2 June 2010 print
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Fifth European Conference on Rare Diseases
Krakow 2010: A magic moment


Neither drifting volcanic ash nor heavy rainfall could dissuade over 600 international stakeholders from getting to the Fifth European Conference on Rare Diseases that took place in Krakow, Poland in mid-May. The event, sublimely organised by European patient umbrella organisation Eurordis - in particular the effort of the group’s Health Policy Officer François Houÿez and Event Manager Sharon Ashton - was deemed a “magical moment” in the history of the European rare disease movement as the charm of the city of Krakow worked its way into the very heart of the event. With the European Commission Communication on Rare Diseases: Europe’s challenges and the European Council Recommendation on an action in the field of rare diseases firmly established, the atmosphere was jubilant and the agenda practical: From Policies to Effective Services for Patients. Each of the eight themes of the conference, divided into twenty-four sessions, sought to address different aspects of the topic. With over 35% of participants coming from Central and Eastern Europe, expectations were high that individual Member State (MS) strategies would be moved forward during the sessions, for which simultaneous translations were available in up to five languages.

We have a dream …
Equating the quality of life of today’s European rare disease patients with pre-civil rights African-Americans, in the opening address Torben Groennebaek (Rare Disorders Denmark) evoked the dream of the rare disease community for equality and access. Meanwhile, a letter that was read aloud from the Polish Minister of Health underscored Poland’s commitment to the cause. Dr Andrzej Rys (Director of Public Health, European Commission) spoke of the cooperation between the Commission and the MS and the need for a unified EU strategy to combat knowledge fragmentation and scattered resources. The newly-formed European Union Committee of Experts for Rare Diseases will serve as a base of expertise to inform policy.

The first session of the conference exposed the Dynamic of National Initiatives for Rare Diseases. Co-chaired by Dr. Rys and Avril Daly (Genetic and Rare Disorders Organisation, Ireland) after a brief and excellent film in which Nick Fahy (DG Sanco) called for “efficiency, solidarity, and innovation”, Eurordis president Terkel Andersen took stock of the current situation, offering a brief tutorial on the history of rare disease advocacy in Europe, starting with Norway in the 1970s (the first RD conference took place in Oslo in 1979). He defined the main challenges in developing national plans as 1) the decentralised health care systems of some countries; 2) the need for supportive EU policies; and 3) sustainability. He also made reference to the European community’s three “founding texts” (Regulation (EC) No 141/2000 on Orphan Medicinal Products; the Council Recommendation on an action in the field of rare diseases; and the European Commission Communication on Rare Diseases: Europe’s challenges). Former chair of the EC Rare Disease Task Force Ségolène Aymé next took the microphone to discuss some current problems: Each country needs to have an adequate healthcare infrastructure in place, on top of which expert services can be built. Services need to be available AND affordable. Amongst the various elements to be considered are genetic services; disability and rehabilitation services; neonatal screening for at least PKU and hypothyroidism; academic research; laboratory networks; information; centres of expertise; funding for networks; patient group support; and access to innovative therapies. Networks are needed for developing clinical guidelines. A process that allows submitting questions to experts must be elaborated. Registry networks, which should be public/private partnerships, are crucial strategic tools. Genetic testing needs a reliable, workable cross-border mechanism.

Next, Prof. Johann Matthias Graf von der Schulenburg (Leibnitz University) discussed the German plan for rare diseases from the perspective of the health economist. There are some four million RD patients in Germany – the same amount as the country’s diabetic patients. Is the allocation of funds efficient? Is there fair allocation? Germany still lacks concrete knowledge on the situation of its RD patients. The recently-formed action league NAMSE (see OrphaNews Europe 07 April 2010) will address the knowledge gap. Germany’s timeline will lead to a strategy in 2013.

In the discussion part of the session, the need for plans specifically tailored to smaller countries (such as Macedonia) was educed. Participants representing extremely rare single gene diseases and chromosomal rearrangement disorders also emphasised their needs.

Choices to be made
After the opening of the conference, attendees were forced to choose between sessions addressing various aspects of the key theme offered simultaneously over the next two days, including the Added Value of Centres of Expertise; Improving Access to Orphan Drugs; Help Lines for Rare Diseases; National Plans and Centres of Expertise in Eastern countries; Access to Cross Border Care; Making the Best Use of Funds for Genetic Testing; Orphan Drug Development, Paediatric Investigation Plans and Advanced Therapies; Medical Education; The International Classification of Diseases Revision; Centres of Expertise for Ultra Rare Diseases; Involvement of Patients in Clinical Trials; and Databases and Registries.

Presentations were made by some familiar faces on the RD scene, including: Prof Josep Torrent-Farnell (former COMP chairman; Dr Robert Foundation); Antoni Montserrat (Policy Officer for Rare and Neuro-developmental Diseases, European Commission); Prof Hans Georg Eichler (Senior Medical Officer, European Medicines Agency); Yann Le Cam (CEO Eurordis), and Ségolène Aymé (RDTF leader; director of Orphanet). Orphanet, the pan-European portal for rare diseases and orphan drugs, was mentioned frequently throughout the conference for its successful offer of information useful to researchers, health professionals and patients alike.

