most of which result in chronic long-term disability posing a significant health care burden for society. Currently none of these conditions benefit from curative treatments. Molecular genetic advances and knowledge of disease-causing genes have allowed the development of specific diagnostic tests for many types of NMDs, as well as the elucidation of the underlying molecular pathological mechanisms, leading to plans for specific gene-based therapies or targeted pharmaceutical approaches. Some of these treatment options are beginning to move to limited human studies. These developments have exposed the lack of harmonisation of approaches and infrastructures to possible beneficial therapeutics in NMDs, which is delaying or even preventing a smooth move into clinical trials. Most innovative therapies for patients suffering from rare NMDs are expected to act on gene-specific molecular pathways. In some areas, for example current approaches to Duchenne muscular dystrophy (DMD), the specific mutation will determine the applicability of a particular therapeutic technique [1]. European or global resources are therefore necessary to identify patients suitable for these therapies. Gene-based patient registries are useful tools to overcome fragmentation and to facilitate research for a number of goals: epidemiology, genotype–phenotype correlation, natural history, standards of care, etc. Moreover, they greatly facilitate feasibility studies for and recruitment into clinical trials. Currently, European and global efforts to set up patient registries are mainly targeted towards DMD and spinal muscular atrophy (SMA), though other less frequent inherited muscle disorders would certainly benefit from similar concerted action and resources sharing. For some of these disorders, leading scientists have set up registries or databases that may not be generally available to the research community, and use different tools and practices.

The aim of the current workshop was to encourage collaborative action towards gene-based patient registries for rare, inherited muscle disorders in Europe and world-wide. Harmonizing practices, joining forces and merging experience on gene-based patients’ registries may facilitate research into rare, inherited muscle disorders, support upcoming clinical trials and deliver standards of care.

2. Patients registries and databases: what are they and what are they good for 

Christophe Béroud (Montpellier, France) reviewed different types of databases and patients’ registries and clarified their value and usefulness. According to the purpose and objectives, the data part of a database/registry may include records regarding mutations, patients and/or phenotypes. To make them useful for research purposes, stored data need quality control (curation) and regular updates. These are frequently done by experts, known as “curators”, who validate the data and standardize clinical and biological descriptions.

Patients’ registries are specific databases devoted for medical purposes, and are organized systems that collect data for scientific, clinical, or policy purposes. Conversely, mutation databases collect information about mutations and sequence variants in one or more genes. Databases may therefore be “core” or central databases, collecting published mutations from a number of genes, or locus-specific databases (LSDBs). In core databases, such as the Human Gene Mutation Database (HGMD; www.hgmd.cf.ac.uk) [2], the Online Mendelian Inheritance in Man (OMIM, www.ncbi.nlm.nih.gov/omim) [3] and the Single Nucleotide Polymorphism database (dbSNP; www.ncbi.nlm.nih.gov/projects/SNP) [4], each mutation is entered only once, with limited phenotypic description. Conversely, LSDBs collect all published and unpublished mutations from a single gene, with full molecular, biological, and phenotypic description, allowing recognition of mutation hot spots. According to the interest of the curators, LSDBs may be patient-, sequence variation-, disease-, or protein-centred. A complete list of LSDBs can be found through the Variation databases page of the Human Genome Variation Society (HGVS; www.HGVS.org) or the HGMD. Ready to use software and management systems such as Mutation view (mutview.dmb.med.keio.ac.jp) [5], the Universal Mutation Database (UMD) (www.umd.be) [6], the Leiden Open (source) Variation Database (LOVD) (www.LOVD.nl) [7], the MutBASE (www.uta.fi/imt/bioinfo) [8], or the Mutation Storage and Retrieval Program (MutStaR, www.hgu.mrc.ac.uk/Softdata/Mustar) [9], are available and applied in existing mutation databases. Published or unpublished data are collected from different sources, such as the literature, the patients themselves, or via the clinicians, geneticists, or counsellor. If the data are not fully and irreversibly anonymized, a signed informed consent of the patient and the ethical committee approval is required. Harmonization of clinical criteria, with a minimal set of mandatory items, of language and of molecular data, via guidelines and recommendation for sequence variants description is crucial to allow transversal queries and comparisons between different databases and registries [10].

