26 November 2008 print
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Champagne, anyone? EC adoption of the Communication moves one step closer to bringing rare diseases out of the shadows

The news was reported as far away as China. The European Commission on 11 November adopted a Communication and a proposal for a Council Recommendation on rare diseases that delineate a strategy supporting Member States in diagnosing, treating and caring for citizens with rare diseases. Rare diseases are perhaps the textbook example of the necessity to collaborate at the European level in order to maximise resources and expertise to address a common cause. In an official press release, European Commissioner for Health Androulla Vassiliou remarked that working together at the European level will "…bring patients with rare diseases out of the shadows. Expertise on rare diseases is fragmented across the Union. Even the very existence of some of these diseases is not fully recognised. That means that too many patients spend years of uncertainty before their conditions are correctly diagnosed and treated”. The Communication lays out a Community strategy for action in three key areas: improving recognition and visibility; supporting Member State national plans for rare diseases; and strengthening EU-level cooperation and coordination in the field.

The long and winding road
The adoption of the Communication and a proposal for a Council Recommendation on rare diseases is being celebrated as one of many hurdles successfully cleared on the path leading to a cohesive harmonised approach to rare diseases across Europe. It has been a long journey, beginning with the original penning of the future Communication on European Action in the Field of Rare Diseases, entitled Rare Diseases: Europe’s Challenges, drafted by the European Commission in close collaboration with the Rare Disease Task Force between June and October 2007. The document opened for public consultation in mid-November. Readers may recall that the public consultation to the Communication garnered an unprecedented number of responses: Almost 600 contributions were received from 15 MS during the three-month consultation period, outdistancing the previous contender for most responses by over 400 comments. (The average number of responses to a consultation is 60). This overwhelming reaction was taken as a sign of proof of the pertinence of the Consultation on Rare Diseases and the desire across Europe to see its provisions implemented in the near future. The comments received were consulted and the document was adapted accordingly. Next, the Communication was subject to an impact assessment that studied the political and financial consequences, amongst other considerations, between March and June 2008. It then went for an inter-service consultation from July 2008 through October 2008 involving DG Enterprise, DG Research, DG Information and Society, DG Budget, DG Employment, DG Relex, DG Market and the legal service of the European Commission. Finally, on 11 November 2008, the Communication on rare diseases was adopted via oral procedure, by the college of Commissioners, along with a proposal for a European Council Recommendation on a European action in the field of rare diseases.

But it ain’t over ’til it’s over
The two documents are now available on the Commission website in the 23 EU languages. They have already been officially transmitted to the Parliament, the Council, the European Economic and Social Committee and the Committee of Regions. The first discussions will take place on 27 November at a Council working party. The upcoming meeting of the Employment, Social Policy, Health and Consumer Affairs Council under the French EU Presidency (15 and 16 December) has given the rare disease texts priority status on the agenda, demonstrative of the commitment of the French presidency to keep the process moving forward. The meeting of the Council of Ministers for adoption of the documents is scheduled for 9 June 2009, under the Czech Presidency, providing that the Parliament has already expressed its opinion (which is not mandatory but is desirable). The possibility exists that the Parliament will not deliver on time. With the upcoming elections taking place in June, most parliament members will be busy campaigning. If the documents are not adopted in June 2009 they will have to be submitted to the Council under the Swedish Presidency, most likely in November 2009.

The RDTF weighs in
At the annual European Commission’s Rare Disease Task Force meeting earlier in the month, the significance of the proposal adoption was reviewed. Despite overall satisfaction that the process is moving forward, discussions arose over certain key elements of the initial text that were removed from the final version. RDTF members expressed their disappointment and concern that the proposal for a public-private partnership in the field of R&D for rare diseases was removed. They also deeply regret that the proposal for a scientific assessment, at EMEA level, of the medical added-value of each orphan drug was deleted. The explanation given revealed that the decision was based on a misunderstanding. Despite the overall joy that adoption of the Communication elicits, it is difficult to understand and accept the absence of this crucial proposal that would do so much to ensure timely access to orphan medicines across Europe.

RDTF members will be lobbying their national MEPs sitting on the Committee in charge in order to press forward action. RDTF members will also establish contact with the two key persons responsible for the Communication adoption at the Council level: the national representative at the European Commission and the individual in charge of commenting on the document at the national ministry of health level.

