Chaperone Dysfunction in muscle disease

Location: Naarden, The Netherlands

The 234th ENMC Workshop on Chaperone Dysfunction in Muscle disease

Translations:
Italian by S. Carra
Hebrew by Anat Ben-Zvi
German by A. Roos
Finnish by J. Sarparantaa
Dutch by H. Kampinga and V. Timmerman

December 8-10th 2017, in Naarden, The Netherlands

Organizers: Prof. Conrad Weihl (USA), Prof. Bjarne Udd (Finland), Prof. Michael Hanna (UK)

The workshop was held in Naarden, The Netherlands on 8 – 10th of December in 2017. It was attended by 20 active participants from Australia, Belgium, Denmark, Finland, France, Germany, Italy, Israel, The Netherlands, Sweden, UK and the USA. This group included clinicians, clinical trialists, basic scientists, industry and patient representatives.

With a special thanks to the co-sponsors of this workshop:

Chaperones are essential for the development and maintenance of skeletal muscle. Specifically this large group of proteins ensures that other proteins keep their correct structure and function or facilitates their degradation if this is not possible. Thus, chaperone dysfunction is responsible for many rare hereditary myopathies. Correcting chaperone function may be a therapeutic ption.

The participants reported on various aspects of the involvement of chaperones in a large variety of muscle diseases and disease processes, ranging from primary defects in chaperone genes such as DNAJB6, BAG3 and HSPB8, to the involvement of chaperones in the larger group of degenerative myopathies including sporadic inclusion body myositis (sIBM), and beyond. Because the activity of the chaperones can be increased by different drugs, the main scope of the workshop was to identify opportunities to use the available current knowledge for direct therapies. One therapy, known to increase the activity of protein chaperones, arimoclolol, is already entering the second phase of clinical trials in patients with sIBM. Chaperonopathy patients had their own representatives at the workshop who made highly appreciated contributions focusing on the difficulties in diagnosis and therapies for ultra-rare disorders. Other discussions related to utilizing large datasets and patient cohorts to study these diseases.

Quotations from the participants:

Outcomes and how they will benefit patients:

Improved understanding of the common and shared complexities of disease processes in different chaperone diseases.
Shared lessons regarding using arimoclomol in a clinical trial.
Exchange of data and knowledge amongst participants
Appreciation of the complexity of the chaperone network in skeletal muscle
These outcomes will improve the identification of chaperone associated myopathies and facilitate the treatments of these diseases that share overlapping pathologies.

Future plans and deliverables:

  1. Extended report of the meeting to be submitted for publication in the Neuromuscular Disorders.
  2. Establishment of natural history and biomarkers in chaperonopathies.
  3. Sharing of putative chaperone gene variants with other clinical and basic researchers.
  4. Agreement on muscle features of “chaperone” dysfunction
  5. Maintain collaborations amongst this group.

Participants of the 234th ENMC workshop on Chaperone Dysfunction in Muscle Disease

For the last time in NH Hotel in Naarden!

A full report is published in Neuromuscular Disorders (pdf).

Clinical trial readiness for Calpainopathies

Location: Naarden

Translation in:
French
Italian
Spanish
German
Danish

Organizers:

Dr. Isabelle Richard (Evry, France), Dr. J. Andoni Urtizberea (Hendaye, France)

Description of the workshop:

The 233rd ENMC workshop entitled “Clinical trial readiness for Calpainopathies” took place from the 15th to the 17th of September 2017 in Naarden, The Netherlands. A multidisciplinary group of 20 persons from 9 countries (France, Germany, Italy, Denmark, Spain, UK, Japan, Brazil and USA) attended the workshop, including 18 clinical and basic science researchers, and two representatives of patient organizations (Associazione Italiana Calpaina 3, Italy and Coalition to Cure Calpain3, USA).

Background:

Calpainopathy or Limb-Girdle Muscular Dystrophy type 2A is due to mutations in CAPN3, a gene encoding an enzyme named calpain 3. This disease is characterized by slowly progressive muscle weakness affecting selectively the musculature of both girdles. There is no treatment for this disease to date. The emergence of novel therapeutic approaches in the field, like gene therapy, has prompted a much awaited discussion between physicians and researchers about the readiness for clinical trials in calpainopathy.

Discussions and achievements:

After an invigorating historical introduction of the topic by Michel Fardeau, the discussion was divided in 5 sessions, encompassing the following topics: 1) Overview of LGMD2A 2) Patient landscape, databases and registries 3) Outcomes measures including natural history of LGMD2A 4) CAPN3 function, models and therapies; biomarkers and 5) workplan for future actions.

In most countries, it appears that LGMD2A is usually the most frequent form of LGMD. Most of the patients present a classical clinical phenotype with a significant, selective involvement of the posterior compartment of the thigh. Unusual presentations of calpainopathy with pseudo-metabolic or important joint contractures, benign forms or non-conventional mode of transmission (autosomal dominant) have been presented and discussed. Respiratory function may be compromised in a proportion of patients. Although it seems to be rarely severe in LGMD2A, assessment and monitoring of respiratory function should be part of the standards of care. Cardiac issues are rarely observed and are probably coincidental. The disease course is usually slow. Muscle imaging could be as well used as a monitoring tool to follow the progression of affected muscles.