There were also many experts from Poland and surrounding countries present: Prof. Cristina Rusu (University of Medicine and Pharmacy, Lasi, Romania); Miroslaw Zielinski (National Forum for Therapies for Rare Diseases Poland); Prof Rumen Stefanov (Bulgarian Association for Promotion of Education and Science); Dr Gabor Pogany (Huferdis, Hungary); Dorica Dan (Prader Willi, Romania); Mirando Mrsic (Croatian Society for Patients with RD); Prof Anna Tylki Szymanska (Children’s Memorial Health Institute, Metabolic Diseases); Prof Jolanta Sykut-Cegielska (Children’s Memorial Health Institute, Poland); Silvia Stuppäck (Central European Countries Plan Extensive Cooperation for Rare Diseases); Prof Krystyna Chrzanowska (Department of Medical Genetics, Children’s Memorial health Institute Poland); Prof Milan Macek (Faculty of Medicine, University Hospital Motol, Charles University Prague, Czech Republic); Prof Tomasz Grodzicky (Dean of the Faculty of Medicine, Krakow); Dr Marie Louise Borg (Ministry of Social Policy, Malta); Dr Bozenna Dembowska-Baginska (COMP); Pawel Wojtowicz (President of Polish Cystic Fibrosis Foundation MATIO); and Prof. Wojciech Cichy (Medical University in Poznan). Despite the presence of so many luminaries in the rare disease field, the absence of Poland’s First Lady Maria Kaczynska, who died in the 10 April plane accident that also took the life of the country’s president and other leading political, military, and church figures, was still felt.

A Poster Session allowed for networking - one of the most satisfying aspects of the conference. Two of the 70 posters displayed were singled out for special recognition: one based on a pan-European study of cystic fibrosis (Mehta et al; see OrphaNews Europe 12 May 2010) and the other describing data from a longitudinal study involving patients with congenital neutropenia from 23 countries.

There were also audience participatory sessions of the PlayDecide game, a method for introducing complex scientific and medical topics into the arena of public debate. PlayDecide allows patients to learn more about policy issues while fostering their ease in contributing to the discussion in multi-stakeholder events.

The final session of the conference regrouped the participants together again to learn more about the European Union Committee of Experts for Rare Diseases (EUCERD). In the Road Map 2010-2015 for the implementation of the Commission Communication session, Toni Montserrat (Policy Officer for Rare and Neuro-developmental Diseases, European Commission) evoked the little known science of “commitology” – how to best organise a new committee. The EUCERD, which will convene for the first time in October, will consist of almost 60 members - some of whom were asked to take the stage (S. Aymé; S. Koutouzov; Y. Le Cam; and D. Taruscio). Catherine Berens (DG Research) spoke of the desire for FP7 and other future calls to target the real needs of the RD community. The conference drew to an end with a presentation from Usher syndrome advocate Steffen Suchert (Faun-Stiftung, Germany) who left attendees with a demonstration of how a patient organisation can forward research and ultimately treatment. Mr. Suchert reminded the audience that, “We can move mountains, if we try.” ECRD 2010 in Krakow proved that the willingness to try is certainly present.


Task Force Update
Final report on health indicators for rare diseases now available
The European Commission’s Rare Diseases Task Force report Health Indicators for Rare Diseases: Conceptual Framework and Development of Indicators from Existing Sources is now available online.
Have you completed the OrphaNews Europe Five Minute Survey?
OrphaNews Europe strives hard to bring readers the latest rare disease research and policy news. To best target your needs, a five-minute electronic survey was sent by email to all subscribers last week. If you have not yet done so, please complete this survey. The results will be published in an upcoming issue of the newsletter.

Spotlight on...
Stakeholders help the European Medicines Agency celebrate ten years of Orphan Drug Regulation
The European Medicines Agency (EMA) last month celebrated the tenth anniversary of Regulation (EC) No 141/2000 of the European Parliament and of the Council on Orphan Medicinal Products (Orphan Drug Regulation) which came into effect in early 2000, along with Commission Regulation (EC) No 847/2000 defining the provisions for implementation of the criteria for orphan designation. The legislation was brought forward in order to improve the offer of products for patients with rare conditions by providing drug developers with a bouquet of economic and regulatory incentives, including 10-year market exclusivity, protocol assistance, and access to the Centralised Procedure for Marketing Authorisation.