EU Policy News
Second E-Rare call for proposals to launch in early December

E-Rare (ERA-Net for research programs on rare diseases) is a network of ten partners – public bodies, ministries and research management organizations – from eight countries, responsible for the development and management of national/regional research programs on rare diseases. E-Rare is supported by the European Commission under the Sixth Framework Program ERA-Net scheme for a 4-year period that began 1 June 2006. The aim of E-Rare is to foster research on rare diseases in Europe. Following the successful organization of the first Joint Transnational Call in 2007, the E-Rare consortium now announces the launch of its second Transnational Joint Call, opening 3 December 2008. The aim of the call is to enable scientists in different countries to build an effective collaboration on a common interdisciplinary research project based on complementarities and sharing of expertise, which takes into account the importance of a translational research approach and the need to strengthen the European Research Area (ERA). Projects shall involve a group of rare diseases or a single rare disease following the European definition (a disease affecting not more than five in 10 000 persons in the European Community). Research groups based in France, Germany, Israel, Italy, The Netherlands, Portugal, Spain and Turkey and are eligible to receive funding. The deadline for submitting the proposals is the 5 February 2009. Further information can be obtained by contacting the Call Secretariat by telephone (+49 228 3821 775 / 233) or email, or by consulting the preliminary announcement available on the E-rare website.

As France’s turn at the helm of the EU draws to a close, a last conference moves the rare disease Communication forward
The National Strategies and Action for Rare Diseases in Europe conference that took place in Paris on 18 November was the fourth and last official event held under the auspices of the French Presidency of the European Union. The conference followed the announcement exactly one week earlier of the European Commission’s adoption of the Communication and a proposal for a Council Recommendation on Rare Diseases that delineates a strategy designed to support Member States (MS) in diagnosing, treating and caring for their rare disease patients (see Editorial). The conference saw stakeholders already rolling up their sleeves to determine the best methods for advancing action in this domain in anticipation of the final adoption by the European Council and Parliament, tentatively scheduled for 9 June 2009 under the Czech presidency of the EU. The daylong event kicked off with French Ministry of Health Roselyne Bachelot-Narquin reiterating France’s support of an EU-coordinated effort and a reminder that the French national plan for rare diseases is available to use as a model. This plan, due to expire at the end of the year, is being renewed following a period of assessment and appraisal that will serve to tweak priorities. Indeed, one interesting presentation that took place during the conference explored the methodology used to evaluate and monitor the plan. Presentations were given by some of the leading stakeholders in the field, each contributing their knowledge and expertise geared to move forward and keep the initiative in motion: Nick Fahy from DG Sanco gave a historical perspective of European actions on rare diseases and orphan drugs, and also took the time to delineate the following steps the Communication must pass through to be officially adopted by the Council. Eurordis President Terkel Andersen evoked the traditional French annual march for rare diseases as a symbol of the actions taking place now at the EU level. He defined the Communication as the most important event since the development of the orphan drug regulation some ten years ago. EC Rare Disease Task Force leader and Orphanet director Ségolène Aymé reminded participants that we are presently in the middle of a process. She outlined the various rare disease initiatives taking place nationally across Europe and spoke of the specific achievements accomplished under the French plan. Each country must construct their plan according to the specifications of their respective health system and patient needs. Despite the inevitable diversity across Europe, Dr. Aymé assured participants that there is enough goodwill and agreement on objectives to move forward. Four countries (Bulgaria, Italy, the Netherlands, and Portugal) illustrated European diversity by outlining how each organises their efforts on behalf of their rare disease patients. During the open discussion, many valuable comments were made, and patient group representatives did not shy away from asking for specific support and involvement. The point was made over and again that industry needs to be included more. The body of the morning’s events were summed up in twelve key themes: tailor-made plans suiting each country’s specifications; a European vision; establishing a baseline for identifying centres of expertise; defining clear and measurable objectives; creating indicators to measure progress; building networks of centres of expertise; training of medical professionals; coordination; multi-disciplinarity; evaluation; funding; and patient involvement. Whew!

The afternoon gave over to discussing the European Project for Rare Diseases National Plans Development (Europlan). Funded for a three-year period that began in April 2008, Europlan seeks to elaborate recommendations on how to define a strategic plan for rare diseases at the national level. Organised into eight work packages, Europlan includes 23 countries and stresses its inclusive nature (countries outside the EU are welcome to benefit from its expertise). The various work packages will gather information on the initiatives undertaken by individual MS, develop indicators geared to monitor implementation and evaluate impact, and, with Eurordis, organise national conferences to present the recommendations and work with local stakeholders toward transferring them into national actions. Eurordis leader Yann Le Cam emphasised the necessity for an integrated, comprehensive strategy that has long-term sustainability. He delineated five key priorities: research that is linked with centres of expertise, takes a public-private approach, and has sustainable funding mechanisms; networks of centres of expertise; information services for professionals and patients, such as Orphanet; expert opinions (EU common protocols); and the empowerment of patient groups. Italy and France both presented methodologies for evaluating national plans for rare diseases. Gill Tchernia, from the Evaluation Committee of the French High Council of Public Health, ended his discussion on a poignant note, reminding participants to consider immigrant-status rare disease patients in the EU, a particularly vulnerable sector of the population.