3. Review of existing registries and databases for rare, inherited muscle disorders 

Johan Den Dunnen (Leiden, the Netherlands) gave an overview about the LOVD, a web-based database for the collection, display and curation of DNA variations in 32 NMD-related genes [7]. The freely accessible database, running since 1995, has been designed for scientist and medical doctors performing research and/or diagnosis in NMDs. The database collects and shares anonymous data on mutations and known variants, the detection methods used, and some associated phenotypic data. Data are collected from the literature and by direct submission. Mutation nomenclature standardization, in accordance with the HGVS guidelines and recommendations, guarantees data harmonization. The home-made LOVD software, freely available for download under GPL licence, allows www-based operation, error checks and links to genome browsers. The recently developed Mutation Analyzer Sequence Variation Nomenclature Checker (www.lovd.nl/mutalyzer) facilitates the interpretation of the effects of sequence variants [11]. Hierarchy of access with IP address restriction is set for different users ensuring the security of the database.

Currently, three UMD-LSDBs for NMD-related genes have been constructed and made publically available via the internet, and additional eleven databases for further genes and conditions are in progress. Giséle Bonne (Paris, France) reviewed the UMD-LSDBs for Lamin A/C and Emerin [6], [12]. Created in the context of the Myocluster European network in 2000, these LSDBs list all reported mutations and relevant clinical information for these genes responsible for Emery Dreifuss muscular and a number of overlapping NMDs [13]. The original generic UMD software, created to collect and analyze clinical and molecular data, includes an optimized structure to assist and secure data entry and to allow the input of a wide range of clinical data. The generic UMD was subsequently modified by Béroud et al., allowing the creation of LSDBs for virtually any gene [6], [12]. A large set of analysis tools allows phenotype–genotype correlations and obtaining data regarding distribution and frequency of mutations and epidemiological information. Published LMNA and EMD mutations are freely accessible, while unpublished changes are available only to the curators and collaborators. In addition, the UMD central tool is designed to query multiple UMDs and allow a comprehensive analysis. Martin Krahn (Marseille, France) reviewed the UMD-LSDBs for DYSF and CAPN3 for LGMD2A and LGMD2B. He more specifically gave examples of the UMD-predictor® tool that allows the prediction of the pathogenic impact of substitutions (synonymous or non-synonymous changes). He demonstrated the high efficiency of this tool and showed how it was integrated in the molecular diagnostic procedures in Marseille.

Baziel van Engelen (Nijmegen, the Netherlands) illustrated the Computer Registry of Myopathies and Polyneuropathies (CRAMP), a registry conceived to obtain national morbidity data on NMDs (isno.nl/registratie.php) [14]. CRAMP is a disease database, developed among seven neuromuscular centres in the Netherlands, to store information on diagnosis and characteristics of patients affected by NMDs. Aim of the database is to recruit patients for treatments and research, in particular population-based epidemiological studies. The database has a tree like structure based on the Walton classification of NMDs. Collected data includes hospital and personal information (in particular postal code) and the diagnosis, while genotypic data are not recorded. CK levels, EMG findings and muscle biopsy findings are also registered to enter patients without diagnosis. CRAMP was developed with Microsoft Access, a fast and user-friendly software. Future developments include expanding the amount of the participating centres to paediatric neurology departments, rehabilitation and non-academic centres, to avoid enrolment biases.

Charles Thornton (Rochester, USA) illustrated the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FHSD) (www.urmc.rochester.edu/nihregistry/). This registry was developed primarily as a tool to facilitate research on DM and FHSD. The primary goals are to provide a mechanism for researchers to establish contact with people who have DM or FSHD, and to develop a pool of patients who are interested to learn about, and possibly participate in, research. The registry also collects self-reported data and serves as an educational tool for patients and families as well as care providers, who get annually a review form on their status and a newsletter reporting on research from registry. Investigators and researchers may approach the registry to access anonymized data or to recruit patients for clinical studies.