The EMA’s Committee for Orphan Medicinal Products (COMP), created in the year 2000 to review designation applications, has logged some 1100 applications for orphan designation in the past decade. Of these, more than 700 have been granted orphan status by the European Commission, and over 60 products have crossed the finish line to receive marketing authorisation in the European Union. The number of applications for orphan designation has steadily increased, from 72 in the year 2000 to 164 in 2009. While oncology products receive the lion’s share of COMP positive opinions (45%), immunology, cardiovascular and respiratory, metabolism, musculoskeletal, nervous system, and anti-infectious indications are also represented. The EMA celebration in London brought together participants from the European Parliament, the European Commission, international and European regulatory agencies, COMP members, patient groups, health professionals, and members of the biopharmaceutical industry. During the two-day event, participants reviewed the impact of the Orphan Drug regulation and examined future challenges.

Amongst the major issues broached was whether the current Orphan Drug Regulation needs updating in order to expand the responsibilities of the COMP in light of two key committees created in the years since the Regulation came into force: the Committee for Advanced Therapies (CAT), created in accordance with Regulation (EC) No 1394/2007, was established in 2009 - nine years after the Orphan Drug Regulation was passed – to evaluate gene therapy, somatic cell therapy and tissue-engineered products; and the Paediatric Committee (PDCO), created to assess the content of paediatric investigation plans and adopt opinions on them in accordance with Regulation (EC) 1901/2006. As with these new committees, the COMP could similarly chaperone orphan drug development through the entire designation and authorisation procedures, becoming a “one-stop shop” for sponsors developing orphan products. It was suggested that the current Regulation might be amended to achieve this, thus avoiding the need to introduce a new piece of legislation.

Another topic centred on the post-marketing studies for products granted conditional authorisation. How to best organise registries and how to enhance access to the vital data they contain? The issue becomes more complex when there is more than one product on the market or under development for the same indication. How to promote collaboration within industry and encourage data sharing between industry and academia and the patient organisations? Another consideration involves incorporating data from untreated patients. The data from registries could provide national authorities with crucial information for cost assessment and reimbursement purposes. It was suggested that the EMA could take a regulatory role in establishing and managing post-marketing registries.

There was also the perspective of the patients, offering their analysis of what is still needed to encourage the development of more products for rare conditions. The desire for a “one-stop shop” to chaperone products through the entire development procedure was echoed. Patient representatives also called for improvements to the current pricing and reimbursement systems. This is a challenge that needs to address the current system of assessing drugs at the national level, which results in marked disparity in availability between countries.

Participants also celebrated the growing collaboration between Europe and the USA, resulting in the harmonisation of administrative procedures, the most recent of which is the streamlined procedure for the annual report for orphan designated products (see OrphaNews Europe 19 March 2010).

In honour of the Regulation’s tenth birthday, staff from the Orphan Section at the EMA published an article in the journal Drug News and Perspectives entitled European Medicines Agency Support Mechanisms Fostering Orphan Drug Development. Offering a review of how the orphan drug legislation operates and a consideration of the impact the regulation has had over the past decade, the article can be viewed here, reprinted from Drug News and Perspectives with the kind permission of Thomson Reuters.

Molecules and other substances receiving an orphan designation are entered in the Community Register for Orphan Medicinal Products. The EMA issues a detailed report listing positive opinions following each COMP meeting, including summaries for the public. Orphanet also keeps close tabs on orphan drug activity. The List of Orphan Designations in the Orphanet database includes all substances which have been granted an orphan designation for disease(s) considered rare in Europe, whether or not they have been developed into drugs with marketing authorisation. The Orphanet Report Series itemises all medicinal products in Europe with marketing authorisation for rare conditions and provide indication details. Data on products with marketing authorisation and/or orphan designation are cross-referenced by trade name, authorisation date; Anatomical Therapeutic Chemical (ATC) classification; and by authorisation holder. Available in English, French, German, Italian and Spanish, this information is regularly updated.

It is expected that all the various registers and listings for orphan designated substances and market authorised products will expand significantly in the next ten years of the Orphan Drug Regulation under the efficient guidance of the COMP, the CHMP, the CAT and the entire EMA. Many of the keynote lectures from the 10 Years of the Orphan Regulation in Europe workshop are available for consultation on the EMA website.


EU Policy News

European Commission issues roadmap for overhauling the Clinical Trials Directive
After years of argy-bargying, it looks as though the infamous Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 (the Clinical Trials Directive) will get a much-needed overhaul. Deemed “arguably the most criticised piece of legislations” (on medicines), the Directive has been lambasted over three principle points:

“(1) the divergent application of the Clinical Trials Directive in the Member States; (2) the increased administrative burden for clinical trials in view of regulatory requirements which do not take into account practical necessities and constraints; and (3) the fact that clinical trial regulation does not sufficiently take into account the increasingly global scale of clinical trials".

Following, amongst other things, the damning results of the FP7-funded Impact on Clinical Research of European Legislation (ICREL) project, the European Commission has consequently issued a legislative proposal on a Regulation/Directive amending the Clinical Trials Directive 2001/20/EC. Whether the current legislation is to be amended or an entirely new regulation will be introduced is still uncertain. With the particular challenges and cost concerns of the average rare disease clinical study, the revamping of the Clinical Trials Directive is an affair to follow closely.