The conference concluded with a discussion from a “panel of policy makers”: DG Sanco project officer Antoni Montserrat and an “EU Presidency Troika” represented by France (Annie Podeur, French Director for Hospitals and Care Offer) the Czech Republic (Milan Macek, Chairman of the Department of Biology and Medical Genetics, Czech Republic), and Sweden (Olivia Wigzell, Director of the Health Care Division at the Ministry of Health and Social Affairs, Sweden). Each in turn offered their understanding of the urgency of the Communication and recommendations, and their commitment to guard its “priority status”. Despite such assurance, many rare disease stakeholders may be keeping their fingers crossed until 9 June 2009!

Hark! Who goes there? European Commission responds to the call for improved telemedicine
Earlier this month the European Commission adopted a Communication proposing concrete actions designed to support and improve access to telemedicine for both citizens and healthcare professionals throughout the European Union. Telemedicine, defined as the “delivery of healthcare services through the use of Information and Communication Technologies (ICT) in a situation where the actors are not at the same location” is especially pertinent to rare diseases, for which health expertise is often scattered and rare itself. The overarching goals of the Communication seek to build consumer confidence and acceptance of telemedical services, clarify legal issues, and solve problems in the technology relating to teleservices, which can include teleradiology, telepathology, teledermatology, teleconsultation, telemonitoring, telesurgery and teleophthalmology. Other potential related services include call centres/online information centres for patients, remote consultation/e-visits or videoconferences between health professionals. The Communication furthermore defines actions needed to be taken by Member States, the European Commission, and other stakeholders, including healthcare providers and the industry. Consult the EC Communication (also available in French and German languages).
European research group calls for rethinking of JTI innovative medicine funding model
As was reported in the 30 January 2008 issue of OrphaNews Europe, the European Council adopted four Joint Technology Initiatives (JTIs) in December 2007 – including the Innovative Medicine Initiative Joint Undertaking (IMI JU). JTIs are public-private partnerships between the Commission and industry (and in some cases the Member States), implemented by Joint Undertakings on the basis of Article 171 of the EU Treaty. Founded by the European Commission and the EFPIA (European Federation of Pharmaceutical Industries and Associations), the IMI JU will support pre-competitive pharmaceutical research and development – including medicinal products for rare diseases. The first call for proposals launched on 30 April. Now, EARTO, the European Association of Research and Technology Organisations (RTOs) representing over 350 organisations across Europe has issued a declaration expressing concern over the funding policy of the JTIs, particularly the 20% reimbursement limit for overheads. The sharply worded document states that:

“Such unrealistic capping of overhead costs displays grave ignorance of the economic realities of research. RTOs have overhead costs…equivalent, typically, to 100% or more of direct project costs. Universities and SMEs, too, have significant overhead costs…. RTOs, universities, SMEs and others will turn their backs on the JTIs – as many of them did on the occasion of the first IMI Call for Proposals – if the conditions offered are not realistic. Regrettably, the funding models instituted by the Innovative Medicines JTI (IMI) in the summer of this year…will discourage many of the best research performers from participating in the R&D programmes promoted by these JTIs."

In its declaration, EARTO asserts that the European Universities Association is also actively pursuing the matter with the European Commission. Read the declaration of the EARTO executive board

The FDA and EMEA agree on success of transatlantic cooperation over past five years
It has been five years since the European Medicines Agency (EMEA) and the United States Food and Drug Administration (FDA) first initiated a framework designed to enhance cooperation between the two continents, with a view to reducing regulatory burden and costs and accelerating the process of bringing innovative medicinal products to market. Orphan drug designation is one of the areas that benefits from the agreement. It is also the first-year anniversary of the Transatlantic Administrative Simplification initiative. The European Commission, the EMEA and the FDA report satisfaction with the progress the cooperative measures have brought and are committed to expanding cooperation further, particularly into the areas of advanced-therapy medicines and nanotechnology-derived products. This widening of the scope should please rare disease patients and their entourages on both side of the Atlantic, as innovative medicinal products frequently target rare disorders.
Treat-NMD and EMEA hold successful joint workshop on clinical outcome measures for spinal muscular atrophy
Network of excellence for rare inherited neuromuscular diseases Treat-NMD hosted a workshop in collaboration with the European Medicines Agency (EMEA) recently to determine outcome measures for spinal muscular atrophy pertinent to future clinical trials. Some 50 international participants included health professionals, scientists, industry representatives and patients from the neuromuscular field as well as the EMEA chairs of the Medicine, Paediatric, Orphan Drug and Scientific Assessment committees. Results are to be shared with the USA Food and Drug Administration. The gathering sought to establish “broader common ground” between regulatory agencies and researchers conducting clinical studies. Specifically, outcome measures were discussed for the three major paediatric forms of the disease. For SMA type I it was determined that time-to-event as a primary outcome measure would be reasonable, while secondary outcome measures and protocols suitable for this population need ongoing development. For SMA type II (non-ambulant), demonstrating internal consistency, clinical meaningfulness and responder profiles for the functional scales intended to be used is important. Secondary measures trending in the same direction are also critical; For SMA type III (ambulant) participants determined that the 6 minute walk test seems reasonable – but the clinical meaning of an improvement needs to be carefully described. Secondary measures also need to be further defined.
Read the press release