Diagnosis is achieved by gene sequencing. The molecular diagnosis of calpainopathy is complicated by the fact that, in a number of cases, the protein level is preserved in Western Blot or when a decrease is observed, it may be caused by secondary deficiencies. A possible correlation between protein expression – type of mutation and disease severity has been reported but collaborative studies are required for a full understanding of the mechanism. Experts highlighted the value of muscle biopsies for diagnosis and research purposes. Despite the introduction of Next Generation Sequencing in the diagnostic algorithm of primary calpainopathy, biopsy analysis can be of tremendous help for a better understanding of the correlation between protein expression and clinical course.

The discussion pointed out that for now, no specific clinical outcomes have been clearly defined, highlighting the need of additional data on the clinical evolution of LGMD2A in preparation of future clinical trials. The importance of patient registries whatever their scope and process (more centralized, patient self-reported or not) was also discussed. LGMD2A specific registries exist in few countries and there is an international database handled by Coalition to cure Calpain3. A global European database would be of great interest while a global worldwide register seems out of reach at this point due to divergent policies regarding data protection across the Atlantic.

In the last session, and among other therapeutic options, an AAV-mediated gene transfer approach was presented with promising results. Nevertheless, it is clear that more fundamental studies are still needed at a time when the function itself of calpain 3 is not fully understood yet.

Participants:

Alicia Alonso (Barcelona, Spain); Robert-Yves Carlier (Garches, France); Vincent Carson (Lancaster, PA, USA); Bruno Eymard (Paris, France); Michel Fardeau (Paris, France); Marie-Laurence Gourlay (Evry, France) ; Michela Guglieri (Newcastle, UK); Jean-Yves Hogrel (Paris, France) ; Bruno Kullmann (Milan, Italy) ; Jennifer Levy (USA) ; William Lostal (Evry, France) ; Yasuko Ono (Tokyo, Japan) ; Helene Prigent (Garches, France) ; Isabelle Richard (Evry, France) ; Amets Saenz (San Sebastian, Spain); Claudio Semplicini (Padova, Italy); J. Andoni Urtizberea (Hendaye, France); Mariz Vainzof (Sao Paulo, Brazil); John Vissing (Copenhagen, Denmark); Maggie Walter (Munich, Germany)

A full report of this workshop is published in the Neuromuscular Disorders (pdf).

 

Recommendations for treatment of Mitochondrial DNA maintenance disorders

Location: Heemserk

Now also available in the following translations:
French
Spanish
Catalan
Danish
Hebrew
Dutch
Italian
Finnish

232nd ENMC International Workshop: Recommendations for Diagnosis and Nucleoside Treatments of Mitochondrial DNA Maintenance Disorders

Organisers:

Ramon Martí (Barcelona, Catalonia, Spain) and Michio Hirano (New York, NY, U.S.A.)

Description:

During the weekend of the 16th through 18th June 2017, fifteen clinicians, basic scientists, patient relatives, and pharmaceutical representatives met in Heemskerk, The Netherlands. The delegates work in four ENMC member countries, one associated member country, and four non-member countries. The meeting was the third ENMC workshop devoted to disorders of mitochondrial DNA (mtDNA) maintenance. The two prior workshops dedicated to this topic were held in September 2007, workshop 155, “Polymerase gamma and disorders of mitochondrial DNA synthesis, and December 2008, workshop 163, “Mitochondrial DNA disorders”.

Background and Aims of the Workshop

Tiny structures called mitochondria, present in almost all human cells, produce energy that drives chemical reactions in the cells and hence regular cell functioning. For this reason, they are sometimes called the ‘powerhouses’ of the cell. Mitochondria contain their own “gene material” (DNA), which is called “mitochondrial DNA” abbreviated as mtDNA. This mtDNA is essential for the normal functioning of mitochondria. An important group of mitochondrial diseases, called “mtDNA maintenance disorders”, is caused by changes (“mutations”) in genes that encode proteins needed to replicate and maintain mtDNA, which results in mtDNA damage. Because many important proteins and other elements required for the correct mitochondrial function are manufactured based upon blueprints contained in mtDNA, the defective maintenance of this molecule results in mitochondrial dysfunction associated with many clinical problems that severely affect patients. Depending on the particular affected gene and other factors, different symptoms appear. In some cases, the disease mainly affects the muscle function, which may lead to respiratory failure and death in infancy or childhood. Other clinical presentations include severe dysfunction of the liver, gastrointestinal tract, or the central nervous system, which are also often fatal at early ages.

This workshop aimed to improve the clinical recognition, diagnosis, and treatment of these patients with focused discussion on treatments for two diseases: thymidine kinase 2 (TK2) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

Aims of the Workshop

(i) To present and discuss the latest updates and the state of the art in the diagnosis and treatment of mtDNA maintenance diseases, including the compilation of new genes, new findings on why and how these dysfunctional genes and related proteins lead to the associated severe symptoms, as well as preclinical and clinical evidence on the plausibility of new treatments.

(ii) To develop consensus management guidelines for treating TK2 deficiency and other mtDNA maintenance diseases.

(iii) To develop a strategy to recruit patients for an international clinical trial to treat patients with TK2 deficiency, since the workshop included neurologists, paediatric neurologists, and representatives of patients’ groups.

