Patient registries in neuromuscular diseases - Dystrophinopathies (DMD/BMD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy (DM1/DM2), FKRPopathies (MDC1C/LGMD2I), Hereditary Neuropathies (CMT) and Myofibrillar Myopathies (MFM)
Olivia Schreiber
Friedrich-Baur-Institute, Munich
Until now, neuromuscular diseases cannot be cured or treated sufficiently. New therapeutic concepts were developed experimentally during the last years but are not available yet. First, their safety and effectivity in patients must be proven. The main objectives of the TREAT-NMD registries are to assess the feasibility and to facilitate the planning of appropriate clinical trials in this field of rare neuromuscular diseases and to support the enrolment of patients in these trials, in compliance with ethical guidelines.
In the framework of the European Network of Excellence TREAT-NMD several registries for patients suffering from different neuromuscular diseases were set up in Germany. The German cooperating partner was the BMBF-funded Network for Muscular Dystrophies MD-NET. An international harmonised dataset is recorded in the national registries and sent to a global data server in Montpellier, France, in a pseudonymous way. European legislation and ethical recommendations are strictly followed in this process as specified in the TREAT-NMD registry charter. Decisions are made by an Oversight Committee.
The German-Austrian registries for DMD/BMD and SMA started operating in April 2008. Until today (06th of July 2011), 928 patients with Dystrophinopathies and 425 patients with SMA registered online ( / This success is due to the near cooperation of paediatrics, neurologists, geneticists and patient organisations. Besides, the Friedrich-Baur-Institute in Munich hosts the new international registry for FKRPopathies which is available online since April 2011 ( Further registries are planned, e.g. the international registries for Myotonic Dystrophies and Myofibrillar Myopathies as well as the German-Austrian registry for Hereditary Neuropathies (HMSN, HMN, HSAN, HNPP and HNA).
Since their establishment the German-Austrian TREAT-NMD registries helped to set up international “Standards of Care” for DMD and SMA, to use patient’s data to plan clinical trials and to recruit and enrol patients into these trails. The registries are well accepted by patients and clinicians and aim to forward diagnostics and therapeutic options for patients with rare neuromuscular diseases.

Creation of Databases for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy in Turkey
A. Ayşe Karaduman, Öznur Yılmaz, İpek Alemdaroğlu, Haluk Topaloğlu
Hacettepe University, Faculty of Health Sciences, Physiotherapy and Rehabilitation Department
Purpose: We planned to develop a national registry database for Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA) patients by this project. Thus; national patient registries were planned to transfer regularly to international database via TREAT- NMD global communication network to participate clinical trials. We also aimed to inform professionals, patients and their care givers about recent developments on neuromuscular diseases in their mother language and increase the number of institutions in national registry system.
Material and Methods: The National Registry System was created for patients with DMD and SMA in Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation and Faculty of Medicine, Unit of Pediatric Neurology. Our project was supported from AFM (Association Française contre  les Myopathies). Thus; a software was developed to keep patients data in secure. This software provided patients/caregivers online registration. Assessments of the patients were structured base on biopsychosocial model and datas were recorded to the management system of the software by project team.  
Results: Datas of 289 DMD patients and 65 SMA patients have been collected in our national registry system from January 2007. Since February 2011, our web site was established and began the broadcasting. Seminars for the families were planned to present the project in October 2011
Conclusion: National registry system for DMD and SMA patients has been in progress with increased patient number and registration center in Turkey. We concluded that many neuromuscular patients will be in touch with professionals and have knowledge about their disease via our website easily in the coming days. Recent improvements and international studies concerning neuromuscular diseases will be declared on website.

The New Zealand Neuromuscular Disease Registry
Miriam Rodrigues, Chris Higgins, Graeme Hammond-Tooke, Alexa Kidd, Donald Love, Gina O'Grady, Rakesh Patel, Hilary Rayner, Jill Waldron, Richard Roxburgh
Muscular Dystrophy Association of New Zealand, Auckland District Health Board, Centre for Brain Research, University of Auckland, Canterbury District Health Board, Otago District Health Board, University of Otago
The Muscular Dystrophy Association of New Zealand has set the establishment of a national registry for neuromuscular disease as one of their main priorities to advance the potential of enabling clinical trials to take place in New Zealand. New Zealand has a relatively small total population just in excess of four million and it is expected that approximately 4000 people have a neuromuscular condition. Standards of care for people with neuromuscular conditions in New Zealand are comparable to much of Europe and North America meaning that selected endpoints used in clinical trials are equally measurable in the NZ population. Most neuromuscular diseases are rare and any study of disease-modifying medication will require the enrolment of participants from many countries to achieve sufficient numbers to draw significant conclusions. Some treatments for neuromuscular conditions are being developed based on the specific genetic cause of the disease and it is therefore important for any registry to also collect genetic information. The New Zealand Neuromuscular Disease Registry working group decided to set up one database for all neuromuscular conditions rather than separate databases for each condition. The New Zealand Neuromuscular Disease Registry has received ethics approval to collect voluntary participant information. The registry will send anonymised data to international registries approved by the New Zealand Neuromuscular Disease Registry oversight committee including the TREAT NMD databases for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy and the Rochester registry for Myotonic dystrophy. In addition the registry will be a useful resource for locally-based clinicians and researchers thereby increasing the likelihood of obtaining treatments for these diseases in the future.