The forefront of innovation: rising to the challenge of advanced therapy medicinal products
The European Medicine Agency’s Committee for Advanced Therapies (CAT) and the CAT Scientific-Secretariat contributed an opinion piece to Nature Reviews Drug Discovery in March of this year in which the authors demonstrate the complexity involved with the burgeoning field of advanced therapy medicinal products (ATMP), encompassing gene therapy products, somatic cell therapy products and tissue-engineered products. Working within the regulatory parameters established under Regulation (EC) No 1394/2007, the CAT illustrates some of the complex issues inherent in both the development and the evaluation of ATMPs. Take, for example, the case of the gene therapy product that virtually cures a fatal monogenic disease, but which eventually causes leukaemia in later years. How to evaluate the benefit-risk ratio, which “risk could still be considered positive, although sponsors and regulators would work together in an attempt to circumvent this side effect”? Establishing sound policies on such issues is crucial. As the authors point out, “Many ATMPs will be developed for rare diseases. At the EMA, the Committee for Orphan Medicinal Products (COMP) is responsible for reviewing applications seeking orphan medicinal product designation for products that diagnose, prevent or treat life-threatening or serious conditions that affect less than 5 in 10,000 persons in the European Union. The CAT considers it important that there is an active and early link with the COMP for exchange of information on orphan ATMPs, which may qualify for orphan designation, and initial discussions have already commenced. Some of the CAT members were formerly members of the COMP, so there is already a clear understanding of the needs of orphan drugs in the CAT”. The article underscores the regulatory advice that the EMA and CAT offer to drug developers stepping into this promising new field of drug development.
Consult the PubMed abstract
Learn more about the CAT

Annual report guidance for orphan designations updated
Sponsors of designated orphan medicinal products are required to submit to the European Medicines Agency an annual report on the development of their product. The note for guidance on the format and content of this annual report has been updated, taking into account the new harmonised procedures between the EU and the USA. Consult the revised guidelines

National & International Policy Developments
OECD report takes stock of country health care information technologies
A project of the Organisation for Economic Co-operation and Development (OECD), co-financed by the Directorate General for Health and Consumers of the European Commission, analysed the health care system information and communication technologies (ICT) of the OECD countries. The resulting report, entitled Achieving Efficiency Improvements in the Health Sector Through the Implementation of Information and Communications Technologies examines the value of various ICT applications in the field of health, looks at the obstacles keeping efficient ICT from being implemented, and considers cost, incentives, benchmarking and security issues. Data from the case studies of six OECD countries (Australia, Canada, the Netherlands, Spain, Sweden, and the United States) are included in the report which provides advice on various policies and practices that could accelerate and harmonise the implementation of ICT in the health field. These topics are particularly valuable to the rare disease field, where both patient populations and expertise are scattered, leading to data fragmentation.
Consult the OECD report

Other International News
First FDA orphan drug workshop bears fruit
Nature Biotechnology reports that the first of the USA’s Food and Drug Administration (FDA) Orphan Drug workshops, which took place in February, culminated in 14 submissions from amongst the almost 30 sponsors attending the event. Designed for academia and small biotech firms as well as the large pharmaceutical companies, the workshops provide regulatory assistance and help sponsors “complete the best application possible”. An orphan designation does not guarantee marketing authorisation down the road, but it can attract investors via the incentives it allows (in the USA, seven years of market exclusivity and various tax credits). The next workshop is scheduled for early August. Learn more about the FDA Orphan Drug Workshops

Ethical, Legal & Social Issues

Spanish Rare Disease Research Institute issues ethical guidelines for registries and biobanks
The Ethics Committee of the Instituto de Investigación de Enfermedades Raras (Ethical Committee of the Rare Diseases Research Institute) has published documents grouping together guidelines for certain elements crucial to rare disease research and care: registries, biobanks, and screening. Originally published as separate articles in the Spanish Health Ministry publication Revista Española de Salud Pública, the Ethics Committee has now grouped the guidelines into one document, entitled Ethical Guidelines for Biomedical Research, which it has made available in both Spanish and English languages. The guidelines address issues pertaining to creation, organisation, management, consent, privacy, post-mortem data, and ownership, within the context of existing ethical principles and norms, legal provisions, and international practices.
Consult the guidelines in English
Consult the guidelines in Spanish


