Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. While many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence < 5/10,000).
Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients.
The harmonized implementation of national and ultimately, global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardised patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries.
Here we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organisations and industry.
Significant Hidden Costs Revealed in International Study of Duchenne Muscular Dystrophy
In the first international study of its kind, researchers have found that there are many different costs accompanying a rare condition such as Duchenne muscular dystrophy (DMD) and that there is a considerable financial burden carried by affected families.
The research, published in the journal Neurology, was led by Newcastle University (UK) and the Karolinska Institutet (Sweden) and carried out in collaboration with patient registries for DMD in Germany, Italy, the UK and the United States. Funded by GSK, the aim of the study was to estimate the total cost of illness and the economic burden of DMD.
DMD affects one in 3,500 male births every year. The condition is caused by a faulty gene and the main symptom is severe and progressive muscle weakness, leading to falls and difficulty with motor skills. By the age of twelve most patients need a wheelchair, though treatment with steroids can extend walking ability. Ultimately, patients are unable to look after themselves, and are prone to breathing and heart difficulties which usually result in a life expectancy of around 30 years.
The national DMD registries from the global TREAT-NMD network helped identify the patients with DMD in Germany, Italy, UK, and USA. Researchers asked 770 patients and their primary caregivers in Germany (173), Italy (122), the UK (191) and the USA (284) to complete a questionnaire on their experience of living with DMD and the impact this had on the need to access medical care, employment, leisure time and quality of life.
Researchers found that there are many different costs accompanying DMD. The analysis of the data showed that the direct cost of the illness across the countries was between eight and sixteen times higher than average health expenditure per person. The study also showed that the indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs.
Professor Kate Bushby, co-author of the study and one of the founding co-ordinators of the TREAT-NMD Network, said: “Rare diseases are massively underfunded generally and the cost to society is often hidden as so many costs are borne by the family themselves. Our figures show that DMD imposes a severe economic burden on the family and friends of affected people, as well as society as a whole. It is essential that more money is spent trying to find ways of easing this burden on patients and families.”
Olivia Schreiber-Katz, a curator of the German DMD patient registry used in the study, said: “This study shows important results which could represent the first step towards a systematic health economic assessment of Duchenne muscular dystrophy. These can be used for further analyses and, hopefully, can contribute to a smooth translation of new DMD therapies to their implementation into DMD care. For us, the most important aspect is that the significance of indirect and informal cost was shown. It would be good to see some more detailed discussion and analysis of the reasons why some costs considerably differ in between the analyzed countries, such as differences in DMD care and in national health care systems and how these affect the comparability of the results.”
Fernanda de Angelis, a curator of the Italian DMD Registry, said that “As far as we know, this is the first time that costs other than direct costs have been considered and quantified on an international basis. The estimation of indirect and intangible costs presented in the study strongly indicate that they should definitely be considered by national authorities’ social and health intervention programmes”.
Diana Ribeiro, a representative from Action Duchenne, who run the UK patient registry used in the study, said: “This highlights the significant burden of living with Duchenne muscular dystrophy on individual families in the UK, as well as the hidden costs to society as a whole with many carers providing unpaid care and unable to continue in full-time employment. It sends a powerful message that our healthcare policymakers must not only help to support families affected by the condition, but also invest in research which will lead to treatments in the future.”
Holly Peay, Director of the DuchenneConnect Registry in the USA, said: “Outcomes from the study about the costs related to caring for Duchenne muscular dystrophy and the more global impact on families are important and meaningful for informing future care and support of people and families with Duchenne. Recognizing the complete economic context of Duchenne is crucial to fully understand the potential impact of new therapies, and may inform evidence-based health policies, including reimbursement for treatment costs. We appreciate the participation of DuchenneConnect’s United States families in this important study.”
The results underline that there are many different costs accompanying a rare condition such as DMD, and that there is a considerable economic burden carried by affected families. The previously unknown economic context of a rare disease can serve an important role for the health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies.
For more information, please contact the TREAT-NMD Office on +44 (0) 191 241 8617 or e-mail firstname.lastname@example.org
This is a significant update to the 2010 publications, ‘Diagnosis and management of Duchenne muscular dystrophy’ parts 1 and 2 have now been published in The Lancet Neurology.
A multidisciplinary committee of experts was established in 2014 with the task of updating the care considerations from 2010 in order to benefit patient care. The new care considerations address the needs of patients with prolonged survival, offer guidance on assessments and interventions, and consider the implications of emerging therapies for Duchenne Muscular Dystrophy (DMD). The committee identified three new topics to be addressed in addition to the eight from 2010. These are primary care and emergency management, endocrine management and transition of care across the lifespan. The care considerations are now published online as 3 papers:
This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD.
