Edition of 17 January 2012

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A changing of the guard…
After fifteen years of heading Orphanet, Dr. Ségolène Aymé steps down as leader, handing the torch to Dr. Odile Kremp

It is disconcerting to imagine what might have happened – or, rather, what might have failed to happen – had Dr. Ségolène Aymé been absent from a meeting that took place in the autumn of 1996 and which was the genesis of Orphanet, the pan-European information portal for rare diseases and orphan drugs. After fifteen years of tireless devotion, Dr. Aymé steps down as Director of Orphanet, passing the torch to the very capable hands of Dr. Odile Kremp (see below). Here, Dr. Aymé kindly shares with the readers of OrphaNews Europe the story of how Orphanet came into being, how it evolved, and where it is heading.

Why and how did Orphanet come into being?
Orphanet was born out of a working group that took place in 1996, convened by Annie Wolf, who was responsible for the Office of Orphan Medicinal Products within the French Ministry of Health. The group was tasked with reviewing the problems encountered by patients and health professionals in the field of rare diseases. In our final report to the French Director General of Health (DGS), we recommended addressing first the problem of information via a website that would be accessible to all stakeholders. This last point was the subject of debate because some members of the working group initially wanted to restrict the site to professionals – a notion that might make some stakeholders smile today. The decision to fund the site was taken immediately by the DGS. SC11, the unit of the National Institute for Health and Medical Research (INSERM) that I had headed since 1992 was selected to implement the website. At the time, the SC11 was located within Infobiogen, the French national resource site for bioinformatics. Thus we already had the technical expertise in place. For the content, we did not have to start completely from scratch because I had been maintaining a personal database since 1974, called Gendiag. This database included some 2500 dysmorphic syndromes described in the literature, indexed by signs and symptoms from a controlled vocabulary. For years, this personal database had served me in establishing the diagnosis for patients I saw in consultation, and had been shared with other colleagues via the Minitel (a French online service accessible through the telephone and a precursor to the World Wide Web). We also had collected data on expert services in France, a directory named Geninfo, which was distributed, free of charge, by postal mail to registered professionals with a trimestrial update. This directory was initially intended to speed up the collaboration between clinicians and researchers to map genes at the origin of diseases. The prospect of making the database more widely available via the Internet was truly a dream come true for me.

How has Orphanet evolved over time?
Orphanet started in 1997 with a team of just three. Today, we have a team of 40 in France alone. We launched with just two sources of funding at the beginning, and now have 18. Orphanet was strictly a Franco-French venture from 1997 to 2000. We now have teams in 38 countries and are negotiating with several others who would like to join. This expansion has not been easy because every day we have to overcome new obstacles. First, the positioning: for whom do we write? This determines the language and the perspective. We chose the non-expert health professional as the target user. We have had to convince colleagues from all specialties to help us through our Scientific Advisory Board in charge of quality control of published information. The battle of credibility has been won over time by consistently demonstrating a rigorous approach coupled with respect for the expertise. The publication of the site content in book format (editions from 1997 to 2005) contributed to further establishing our credibility. The 2500 pages of information reproduced in book format illustrated the scope, depth and breadth of the information we were gathering and making freely available more readily than the website was able to do. We then had to convince other countries that Orphanet was not just a French-language database and cope with the difficulties of translation and validation. We had to find more and more financing to develop all the services requested by our users and accomplish our work within the context of a constantly changing team as our funding limits employment to fixed-term contracts. If we have been able to succeed, it is because the Orphanet team has been talented, diligent and motivated, and because hundreds of experts have accepted to contribute their expertise with no return other than the personal satisfaction of being useful. The ultimate reward is the user satisfaction expressed via our annual satisfaction surveys, along with the worldwide reputation for excellence and accuracy that Orphanet has achieved over the years.

What are the greatest achievements of Orphanet?
We are probably most proud of the list of diseases that had never before been established and their classification. The World Health Organization has thus entrusted me with the presidency of the "Topic Advisory Group" for rare diseases as part of the revision of the International Classification of Diseases (ICD). We are also the only organisation to identify specific expertise on rare diseases in many countries. We also offer an inventory of orphan drugs, both those in development and those already on the market. I am also proud of the Orphanet Report Series that are frequently downloaded as well as our public encyclopaedia, which is used by tens of thousands of people each month. Other triumphs include our newsletter, OrphaNews, which was the idea of the Association Française contre les Myopathies (AFM) and our open-access electronic journal the Orphanet Journal of Rare Diseases which has an Impact Factor of 5.93! The strength of Orphanet is to be attentive to the needs of users, which have evolved over time. The Internet is now a universal communication tool and the scientific and medical research is increasingly relying on information stored in accessible databases. Our latest addition, the site www.orphadata.org is thus a response to the demands of industrial and academic researchers who want to reuse our data.