Outcomes of the Workshop

The workshop began with presentations on the basic biology of mtDNA replication (Drs. Copeland, Rampazzo, and Wang) and on human diseases caused by impaired mtDNA maintenance (Drs. Rahman and Martí). This background session was followed by discussions of the major symptoms and signs, biochemical and genetic alterations, their evolution from pre-symptomatic to end-stage clinical appearance, approaches to quick and correct diagnosis of these disorders, and identification of clinical outcomes to use as objective indicators of efficacy and improvement of treatments for clinical trials (Drs. Lombès, Garone and Saada). Because animal models of the disorders are critical tools for understanding how mutations cause diseases and for testing therapies, investigators described their experiences with several mutant mice and zebrafish models (Drs. Hirano, Karlsson, Suomalainen, Spinazzola, and Horvath). Interestingly, several scientific studies of the mouse and cellular models have revealed the importance of balanced pools of the four deoxynucleoside triphosphates needed for mtDNA synthesis: dATP, dGTP, dCTP and dTTP. These four molecules, collectively known as “dNTPs”, are the building blocks for the maintenance of mtDNA. Some of these diseases affect genes and proteins involved in dNTP synthesis. For example, the protein thymidine kinase (TK2) is needed for the synthesis of dTTP and dCTP within mitochondria, and the protein deoxyguanosine kinase (dGK) is needed for the synthesis of dATP and dGTP in mitochondria as well. There is accumulated evidence of the potential therapeutic benefits of administration of deoxynucleoside and deoxynucleotides, which are precursors or intermediate molecules needed for dNTP synthesis. The administration of these substances to cells (in vitro) or animal models (in vivo) bypasses the dysfunction of TK2 and dGK and may restore dNTP balance.

Additional studies in in vivo models are required to clarify whether the treatment is also potentially translatable to other mtDNA maintenance diseases (Drs. Horvath, López, Cámara and Saada). Based on these laboratory studies, TK2-deficient patients in Europe and North, Central, and South America have been treated with deoxynucleoside and deoxynucleotide therapies under compassionate use protocols with striking and encouraging results (Drs Hirano and Paradas and Mr. Arturo Estopiñán and Mr. Lander Nogués). To obtain full regulatory approvals from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) to use deoxynucleosides to treat TK2 deficiency, a clinical trial must support the efficacy of the product. Towards this goal, clinicians, industry representatives, and a biostatistician/clinical trial expert reported the multiple steps and potential pitfalls involved in moving novel drugs into clinical trials (Peter Barber, Curtis Cui, John Thompson). In contrast to TK2 deficiency, MNGIE has several available therapies (Drs. Hirano, Carelli, Martí, and De Coo). Guidelines for the MNGIE therapies were generated.

How this will Benefit Patients

A major focus of this workshop was on planning for continued testing of deoxynucleoside therapy for TK2 deficiency. If this further confirms the benefit of this promising therapy, regulatory approval will lead to greater availability of the first specific and effective treatment for this disease.

Other topics intended to benefit patients included: 1) more rapid diagnosis of TK2 deficiency; 2) clearer guidelines to help physicians choose the most appropriate option among the multiple innovative therapies for MNGIE; and 3) potential new future clinical trials of deoxynucleoside therapy for other mtDNA maintenance disorders.

List of Participants

Ramon Martí, PhD, Vall d’Hebron Research Institute and CIBERER, Barcelona, Spain

Michio Hirano, MD, Columbia University Medical Center, New York, USA

Peter H. Barber, Meves Pharmaceutical, Inc., New York, USA

Yolanda Cámara, PhD, Vall d’Hebron Research Institute and CIBERER, Barcelona, Spain

Valerio Carelli, MD, PhD, University of Bologna, Italy

René de Coo, MD, PhD, Neuromuscular and Mitochondrial research center (NeMo), Rotterdam, The Netherlands

William C. Copeland, PhD, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Curtis Cui, Hongene Biotechology USA, Morrisville, NC, USA

Arturo Estopiñán, Baltimore, MD, USA

Caterina Garone, MD, PhD, Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK

Rita Horvath, MD, PhD, Newcastle University, Newcastle Upon Tyne, UK

Anna Karlsson, MD, PhD, Karolinska Institutet, Stockholm, Sweden

Juan Cruz Landoni, BSc, University of Helsinki, Finland.

Anne Lombès, MD, PhD, Inserm UMR 1016, Institut Cochin, Paris, France

Carlos López, PhD, Columbia University Medical Center, New York, USA

Lander Nogués, Donostia, Spain

Carmen Paradas, MD, PhD, University Hospital Virgen del Rocio, Seville, Spain

Shamima Rahman, FRCP, PhD, University College, London, UK

Chiara Rampazzo, PhD, Department of Biology, University of Padova, Italy

Ann Saada, PhD, Hadassah-Hebrew Medical Center, Jerusalem, Israel

Antonella Spinazzola, MD, PhD, University College London, London, UK

Anu Suomalainen Wartiovaara, MD, PhD, Research Programs Unit, Molecular Neurology, University of Helsinki, Finland.

