Guideline on processing and evaluation of Sural Nerve Biopsies

The 147th ENMC International Workshop on a “Guideline on processing and evaluation of sural nerve biopsies” organized by Claudia Sommer (Würzburg) was held in Naarden, Holland on December 15 – 17, 2006. Fourteen clinicians and scientists from eight European countries and the U.S. participated in the workshop. The workshop is endorsed by the ENMC and by the Peripheral Nerve Society (PNS).

A guideline for the indication of nerve biopsy as well as for its processing and evaluation was considered necessary, since there are at present no European guidelines on this invasive diagnostic procedure. Although there are some national guidelines, these are incomplete and not evidence based. Since diagnostic nerve biopsy cannot be easily repeated in the work-up of peripheral neuropathies, failures due to lack of adequate standards should be avoided.

The Workshop participants collected evidence on the indications for a sural nerve biopsy, on the methods available for sural nerve workup, and on their diagnostic specificity and sensitivity. Evidence tables composed from the literature and personal experience were discussed. Tasks were distributed for the final composition of the guideline.

Consensus was achieved as to the following points:

The aim of this guideline is to provide, as far as available, evidence based guidance about the indication, procedure, processing, reading and interpretation of nerve biopsies.

The target group are all persons referring patients for a nerve biopsy, performing, processing, or reading nerve biopsies

Indications:

  • Nerve biopsy should be done for specific reasons. These can be questions about diagnosis, classification, or prognosis.
  • Nerve biopsy should not be done before adequate clinical, electrophysiological and laboratory characterization of the patient.
  • The leading indication is that of an interstitial pathological process (e.g. vasculitis, inflammation, infection), because it has diagnostic and therapeutic implications
  • The patient should be properly instructed, and nerve biopsy should only be done with written consent.
  • Requirements for the person evaluating a nerve biopsy:
  • Biopsies should be read by professionals with adequate training and experience in reading and interpretation of nerve biopsies
  • Adequate clinical information should be provided and additional clinical information should be accessible on request.
  • An interactive working relationship with the relevant disciplines involved is encouraged.
  • The results should be discussed with clinicians taking care of the patient; regular nerve conferences are recommended.
  • Details on the procedures recommended will be published in the final guideline.

Finally, open questions were collected and suggestions for further research were made. One example would be a prospective multicenter outcome study on nerve biopsy, including its relevance for treatment and potential side effects.

A full report of this meeting has been published in Neuro Muscular Diseases. (pdf)

Participants:

Sebastian Brandner (London, England), Peter J. Dyck (Rochester, USA), Catherine Lacroix (Le Kremlin Bicêtre, France), Martin Lammens (Nijmegen, The Netherlands), Laurent Magy (Limoges, France), Svein Ivar Mellgren (Tromso, Norway), Michela Morbin (Milan, Italy), Carmen Navarro (Vigo, Spain), Henry Powell (San Diego, USA), Angelo Schenone (Genova, Italy), Claudia Sommer (Würzburg, Germany), Ersin Tan (Ankara, Turkey), Joachim Weis (Aachen, Germany), Yadolla Harati (Houston, USA).

Recent advances in Fibrodysplasia Ossificans Progressiva (FOP)

A workshop on fibrodysplasia ossificans progressiva (FOP) was held for the third time, after an interval of seven years, to discuss the recent exciting advances in FOP research and clinical treatment. Participants included thirteen clinicians and scientists from six countries. FOP is a rare genetic disorder of skeletal malformations and progressive heterotopic ossification that replaces many skeletal muscles with a second skeleton.  FOP is a most distressing genetic disorder that inevitably leads to complete immobility in later life.  Although FOP is a rare condition, genetic, cellular and molecular insights into FOP will lead to increased knowledge of more common disorders that affect muscle and bone formation, such as heterotopic ossification following spinal cord injury, head injury, athletic injuries, and hip replacement surgery.

The meeting opened with each participant identifying their expertise and the resources available to the groups. The major clinical features of FOP were defined and cases of atypical phenotypes described. Recent insights into the cell signalling pathways involved in bone formation as well as the identification of five critical multigenerational FOP families have led to the identification of the mutation causing FOP. Genetic mutations were identified and correlated with severity of clinical phenotype. The causative gene is an overactive cell surface receptor – essentially a cellular switch that triggers the replacement of muscle by bone. Important new research directions were formulated and include investigating the mechanisms by which the switch is activated and the subsequent downstream signalling events, together with the development of relevant animal models to study the biology. A significant focus of future studies will be on therapeutic treatment possibilities for this catastrophically disabling disorder. These aspects, together with recommended current treatment options for FOP patients and counselling for patients and families, were extensively discussed by the workshop participants. The group aims to keep in close contact and reconvene at an appropriate time within the next couple of years when further extensive progress on knowledge of the condition is highly likely.