What are some of the challenges Orphanet faces today?
One major challenge we face involves the sustainability of activity in a context of economic crisis. Another involves keeping up with the avalanche of scientific discoveries that quickly renders information obsolete. Another issue concerns the presentation of knowledge in different formats, to meet the needs of our different users, the translation into new languages such as Russian, Japanese and Chinese. This latter issue poses new challenges for the control of translation quality and the optimisation of search engines.

Now that Dr. Odile Kremp has taken over the helm of Orphanet, what will your responsibilities be in the field of rare diseases?
I remain Chair of the EUCERD (European Union Committee of Experts on Rare Diseases) which involves ensuring the scientific secretariat of the committee, producing an annual report on the rare disease policies in Europe, and editing this newsletter, OrphaNews Europe, which has some 14,000 subscribers. As mentioned above, I am also the Chair of the Topic Advisory Group for rare diseases of the WHO, working on the revision of the ICD. I also play a role in various national and international mandates and hope to get involved in the international coordination of research in the field of rare diseases if the European contract which I introduced is funded. I also want to finally write the articles that I have been trying to find the time to write for quite a while now! What can I say? My retirement will be an active one as long as I will be solicited; as working in this field is both an honour and a pleasure!

Interview

Odile Kremp: Orphanet's fearless new leader

On 2 January, Dr. Odile Kremp replaced Dr. Ségolène Aymé as the Director of Orphanet, the pan-European rare disease and orphan drug portal. Paediatrician and Doctor in Public Health from the University of Nancy (France), Dr. Kremp has held various different hospital posts in neonatology and paediatrics. She was Chair of the International Club for Social Paediatrics from 1994 to 1998. In 2008, Dr. Kremp was in charge of monitoring the French Rare Disease National Plan at the General Directorate for Health (the French Ministry of Health). She has carried out 18 paediatric missions to Vietnam since 1993 under a scientific collaboration programme directed by the Ministry of Foreign Affairs. She is Professor Honoris Causae, at the Medical University of Hanoi (2010). Here Dr. Kremp discusses her new role with Orphanet:

Can you describe the path that brought you to Orphanet?
I have always been involved in paediatrics and public health, in the fields of clinical practice, teaching and research. I met Dr. Ségolène Aymé in Montreal in 1986, while doing an internship as a young researcher at the University of Montreal with whom she collaborated. I have always been interested in the comprehensive care of children and their families, and I chaired the International Paediatric Social Club from 1994 to 1998. As a paediatrician at Amiens and as department head at Lille, I of course worked with children with rare diseases, and immediately used the resources of Orphanet, starting with the first paper directories. In 2007, while still a professor of paediatrics at Lille, I became rare disease coordinator at the Institute for Public Health, where I worked on the prioritisation of rare diseases in terms of public health. I also participated in meetings of the Rare Disease Task Force and followed the creation of the European Communication on rare diseases. I joined the French Ministry of Health Directorate General of Health (DGS) in late 2008 as a project manager for the French National Plan for Rare Diseases and contributed to the evaluation of the first plan, and the process in the summer of 2009 to build the second plan (2011 to 2014). From my position with the DGS, I paid most attention to the epidemiology of rare diseases and the training and information for patients and professionals, support for associations, and educational therapy. I continue to participate in EU meetings (including the development of the European Commission Recommendation on rare diseases and implementation of the EUCERD, launch of the Spanish strategy, and meeting of the European Chief Medical Officers on rare diseases). So I have gotten to know and worked with many partners in the field of rare diseases, particularly following the activities of Orphanet and various members of the French rare disease platform.

What are your thoughts on the current situation of rare diseases in France and Europe?
France began to consider rare diseases in the early 1990s, before other European countries, led by patient associations and physicians, through a reflection on orphan drugs. The systems implemented for diseases such as haemophilia, amyotrophic lateral sclerosis, or cystic fibrosis foreshadowed the reference centres in the field of rare diseases, as well as the network of centres of competence. Orphanet has played a major role in informing and training medical professionals. Though of course, all is not perfect, the size of France and its hospital organisation have allowed for the structuration of care. Care, including the social impact of disease and disability, still needs to be improved, and particularly by encouraging young social scientists to get involved. Epidemiological knowledge must also be strengthened, based on a common coding and a collection of structured information in order to build a national database of rare diseases, which will help to tailor the policies of the health system and to focus research.

In Europe, governments have slightly different positions on rare diseases, according to their history, the size of their country, and their health care system, but they all are eventually adopting recommendation on rare diseases. Several countries have already implemented plans or strategies for rare diseases. The fact that many countries are partners in the Orphanet Joint Action, which started in the Spring of 2011 with the support of DG Sanco, will optimise information for patients and professionals, leading to better understanding and identifying of patient needs in terms of care and research, both fundamental and therapeutic. The implementation of the Directive on the rights of patients and cross-border healthcare adopted in 2011, is expected to eventually identify the relevant care networks throughout Europe.