John LP (Seamus) Thompson, PhD, Mailman School of Public Health, Columbia University, New York, USA

Liya Wang, PhD, Swedish University of Agricultural Sciences, Uppsala, Sweden

The participants of the 232nd ENMC workshop on mtDNA maintenance disorders

A full report of this ENMC workshop will be published in Neuromuscular Disorders.

This workshop was co-sponsored by MDA USA MDA_Logo.jpg

International standard for CIDP registry and biobank

Location: Naarden

Translations of the report hereunder:
Spanish
German
Italian
Dutch
French

Organisers:

Dr. Filip Eftimov (Amsterdam, The Netherlands), Prof. Dr. Yusuf Rajabally (Birmingham, United Kingdom), Dr. Luis Querol (Barcelona, Spain).

Description of the workshop:
The 231th ENMC workshop entitled “International Standards for CIDP Registry and Biobank” took place from the 12th to the 14th of May 2017 in Naarden, The Netherlands. A multidisciplinary group of 24 people from 13 countries (The Netherlands, United Kingdom, USA, France, Italy, Spain, Belgium, Denmark, Malaysia, Serbia, Germany, Curacao and Australia) attended the workshop. These included (young) researchers and clinical experts in inflammatory neuropathies and 1 patient representative from the patient organisation “Spierziekten Nederland” and GBS/CIDP Foundation International.

Background
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy causing severe disability. CIDP is a remarkably heterogeneous disorder with various atypical clinical phenotypes. Furthermore, despite various sets of diagnostic criteria, not all patients with treatable CIDP are identified. Despite proven effective treatment, at present no clinical or biological variables are available to predict treatment response, disease activity and outcome. Further research is urgently needed to define the diagnostic clinical and electrophysiological boundaries of CIDP and its subtypes, and to define the role of biomarkers (e.g. nerve ultrasound, blood characteristics) in supporting the diagnosis, monitor disease activity and predict response to treatment and long-term outcome.
To address these research questions, it is required to conduct a prospective study with a large group of well-defined CIDP patients during a long follow-up period, collecting highly standardized clinical data, electrophysiological data and biomaterials.
In recent years, several national registries and biobanks have been developed to enable systematic data collection in CIDP. However, even in large countries, these registries will not be able to include sufficient patients to address the most important challenges described above. An international registry with large number of patients is needed to allow validated prognostic models to predict outcome in individual patients with CIDP.

Aim of this workshop:
To reach international consensus on the inclusion of CIDP patients, and the collection of clinical and diagnostic datasets and biomaterials.

Achievements:
Eight currently ongoing international CIDP registries were compared to assess infrastructure and collected clinical data, diagnostic data and biomaterials.

Consensus was reached on:
– Inclusion criterion: clinical suspicion of CIDP; Exclusion criterion: other diagnoses.
– Extended baseline characteristics needed to define clinical and diagnostic characterisation of patients but minimal core of clinical data is yet to be defined.
– Flexible follow-up visits with preferably at least a 2-year follow-up. Minimal outcomes during follow-up: a) grip strength, fatigue, disability (INCAT and RODS), quality of life (EuroQol) in all participants and b) impairment outcome measures based on individual patient characteristic at physicians discretion.
– A minimal protocol for nerve conduction study was suggested.
– Collection of biomaterials (serum, CSF, nerve biopsy) should be according to standardised protocols, with at least serum collection at baseline. Biomaterials are stored in participating centers or coordinating centers.
– Infrastructure: a central database (INCbase) will be developed to which data from existing database can be uploaded. A set of requirements for INCbase was defined. Current registries and databases continue to exist.
– All centers remain owner of data and can withdraw data from INCbase.

Proposed plans:
– Task force to A) combine current data of existing CIDP registries; B) harmonize the current registry protocols C) set up of a central database.
– The task force has proposed a timeline for the development and finalization of this registry with a plan to include first new CIDP patient into the registry by March 2018.
– Information on proposed consensus/registry protocol will be presented and discussed in the coming Peripheral Nerve Society meeting.

Participants:
Dr. S. Reddel (Sydney, Australia), Prof. dr. J. Vallat (Limoges, France), Prof. dr. J. Antoine (Saint-Etienne, France), Dr. J. Allen (Minnesota, USA), Dr. I. Basta (Belgrade, Serbia), Prof dr. A. Uncini (Chieti, Italy), Dr. K. Doppler (Wurzburg, Germany), Dr. R. Hadden (London, UK), Dr. T. Harbo (Aarhus, Denmark), Dr. H. Lehmann (Cologne, Germany), Prof. dr. P. Van den Bergh (Brussels, Belgium), Prof. dr. D. Cornblath (Baltimore, USA), Dr. S. Goedee (Utrecht, The Netherlands), Dr. M. Lunn (London, UK), Dr. I. Merkies (St. Elizabeth hospital, Curacao), Prof. dr. E. Nobile-Orazio (Milan, Italy), Prof. dr. B. Jacobs (Rotterdam, The Netherlands), Mrs. P. Blomkwist-Markens (GBS/CIDP Foundation International, patient representative), Drs. FL. Hiew (Kuala Lumpur, Malaysia), Drs. M. Adrichem (PhD-student Amsterdam, The Netherlands), Drs. C. Bunschoten (PhD-student Rotterdam, The Netherlands), Prof. dr. Y. Rajabally (Birmingham, UK), Dr. L. Querol (Barcelona, Spain) and Dr. F. Eftimov (Amsterdam, The Netherlands).