This review is based on the internationally agreed care recommendations for DMD and aims to provide some guidelines to paediatricians for the management of these patients.
Analysing the type and frequency of patient specific mutations that give rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. Locus specific databases (LSDBs) allow for the collection, organization, storage and analysis of genetic variants of disease.
Survival in Duchenne muscular dystrophy (DMD) has increased in recent years due to iterative improvements in care. This paper describes the results of the CARE-NMD survey of care practices for adults with DMD in the UK in light of international consensus care guidelines. It also compares the UK experience of adult care with the care available to pediatric patients and adults in other European countries (Germany, Denmark, Bulgaria, Czech Republic, Hungary, and Poland).
Spinal muscular atrophy (SMA) is a progressive muscular disorder caused by mutations in the SMN1 gene. Since little studies have been performed into its epidemiology, a study was performed using multi-resources.
Firstly the incidence (proportion of newborns with SMA) was determined by questioning genetic laboratories in different countries about the number of positive SMN1 diagnoses from 2011 to 2015. This lead to enough response in 18 countries within whole Europe, where an incidence between ~1 in 3900 to16,000 newborns per year was found.
Secondly the prevalence (number of patients alive at a certain time point compared to the total population) of the number of patients really known, and thereby ready for research and clinical trials, was investigated by enquiring the CTSR (on 15 Dec 2015) and the patient registries (on 1 Sept 2015). The CTSR retrieved data from 42 countries and the patient registries from 29 countries (26 registries). This revealed large differences between countries in the relative amount of patients known, whereby by far the largest amount of registered patients lived in Europe. In general the trial ready population was around two to five times lower than expected prevalence.
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene (SMN1) on chromosome 5.
SMA shows a wide range of clinical severity, with SMA type I patients often dying before two years of age whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here we describe the design, set-up and utilisation of the TREAT-NMD national SMA patient registries characterized by a small, but fully standardized set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care.
Our study included 5068 SMA patients in 25 countries. 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high income countries with comparable wealth and health care system. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.
This is an update of the standard of care recommendations for spinal muscular atrophy (SMA) published in 2007 (‘Consensus statement for standard of care in spinal muscular atrophy‘) is now available. The 2-part report is published in Neuromuscular Disorders.
Consensus statement on standard of care for congenital muscular dystrophies
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Consensus-based care recommendations for adults with myotonic dystrophy type 1.
Ashizawa T, Gagnon C, Groh WJ, et al. Neurol Clin Pract. 2018;8(6):507-520. doi:10.1212/CPJ.0000000000000531
Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy.
Morís G, Wood L, Fernández-Torrón R, et al. Muscle Nerve. 2018;57(3):380-387. doi:10.1002/mus.25991
Global FKRP Registry: Observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9
Murphy LB, Schreiber-Katz O, Rafferty K, et al. Ann Clin Transl Neurol. 2020;7(5):757-766
Limb-girdle muscular dystrophies — international collaborations for translational research
Thompson R, Straub V. Nat Rev Neurol. 2016;12(5):294-309
218th ENMC International Workshop: Revisiting the consensus on standards of care in SMA, Naarden, The Netherlands, 19-21 February 2016.
Finkel RS, Sejersen T, Mercuri E; ENMC SMA Workshop Study Group. Neuromuscul Disord. 2017;27(6):596-605. doi:10.1016/j.nmd.2017.02.014
International workshop on assessment of upper limb function in Duchenne Muscular Dystrophy: Rome, 15-16 February 2012.
Mercuri E, McDonald C, Mayhew A, et al. Neuromuscul Disord. 2012;22(11):1025-1028. doi:10.1016/j.nmd.2012.06.006
The development of antisense oligonucleotide therapies for Duchenne muscular dystrophy: report on a TREAT-NMD workshop hosted by the European Medicines Agency (EMA), on September 25th 2009.