EU Project Follow-up
New project seeks to improve DMD patient quality of life via harmonised European care recommendations
The €1 million CARE-NMD project had its official launch in mid-May. CARE-NMD (Dissemination and Implementation of the Standards of Care for Duchenne Muscular Dystrophy in Europe) was selected for funding by the Executive Agency for Health and Consumers (EAHC) out of 257 applications. The project spans Europe, with partner institutions and patient advocacy groups in Bulgaria, the Czech Republic, Denmark, Germany, Hungary, Poland and the United Kingdom (funded partners), as well as Belarus, Croatia, France, Ireland, Macedonia, Netherlands, Romania, Russia, Serbia, Slovakia, Sweden and the Ukraine (collaborating partners). Between the project partners and representatives of patient organisations, the kick-off meeting was a fruitful, productive first interaction to reach the ambitious aims of this project. As a whole, CARE-NMD aims to improve quality of life of patients with DMD through implementation of up-to-date treatment recommendations. Hurdles in their implementation will be identified in each country. This may help stakeholders and decision-makers to take further actions to improve the care of patients with DMD and other neuromuscular disorders. Under the leadership of Dr. Janbernd Kirschner (Department of Neuropediatrics and Muscle Disorders at Freiburg University Medical Center), existing treatment standards and availability in these countries will be evaluated and improved through specific training sessions and other measures. “With a secured diagnosis and adequate treatment, children with DMD and their families can be helped to a far higher life expectancy and improved quality of life,” explained project partner Professor Kate Bushby of Newcastle University (UK). “Better availability of specialist care will also benefit patients with other forms of neuromuscular disease across Europe”.


Orphanet News

New Texts
New Orphanet Journal of Rare Diseases publications
A review of trisomy X (47,XXX)
Aldosterone-producing adenoma and other surgically correctable forms of primary hyperaldosteronism


New Syndromes
Microcornea, posterior megalolenticonus, persistent foetal vasculature, and coloboma: a new syndrome
The authors report a newly identified syndrome of bilateral microcornea, posterior megalolenticonus, persistent fetal vasculature, and chorioretinal coloboma (MPPC) in eight patients. Eight eyes of six patients underwent lensectomy, vitrectomy, membrane peeling, and fluid-Healon exchange (Healon OVD [sodium hyaluronate]; Advanced Medical Optics, Santa Ana, CA) with functional vision in at least 4 of the 5 patients with post surgical follow-up.
Read the PubMed abstract

Ophthalmology ; Epub ahead of print ; 22 April 2010

New Genes

Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase
The authors report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein.
Read the PubMed abstract

To read more about "Amyotrophic lateral sclerosis"

PNAS USA ; 7556-7561 ; 20 April 2010
Fanconi anaemia: mutation of the RAD51C gene
Fanconi anaemia (FA) is a rare chromosomal-instability disorder associated with a variety of developmental abnormalities, bone marrow failure and predisposition to leukaemia and other cancers. The authors identified a homozygous missense mutation in the RAD51C gene in a consanguineous family with multiple severe congenital abnormalities characteristic of FA.
Read the PubMed abstract

To read more about "Fanconi anemia"

Nat Genet ; 406-409 ; May 2010

Research in Action

Fundamental Research
Congenital myasthenic syndromes: Dok-7 promotes slow muscle integrity and neuromuscular junction formation in zebrafish model
The small signalling adaptor protein Dok-7 has recently been reported as an essential protein of the neuromuscular junction (NMJ). Mutations resulting in partial loss of Dok-7 activity cause a distinct limb-girdle subtype of the inherited NMJ disorder congenital myasthenic syndromes (CMSs), whereas complete loss of Dok-7 results in a lethal phenotype in both mice and humans. Here the authors describe the zebrafish orthologue of Dok-7 and study its in vivo function. Dok-7 deficiency leads to motility defects in zebrafish embryos and larvae. The relative importance of Dok-7 at different stages of NMJ development varies; it is crucial for the earliest step, the formation of acetylcholine receptor (AChR) clusters in the middle of the muscle fibre prior to motor neuron contact. At later stages, presence of Dok-7 is not absolutely essential, as focal and non-focal synapses do form when Dok-7 expression is downregulated. These results suggest an additional role of Dok-7 in muscle.
Read the PubMed abstract

To read more about "Congenital myasthenic syndromes"

Hum Mol Genet ; 1726-1740 ; 1 May 2010
SCID and Omenn syndrome: the Rag2 PHD domain has a central role in regulating V(D)J recombination
Rag2 plays an essential role in the generation of antigen receptors. Mutations that impair Rag2 function can lead to severe combined immunodeficiency (SCID), a condition characterised by complete absence of T and B cells, or Omenn syndrome (OS), a form of SCID characterised by the virtual absence of B cells and the presence of oligoclonal autoreactive T cells. The authors present a comparative study of a panel of mutations that were identified in the noncanonical plant homeodomain (PHD) of Rag2 in patients with SCID or OS. They show that PHD mutant mouse Rag2 proteins that correspond to those found in these patients greatly impaired endogenous recombination of Ig gene segments in a Rag2-deficient pro-B cell line and that this correlated with decreased protein stability, impaired nuclear localisation, and/or loss of the interaction between Rag2 and core histones. These findings illustrate the various deleterious effects of PHD Rag2 mutations, demonstrate the crucial role of this domain in regulating antigen receptor gene assembly, and reveal new mechanisms of immunodeficiency in SCID and OS.
Read the PubMed abstract

To read more about "Severe combined immunodeficiency"
To read more about "Omenn syndrome"