Characterization of the DMDBMD patient population in Japan from national basis database, Remudy (Registry of muscular dystrophy).
Harumasa Nakamura a,c, En Kimura b, Yukiko Hayashi c, Hirofumi Komaki d, Madoka Mori e , Yasushi Oya e, Yasufumi Motoyoshi f, Ichizo Nishino c, Shin‘ichi Takeda b, Mitsuru Kawai g
a) TREAT-NMD, Institute of Human Genetics, Newcastle University, b) Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan, c) Department of Neuromuscular Research, National Institute of Neurosciences, National Center of Neurology and Psychiatry, Tokyo, Japan, d) Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan, e) Department of Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan, f) Department of Neurology, National Hospital Organization, Shimoshizu National Hospital, Chiba, Japan, g) Department of Neurology, National Hospital Organization, Higashi-Saitama National Hospital, Saitama, Japan.
Clinical trials with new therapeutic strategies are now being planned and conducted for Duchenne and Becker muscular dystrophy (DMD/BMD). Under these circumstances, patient registries are an important infrastructure all over the world, especially in the case of rare diseases such as DMD/BMD. We have developed a registry of Japanese DMD/BMD patients on the national basis from 2007. It comprises 83%, 15%, 2% of DMD, BMD, and IMD respectively. The database includes clinical data and molecular genetic data. As of July 2011, 750 patients have been registered in the database. The main purpose of this registry is the effective recruitment of eligible patients for a clinical trial and may provide timely information to individual patients. The registry provides a phenotypic and genotypic description of Japanese patients. The registry data gives us more detailed knowledge of natural history, epidemiology, and clinical care. This data will gain trial readiness in Japan and accelerate more effectively harmonization with other countries.

The Italian Mitochondrial Registry: design and preliminary results
M Mancuso, G. Uziel, G. Comi, M. Moggio, A. Cosi, M.L. Valentino, V. Carelli, A. Toscano, O. Musumeci, E. barca, E. Bertini, M. Catteruccia, D. martinelli, C. Minetti, C bruno, , M. Zeviani, C.Lamperti, T. Mongini, L. Vercelli, E. Pilati, P. Tonin, M. Filosto, M. Scarpelli, S. Servidei, C. Cuccagna, G. Primiano,M. Spinazzi, L. Bello, D. Orsucci, C. Angelini, G. Siciliano
Department of Neuroscience, University of Pisa, Italy
In the past 15 years there has been a surge of interest in human mitochondrial diseases (MD). A flurry of epidemiological studies in recent years has confirmed the notion that MD are, in fact, among the most common genetic disorders and a major burden for society.
Treatment-wise, we are still extremely limited. For rare diseases, small patient populations represent the major impediment to progress in research and care. This limitation is most effectively overcome by a patient register in combination with a biomaterial bank.
Here we present the preliminary data of the web based registry of patients with MD, developed by the Italian Mitochondrial Registry Investigators granted by Telethon (GUP09004). We have already collected 1000 patients, with both adulthood and childhood onset of the disease.
The network has reached the following goals: 1. Establishment of an Italian network of clinical centers with expertise on MD; 2. Creation of a validated web based database, harmonized with other European Databases and Networks (i.e. Treat-’NMD); 3. Characterization of a big cohort of MD cases, clinically, histologically and genetically.
We believe these fundamental steps are necessary to better understand the natural history of the MD, to facilitate translational research, and, finally, to improve  the management of these disorders.