National & International Policy Developments
Latin American rare disease umbrella group extends actions into Panama, Colombia, Dominican Republic and Haiti
Following the momentum of the very first conference in Latin America dedicated to rare diseases that took place in Buenos Aires in March of this year, the Geiser Foundation, a regional initiative created in 2001 to pool rare disease resources, continued its campaign in September with a multitude of activities in the region. A three-day meeting was held at the Children’s Hospital of Panama in cooperation with Angeles de Cristal, the local osteogenesis imperfecta patient group. The second day of the event was devoted to seeking strategies for uniting patient associations and bringing academia and government into play. One outcome from the meeting is the first national congress to be announced shortly. In addition, dialogue with government representatives to promote policies for patients with disabilities is underway. Geiser (which stands for the Grupo de Enlace, Investigación y Soporte - Enfermedades Rares) will work with local officials to develop a plan to promote patient rights on many issues, including orphan drug accessibility. These strategies are to be extended to neighbouring countries. In the true spirit of exchange, members from different institutions offered their own expertise and support to further the general goals of Geiser. Some particular concerns in the region involve native populations whose children with malformations and disorders are particularly vulnerable, being subject to rejection by their families. Chemicals used in farming have also produced certain rare conditions in the area. Finally, some cultural aspects of nutrition are implicated in not well-described cases of disability and intellectual deficit in children. Geiser will pursue educative and sanitary actions through local organisations in order to include groups of affected individuals who cannot be immediately self-organised.

Elsewhere, Geiser representatives held discussions with Dr. Honna Silfa, an orthopedic surgeon expert in rare skeletal disorders and co-founder of the Niños de Cristal Foundation in the Dominican Republic. A first meeting for rare diseases and orphan drugs is being planned for 2009 in the country. Geiser also is keen to include Haiti. Being one of the most economically neglected countries in the world, Haitian rare disease patients have a high level of vulnerability, and Geiser is scheming to work in tandem with patient groups from the Dominican Republic, Haiti’s closest neighbor, as a pragmatic strategy for reaching affected individuals.

Geiser was also in Bogota, Colombia, in September, meeting with patient groups at the Universidad Javeriana to discuss a first National Rare Diseases Congress targeted for 2010. The particular status of Colombia was discussed, along with the need to work cooperatively versus focusing separately on each specific condition. Again the need for a joint venture implicating patients, academia, industry and the state was highlighted. A national law on orphan drugs, which would also benefit researchers is being developed. Geiser met with the members of academia and organisations who are serving as advisors to government representatives and insisted upon the active participation of patient organisations in order to enhance transparency and communicate priorities and the most critical needs. Finally, Geiser met with the organisation responsible for officially identifying rare diseases within the country’s national health service. Professional certification and global medical education are needed in order to avoid underestimating rare disease prevalence. An underestimated rate of rare disorders will delay intervention and priorities.

Finally, on 7 and 8 November, GEISER hosted the Pro National Rare Disease Congress meeting in coordination with Brazilian rare diseases organizations Instituto Canguru, ABAHE, Alianza Brazileña de Genetica, and IGEIM, held at the Clinicas Hospital of Sao Paulo. More than 100 participants from non-government organisations, academy, industry and government shared their experiences concerning rare diseases and orphan drugs in Brazil and formed a working group for the Brazilian Congress of Rare Diseases and Orphan Drugs to be held in 2009. As part of its commitment, GEISER is promoting the constitution of a Brazilian rare diseases organization.

Geiser is also planning interventions in Bolivia and Paraguay and will share the results of all these local meetings via an international forum, the 2010 ICORD conference.