A full report of this ENMC workshop is published in Neuromuscular Disorders (pdf).

This workshop was co-sponsored by Grifols S.A. 

Limb Girdle Muscular Dystrophies, Nomenclature and reformed Classification

Location: Naarden, The Netherlands

Translation of the lay report:
German
Dutch
Russian

Description:
To reassess the nomenclature of the limb girdle muscular dystrophies (LGMD)

Organizers:
Prof. Volker Straub (Newcastle, United Kingdom), Prof. Bjarne Udd (Tampere, FInland).

Description of the workshop:

The 229th ENMC workshop entitled ‘Limb Girdle Muscular Dystrophies – Nomenclature and reformed Classification’ took place from the 17th to the 19th of March 2017 in Naarden, The Netherlands. A multidisciplinary group of 20 people from 9 countries (UK, Italy, France, USA, Netherlands, Georgia, Finland, Germany and Denmark) attended the workshop. These included: clinicians, experts in disease classification systems, patients with LGMD, and representatives from patient organisations (Jain Foundation Inc, the Beta-Sarcoglycanopathy Family Group, Spierziekten Nederland and Muscular Dystrophy UK). This workshop had the difficult task of revisiting the definition of LGMD and to discuss and propose a new classification system for LGMD sub-types that will be most useful to patients, researchers and clinicians and comply with classification systems established by OMIM (Online Mendelian Inheritance in Man), Orphanet and ICD (International Classification of Diseases)-11.

Background:

The term ‘Limb girdle muscular dystrophy’ was introduced in 1954 by Walton and Nattrass to describe a group of patients who had weakness affecting the muscles of the shoulders and the pelvic region and that were clinically different from patients with other, more clearly defined muscle disease, e.g. Duchenne muscular dystrophy. Through advances in genetic diagnostic testing more than 30 different sub-types of LGMD have now been identified and named according to a classification system introduced 22 years ago. As the term LGMD was used in a fairly unspecific manner, many conditions being classified as LGMD had very little in common with other sub-types. Because of the inconsistent clinical presentation among the various subtypes and due to the limits of the current classification system, it was felt that a new classification system should be established.

Discussions and achievements:

The experts in disease classification systems highlighted some of the common pitfalls and the purpose of developing clear systematic nomenclature. It was explained how new discoveries of LGMD sub-types are classified currently and how they are entered into the online genetic resources used by clinicians and researchers such as OMIM or the ICD. A very important point that was made was that when a disease gets a new name, the old name will not disappear. OMIM will put the new name on top, but all former names will remain listed as well. Next, several presentations pointed out the wide range of clinical differences between sub-types, such as the development of joint stiffness, heart or respiratory problems, central nervous system involvement, and which muscles are affected first. The group focused on defining the common features of the LGMDs. Opinions from patients, patient groups from social media, and surveys of clinicians were factored into discussions and it was suggested that changing the name of these conditions was appropriate, as long as it is made clear to patients why it is important to do so.

The main challenge of this workshop was to develop a clear definition of what an LGMD is. It was felt that the overall term, LGMD, should be retained but the definition should be clarified. The consensus was that the definition would include the following factors:

  • Genetic cause of the disease
  • Progressive, predominantly proximal muscle weakness (proximal means nearest to the body)
  • Condition which primarily affects skeletal muscle
  • Achievement of independent walking at some point
  • Weakness is caused by the loss of muscle fibres,
  • Elevated serum creatine kinase (CK) activity detected in the blood (CK is an enzyme that is released from muscle cells following damage),
  • Degenerative changes on muscle imaging over the course of the disease, and changes in muscle tissue (biopsy) that are in accordance with a muscular dystrophy. This means that certain characteristic changes must be seen that in the final stage of the disease will be seen in all affected muscles.
  • For a new disease to be considered a LGMD, the disease must have been identified in at least two different families.
  • Several potential sub-type classification systems were proposed and discussed. It was agreed that a system that incorporates the name of the protein affected in the muscle cell and includes the mode of inheritance would be the most informative for patients and useful for genetic counselling. A number will be assigned according to the order of subtype discovery. Once the final definition was applied to the current list of LGMD, ten no longer fulfilled the criteria. The workshop also suggested to include conditions as new subtypes that previously were not classified as LGMD.
  • Patients and patient organisations were asked to give their opinions on the new definition and classification. The overall consensus was that the new classification added clarity to the field of LGMD. The workshop acknowledged that appropriate support from clinicians and patient organisations would be important in establishing the new nomenclature.

The following key deliverables were achieved:

  1. A consensus was reached on an updated definition of LGMD and current sub-types were evaluated by application of the updated definition.
    Consensus was reached on the most useful LGMD classification system that also allowed space for further discoveries of new sub-types.
  2. Potential ramifications of the new definition and classification of LGMD for patients was discussed and several action points around how to disseminate this proposal were identified.