Workshop Convenors: James T Triffitt and Frederick S. Kaplan

Workshop Participants: D. Antisevic, S. Brown, J.M. Connor, D. Graf, M. le Merrer, C. Netelenbos, K. Petrie, R.J. Pignolo, H.I. Roach, E.M. Shore, R. Smith

Planning for an international trial of steroid dosage regimes in DMD

Workshop organisers: Professor Kate Bushby and Dr Robert Griggs.

The 145th ENMC Workshop was held in Naarden, the Netherlands, from 22nd-24th October 2006, with support from MDA for the travel expenses of the US participants. The aim of the workshop was to finalise the development of a full protocol for an international trial of steroid dosage regimes in DMD for submission to the NIH. Attendees included the trial writing group from Newcastle (UK) and Rochester (USA) led by the co-principal investigators on the project, Professor Kate Bushby and Dr Robert Griggs, as well as representatives of the trial investigators from Belgium, France, Italy, Scandinavia and the US. At the first meeting of the ENMC corticosteroid trial group in April 2004 the need for a trial in this area was highlighted by doctors and international patient group representatives who were dissatisfied with the confusion of corticosteroid regimes in common use. Since then, NIH funding for a planning grant to develop a trial protocol has been achieved and a group of investigators representing around up to 55 sites in 14 countries has been assembled.

The protocol for the trial was discussed. The trial will test three corticosteroid dosage regimes in a randomised double blind manner (prednisone 0.75mg/kg/day, deflazacort 0.9mg/kg/day and prednisone 0.75mg/kg/day 10 days on and 10 days off). 300 children between the ages of 4 and 7 years will need to be enrolled for at least 36 months within a core five year study to see how the regimes differ with respect to how effective they are and how their tolerability differs. The primary outcome measure has been chosen to combine three key elements of effectiveness – time to rise from the floor (as a proxy for overall muscle function), forced vital capacity (as an indicator of respiratory muscle strength) and satisfaction with medication. Secondary outcomes will include the achievement of new skills such as jumping and running and the profile of side effects with the different regimes. Quality of life will also be addressed. As corticosteroid use in DMD is a lifelong issue, a five year follow on study to look (unblinded) at the long term effects of use of these different regimes will also be developed. A further innovative feature of this trial is the close attention which has been paid to the standardisation of the management of possible steroid related side effects, and the management of DMD in general. Working groups have concentrated on these areas, producing guidelines for weight control, physiotherapy, behaviour management, cardiac follow up and bone health which will be widely disseminated. The trial group brought together to work on this protocol will form the basis for an important network for the development of this and future trials in DMD. The next task for the group is the submission of two parallel grants to NIH in early 2007. These will address the clinical/trial conduct and statistical/ data handling issues for the full trial in two separate documents. The clinical trial will be run from the Clinical Trials Unit in Newcastle with co-principal investigators Professor Bushby and Dr Griggs. The statistics and data handling will be led from the University of Rochester, PI Dr Mc Dermott.

A full report of this meeting is published in Neuro Muscular Diseases. (pdf)

Outcome Measures in McArdle Disease

144th International ENMC workshop on “Outcome Measures in McArdle Disease” (29 September – 1 October 2006)

Sixteen clinicians and scientists from seven countries met for the first time to develop an international consortium for McArdle disease and to agree on outcome measures for future clinical trials.

At the start of the meeting each group identified resources available to them and the numbers of patients under their care with the condition. A total of 297 patients were identified. A clinical and metabolic overview of the condition was presented together with some case histories of atypical phenotypes. An update of the genetic mutations identified so far was presented with regional variations identified. An overview of previous clinical trials was presented as outlined in a systematic review for the Cochrane database. In addition, further studies were discussed which included: aerobic training, pre-exercise glucose supplementation, creatine supplementation, ketogenic diet, Ace inhibitors, resistive training and carbohydrate diet. A presentation was given of a novel agent currently being trialled in the USA for Duchenne Muscular Dystrophy and some useful overlaps were identified with McArdle disease.

Various outcome measures were presented including: Cycle ergometry, walking assessment, 31P-MRS, NIRS, 31C-MRS, self reported questionnaires and biochemical evaluations in blood and muscle.

It was agreed that future evaluations would include cycle ergometry, a shortened walking assessment, strength testing, self evaluation questionnaires, genetic and biochemical analysis on blood and muscle. A detailed multi-centre evaluation of the clinical phenotype of McArdle disease would be undertaken by the participating groups to be completed by august 2007. The group would aim to reconvene soon afterwards.