Other European news
Italian rare disease conference emphasises importance of international collaboration
The Italian National Centre for Rare Diseases (Istituto Superiore di Sanità) organised a week-long congress in late October to address major public health issues related to rare diseases and orphan drugs and to discuss the progress of projects funded within the bilateral agreement between Italy and the USA (NIH; Office for Rare Diseases). The congress was also an opportunity to report on the status of rare diseases in Italy. The commitment of the minister of health to rare diseases was confirmed and the funds dedicated to strengthen the regional networks for rare diseases were mentioned as an example of such commitment. Three days were given over to scientific researchers who presented the results of research project, funded within the bilateral agreement with the USA. The first day was dedicated to “aspects of pathogenesis” and presented the results of projects targeting disease gene discovery and functional studies on congenital heart defects and neurodegenerative diseases, as well as defects and regulation of gene expression in rare tumours and rare blood diseases. The second day considered “diagnosis” including i) genomic diagnosis and classification of both rare disorders with mental retardation and neurodegenerative disorders using high throughput technologies; ii) development of new diagnostic approaches for neuropathies and cardiovascular defects; iii) investigation of genetic and epigenetic mechanism underlying large cohort of Beckwith-Wiedemann Syndrome, inherited epidermolysis bullosa, rare lymphomas and tumours; iv) diagnostic and therapeutic target of rare metabolic, cardiac and blood diseases. The last section of the workshop was dedicated to “treatment and clinical management”; in particular the recent development of new strategies and therapies for rare neurodegenerative, muscular, immunological and metabolic disorders. While certain major results presented were obtained at the national level, the conference demonstrated that many projects were developed via international efforts due to networking activities amongst different world-wide institutions and patients associations; this clearly illustrates the fundamental role of interdisciplinary approaches in tackling rare diseases.

Ethical, Legal & Social Issues
Does one size really fit all? Study finds that consent procedures might be better tailored to suit the type of study conducted
An article published in the September issue of the Journal of Medical Ethics studies the consent process for a molecular genetic research study. Genetic research on rare familial disorders: consent and the blurred boundaries between clinical service and research took as a model the Genetics of Learning Disabilities (GOLD) Study seeking new mutations in new genes that could be responsible for intellectual deficit (ID) in families with two or more affected males where the cause of the ID is unknown despite full investigation. Some 78 participants from 52 families took part in semi-structured interviews to determine how the consent process unfurled and how it was experienced by participants. The authors conclude that for rare genetic disorder studies for which the research has been discussed thoroughly within the clinical setting, the consent form procedures could be more flexible.
Read the full free-access study


Orphanet News
New Texts
New Orphanet Journal of Rare Diseases Publications
Kallmann syndrome (published in the European Journal of Human Genetics, in association with Orphanet)
The inv dup (15) or idic (15) syndrome (Tetrasomy 15q)
Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia
Nevoid basal cell carcinoma syndrome (Gorlin syndrome)


New Syndromes
The H syndrome: a new disorder caused by mutations in the nucleoside transporter hENT3
The H syndrome is a recently reported autosomal-recessive disorder characterised by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. Homozygosity mapping in five consanguineous families resulted in the identification of mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Three mutations were found in 11 families of Arab and Bulgarian origin. The finding of several different mutations in a small geographic region implies that the H syndrome might be rather common. The identification of mutations in the SLC29A3 gene in patients with a mild clinical phenotype suggests that this is a largely underdiagnosed condition and strongly suggests that even oligosymptomatic individuals might have the disorder. The authors recently published two studies describing this new entity.
Read the first PubMed abstract
Read the second PubMed abstract

Am J Hum Genet ; 529-534 ; October 2008
J Am Acad Dermatol ; 79-85 ; July 2008


New Genes
Heart-hand syndrome of Slovenian type: a new kind of laminopathy
Heart-hand syndromes are a heterogeneous group of genetic disorders characterised by the association of congenital cardiac disease and limb deformities. Laminopathies are a group of diseases caused by mutations in the LMNA gene encoding A-type lamins. The authors report a new LMNA gene mutation that segregates with a new type of heart-hand syndrome in a previously-reported family suffering from adult onset progressive conduction system disease, atrial and ventricular tachyarrhythmias, sudden death, dilated cardiomyopathy, and brachydactyly with predominant foot involvement. This new heart-hand syndrome should be considered as a new kind of laminopathy.
Read the PubMed abstract

J Med Genet ; 666-671 ; October 2008
Kallmann syndrome: mutations in CHD7, causing CHARGE syndrome, also cause idiopathic hypogonadotropic hypogonadism
CHARGE syndrome and Kallmann syndrome (KS) are two distinct developmental disorders sharing overlapping features of impaired olfaction and hypogonadism. KS is a genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia, and is most commonly due to KAL1 or FGFR1 mutations. CHARGE syndrome, a multisystem autosomal-dominant disorder, is caused by CHD7 mutations. The authors of this study determined that CHD7 is also involved in the pathogenesis of IHH and KS (IHH/KS) without the CHARGE phenotype and that IHH/KS represents a milder allelic variant of CHARGE syndrome.
Read the PubMed abstract