J Clin Invest ; 1337-1344 ; April 2010
Hereditary spastic paraplegia: functional conservation of human Spastin in a Drosophila model
Mutations in spastin are the most frequent cause of the neurodegenerative disease autosomal dominant-hereditary spastic paraplegia (AD-HSP). Drosophila melanogaster lacking spastin exhibit striking behavioural similarities to human patients suffering from AD-HSP, suggesting conservation of Spastin function between the species. The authors show that exogenous expression of wild-type Drosophila or human spastin rescues behavioural and cellular defects in spastin null flies equivalently. Transgenic AD-HSP flies provide a powerful and tractable model to enhance understanding of the cellular and behavioural consequences of human spastin mutations and test hypotheses directly relevant to the human disease.
Read the PubMed abstract

To read more about "Familial spastic paraplegia"

Hum Mol Genet ; 1883-1896 ; 15 May 2010
Lesch-Nyhan disease: human neural stem cells provide a model system for the study of neuronal dysfunction
The study of Lesch-Nyhan-diseased (LND) human brain is crucial for understanding how mutant hypoxanthine-phosphoribosyltransferase (HPRT) might lead to neuronal dysfunction. Since LND is a rare, inherited disorder caused by a deficiency of the enzyme HPRT, human neural stem cells (hNSCs) that carry this mutation are a precious source for delineating the consequences of HPRT deficiency and for developing new treatments. The authors examined the effect of HPRT deficiency on the differentiation of neurons in hNSCs isolated from human LND foetal brain. LND hNSCs demonstrate aberrant expression of several transcription factors and DA markers. HPRT-deficient dopaminergic neurons also demonstrate a striking deficit in neurite outgrowth. These results represent direct experimental evidence for aberrant neurogenesis in LND hNSCs and suggest developmental roles for other housekeeping genes in neurodevelopmental disease. These results evidence aberrant neurogenesis in LND hNSCs and suggest a role for HPRT gene in neurodevelopment.
Read the PubMed abstract

To read more about "Lesch-Nyhan syndrome"

Hum Mol Genet ; 1939-1950 ; 15 May 2010
Fragile X syndrome: protein is required for synapse elimination by the activity-dependent transcription factor MEF2
Fragile X syndrome (FXS), the most common genetic form of intellectual deficit and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterised by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination. The authors demonstrate that MEF2 activation fails to eliminate functional or structural excitatory synapses in hippocampal neurons from Fmr1 KO mice. Similarly, inhibition of endogenous MEF2 increases synapse number in wild-type but not Fmr1 KO neurons. MEF2-dependent synapse elimination is rescued in Fmr1 KO neurons by acute postsynaptic expression of wild-type but not RNA-binding mutants of FMRP. These results reveal that active MEF2 and FMRP function together in an acute, cell-autonomous mechanism to eliminate excitatory synapses.
Read the PubMed abstract

To read more about "Fragile X syndrome"

Neuron ; 191-197 ; 29 April 2010
Clinical Research
Rett syndrome: updating the profile of C-terminal MECP2 deletions
This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype, growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome.
Read the PubMed abstract

To read more about "Rett syndrome"

J Med Genet ; 242-248 ; April 2010
Gene Therapy
Retinitis pigmentosa: restoration of visual function in transgenic rats by BiP/Grp78 gene delivery
The P23H mutation within the rhodopsin gene (RHO) causes rhodopsin misfolding, endoplasmic reticulum (ER) stress, and activates the unfolded protein response (UPR), leading to rod photoreceptor degeneration and autosomal dominant retinitis pigmentosa (ADRP). Grp78/BiP is an ER-localised chaperone that is induced by UPR signalling in response to ER stress. Subretinal delivery of AAV5 expressing BiP to transgenic rats led to reduction in the proapoptotic protein CHOP and photoreceptor apoptosis and to a sustained increase in electroretinogram amplitudes. The authors detected complexes between BiP, caspase-12, and the BH3-only protein BiK that may contribute to the antiapoptotic activity of BiP. The preservation of photoreceptor function resulting from elevated levels of BiP is due to suppression of apoptosis rather than to a promotion of rhodopsin folding.
Read the PubMed abstract

To read more about "Retinitis pigmentosa"

PNAS USA ; 5961-5966 ; 30 March 2010
Pompe disease: neonatal gene transfer using lentiviral vector for murine long-term expression and glycogen reduction
Pompe disease results from the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to accumulated glycogen in the heart and the skeletal muscles, which causes cardiomyopathy and muscle weakness. In this study, the authors tested the feasibility of gene therapy for Pompe disease using a lentivirus vector (LV). Newborn GAA knockout mice were treated with intravenous injection of LV encoding human GAA (hGAA) through the facial superficial temporal vein. The transgene expression in the tissues was analyzed up to 24 weeks after treatment. Their results showed that the recombinant LV was efficient not only in increasing the GAA activity in tissues but also in decreasing their glycogen content. The examination of histological sections showed clearance of the glycogen storage in skeletal and cardiac muscles 16 and 24 weeks after a single vector injection. LV-mediated delivery system was effective in correcting the biochemical abnormalities.
Read the PubMed abstract