Mutation analysis of 755 Japanese DMD/BMD patients in national basis database, Remudy (Registry of Muscular Dystrophy)
Yu Matsuda1, Kanako Goto1, Yukiko K. Hayashi1, Ichizo Nishino1, Mitsuru Kawai2, Harumasa Nakamura3, En Kimurac4,
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan, 2 Department of Neurology, National Hospital Organization, Higashi-Saitama National Hospital, Saitama, Japan, 3 TREAT-NMD, Institute of Human Genetics, Newcastle University, 4 Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan
Remudy (Registry of muscular dystrophy) is a national basis registry system for the patients with muscular dystrophy in Japan. For the coming new applications of mutation specific therapies, detailed mutation analysis is important and necessary. For DMD/BMD patients in Japan, the multiplex ligation-dependent probe amplification (MLPA) analysis for the DMD gene is firstly performed, which is covered by public health insurance. Deletion/duplication of multiple exons in DMD were identified in 443/755 (60%) of the DMD/BMD patients in our series, whereas further analyses should be required for the remaining patients for the registration.
We performed detailed mutation search for 175 DMD/BMD patients by using genomic DNA extracted from peripheral lymphocytes. Direct sequencing of all 79 exons and their flanking intronic regions was performed for 97 patients with normal MLPA result with a deficiency of dystrophin protein in their biopsied muscle. For 78 patients carrying deletion/duplication of single exon on MLPA, PCR and/or direct sequencing of 3 exons (the deleted/duplicated exon and the adjacent ones) were done.
By whole exon sequencing, we found 42 nonsense mutations, 31 small deletion/insertion, 16 intronic mutations and 3 missense mutations. No mutation was identified in 5 patients. Meanwhile, mutation analysis of the selected 3 exons revealed 52 single exon deletion, 14 single exon duplication, 10 small deletion/insertion, and 2 nonsense mutations.
cDNA analysis using biopsied muscle is now on going for the patients carrying an intronic mutation and also with no mutation for the genomic sequence.

Developing Strategic Goals for Patient Reported Registries: Focus on the Congenital Muscle Disease International Registry (CMDIR) Model
Anne Rutkowski, MD, CMDIR Director, Cure CMD Chairman, Kaiser SCPMG, Elizabeth DeChene, MS, CGC, Research Genetic Counselor, Teresa Alcala, BSN, RN, PHN, CMDIR Outreach and Clinical Study Coordinator, Irma Bermudez, RN, CMDIR Clinical Nurse Curator, Editor of CMDIR Newsletter, Monique Millichamp, CMDIR Assistant Curator
CMD International Registry, Cure CMD
Clinical trial readiness for any disease starts with a registry. Patient reported registries offer advantages over traditional physician entered databanks, including awareness driven through patient online communities and alignment with motivated end-users.  Defining registry goals, workflow and scope is an iterative process with the recent validation of patient reported qualitative research best correlated with hard endpoints, including disease specific adverse event rates or markers of disease progression.
The Congenital Muscular Dystrophy International Registry (CMDIR) launched in September 2009, after an international consensus building process and community beta testing, defined registry scope as a global patient list with collection of limited demographic information and a core set of clinical questions.  Parallel development of CMD Consensus Care guidelines highlighted the lack of available clinical data focused on potential markers of disease progression and severity, such as weight, forced vital capacity and % predicted forced vital capacity and validated questionnaires to query clinical symptoms related to morbidity and mortality.  Economies of scale debate supported decisions to expand inclusion criteria to the congenital myopathy community and register through late onset myopathy and limb girdle muscular dystrophy with shared CM and CMD gene involvement, respectively.  
Evaluation of registry capabilities led to expansion of clinical questions, insertion of a breathing questionnaire, medical report retrieval with back-end select medical report curation and links to a growing CMD BioBank at the NIGMS Repository at Coriell Medical Institute and a CMD Genotype and Phenotype study with NCBI and key labs used by community for molecular confirmation.  Ongoing barriers to meeting strategic goals include challenges in promoting universal registration, lack of an interactive user interface that gives back to registrant real time and conversion of a volunteer staff to a cadre of trained CMDIR staff employees.  Registry services include outreach to support early enrollment targets for all posted CMDIR clinical studies and planned CMDIR data mining to query both retrospectively and prospectively critical clinical trial endpoints such as adverse event rates.  Developing registry solutions that are sustainable, drive patient relevant clinical research hypotheses and interact within a complex space meeting patient, academician and clinician needs is paramount to maintaining rare disease momentum.