Am J Hum Genet ; 511-519 ; October 2008
Myoglobinuria: mutations in LPIN1 cause recurrent acute form in childhood
Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using homozygosity mapping, the authors identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis. The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis. Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene. Analysis of phospholipid content disclosed accumulation of phosphatidic acid and lysophospholipids in muscle tissue of the more severe genotype.
Read the PubMed abstract

Am J Hum Genet ; 489-494 ; October 2008

Research in Action
Fundamental Research
Amyotrophic lateral sclerosis: induced pluripotent stem cells generated from patients can be differentiated into motor neurons
The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient’s disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. The authors have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.
Read the PubMed abstract

Science ; 1218-1221 ; 29 August 2008
Clinical Research
Lysosomal storage diseases: The Lancet presents three review articles targeting Gaucher, Pompe and Fabry diseases
During the month of October 2008, The Lancet published three reviews, each dedicated to a different lysosomal storage disease. For each of the diseases - Gaucher disease, Pompe disease and Fabry disease - the review article presents epidemiologic, clinical and diagnostic data and reviews the enzyme replacement treatment available for each of the illnesses, considering the benefits, limitations, cost, and the ramifications of such treatments for patients with other lysosomal diseases.
Read The Lancet abstract for Gaucher disease
Read The Lancet abstract for Pompe disease
Read The Lancet abstract for Fabry disease

The Lancet ; 1263-1271 ; 4 October 2008
The Lancet ; 1342 - 1353 ; 11 October 2008
The Lancet ; 1427 - 1435 ; 18 October 2008

Large B-cell lymphoma: structural profiles of TP53 gene mutations predict clinical outcome
The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma assembled from 12 medical centres. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53. However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS. This international collaborative study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with diffuse large B-cell lymphoma.
Read the PubMed abstract

Blood ; 3088-3098 ; 15 October 2008
Brugada syndrome: fragmented QRS as a marker of conduction abnormality and a predictor of prognosis
Conduction abnormalities serve as a substrate for ventricular fibrillation (VF) in patients with Brugada syndrome (BS). Signal-averaged electrograms can detect late potentials, but the significance of conduction abnormalities within the QRS complex is still unknown. The latter can present as multiple spikes within the QRS complex (fragmented QRS [f-QRS]). The authors hypothesized that f-QRS could indicate a substrate for VF and might predict a high risk of VF for patients with BS. They analyzed the incidence of f-QRS in 115 patients with BS (13 resuscitated from VF, 28 with syncope, and 74 asymptomatic). They found that f-QRS appears to be a marker for the substrate for spontaneous VF in BS and predicts patients at high risk of syncope.
Read the PubMed abstract

Circulation ; 1697-1704 ; 21 October 2008
Therapeutic Approaches
Huntington disease: striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in vivo
Substitutive cell therapy using foetal striatal grafts has demonstrated preliminary clinical success in patients with Huntington disease, but the logistics required for accessing foetal cells preclude its extension to the relevant population of patients. The authors designed an in vitro protocol combining substrates, media, and cytokines to push hES cells along the neural lineage, up to postmitotic neurons expressing striatal markers. The therapeutic potential of such hES-derived cells was further substantiated by their in vivo differentiation into striatal neurons following xenotransplantation into adult rats. These results open the way toward hES cell therapy for Huntington disease. Long-term proliferation of human neural progenitors leads, however, to xenograft overgrowth in the rat brain, suggesting that the path to the clinic requires a way to switch them off after grafting.
Read the PubMed abstract

Proc Natl Acad Sci USA ; 16707-16712 ; 28 October 2008

Patient Management and Therapy
Polycythemia vera and essential thrombocythemia: the effect of hydroxyurea on the JAK2V617F allelic ratio
The authors analyzed the effect of hydroxyurea on the JAK2V617F allelic ratio, measured in purified blood granulocytes, in patients with polycythemia vera and essential thrombocythemia . Thirty-six patients were examined sequentially prior to and after start of hydroxyurea therapy (8 polycythemia vera, 17 essential thrombocythemia), or while remaining untreated (2 polycythemia vera, 9 essential thrombocythemia). Hydroxyurea therapy reduced the JAK2V617F allelic ratio by >30% in 13/25 patients. In addition, a single time point study of two large cohorts of patients, examined either at the time of diagnosis (99 polycythemia vera, 178 essential thrombocythemia) or while receiving hydroxyurea (36 polycythemia vera, 98 essential thrombocythemia) confirmed reduction of JAK2V617F allelic ratio in the hydroxyurea-treated group. Prospective studies are needed to determine the prognostic value of reduced JAK2V617F allele burden under cytoreductive therapy.
Read the PubMed abstract