Participants:

Corrado Angelini (Padua, Italy), Segolene Ayme (Paris, France), Carsten Bonnemann (Bethesda, USA), Marianne de Visser (Amsterdam, Netherlands), Ada Hamosh (Baltimore, USA), Laura Jacobs (London, UK), Nina Khizanishvili (Tblisi, Georgia), Madelon Kroneman (Zaltbommel, Netherlands), Pascal Laforêt (Paris, France), Alex Murphy (Newcastle, UK), Vincenzo Nigro (Naples, Italy), Laura Rufibach (Seattle, USA), Anna Sarkozy (London, UK), Volker Straub (Newcastle, UK), Shaun Swanepoel (High Wycombe, UK), Yvan Torrente (Milan, Italy), Bjarne Udd (Tampere, Finland), Andoni Urtizberea (Hendaye, France), John Vissing (Copenhagen, Denmark), Maggie Walter (Munich, Germany).

A full report is published in the Neuromuscular Disorders (pdf).

Airway clearance techniques in Neuromuscular Disorders

Location: Naarden, The Netherlands

Translations of the lay report:
Spanish
Italian
French
Norwegian

Acknowledgements:

This workshop was made possible with generous support from:

           

On 3 March 2017, 21 participants from 12 countries across the world (including Australia, Europe; United Kingdom; United States of America; and South Africa) met in Naarden, Netherlands, to attend and contribute to the 228th ENMC International Workshop entitled, “Airway Clearance Techniques In Neuromuscular Disorders”. Participants represented clinicians, researchers, patients and patient advocacy groups, from a range of socioeconomic and geographical backgrounds and disciplines. The workshop was conducted under the leadership of Michel Toussaint (Belgium); David Berlowitz (Australia); Jesus Gonzalez (France) and Michelle Chatwin (United Kingdom). Professional participants for this ENMC Workshop were selected for their active involvement in neuromuscular disorder (NMD) research, clinical care, advocacy, policy development and/or education, and are all considered experts in their respective areas.

Workshop rationale and scope

There are a number of congenital and acquired NMDs, which may affect the respiratory muscles, to varying degrees and at different life stages (from infancy, through childhood, and to adulthood). This weakness results in patients not being able to effectively cough and clear pulmonary (lung) secretions on their own, leading to recurrent chest infections and ultimately, chronic changes in the lungs. Airway clearance techniques (ACTs), to facilitate clearance of pulmonary secretions, along with ventilatory support as needed, are therefore essential components in the care of people with NMDs and associated respiratory muscle weakness.

Currently, national and centre- specific practices vary substantially and adherence to published guidelines for the management of secretion encumbrance is not optimal. This workshop was therefore conducted with the primary aim of developing a consensus guideline for the minimum and optimal standards of ACT care for patients with a range of NMDs and clinical presentations, from childhood through to adulthood.

The following major topics were discussed during the workshop proceedings:

  1. The pathophysiology of secretion encumbrance in people with NMDs.
  2. The principles of proximal and peripheral airway clearance.
  3. The effect of respiratory tract infection on respiratory muscles, lung volumes and blood gas exchange in people with NMDs.
  4. Detailed description of all peripheral and proximal ACTs available for use in patients with weak respiratory muscles.
  5. The limits of effectiveness of each ACT, the need for a learning period/training, financial cost, availability and possible complications.
  6. Specific treatment algorithms (protocols) were defined for ACT management in NMDs in terms of: context, patient age and ability to cooperate, presence of invasive or noninvasive device interface, glottic control and objective measures of respiratory muscle strength.
  7. Optimal outcome measures for future research studies were identified.

The workshop generated enthusiastic discussion from all participants and achieved its stated objectives, with a high level of agreement for all final recommendations reached.

The full report (to be published in the journal Neuromuscular Disorders) will provide practical recommendations that can be used by physicians, respiratory therapists/physiotherapists, patients and their carers. In addition, a state of the art review of ACT in patients with NMDs will be published. These publications will provide a novel framework for practical implementation in different clinical settings, as well as identifying priority areas for research. By optimising ACT management, it is hoped that duration and quality of life will be optimised, and the number of pulmonary exacerbations requiring hospitalisation and invasive ventilation be reduced in people with NMDs throughout the world.

A full report is published in Neuromuscular Disorders (pdf)

Improving future assessment and research in IgM anti-MAG peripheral neuropathy; a consensus collaborative effort

Location: Naarden

IgM anti-MAG peripheral neuropathy: a consensus collaborative effort

Translations of the lay report:
in French
in Italian
in German
in Dutch

This workshop took place from February 24th -26th, 2017 in Naarden, The Netherlands. A collaborative group of clinical experts in the field of neuropathy associated with anti-nerve antibodies in the blood (focusing on IgM paraprotein), patients and their representatives met for the 230th ENMC meeting with the purpose of improving the future assessment of patients and research in IgM anti-myelin associated glycoprotein (anti-MAG) peripheral neuropathy. The workshop was conducted under the leadership of Nicolette C. Notermans, Ingemar S.J. Merkies and Michael P.T. Lunn.

The group gathered to address different aspects of the disease. They embraced the principle that specific valid functional outcome measures should be developed for studying and following clinical patients with these conditions.

The IMAGiNe project will collect data to classify patients and understand their natural history, the neurological and haematological characteristics of the disease and treatment responses, both past and future. The project will be inclusive of all worldwide centres with disease expertise, which can include at least 10 participants.