Muntoni F; Meeting Steering Committee and TREAT-NMD Network. Neuromuscul Disord. 2010;20(5):355-362. doi:10.1016/j.nmd.2010.03.005
Patient Registries and Trial Readiness in Myotonic Dystrophy – TREAT-NMD/Marigiold International Workshop Report
Thompson R et al. Neuromuscul Disord. 2009; 19(12):860-866
171st ENMC International Workshop: Standards of care and management of facioscapulohumeral muscular dystrophy
Tawil R et al. Neuromuscul Disord. 2008; 18:97-1001
Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; report of three expert workshops
Mercuri E, Mayhew A, Muntoni F, et al. Neuromuscul Disord. 2008;18(11):894-903. doi:10.1016/j.nmd.2008.07.003
149th ENMC International Workshop and 1st TREAT-NMD Workshop on: “Planning phase I/II clinical trials using systemically delivered antisense oligonucleotides in Duchenne muscular dystrophy”
Muntoni F, Bushby KD, van Ommen G. Neuromuscul Disord. 2008;18(3):268-275. doi:10.1016/j.nmd.2007.11.010
Publications regarding outcome measures:
T.P.3.06 The TREAT NMD registry of outcome measures for neuromuscular disease – An introduction.
Auld JM, Seyedsadjadi R, Rose M. Neuromuscular Disorders. 2008;18(9-10):795. doi:10.1016/j.nmd.2008.06.245
A decade of optimizing drug development for rare neuromuscular disorders through TACT.
Wagner KR, De Luca A, Caizergues D, et al. Nat Rev Drug Discov. 2020;19(1):1-2. doi:10.1038/d41573-019-00199-1
Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT).
Willmann R, Lee J, Turner C, et al. Dis Model Mech. 2020;13(2):dmm042903. Published 2020 Feb 7. doi:10.1242/dmm.042903
The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development.
Heslop E, Csimma C, Straub V, et al. Orphanet J Rare Dis. 2015;10:49. Published 2015 Apr 23. doi:10.1186/s13023-015-0258-1
Publications from the national registries:
Health related quality of life in European adults with DMD: Results from the Care-NMD-project.
Steffensen B, Otto C, Werlauff U, Rahbek J, Hoejberg A, Kirschner J, Vry J, Gramsch K. Neuromuscular Disorders. 2015;25:S302. doi:10.1016/j.nmd.2015.06.412
Infrastructure for new drug development to treat muscular dystrophy: current status of patient registration (Remudy)
Nakamura H, Kimura E, Kawai M. Brain Nerve. 2011;63(11):1279-1284.
P1.4 Molecular profile of 307 Portuguese patients with dystrophinopathy, including 39 new variants.
dos Santos MR, Gonçalves AR, Vieira EM, Santos M, Fineza I, Moreno T, Vieira JP, Bronze-da-Rocha E. Neuromuscular Disorders. 2011;21(9-10):642. doi:10.1016/j.nmd.2011.06.76
G.P.258 National registry of Japanese dystrophinopathy patients: Remudy.
Takeuchi F, Nakamura H, Mitsuhashi S, Mori-Yoshimura M, Hayashi YK, Shimizu R, Komaki H, Nishino I, Kawai M, Takeda S, Kimura E. Neuromuscular Disorders. 2014;24(9-10):894. doi:10.1016/j.nmd.2014.06.334
P4.60 New horizons in the DuchenneConnect registry.
Peay HL, Rangel VM, Brown K, Martin AS, Furlong P. Neuromuscular Disorders. 2011;21(9-10):722. doi:10.1016/j.nmd.2011.06.1025
Preliminary data of National Romanian Registry of DMD patients
Butoianu N, Sandu C, Iancu D, Neagu E, Iliescu C, Barca D, Burloiu C, Budisteanu M, Tarta-Arsene O, Minciu I, Motoescu C, Gherghiceanu R, Barbarii L, Craiu D. European Journal of Paediatric Neurology. 2013;17:S133-S134. doi:10.1016/S1090-3798(13)70470-7
P159 – 2412: First drug registry in Duchenne muscular dystrophy (DMD) to assess Translarna use, safety, and effectiveness in routine clinical practice.
Bushby K, Reha A, Northcutt VJ, Luo X, Ong T, Spiegel RJ. European Journal of Paediatric Neurology. 2015;19:S138. doi:10.1016/S1090-3798(15)30472-4
Current status of dystrophinopathy national registry in Japan.
Kimura E, Mori-Yoshimura M, Mitsuhashi S, Takeuchi F, Nakamura H, Komaki H, Nishino I, Kawai M, Takeda S. Neuromuscular Disorders. 2016;26:S119.
CARE-NMD: The role of patient registries in an international study of care in Duchenne muscular dystrophy.
Rodger S, Antonova V, Brabec P et al. Neuromuscular Disorders. 2012;22(9-10):880. doi:10.1016/j.nmd.2012.06.255
A comprehensive database of Duchenne and Becker muscular dystrophy patients (0-18 years old) in East China.