Haematologica ; 1723-1727 ; November 2008
Acromegaly: quality of life in patients undergoing long-term somatostatin analog treatment with and without pegvisomant
The objective of the study was to assess whether weekly administration of 40 mg pegvisomant (PEG-V) improves quality of life (QoL) and metabolic parameters in patients with acromegaly in patients with IGF-I concentrations during long-acting somatostatin analog (SSA) treatment. Twenty acromegalic subjects received either PEG-V or placebo for two consecutive treatment periods of 16 weeks. Efficacy was assessed as change between baseline and end of each treatment period. QoL was assessed by the Acromegaly Quality of Life Questionnaire (AcroQoL) and the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ). Improvement in quality of life was observed without significant change in IGF-I after the addition of 40 mg pegvisomant weekly to monthly SSA therapy in acromegalic patients who had normalized IGF-I on SSA monotherapy. These data question the current recommendations in how to assess disease activity in acromegaly. Moreover, the findings question the validity of the current approach of medical treatment in which pegvisomant is used only when SSA therapy has failed to normalize IGF-I.
Read the PubMed abstract

J Clin Endocrinol Metab ; 3853-3859 ; October 2008

Orphan Drugs
50 good reasons to be happy…the EMEA approves the 50th orphan drug
The European Medicines Agency (EMEA) has announced the passing of yet another milestone. Vidaza (azacitidine) produced by Celgene Europe has the honour of being the 50th orphan medicine to receive a positive opinion for marketing authorisation from the CHMP for the treatment of myelodysplastic syndromes and acute myeloid leukaemia in adults not eligible for haematopoietic stem-cell transplantation. On 6 November, the EMEA issued a press release announcing the approval of the 50th medicinal product. To mark the occasion, the agency also issued a list of the authorised orphan-designated medicines organised by therapeutic area along with a batch of statistics concerning the status of orphan applications. More than half of the products receiving a positive orphan designation opinion are indicated for conditions affecting children. Medicines treating cancer have received the most marketing authorisations to date. Some 569 products have received orphan designation from the EMEA.
Two orphan products net prestigious Prix Galien
The Prix Galien USA 2008 winners include two orphan medicinal products. Soliris (eculizumab), produced by Alexion Pharmaceuticals for the treatment of paroxysmal nocturnal hemolglobinuria won in the category of “Best Biotechnology Agent” while Celgene Corporation’s Revlimid (lenalidomide) used in the treatment of transfusion-dependent anemia due to low- or intermediate-1–risk myelodysplastic syndromes won in the Special Therapeutic Development category. The Prix Galien, which originated in France as way of promoting innovation in pharmaceutical research, honours innovative biopharmaceutical drugs and devices “that have made a deep impact on the quality of human life”. It has since been inaugurated across Europe and Canada and is now considered the most prestigious award of its kind in 11 countries. The USA Prix Galien, which debuted in 2007, has a committee that includes seven Nobel Laureates.
Ten EMEA orphan drug designations for November

The COMP (Committee for Orphan Medicinal Products) adopted the following ten positive opinions on orphan medicinal product designation at its November meeting for the treatment of:

- Huntington disease
- chronic lymphocytic leukaemia
- multiple myeloma (2 products)
- Behçet Disease
- Duchenne muscular dystrophy (2 products)
- nonpapillary transitional cell carcinoma of the urinary bladder
- prevention of the ischaemia/reperfusion injury associated with solid organ transplantation
- spinal cord injury
Consult the European Registry for Orphan designations
Consult the Orphanet list of orphan drugs authorised for marketing in Europe


News from the Patients' Associations
New project promoting patient group participation in clinical trials seeks information from associations
PatientPartner, a three-year project funded via the EC 7th Framework Programme, aims to help patient organisations participate as equal partners in all stages of clinical trials and clinical research, in order to gear the results of such research to better meet the needs of patients. The project, established in May of this year by the Dutch Genetic Alliance (VSOP), the UK-based Genetic Interest Group (GIG), the European Genetic Alliances’ Network, and the European Forum for Good Clinical Practice, is conducting a survey of patient organisations in Europe on their experience and involvement in clinical trials. The deadline to answer the survey is 1 December 2008 and the questionnaire is available in several EU languages.

