Workshop report134th ENMC International Workshop: Outcome Measures and Treatment of Spinal Muscular Atrophy11–13 February 2005Naarden, The Netherlands
Introduction
The 134th ENMC workshop on outcome measures and treatment of SMA attended the meeting in Naarden, The Netherlands, during the weekend of the 11–13th February 2005. It was attended by 30 active participants from Belgium, France, Germany, Italy, Poland, Spain, Switzerland, Turkey, The Netherlands, United Kingdom and USA, including three patient representatives.
The aim of the meeting was to put forward a concerted action to obtain consensus on the methods for following up patients with SMA, and measuring their motor disability.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the spinal cord neurons, and is clinically characterized by muscle weakness and genetically by mutations in the Survival Motor Neuron (SMN) gene. Children with SMA experience weakness over a wide range of severity. Type 1 SMA are never able to sit independently and generally die in infancy. Type 2 SMA can sit but often develop severe pulmonary and orthopaedic complications, and SMA type 3 children acquire the ability to walk although this might be lost during the course of the disease. In all forms of SMA the most rapid rate of decline is early in the course of the disease, with a progressively slower rate of decline over time, and sometimes years are needed to appreciate any further deterioration [1]. Recent understanding of the pathogenesis of SMA has raised hopes that specific therapeutic approaches might be possible. There are normally two copies of SMN on each chromosome, the primary gene copy called SMN1, and almost an identical copy, SMN2. Loss of SMN1 is essential to the pathogenesis of SMA, while the severity of the disease is primarily related to the number of copies of SMN2. Approximately two copies of SMN2 (∼20% normal protein levels) very frequently produce SMA type 1, three copies are correlated mostly with SMA2, four copies with SMA3, while carriers for SMA (presumably ∼60% normal SMN protein abundance) are asymptomatic [2], [3], [4]. Thus, administration of agents capable of increasing the expression of SMN protein levels may improve outcome in SMA. Recent indications suggest that such agents exist, even among drugs already licensed for use. A concentrated effort to discover the best of the candidate agents is now proceeding, and these agents are being evaluated in well-characterized SMA mouse models and human cell lines, prior to human testing.
Section snippets
Pathogenic mechanisms in SMA. Challenges for therapy
In a brief introduction, Anita Macaulay from the UK Jennifer Trust on SMA, representing the SMA patient organisations emphasized the role of the SMA patient organisations in helping with the funding and recruitment of patients.
The first part of the meeting summarised the recent knowledge achieved on the pathogenesis and physiopathology of SMA. Arthur Burghes gave a broad introduction on the pathogenesis of SMA derived from his experience on animal models. Both SMN genes are ubiquitously
Experience from completed trials as lessons for trials in SMA
A natural history study of SMA was completed in 1994 by the Dallas-Cincinnati-Newington (DCN) group [37]. Results from the DCN study were used to design later trials conducted by AmSMART and Susan Iannaccone presented the trial using riluzole in SMA type I [38] (Box 1) and gabapentin in SMA type III [39] (Box 2). Bertini summarized the multicentre Italian randomized, controlled, open label trial of gabapentin in SMA type II and III patients (Box 3). Eugenio Mercuri presented his preliminary
Natural history, standard care, and outcome measures
Preliminary data obtained from the longitudinal application of reliable measurements on functional scores and strength in SMA patients have already shown important background information for comparing the outcome in future trials using therapeutic interventions [42], [43]. Klaus Zerres made a general introduction on his personal experience and what is known on the natural history of SMA (Box 5).
SMA type I
The group related to SMA type I was lead by Eugenio Mercuri and Richard Finkel who defined inclusion and exclusion criteria for clinical trials in SMA-1. SMA-1 patients should be clinically as homogeneous as possible within a trial or separate cohorts should be used for analysis of differing subtypes. The clinical phenotype of type 1 can be subdivided into three fairly discrete groups that have distinctly different natural histories. Type 1a, the severe neonatal variant with joint contractures
Trials for SMA in preparation
Trials in preparation are summarized in Box 8., Box 9., Box 10., Box 11., Box 12., Box 13..
Conclusions
After two days discussion it became clear that future trials will have to be stratified with great attention, producing on one side a careful selection of patients and on the other matching the requirement of an adequate number of patients to accomplish the acceptable power for a randomized double blind controlled trial. Thus, everyone came to the agreement for the need of an international effort. The Workshop appointed a task force to harmonise Outcome Measures, and another separate task force
Acknowledgements
This workshop was made possible by the financial support of the European Neuromuscular Centre (ENMC) and its main sponsors and associated members:
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Association Française contre les Myopathies (France)
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Deutsche Gesellschaft für Muskelkranke (Germany)
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Telethon Foundation (Italy)
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Muscular Dystrophy Campaign (UK)
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Muskelsvindfonden (Denmark)
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Prinses Beatrix Fonds (Netherlands)
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Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland)
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Österreichische Muskelforschung (Austria)
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Vereniging
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2019, NeuroImage: ClinicalCitation Excerpt :Animal models of SMA have allowed insight into the development of pathology (Kariya et al., 2008). However, additional techniques are needed to elucidate the mechanisms in vivo that underlie SMA pathogenesis and which can monitor the response to recently introduced SMN protein augmenting therapies at an early stage (Sumner and Crawford TO, 2018) as the execution of clinical trials in SMA is complicated by the lack of sensitive outcome measures (Bertini et al., 2005). Magnetic resonance imaging (MRI) can provide potential biomarkers for SMA.
Prenatal aspects in spinal muscular atrophy: From early detection to early presymptomatic intervention
2018, European Journal of Paediatric NeurologyCorrelation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases
2018, Neuromuscular DisordersCitation Excerpt :However, a few patients who harboured three copies of the SMN2 gene were unambiguously diagnosed with type I SMA (17/286; 6%) based on a disease onset between 3 and 6 months and the fact that they never sit (Fig. 1). These patients usually have better clinical evolution and higher survival rates compared to “classical” type I cases, and can be classified as type Ic [26]. The natural history of these patients may be explained by the non-equivalency of their SMN2 copies, which renders their phenotype more severe than expected in patients with three SMN2 copies.