The group will also evaluate current outcome measures and develop a new disability scale or scales with a focus on patients. The outcome measures will represent their impairments, disabilities, quality of life and treatment expectations. Following the development of scales consensus will be reached on defining “being a responder” to treatment.

We will explore new avenues in diagnosis, disease classification, pathogenesis and treatment, collaborating with our haematological colleagues who are essential to this effort. The IMAGiNe project will lead to proposals for new therapeutic strategies, with a plan to commence our first clinical trial utilizing novel outcomes by the end of 2018.

We will review progress annually through the Inflammatory Neuropathy Consortium and Peripheral Nerve Society congresses, and periodically inform the ENMC of the impact and outcomes of our projects.

Participants:

Prof. Dr. P. van den Bergh (Brussels, Belgium), Mrs. P. Blomkwist-Markens (GBS/CIDP Foundation International, patient representative), Prof. Dr. D. Cornblath (Baltimore, Maryland, USA), Dr. S. D’Sa (London, UK), Prof. Dr. C. Faber (Maastricht, the Netherlands), Dr. S. Goedee (Utrecht, the Netherlands), Prof. Dr. K. Gorson (Boston, Massachusetts, USA), Prof. J-M Léger (Paris, France), Prof. Dr. R. Lewis (Los Angeles, California, USA), Dr. M. Lunn (London, UK), Mr. L. Mazawey (patient), Dr. I. Merkies (Maastricht, the Netherlands), Prof. Dr. E. Nobile-Orazio (Milan, Italy), Dr. N. Notermans (Utrecht, the Netherlands), Dr. L. Padua (Rome, Italy), Dr. L. van der Pol (Utrecht, the Netherlands), Drs. M. Pruppers (Maastricht, the Netherlands), Dr. L. Querol (Barcelona, Spain), Prof. Dr. A. Steck (Lausanne, Switzerland), Prof. Dr. Hugh Willison (Glasgow, UK).

A full report is published in the Neuromuscular Disorders (pdf)

Finalizing a plan to guarantee quality in translational research for Neuromuscular diseases

Location: Naarden

227th ENMC International Workshop: Finalizing a plan to guarantee quality in translational research for Neuromuscular diseases

Translations of the report:
Italian
German
Dutch

This workshop was supported by:

High quality translational research data are critical to successfully move new drugs from laboratory bench to patient bedside especially for rare neuromuscular diseases. The development of new medicines for rare diseases mostly starts in an academic lab, where researchers follow an idea or a hypothesis and plan the first experiments to test its validity. Such proof-of-concept studies are studies that investigate the mechanism of action of a drug at the molecular level, or test in cell systems and mice if a drug has an effect on a pathological feature. In a later phase, more detailed studies on animal models of a disease are necessary to see if the drug overall ameliorates the pathology of the animal (efficacy studies). This final pre-clinical stage should be carefully designed to try and closely match the conditions to be used for a potential human clinical trial using this same drug. If these last animal studies give positive results, the drug may be considered to be applied in a clinical study on patients, to see if the efficacy is shown also in humans. The passage from the preclinical study phase on animals to the clinical phase on persons is called translation.

Academic researchers record the progress made in their research projects in form of articles (papers) that they submit for publication to scientific journals. The number of papers and the journals where these are published mean a lot for the researcher’s career and for the future probability to get their research funded. Journal editors select the quality of submissions by the process of peer reviewing and they are interested in publishing papers that will make an impact, because these will be cited in the future and will increase their visibility. Because of these reasons, titles of papers sometimes suggest amazing results even for early proof of concept studies.

Fortunately, in the last decade the interest in finding cures and medicines for rare diseases has increased considerably. More research projects are funded; more clinical studies are initiated both by academics and by companies. The exchange of know-how between clinicians (expert on the disease), patients (expert on the daily management of the disease), researchers (familiar with experiments and their evaluation), companies (advanced in the development of drugs and organisation of clinical trials) and regulators (experts in the requirements for approval of medicines) becomes important. The need of selecting the most promising treatments prior to starting a costly clinical trial has increased. The failure of many human trials in the past has driven attention to the quality of the published preclinical work: were animal experiments conducted with the rigor of a clinical study? Can they be reproduced by another laboratory? Are results powered enough to make the statement they make?

In this landscape, to more rigorously select strongly justified clinical trials, we identified the following discussion topics, for which we invited representative stakeholders to agree together on measures to improve more efficient and effective translation of preclinical work and collaboration among professionals.:

  • How to increase cross-talk between clinicians, researches, industry and patients
  • How to improve quality of animal studies that aim at showing efficacy of a treatment for a particular disease
  • How to encourage funding and publication of not novel studies that aim at reproducing data observed by others, and publication of negative results.