What are your hopes in working with Orphanet? How would you describe the Orphanet of your dreams?
It is a real challenge to take over from Ségolène Aymé, who developed a very powerful tool, one that is renowned in France, Europe, and internationally. I hope to contribute, with the help of the highly motivated team, to pursuing the national and international development of Orphanet, in order to better meet the needs of patients and health professionals.

Ideally, the Orphanet nomenclature will be used in all the medical information systems, to better describe the disease and patient outcomes. It is hoped that using Orphanet will become an automatic reflex for physicians seeking a diagnosis as well as a therapeutic strategy. Orphanet can also be better harnessed to help researchers communicate, and to help both researchers and patients to identify experts and other patients. Many elements to accomplish these goals are already in place! But my vision for Orphanet will grow as I get to know the many different facets of its unique offer. Indeed, I realize that I do not yet know the full potential of Orphanet - particularly in terms of bioinformatics and analytical knowledge, and I look forward to learning a lot through working with the team.

In your experience, what does the field of rare diseases most need now in order to evolve?
Collaboration between patients and professionals, which is already narrower than in other areas of medicine, needs strengthening. The public support must remain strong in the face of illnesses that, taken one by one, affect few patients, but collectively are a public health issue as important as diabetes, asthma or chronic kidney failure. The investment of the pharmaceutical industry, supported by epidemiology and basic and clinical research, is essential to the development of innovative medicinal products, for treating rare diseases, and as models for less rare diseases.

DG SANCO

Fundamental Research

Clinical Research

Gene Therapy

Therapeutic Approaches

Diagnostic Approaches

OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01)
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Divya Unni
Editors for Scientific Content: Sophie Höhn
Contact Us
Editorial Board: Ségolène Aymé, Paul Boom, Anna Bucsics, Kate Bushby, Lorenzo Dagna, Adam Heathfield, Lilian Lau, Yann Le Cam, Jordi Llinares-Garcia, Antonia Mills, Antoni Monserrat, Ana Rath, Charlotte Rodwell, Gerhard Steffes, Till Voigtländer, Jaroslaw Waligora

INTERNATIONAL CORRESPONDENTS
Orphanet Partner Country Representatives: Kristine Hovhannesyan (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Riitta Salonen (Finland), Joerg Schmidtke (Germany), Helen Michelakakis (Greece), Eileen Treacy (Ireland), Annick Raas-Rothschild (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Vaidutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Jorge Sequeiros (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Borut Peterlin (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Ugur Ozbek (Turkey), Dian Donnai (UK)
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Photo credit : Serimedis http://www.serimedis.inserm.fr/ (unless otherwise stated)

2012 a busy year for EUCERD members as a new joint action between the European Commission and the EU Member States gets ready to launch

A changing of the guard… After fifteen years of heading Orphanet, Dr. Ségolène Aymé steps down as leader, handing the torch to Dr. Odile Kremp

Interview

Odile Kremp: Orphanet's fearless new leader

DG SANCO

A new European eHealth network could be especially useful in promoting cooperation in the field of rare disease care

Serbia considers its national plan for rare diseases and makes a financial commitment to treating patients

Poland stakeholders commit to drafting a rare disease plan by end of February

Sweden’s Agrenska signs contract with government for National Function for Rare Diseases

Spanish Society of Genetic Counseling launches

How does the death of a child affect siblings?

OrphaNews Italia offers readers an Italian language translation of the contents of OrphaNews Europe

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Familial keratoconus with cataract caused by a mutation altering the miR-184 seed region

A fatal mitochondrial disease is associated with defective NFU1 function

Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome

A new autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to 14q31

A mitochondrial hypertrophic cardiomyopathy with psychomotor retardation caused by MRPL3 defects

Sensenbrenner syndrome, Jeune syndrome, and isolated nephronophthisis: WDR19 mutations identified

Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum: POLR3A and POLR3B at cause

Hypomyelination, hypodontia, and hypogonadotropic hypogonadism (4H syndrome): recessive mutations in POLR3B identified

Say-Barber-Biesecker variant of Ohdo syndrome: mutations in histone acetyltransferase gene KAT6B responsible

Hypoinsulinaemic hypoglycaemia with hemihypertrophy: a de novo activating mutation of AKT2 found at cause

Hereditary hypotrichosis simplex: a dominant mutation in ribosomal protein L21 (RPL21 gene) found in two Chinese families

Angiotensin-converting enzyme inhibitor induced angioedema: significant association with an XPNPEP2 promoter haplotype