Patients’ organizations are crucial for the establishment of patients driven registries. Ria Broekgaarden (Baarn, the Netherlands) emphasized the role of the International Pompe Association (www.pompe.com), funded by Industry and Charities, in the establishment and development of the registry for Pompe disease (www.lsdregistry.net/pomperegistry). The purpose of the Pompe registry is to get information about the natural course of the disease and about the nature of complaints. The designed Erasmus questionnaire has allowed collecting more than 300 participants with juvenile or adult onset Pompe disease so far. The Pompe Association was also pivotal to initiate and design trials, manage patients’ expectations, recruit patients, identify expert centres, provide information and report on outcomes.

Hanns Lochmüller (Newcastle, UK) identified the feasibility and patients’ recruitment for clinical trials as the most important objective of patients’ registries for the Network of Excellence TREAT-NMD (www.treat-nmd.eu). Harmonization of patients’ registries on a European and global level is important for translational research and it is one of the main activities of TREAT-NMD. Within the network, national registries for DMD and SMA collect data in a harmonized way and contribute them to a European meta-database, hosted in Montpellier and supervised by Christophe Béroud (www.treat-nmd.eu/healthcare/patient-registries). Data are internationally harmonized and include mandatory and optional items. TREAT-NMD registries require informed consent and frequent updates, but will provide feedbacks to the patients and allow them data withdrawal. TREAT-NMD drafted an internationally approved patients’ registries charter for best practice and designated an oversight committee and access rules for researchers and industries (www.treat-nmd.eu).

4. Overview on present and future databases/registries and breakout sessions 

All participants contributed to the debate illustrating various approaches, ranging from laboratory-based databases to patient led initiatives for rare NMDs. Current practice, specific objectives and requirement, impact on standards of care, level of patient and professional involvement, national, international scope, future plans and goals, in particular expectance of a clinical trial in the next 3–5 years, have been illustrated and discussed for each of them. The following list summarizes the databases and registries reviewed during the workshop: congenital muscular dystrophies and dystroglycanopathies, by Judith Pagan (London, UK), Central core and Multi-minicore disease, by Heinz Jungbluth (London, UK); Myotubular myopathies, by Valérie Biancalana (Strasburg, France); Myofibrillar myopathies, by Montse Olivé (Barcelona, Spain), Nemaline myopathies, by Carina Wallgren-Petterson (Helsinki, Finland); Sarcoglycanopathies, by Gabriele Dekomien (Bochum, Germany); FSHD, by Silvère van der Maarel (Leiden, the Netherlands); Oculopharyngeal muscular dystrophy (OPMD), by Tobias Müller (Halle, Germany); Ullrich congenital muscular dystrophy and Bethlem myopathy (COL6A1-A2-A3-UMD), by Valérie Allamand (Paris, France); congenital muscular dystrophies due to merosin deficiency (LAMA2-UMD), by Christophe Béroud (Montpellier, France); the ACTA1 LOVD database for Laing distal myopathy, illustrated by Carina Wallgren-Petterson (lovd.waimr.uwa.edu.au); the CAPN3 and DYSF-UMD for LGMD2A and LGMD2B, by Martin Krahn (Marseilles, France); the Jain Foundation registry for LGMD2B and Myoshi myopathy (jain-foundation.org/patients.php), by Laura Rufibach (Redmond, USA), and finally the protocol-based database for DM, illustrated by Mark Rogers (Cardiff, UK).