Li X, Zhao L, Zhou S, et al. Orphanet J Rare Dis. 2015;10:5. Published 2015 Jan 23. doi:10.1186/s13023-014-0220-7
Study of medical practices for patients with myotonic dystrophy in Japan-Nationwide specialist survey
Matsumura T et al. Rinsho Shinkeigaku. 2020; Jan 18. doi: 10.5692/clinicalneurol.cn-001347
Study of care practices for patients with myotonic dystrophy in Japan-Nationwide patient survey
Takahashi MP et al. Rinsho Shinkeigaku. 2020; Jan 18. doi: 10.5692/clinicalneurol.cn-001349.
Clinical Outcomes in Duchenne Muscular Dystrophy: A Study of 5345 Patients from the TREAT-NMD DMD Global Database
Lochmüller et al. J Neuromuscul Dis. 2017;4(4):293-306
P.7.8 The national Dutch dystrophinopathy patient registry.
Bergen van den JC, Koeks Z, Straathof CSM, Ginjaar HB, Groot I, Kooi van der A, Fock A, Pangalila R, Tol van der M, Faber C, Wolf N, Coo I, Hendriksen J, Vroom E, Horemans A, Aastsma-Rus AM, Niks EH, Verschuuren JJG. Neuromuscular Disorders. 2013;23(9-10):775-776. doi:10.1016/j.nmd.2013.06.489
Kimura E, Nakamura H, Nishino I. Brain Nerve. 2014;66(11):1396-1402. doi:10.11477/mf.1416200045
P4. 41 Remudy – DMD/BMD patient registry in Japan.
Nakamura H, Nishino I, Komaki H, Mori M, Ooya Y, Motoyoshi Y, Matsumura T, Takeda S, Kawai M. Neuromuscular Disorders. 2010;20(9-10):670-671. doi:10.1016/j.nmd.2010.07.237
Registry of muscular dystrophy (Remudy): Construction of the patient self-report registry and collaboration with overseas network
Nakamura H, Kawai M. Rinsho Shinkeigaku. 2011;51(11):901-902. doi:10.5692/clinicalneurol.51.901
The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations
Lochmüller et al. Hum Mutat. 2015 Apr;36(4):395-402
The Italian neuromuscular registry: a coordinated platform where patient organizations and clinicians collaborate for data collection and multiple usage.
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Dystrophin gene analysis in Hungarian Duchenne/Becker muscular dystrophy families – Detection of carrier status in symptomatic and asymptomatic female relatives
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Characterization of the DMD/BMD patient population in Czech Republic and Slovakia using an innovative approach
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DuchenneConnect Registry Report
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A Modular Approach to Disease Registry Design: Successful Adoption of an Internet-based Rare Disease Registry
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Can outcomes in Duchenne muscular dystrophy be improved by public reporting of data?
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Prednisolone improves walking in Japanese Duchenne muscular dystrophy patients
Takeuchi F et al. J Neurol. 2013 Sept.
Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease [published correction appears in Orphanet J Rare Dis. 2019 Aug 15;14(1):199].
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Benign and malignant tumors in the UK myotonic dystrophy patient registry.
Alsaggaf R, Wang Y, Marini-Bettolo C, et al. Muscle Nerve. 2018;57(2):316-320. doi:10.1002/mus.25736
The myotonic dystrophy registry of Japan: Current status and analysis for clinical research.
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The UK Myotonic Dystrophy Patient Registry: facilitating and accelerating clinical research.
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The UK Myotonic Dystrophy Patient Registry: a key tool in the facilitation of clinical research.
Cammish P, Wood L, Lochmuller H, Gorman G. Neuromuscular Disorders. 2018;28:S17-S18. doi:10.1016/S0960-8966(18)30341-9
Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry.
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UK facioscapulohumeral muscular dystrophy (FSHD) patient registry.
Wood L, Evangelista T, Norwood F, Orrell R, Pohlschmidt M, Busby M, Graham A, Hilton-Jones D, Longman C, Lunt P, Roberts M, Watt S, Watt S, Willis T, Lochmüller H. Orphanet J Rare Dis. 2014;9(Suppl 1):P6. doi:10.1186/1750-1172-9-S1-P6
P.93 Collaborative data collection by TREAT-NMD registries to support post-marketing surveillance in spinal muscular atrophy.
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Characteristics of Japanese Duchenne and Becker muscular dystrophy patients in a novel Japanese national registry of muscular dystrophy (Remudy)
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P4.43 Spinal muscular atrophy national registry of Turkey.
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Establishment of the Australasian paediatric Charcot-Marie-Tooth disease registry.
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The TREAT-NMD care and trial site registry: an online registry to facilitate clinical research for neuromuscular diseases.
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