A full report of this meeting is published in Neuro Muscular Diseases. (pdf)

Participants:

Professor R Beynon, Dr C Bruno, Dr R Finkel, Dr R Haller, Dr D Hilton-Jones,

Dr P Laforet, Dr M Martin, Dr A Martinuzzi, Dr A Mulas, Dr M Orngreen, Dr P Portero, Dr R Quinlivan, Dr B Schoser, Dr J Vissing, Dr M Vorgerd, Dr J Zange

2nd Annual Plenary Meeting EUMITOCOMBA

This meeting was held from 18 – 20 May 2006 in the Crowne Plaza Hotel in Hoofddorp, The Netherlands.

The summary of this meeting will be published within short.

Guidelines on Preclinical studies in ALS

The 142nd ENMC International Workshop on “Preclinical Studies in ALS” organized by Caterina Bendotti (Milano) and Albert Ludolph (Ulm) was held in Naarden, Holland on March 24 – 26, 2006. Nineteen scientists from Europe, Israel and the U.S. participated in the workshop and discussed and established “Guidelines for the conduct of preclinical and proof of concept studies in ALS/MND models”.

The group decided to develop guidelines

I. since they felt that a number of current drug-finding studies in preclinical ALS/MND research are found to be unreliable by many in the field. The guidelines are developed to improve the methodology and the quality of the studies and consequently save resources for both, preclinical and clinical studies.

II. It was decided to consider “proof of concept” and “preclinical studies” separately. Aproof of concept study has the goal to elucidate the mechanism of the disease, may it be biochemical or physiological. Such a study may use a drug as an investigational tool. A preclinical study has the primary goal to develop a drug for use in humans; for these studies higher methodological standards must be met.

III. The group expressed the opinion that the current disease models are not satisfying since they only represent selected etiological factors of ALS/MND.  On the other hand the presence of transgenic disease models represents a unique advantage for the field to further develop long-awaited preclinical and clinical therapeutic strategies for this devastating disease. The group agreed that a major justification for the use of these disease models exists: they mirror important aspects of the pattern of vulnerability of ALS/MND.

The group agreed that it was the goal of the workshop that guidelines were developed in order to improve quality of the work without restricting individual groups without major resources. During the workshop the work was successfully completely and a draft consensus paper describing the guidelines for both proof of concept andpreclinical studies was developed and agreed on. Based on the draft, a full report will be written by the organizers, distributed to the participants of the workshop and discussed within the scientific ALS/MND community. Eventually the report will be published in a scientific journal which is widely read by the members of this community.

In a final effort, unmet needs of translational research (“mice to men”) were identified and suggestions were made to resolve these issues by individual working groups representing the necessary expertise.

EURO-laminopathies Kick-off meeting

Twenty scientists and clinicians from 9 countries met in Naarden, The Netherlands on March 10-12, 2006 for the kick-off meeting of the EURO-laminopathies consortium.

The consortium consists of 11 participating institutions with 13 scientific group leaders and 1 administrative manager from 8 different countries forming an interdisciplinary team of human geneticists, clinical researchers, structural biologists, molecular cell biologists, and industrial partners.

The EURO-Laminopathies project aims at understanding the molecular mechanisms of laminopathies, which are rare human diseases linked to mutations in the nuclear protein lamin A and include muscle dystrophy, lipodystrophy, and premature ageing. Using a variety of clinical and basic research approaches we shall explore various disease models on the cellular and molecular level and shall test disease-linked defects in lamin assembly, chromatin organization, gene expression, cell cycle regulation, senescence, cell differentiation, and tissue regeneration. The ultimate goal is to identify reliable diagnostic markers and drug targets in order to develop new therapeutic interventions and to improve existing therapies for laminopathy patients.

The official starting date of EURO-Laminopathies was the 1st February 2006. The project duration will be 36 months.

ENMC Workshop

At the kick-off meeting the Scientific Officer of the European Commission and the representatives of the 11 participating institutions, including the research group leaders, several key senior lab and subgroup members, sub-contractors of two partners, and the management board of the project were invited.

The major scientific goals of the workshop were to present and discuss the scientific state of the art of research in the participating groups and in the field and decide on the specific collaborations between members of EURO-Laminopathies and on the deliverables for the coming 18 months. The major administrative goals were to present, discuss and decide the EURO-Laminopathies’ organisation, internal and external communication, reporting and finances.