To read more about "Glycogen storage disease type 2"

Gene Ther ; 521-530 ; April 2010
Therapeutic Approaches
X-linked adrenoleukodystrophy: Valproic acid induces antioxidant effects
X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. The authors demonstrate that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, the authors propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.
Read the PubMed abstract

To read more about "X-linked adrenoleukodystrophy"

Hum Mol Genet ; 2005-2014 ; 15 May 2010

Patient Management and Therapy

Acute promyelocytic leukaemia: very long-term outcome of after treatment with all-trans retinoic acid and chemotherapy
Acute promyelocytic leukaemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In a APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses. The early addition of CT to ATRA significantly improved 10-year event-free survival but without significant effect on overall survival.
Read the PubMed abstract

To read more about "Acute promyelocytic leukemia"

Blood ; 1690-1696 ; 4 March 2010
Pompe disease: a randomised study of alglucosidase alfa in late-onset patients
Late-onset Pompe disease is characterised by progressive muscle weakness and loss of respiratory function, leading to early death. The authors conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe disease in 90 patients who were 8 years of age or older, ambulatory, and free of invasive ventilation.: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period.
Read the PubMed abstract

To read more about "Glycogen storage disease type 2"

N Engl J Med ; 1396-1406 ; 15 April 2010

Orphan Drugs

Seven positive opinions adopted at May COMP meeting
The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) adopted seven positive opinions issued at the May 2010 COMP meeting for the treatment of:

- ovarian cancer (two products)
- cystic fibrosis
- chronic myeloid leukaemia
- non-infectious uveitis affecting the posterior segment of the eye
- tuberous sclerosis
- mastocytosis

Consult the European Register of Designated Orphan Medicinal Products
Consult the Orphanet list of orphan drugs authorised for marketing in Europe

GSK creates special rare disease unit
Earlier this year, pharmaceutical giant GlaxoSmithKline (GSK) announced a new standalone unit directly targeting the development and commercialisation of products for rare disorders. In a press release, it was announced that the new unit will “seek to leverage existing capabilities and partnerships and establish further in-licensing opportunities”. Last year, GSK began collaborating with Leiden-based SME Prosensa, focusing on four RNA-based compounds for different types of Duchenne muscular dystrophy. GSK also entered into an alliance with JCR Pharmaceuticals (Japan), obtaining global rights to certain enzyme replacement treatments potentially targeting Hunter syndrome as well as Fabry and Gaucher diseases. Patrick Vallance, GSK Senior Vice President of Drug Discovery, commented that “The risk associated with product discovery and development in rare diseases is generally lower than other disease areas as disease definitions are very clear and clinical trials tend to be small with robust endpoints. In most cases the molecular target is known, making it easier for specialised physicians to diagnose patients”. Furthermore, Marc Dunoyer, GSK President of Asia Pacific and Chairman of Japan, observed that "This complementary approach will combine our existing global expertise with specialist partners. Overtime, this new unit has the potential to deliver multiple therapies responding to high medical needs of underserved populations of patients”. In March, GSK signed another deal with Isis Pharmaceuticals, using the California-based company’s antisense drug discovery platform “to seek out and develop new therapeutics against targets for rare and serious disease, including infectious diseases and some conditions causing blindness”.
New report captures the orphan drug market in the Asia-Pacific region
Orphan Drugs in Asia-Pacific: From Designation to Pricing, Funding & Market Access is a freshly published study that presents a comprehensive guide to the orphan drug scenario in five key markets - Japan, South Korea, Taiwan, Singapore and Australia. The author sets out and compares the incentives available to drug sponsors in each market, dissecting the specific measures in place to promote the development, registration and commercialisation of orphan drugs as well as special funding schemes, HTA, risk sharing, and reimbursement issues. Contact details for patient organisations are also provided. Learn more


Erdheim-Chester disease - request for proposals
The ECD Global Alliance seeks to help those affected by Erdheim-Chester disease (ECD) by providing support, promoting research, raising awareness and sharing educational material related to ECD. The organisation is currently soliciting grant applications from qualified researchers regardless of location for funding of up to USD $50,000 for research projects focusing on the pathophysiology or treatment of ECD.
Application Deadline: 11 August, 2010
For further details


Courses & Educational Initiatives

TREAT-NMD Clinical Trials in Neuromuscular Disorders and Other Rare Diseases Workshop
Date: 24-26 June 2010
Venue: The Clinical Trials Coordination Centre, Freiburg, Germany

One of the most common reasons for failed trials is poor protocol design. As neuromuscular disorders are very rare, clinical trials have to be multi-centre or even multinational to include enough patients. As a result, the study design for these trials is usually complex. Also, academic trials have come to face a changed regulatory environment following the implementation of the EU Clinical Trials Directive 2001/20/EC. This TREAT-NMD workshop will explore these issues.
For further details

4th Inborn Errors in Neonatology Course
Date: 21-23 October 2010
Venue: Dubrovnik, Croatia

This practical course is run by an experienced team of paediatricians, neonatologists, molecular biologists and biochemists specialised in metabolic medicine, who already contributed substantially to the understanding of metabolic disorders in childhood. The two and a half days course includes lectures and seminars for 35 participants. The course is aimed at paediatricians with about 2-3 years clinical experience in the neonatology field.