What's on Where?
Conference on the Impact on Clinical Research of European Legislation
Date: 2 December 2008
Venue: Brussels, Belgium

The European Union Clinical Trials Directive 2001/20/EC was released with the objective of harmonising the regulatory systems, improving the protection of study participants, optimising the use of safety information, and ensuring the quality of studies and the credibility of data. This conference is intended to review the impact of the directive in order to improve the clinical trial environment in the EU.
For further details

IBC Conference: Ushering in the New Era of Orphan Disease R&D, Clinical & Business Strategies
Date: 5-6 February 2009
Venue: Bethesda MD, USA

Conference organiser IBC’s Inaugural Orphan Diseases conference will aim to deliver valuable information in a strategically organized and refined format for both industry and non-profit organizations. Regulatory Perspectives from the FDA & EMEA will provide global advice for successful commercialization; scientists from Siena Biotech, NIH & Novartis will help understand common orphan disease mechanisms; and the National Organization for Rare Disorders (NORD) will describe effective mentoring strategies for new orphan disease companies to ensure success. Please mention D9224ONA when registering.
For further details

EuroGentest Workshop: Validation of Diagnostic Tests in Clinical Molecular Genetics
Date: 8-9 January 2009
Venue: Prague, Czech Republic

Genetic tests must be validated before diagnostic use to ensure that they perform according to the laboratory requirements, and test validation is a formal requirement of many accreditation standards including ISO 15189. This workshop will examine the validation requirements of ISO 15189 and address practical ways of meeting them in the laboratory.
For further details

British Paediatric Surveillance Unit 2009 Conference
Date: 3 March 2009
Venue: London, England

The British Paediatric Surveillance Unit(BPSU) has put together a programme that reviews the contributions the unit has made to the understanding and control of uncommon childhood conditions, and the consequential impact on public health policy and development of partnerships.
For further details

3rd International Congress on Rare Pulmonary Diseases and Orphan Drugs
Date: 20-21 March 2009
Venue: Milan, Italy

This conference will consider new issues in rare pulmonary diseases and examine aspects of individual disorders.
For further details

Molecular Mechanisms of Neurodegeneration
Date: 8-10 May 2009
Venue: Milan, Italy

Addressing the most important issues involved in protein toxicity in neurons, providing participants with updated information that could be useful to researchers in the field of neurodegenerative disorders.
For further details

7th World Congress on Melanoma
Date: 12-16 May 2009
Venue: Vienna, Austria

A joint meeting with the 5th Congress of the European Association of Dermato-Oncology. Clinicians and researchers will focus on the state of the art in prevention, recognition, and treatment of cutaneous neoplasms covering melanoma and non melanoma skin cancer as well as lymphomas and rare skin tumours. Deadline for submission of abstracts: 31 January, 2009.
For further details

8th Balkan Meeting on Human Genetics
Date: 14-17 May 2009
Venue: Cavtat, Croatia

"Rare diseases – public policy, research, diagnosis and management" is one of the topics featured in this conference. Deadline to submit an abstract is 20 January 2009.
For further details

12th International Congress on Neuronal Ceroid Lipofuscinoses
Date: 3-6 June 2009
Venue: Hamburg, Germany

The aim of this meeting is to facilitate and speed up exchange between expert scientists and physicians, but also to confront young researchers with the challenges of the largest group of degenerative brain diseases in young people. Deadline for submission of abstracts: 28 February, 2009.
For further details


Press & Publications
New OECD publication compares global pharmaceutical pricing policies
The Organisation for Economic Cooperation and Development (OECD) has released a comprehensive publication that assesses national pharmaceutical pricing and reimbursement policies and considers how they contribute to attaining health policy objectives. Pharmaceutical Pricing Policies in a Global Market demonstrates how pharmaceutical policies impact product prices, medicinal usage, profits for industry, and innovation incentives. The authors delineate the drawbacks of commonly used pricing strategies such as external benchmarking. This report comes at a critical moment for rare disease stakeholders, providing a backdrop of information on the mechanisms that steer pharmaceutical pricing policies around the world as individual nations and the EU as a whole grapple to develop policies that equitably accommodate the growing number of pricey medicinal products targeting rare conditions.
Read the Executive Summary of the report
Pharmaceutical Pricing Policies in a Global Market
ISBN 978-92-64-04414-2
OECD, 2008


Orphanews Europe, the newsletter of the Rare Diseases Task Force
Orphanews Europe is supported by the European Commission's DG SANCO
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Louise Taylor
Contact Us
Editorial Board: Ségolène Aymé, Catherine Berens, Olaf Bodamer, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Manuel Posada de la Paz, Ewa Pronicka, Claire Scharf-Kroener, Armelle Regnault, Janos Sandor, Domenica Taruscio, Paloma Tejada, T.O.F. Wagner
For more information on the Rare Diseases Task Force
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