The clinical teams within the EURO-Laminopathies project coordinated the proposed search for novel genes potentially involved in laminopathy-type diseases. It has been decided to provide detailed information on collected samples, protocols and tools accessible for all consortium members on the extranet of the EURO-Laminopathies website. Furthermore, the different clinical labs in the consortium decided to focus on the generation and phenotypical analyses at molecular level of specific patient-derived cell systems, including adipocytes and myoblasts. The structural biology experts agreed to primarily analyse lamin domains involved in oligomerization, and lamin complexes with LAP2 and retinoblastoma protein. It has also been decided to exchange and jointly analyse the available and newly generated mouse models by in vivo and ex vivo cell culture approaches, with an interactive communication with the teams studying patient cells. The results obtained in C. elegans and zebrafish models will directly feed into the phenotypical analyses of mouse and patient cell models. This concept will allow testing the structural and regulatory functions of lamins in the context of the disease and will also set the base for drug and drug target screening in the second phase of the project.

The participants evaluated the 141st workshop as a very stimulating and constructive meeting and as a perfect start of a successful collaboration within the EURO-laminopathies project.

A full report of this meeting has been published in Neuro Muscular Diseases. (pdf)

Participants:

Ueli Aebi, BIOZ, UNI BAS, Basel, Switzerland; Catherine Berens, European Commission, Brussels, Belgium; Gisèle Bonne, Inserm – U582, Paris, France; Joanna Bridger, Brunel University, United Kingdom; Jacqueline Capeau, Inserm, Paris, France; Annachiara De Sandre-Giovanna, Inserm – U491, Marseille, France; Roland Foisner, MUW, Vienna, Austria; Camilla Giammarini, DIATHEVA, Fano, Italy; Yosef, Gruenbaum, HUJI, Jerusalem, Israel; Joaquin Guinea, ZFBioLabs, Tres Cantos, Spain; Harald Herrmann, DKFZ, Heidelberg, Germany; Chris Hutchison, Durham University, Durham,United Kingdom ;Giovanna Lattanzi, IOR, Bolgona, Italy; Nicolas Lévy, Inserm – U491, Marseille, France; Nadir Maraldi, IOR, Bologna, Italy; Olga Mayans, BIOZ, UNI BAS, Basel, Switzerland; Giuseppe Novelli, UTOVRM, Rome, Italy; Brigitte Rohner, punkt, Vienna, Austria; Manfred Wehnert, EMAU, Greifswald, Germany; Andoni Urtizberea, ENMC, Baarn, The Netherland

The EURO-Laminopathies research project is a Sixth Framework Programme Specific Targeted Research Project (STREP) granted by the European Commission. The topic and thus the title of this project is Nuclear Envelop-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications (Contract LSHM-CT-2005-018690).

Contact www.mfpl.ac.at/euro-laminopathies (from 01.04.2006 online)

EURO-Laminopathies’ Project Management Board:

Prof. Roland Foisner, Medical University of Vienna, Dept. of Medical Biochemistry,

Max F. Perutz Laboratories, Dr. Bohrgasse 9/3, 1030 Vienna, Austria

Phone: +43 1 4277 61 680

roland.foisner@meduniwien.ac.at

NMD report full text and pdf

140th ENMC International Workshop: DM2 and other myotonic dystrophies

20 – 22 January 2006

The ENMC consortium on myotonic dystrophy type 2 (=DM2/PROMM) held its 4th workshop in Naarden, the Netherlands, 20-22th January 2006. It was attended by 21 active participants from Finland, France, Germany, Italy, Spain, and the USA. The meeting opened with a memorial to honour the past pioneer in the DM2-field: Dr Ken Ricker. Participants reported on the occurrence of DM2 in various countries indicating that the prevalence may be very similar to that of DM1. In a region with good ascertainment in Central Finland the estimated prevalence is already 1/10000 and with additional study this value is likely to increase. The DM2 mutation has a common ancestry for all populations dating 5-10000 years back in time. Obtaining the molecular diagnosis of DM2 does not yet lead to specific treatment, but it is of great importance for the patients to have a correct understanding of their symptoms and to receive the best possible supportive management. DM2 is still underdiagnosed which indicates that the treshold for requesting DNA-testing should be lower. There is an Increasing number of patients with just few and mild symptoms and others with unusual phenotypes. At least 20 laboratories now provide molecular diagnostic testing. Much of the effort of the workshop focused upon the challenging task related to ongoing scientific research efforts: to understand the abnormal events taking place in the muscles and other affected organs caused by the DM2 mutation. Real progress has been made in the clarification of the molecular processes taking place in the cells damaged by the mutation, even though they are very complex and involve the complex machineries of how cells generally read and translate genes to make various proteins. These abnormalities have basic similarities with the molecular processes causing DM1, Steinert’s disease.

The workshop agreed on guidelines for genetic testing and management of DM2 which are included in the extended report of the meeting which is published in Neuro Muscular Diseases. (pdf)