Splenic marginal zone lymphoma: somatic BIRC3 inactivation as a common mechanism in lymphomagenesis

Behçet disease: confirmation of UBAC2 as a susceptibility gene

Strategies for improving research participation in rare lung disease studies

Fundamental Research

Hutchinson-Gilford progeria syndrome: progerin production is under tight control of a conserved splicing mechanism

Autosomal recessive limb-girdle muscular dystrophy type 2D: epsilon-sarcoglycan is important in preventing cardiomyopathy

Naxos disease: restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy

Congenital myasthenic syndromes: mice with a F1061S mutation in AGRIN are a valid model

Huntington disease: the huntingtin protein is essential for ciliogenesis, which is altered in the disease

κMyositis: TRAIL is expressed in muscle and may mediate both activation of NF-B and autophagic cell death

Systemic sclerosis: a new mouse model obtained by treatment with DNA topoisomerase I and Freund’s complete adjuvant

Clinical Research

Cystic fibrosis: significant improvements with a CFTR potentiator in patients with the G551D mutation

Haemophilia A: anti-inhibitor coagulant complex prophylaxis decreases the frequency of bleeding in patients with inhibitors

Cryopyrin-associated periodic syndrome: safety and efficacy of canakinumab in children and adults in a two-year phase 3 study

Juvenile dermatomyositis: efficacy of intravenous immunoglobulin therapy in a large cohort

Mevalonate kinase deficiency: on-demand anakinra treatment is effective in patients with HIDS

Systemic sclerosis: two pilot trials showed a large number of adverse events with imatinib

Juvenile idiopathic arthritis: effectiveness of dexamethasone iontophoresis for temporomandibular joint involvement

Chronic myeloid leukaemia: safety and efficacy of bosutinib in chronic phase imatinib resistant or imatinib-intolerant disease

Lymphomas: a phase 2 study of tipifarnib activity in patients with relapsed and refractory disease

Haemophagocytic syndrome: long-term results of chemoimmunotherapy (HLH-94 treatment protocol)

WHIM syndrome: the CXCR4 antagonist plerixafor is a potential therapy for panleukopenia/myelokathexis

Graft versus host disease: inducible apoptosis as a safety switch for adoptive cell therapy

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Pulmonary arterial hypertension: an expert opinion on inhaled treprostinil sodium

Autoimmune lymphoproliferative syndrome: a long-term survey of 90 patients with TNFRSF6 mutation

Hereditary breast cancer with BRCA1 mutation: common variants on the wild-type copy of BRCA1 modify the risk of breast cancer

CINCA syndrome: somatic NLRP3 mosaicism is a major cause of the syndrome

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Gene Therapy

Bardet-Biedl syndrome: U1 snRNA-mediated gene therapeutic correction of splice defects caused by a very mild BBS1 mutation

6-pyruvoyl-tetrahydropterin synthase deficiency: pseudoexon exclusion by antisense therapy

Leber congenital amaurosis: gene therapy using a self-complementary capsid mutant AAV2/8 restores vision in mice lacking AIPL1

Therapeutic Approaches

Spinocerebellar ataxia type 1: exercise improves survival in a mouse model, via the transcriptional repressor Capicua

Tuberous sclerosis: therapeutic benefit and limitations of prenatal rapamycin in a new mouse brain model

Diagnostic Approaches

Facioscapulohumeral dystrophy: molecular combing enables detailed exploration of FSHD locus and accurate diagnosis

Marfan and Loeys-Dietz syndromes: molecular diagnosis with massive parallel sequencing

Chronic autoimmune hepatitis: British Society of Gastroenterology (BSG) guidelines for management

Juvenile idiopathic arthritis: an AHRQ review on disease-modifying antirheumatic drugs in children

Severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation for haematopoietic stem cell transplantation

Congenital hypogonadotropic hypogonadism: a review on neonatal gonadotropin therapy in male patients

Fabry disease: an expert panel report on early diagnosis of peripheral nervous system involvement and treatment of neuropathic pain

Small-cell lung cancer: a review on disease epidemiology, presentation, diagnosis and management

Mucopolysaccharidosis: presentation, diagnosis and management of cardiac disease

Kawasaki disease: a clinical practice review

Ulcerative colitis: a review on current understanding of the pathophysiology, diagnosis, and treatment

A proposal for tax incentives for rare disease medicines … and a call for fair and timely drug supply

ESH-ENERCA Training Course: Diagnosis and Management of Very Rare Anaemias

European Cytogeneticists Association Course

Tenth European Course on the Evaluation of Medicinal Products in Children

A changing of the guard…
After fifteen years of heading Orphanet, Dr. Ségolène Aymé steps down as leader, handing the torch to Dr. Odile Kremp