THE CANADIAN NEUROMUSCULAR DISEASE REGISTRY (CNDR) A Novel Method for Organizing Patients with Neuromuscular Disease in Canada
Campbell, C1; Smith, M2; Benstead, T.3; Biggar, D.4; Bourque, P.5; Briemberg, H.6; Dojeiji, S.5; Dooley, J.3; Genge, A.7; Grant, I.3; Hogan, G.8; Johnston, W.9; Katzberg, H.4; Mah, J.K.1; McAdam, L.10; McCormick, A.5; McMillan, H.5; Melanson, M.11; Schellenberg, K.9; Selby, K6; Smith, G.11; Venance, S.2; Wee, J.11, Korngut, L2
1 University of Western Ontario; 2 University of Calgary; 3 Dalhousie University; 4 University of Toronto; 5 University of Ottawa; 6 University of British Columbia; 7 McGill University; 8 Erin Oak Kids, Mississauga, ON; 9 University of Alberta;  10 Holland Bloorview Kids Rehab, Toronto, ON; 11 Queen’s University
The Canadian Neuromuscular Disease Registry (CNDR) is a Canada-wide clinic-based registry involving 13 academic institutions and over 30 clinicians and academics across the country. The CNDR National Office is located at the University of Calgary in Calgary, Canada.  The registry aims to recruit 4000 patients by December 2013 and all patients in Canada with a diagnosed neuromuscular disease are eligible. The CNDR employs a secure web portal for data entry and data is submitted over a secure connection to the central data server.  Data consists of items prospectively collected during the clinic visit.
Currently the CNDR collects detailed medical information on individuals with myotonic dystrophy (type I or II); Becker muscular dystrophy; Duchenne muscular dystrophy and intermediate muscular dystrophy.  Individuals with any other diagnosed neuromuscular disease can have their name, contact information and diagnosis stored in the registry.  All patients are able to consent to being contacted regarding research and trial opportunities that they may be eligible for.  In April 2011 the CNDR brought together experts from across Canada to derive a medical dataset for amyotrophic lateral sclerosis (ALS).  A software module is being built, and the CNDR plans to begin data collection for ALS in early 2012.  The CNDR is also assessing the feasibility of collecting detailed medical information on patients with spinal muscular atrophy (SMA).
Patients are enrolled in affiliated neuromuscular clinics.  Patients not attending an affiliated clinic are able to register through the CNDR National Office.    
The CNDR aims to accelerate research into neuromuscular diseases by facilitating collaboration between clinicians and researchers across Canada and by connecting patients with research opportunities.
The CNDR is supported by the ALS Society of Canada, Jesse’s Journey, and the Marigold Foundation.    

Improved dystrophin and SMN1 gene analysis in Hungarian Duchenne/Becker muscular dystrophy and spinal muscular atrophy families - Setting up the patient registries in relation to TREAT-NMD
V. Karcagi(1), H. Piko(1), M. Garami(1), B. Nagy(2), L. Timar, A (3), Herczegfalvi(4)
(1) National Institute of Environmental Health, Dept. of Molecular Genetics and Diagnostics, (2) Semmmelweis Univ., Clinic of Obstetrics and  Gynaecology, (3) National Institute of Children’s Health, Genetic Counselling, (4) Bethesda Children’s Hospital, Dept. of Neurology, Budapest, Hungary
A comprehensive study of the Hungarian Duchenne/Becker muscular dystrophy (DMD/BMD) and the spinal muscular atrophy (SMA) families is presented here. Our laboratory is the only one in Hungary which offers mutation screening for the entire dystrophin gene and the SMN1 gene for affected patients and their female relatives using Multiplex Ligation-dependent Probe Amplification (MLPA) technique and quantitative real-time PCR, respectively.
Out of the analysed 278 male DMD/BMD patients, 50 cases (54 %) had deletions, whereas 22 cases (8%) had duplications and in a small portion of the patients (7 cases, 2 %;) pathogenic point mutation has been confirmed. In 100 cases (36%) DNA sequencing should be performed later on. Out of the 204 female relatives investigated, 77 proved to be carriers, including 4 (5%) manifesting carrier females. Since 1993, 684 patients were analysed with the clinical diagnosis of SMA and 293 cases were confirmed as having the most frequent mutation in SMN1 exon 7 and 8. Furthermore, 18 compound heterozygous patients were detected of whom in 4 cases the pathogenic mutation was so far identified. Carrier analysis was requested in 114 cases and 39 relatives were confirmed as carriers. Due to the efficient genetic counselling, 199 prenatal analyses were offered with the outcome 144 healthy and 55 affected fetuses.
All these achievements enabled us to set up the national TREAT-NMD patient registries. Self reporting questionnaire form is used and have been sent out per mail from 2007 on for both diseases. Since then, 99 DMD and 81 SMA patients with confirmed genetic mutation have been registered and all genetic and clinical data were entered into UMD. As a recent development, a constantly renewed provides information to help affected individuals and their families to understand diagnosis, genetic tests, standards of care, new therapeutic developments and trials, and promotes TREAT-NMD registration.

18 Oct 2011