Hanns Lochmüller moderated the discussion about future development and harmonization of existing and future databases and registries. The general overview from the workshop indicates the concurrent presence of six types of registries/databases: (1) single lab-based databases, with privately accumulated data with no or limited data sharing, (2) LOVD genetic databases, allowing sharing of anonymized data, (3) UMD knowledgebases, allowing to share of anonymized data and to utilize sophisticated analysis tools, (4) self-report registries, (5) databases created on clinical protocols, and (6) National, multi-disease databases. The review also indicates that while some conditions, such as Nemaline myopathy and Laing distal myopathy, appear to be covered by a single database, multiple databases have been set up for other genes and conditions (i.e. the LMNA or the DYSF genes) and this may require harmonization of data and practices to avoid duplication of efforts. Lack of detailed personal and clinical information of patients included in existing lab-based databases is an additional point that emerged during the discussion. Moreover, discussion was also focused on the balance of clinical usefulness versus accuracy, harmonization, and reproducibility. Harmonization of items and practices across different genes and diseases is a key point in particular if there is trial readiness of the individual disorder. In this perspective, TREAT-NMD showed that it is possible to harmonize databases and registries and there is a potential to collaborate between different centres and laboratories. Three separate thematic breakout sessions took place and each of the participants contributed to one of them: Congenital muscular dystrophies and myopathies (CMDs) session (participants: Carina Wallgren-Pettersson, Heinz Jungbluth, Valérie Allamand, Valérie Biancalana, Ria Broekgaarden, Johan den Dunnen, Baziel van Engelen, Judith Pagan); limb girdle muscular dystrophies (LGMDs) and myofibrillar myopathies (MFMs) session (participants: Kate Bushby, Jacques Beckmann, Gisèle Bonne, Montse Olivé, Laura Rufibach, Christophe Béroud, Martin Krahn, Gabriele Dekomien) and FSHD, DM and OPMD session (participants: Charles Thornton, Mark Rogers, Silvère van der Maarel, Tobias Müller, Hanns Lochmüller). In each session, participants delineated objectives of existing or future registries, plans for international harmonization, strategies how to involve patients and patients’ organization, the essential items to capture and the standards of diagnostics. The discussion was also focused on the need of a consortium on registries and the role of TREAT-NMD and ENMC for dissemination and support. Ownership, harmonized informed consent and biobanks have been discussed as well. In all three sessions agreement was reached on the importance of European and global harmonized and coordinated patient registries for accelerating progress, in particular in translational research. This will be facilitated by action taken by individual, disease-specific ENMC workshops and consortia, but also through joint action across diseases. The need to go back for informed consent in case of previous informal data collections has been underlined and databases for undiagnosed patients have also been suggested. Creation of a list of available tests and laboratories, via the Orphanet (www.orpha.net) and the Genetests (www.genetests.org) websites will be useful for diagnosis standardization, and the Orphanet Journal of Rare Disease (www.ojrd.com) and the French recommendations represent useful supports for diagnosis, management and standards of care. Lobbying will be an important effort in the long run. Help from patients’ organizations, the ENMC and TREAT-NMD is welcome and needed, especially for legal, ethical, technical, IT issues and funding. Participants to the CMDs session agreed on the necessity of core and disease-specific items to allow genotype–phenotype correlation studies. Pre-existing data are difficult to manage, since many CMDs are lethal in young age. Further email discussions and disease-specific workshop have to be planned to come to a decision on these issues. In the LGMDs/MFMs session, participants agreed on 13 mandatory items and additional highly recommended that could be applied to all LGMDs and MFMs. A scheme for patients and clinicians involvement in the curation process of databases/registries and update of data has been drafted as well (Fig. 1). Participants were in favour of a consortium on registries and a forum for curators to gather questions, ideas that would be shown up in a transversal way to all the databases. The session on FSHD, DM, and OPMD agreed that registries/databases for these conditions may be better planned on a national level, with the objectives to establish a resource of genetic and clinical information, a collection of information about the natural history, with yearly updates, and creation of educational link to other relevant resources. Core items for FSHD and DM were identified, including the willingness of the patients to be contacted about future research studies.

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Fig. 1. Data collection flowchart: the patient with a diagnostic suspicion of NMD is referred to the clinician (1). During the consultation, in case of confirmation of the clinical diagnosis of a NMD, a consent form and a blood sample are taken, a medical certificate of consultation is drafted and the form with the mandatory items is compiled. If the genetic data is already available, not acquirable, or not requested, a more detailed form is directly sent to the database curator (2). The results of the genetic test and the mandatory items are forwarded to the database curator, who includes all the data into the database (3), and who assigns a unique identifier number to the patient (4). This number is dispatched to the clinician and to the patient (5), who via the unique identifier number is allowed to update regularly the personal and clinical data (6).