After a first series of introducing talks and testimonials, the participants divided into discussion groups, and following deliverables were agreed upon:

  1. Workshops will be organized at international meetings to inform stakeholders in the topics they are not familiar with, in order to improve efficiency at all levels of drug development. In particular, it was suggested to make use of the broad expertise represented in the TACT committee, a group created by TREAT-NMD that realistically evaluates the possibility of drug or treatment to translate to humans.
  2. Journal editors agreed to make an effort in requiring some standards in reporting preclinical trials by explicitly stating them in the instructions for authors. This would help also reviewers to search for such criteria in the submitted manuscripts. They suggest that quality requirements by funding agencies, set before a project is funded, may have more impact on quality of the experiments conducted. They recognise that the publication of negative resultsis not attractive to many journals. However, some journal are addressing this important issue, since it is critical that studies that do NOT support use of a drug are also published, to provide a balanced picture . This group also suggests that small, controlled pilot trials on humans before a big clinical trial would help to predict translatability.
  3. Funding agencies proposed to improve awareness on high quality preclinical research among smaller patient organisations that do not have an expert scientific commission in place to evaluate project quality, and to take a leading role in educating such organisations. Furthermore, they propose to use the leverage they have on industry to require strong preclinical data before engaging in a clinical trial.

Workshop participants were researchers, clinicians, industry representative active in the field on neuromuscular diseases; patient organizations that fund research project and the main journals that publish neuromuscular research. They arrived from Europe, USA and Australia. Parent Project Muscular Dystrophy USA kindly supported the travel costs of all overseas participants.

A full report is published in the Neuromuscular Disorders (pdf)

Towards validated and qualified biomarkers for therapy development for Duchenne Muscular Dystrophy

This workshop was supported by:

  

Dutch translation
German translation
Italian translation
Swedish translation

Lay Summary

Biomarkers are substances in our body that can be measured, and that relate to

  1. The presence of a disease, and this is referred to as a diagnostic biomarker. For example, elevated CK (creatine kinase) in the blood indicates muscle damage and is a diagnostic biomarker for Duchenne but also for other muscle diseases.
  2. The disease course, and this is referred to as a prognostic biomarker. Dystrophin is absent for Duchenne patients and altered for Becker patients, and this is considered a prognostic biomarker.
  3. Whether a therapy is having an effect, and this is called a pharmacodynamic biomarker. Detecting dystrophin for a therapy aiming at dystrophin restoration is a pharmacodynamics biomarker. Pharmacodynamic biomarkers can also be used to assess the safety of a therapy, e.g. increased levels of liver enzymes in the blood can be a sign of liver damage induced by the therapy.

The workshop focused on pharmacodynamic biomarkers, and discussed the importance of “context of use”, the purpose of the biomarker. For example, muscle biopsy to detect dystrophin is being used in clinical trials as a pharmacodynamic biomarker in the context of finding the optimal drug dose. Furthermore, pharmacodynamic biomarkers are being used in DMD trials in the context of monitoring safety and side effects with blood samples. As research uncovers new biomarkers in DMD patients in blood and urine, these become candidates for new uses in future clinical trials as markers of either safety or efficacy.

Sometimes biomarkers can also be used as a primary outcome measure in clinical trials instead of functional outcome measures such as the 6 minute walk test and these are considered surrogate endpoints. In Europe biomarkers can only be used as surrogate endpoints after going through a rigorous regulatory process to officially qualify them for this purpose. Similar pathways exist in the USA.

There are no qualified biomarkers for Duchenne muscular dystrophy at the moment. However, in the 204th ENMC workshop on DMD biomarkers, two markers (dystrophin and magnetic resonance imaging (MRI)) were identified as candidates for the qualification process. In parallel work has been ongoing to identify additional biomarkers in serum and urine. For this work serum and urine samples are required from patients and controls, and are preferred because they are less invasive than having a muscle biopsy.

The aims of this follow up workshop were

  • To discuss dystrophin and skeletal muscle MRI as biomarkers to be able to prioritize and align the work that still needs to be done.
  • To compare the biomarkers detected in blood and urine to select the most suitable candidates and discuss future tests to confirm their usefulness
  • To set up a way for collecting, storing and sharing blood and urine for biomarker identification and validation

During the workshop it became clear that for MRI much of the gaps identified in the previous workshop (204th ENMC workshop, 2014) have now been filled. Alignment was reached on a proposed path for qualifying MRI and dystrophin quantification with the regulatory agencies. For MRI, current efforts are focused on showing responsiveness of the biomarker to drugs in human trials.

Furthermore, there was consensus on what criteria new candidate biomarkers need to fulfill. Biomarkers need to be specific, reproducible, reliable and robust. Ideally markers found in animal models need to be also confirmed in humans, markers need to be responsive to drug treatment in animal models, and, ideally markers need to be measurable in easily accessed samples (urine, saliva and blood).

Finally, the group agreed that a virtual biobank is needed, and that this can be achieved using existing platforms such as Eurobiobank (www.eurobiobank.org) and BB-MRI ((Biobanking and Biomolecular Resources Research Infrastructure, www.bbmri.eu)). It is important to identify existing samples, and for the collection of future samples standardized procedures should be used. An oversight committee is required, ideally following the TACT (TREAT-NMD advisory committee for therapeutics, www.treat-nmd.eu/tact) model, with a small core group with equal representation of patient representatives, academics and industry, and a larger extended group for expertise. The management part of this biobank should be funded by patient organisations and industry. Efforts will be undertaken to initiate this committee in a timely fashion.

The three-day workshop (January 20-22, 2017) supported by the European Neuromuscular Center (ENMC) and Marathon Pharmaceuticals, involved academics, industries and patient advocacy groups from the US, UK, Germany, Italy, Sweden and the Netherlands.

A full report is published in Neuromuscular Disorders (pdf)