5. Discussion 

Currently, the field of NMDs appears to move from laboratory-based, private databases to internationally shared datasets and registries, with development of new database tools and patients’ involvement in the process. Participants of the workshop acknowledged that databases and/or registries should collect appropriate items and adhere to practices that serve for specific objectives that may include: collections of all known mutations and sequence variants, study of mutations’ pathogenicity, prospective follow-up of patients, study of clinical history, delineation of standards of care, patients’ enrolment for clinical trials, etc. For clinical trial readiness in the next 3–5 years, and for prospective follow-up and clinical history studies, multi-national patients’ registries need to be planned and developed because of the rarity of most of the inherited NMDs. Accordingly, registration, patients’ consents, method of data collection and patients’ enrolment should be harmonized among different centres and countries. This is currently being achieved for DMD and SMA through the TREAT-NMD network. On the other hand, fully anonymized mutation databases, such as the UMD or LOVD, represent the best solution for conditions where clinical trials are not foreseeable for the next future. Several recommendations were made: (i) to optimize resources parallel developments for the same objectives/disorders (duplication) should be avoided; (ii) international harmonization of practices and data points should be achieved for each condition; (iii) information about the databases and registries as well as anonymized results should be made publicly available through the internet and other means; (iv) anonymized molecular and clinical data should be submitted to an already existing, open access LOVD and/or UMD LSDB; (v) sustainability and long-term financing need to be considered from the outset of a patient registry/database.

6. Conclusions and future plans 

Agreement was reached on the importance of European and global harmonized and coordinated patient registries for accelerating progress, in particular in translational research. This will be facilitated by action taken by individual, disease-specific ENMC workshops and consortia, but also through joint action across diseases. This includes harmonization of registration practices and registry content, increased collaboration with patient organizations and empowerment of patients, and sharing of resources and dissemination through TREAT-NMD and ENMC. To facilitate and harmonize these efforts, TREAT-NMD has developed a toolkit for patient organisation and professionals to assist setting up of registries for neuromuscular disorders (www.treat-nmd.eu/healthcare/patient-registries/toolkit). The toolkit is freely downloadable and includes information regarding legal and ethical framework, data protection, patient information and consent, professional involvement, etc. The establishment of standards of diagnosis and care for rare NMDs, including an inventory of clinical and molecular diagnostic centres, with particular attention to quality standards, represents an additional activity of TREAT-NMD.

All the participants to the workshop agreed to contribute to an inventory of existing registries and databases. The inventory has been completed and it is also available on the TREAT-NMD website (www.treat-nmd.eu/registries/docs/rare_inventory.pdf) (Supplementary Table 1). Continuous update of the inventory through the TREAT-NMD and ENMC websites is necessary and welcome. The participants of the workshop wish to invite additional representatives for rare, inherited muscle disorders to get involved and form a consortium for further work in this area.

Workshop participants: Dr. Valérie Allamand (France), Prof. Jacques Beckmann (Switzerland), Prof. Christophe Béroud (France), Dr. Valérie Biancalana (France), Ms. Annette Boersen (ENMC), Dr. Gisèle Bonne (France), Ms. Ria Broekgaarden (the Netherlands), Prof. Kate Bushby (UK), Dr. Gabriel Dekomien (Germany), Dr. Johan Den Dunnen (The Netherlands), Prof. Baziel van Engelen (the Netherlands), Dr. Heinz Jungbluth (UK), Dr. Martin Krahn (France), Prof. Hanns Lochmüller (UK), Prof. Silvère van der Maarel (the Netherlands), Dr. Tobias Müller (Germany), Dr. Montse Olivé (Spain), Dr. Judith Pagan (UK), Dr. Mark Rogers (UK), Dr. Laura Rufibach (USA), Dr. Anna Sárközy (UK), Prof. Charles Thornton (USA), Carina Wallgren-Pettersson (Finland).

The workshop was possible through the support of ENMC and partners:

Associated members:

Additional funding for the participation of the US members of the group was kindly provided by the American MDA Association.