The Orphan Europe Academy provides healthcare professionals with the opportunity to increase knowledge, develop new ideas and strengthen scientific collaboration by offering training and educational activities for healthcare professionals involved in the diagnosis and management of patients affected by rare diseases.
For further details

EuroGentest Quality Management and Accreditation/Certification of Genetic Testing Workshops
The European network of excellence for all aspects of genetic testing, EuroGentest, under its Quality Management and Accreditation/Certification of Genetic testing Workgroup, has several training workshops available around Europe in coming months that focus on accreditation and quality assurance.
For further details

Institute of Myology Summer Programme
The Institute of Myology offers the possibility to train in myology via a condensed 10-day course organised in Paris, France. The course is open to foreign students with special attention given to those posted in the French Overseas Territories and those working in developing countries. Many aspects of myology are addressed during the course, from basic science to cutting-edge therapies, and clinical and genetic approaches to muscle diseases, taught via a series of lectures and interactive workshops in English. A certificate of attendance is issued upon completion of the Summer School.
For further details


What's on Where?

ISDN 2010: 18th Biennial Meeting of the International Society for Developmental Neuroscience
Date: 6-9 June 2010
Venue: Estoril, Portugal

Featuring the most recent advances in fundamental and disease-focused developmental neuroscience. Fragile X, Rett Syndrome, ciliopathy disorders, Meckel-Gruber syndrome are amongst the rare conditions included in the programme.
For further details

Giving Patients a Voice: Genetic Interest Group Conference 2010
Date: 8 June 2010
Venue: London, England

The 2010 GIG conference will focus on important developments in patient partnership in healthcare. The afternoon will be dedicated to Rare Disease UK and will be focused on gaining views on how services for patients and families with rare diseases can be improved.
For further details

First Regional Forum for Orphan Diseases
Date: 11 June 2010
Venue: Salzburg, Austria

The first half of the day will be devoted to international topics and held in English. The second half will be dedicated to local topics related to orphan diseases and held in German language. The Forum will close with a panel discussion with representatives from insurance companies, health politics, parent support groups and hospitals. View the programme
For further details

European Human Genetics Conference 2010
Date: 12-15 June 2010
Venue: Gothenburg, Sweden

In conjunction with the European Meeting on Psychosocial Aspects of Genetics. With various satellite symposia available including the one-day event taking place on 11 June entitled "Changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe".
For further details

33rd European Cystic Fibrosis Conference
Date: 16-19 June 2010
Venue: Valencia, Spain

The scientific programme has been developed with particular emphasis on a balanced presentation of original contributions in both basic and clinical science. The keynote lectures, symposia and workshops provide an opportunity to keep up with the most recent developments in the field. The invited speakers are well known specialists who will share their valuable experience.
For further details

International Conference on Neuromuscular Diseases: Care and Clinical Trials
Date: 17–19 June 2010
Venue: Sao Paulo, Brazil

This exciting meeting is aimed at healthcare professionals with an interest in neuromuscular disorders (with a special focus on DMD and SMA) and patients and families. Two days of lectures from a strong panel of international and Brazilian speakers will be followed by a dedicated family day with research updates for patients and information on physiotherapy and care.
For further details

Advances in Neuroblastoma Research 2010
Date: 21-24 June 2010
Venue: Stockholm, Sweden

Workshops will address hypoxia, tumour stem cells and vascularization; micro-RNA and neuroblastoma; genome-wide sequencing; novel therapies and more. An update course is also offered.
For further details

11th International Symposium on Mucopolysaccharide & Related Diseases
Date: 23-26 June 2010
Venue: Adelaide, South Australia

This year’s theme is "Translating Research into Clinical Reality" with a focus on the areas of newborn screening, prognostics, understanding pathology and therapeutic options.
For further details

6th Alstrom Syndrome Family Conference, Medical Research Clinic and Scientific Symposium
Date: 24-28 June 2010
Venue: Helen, Georgia, USA

Bringing together patients and professionals to further knowledge of Alstrom syndrome and its treatment.
For further details

16th Retina International World Congress
Date: 26- 27 June 2010
Venue: Stresa, Italy

This year’s theme is “Change our vision – Bridging the gap from the lab to the patients”. Sessions will cover genetic and clinical aspects of inherited retinal degenerations; diagnosing young children; gene therapy; and treatment perspectives.
For further details

International Congress for Tarlov Cysts and Adhesive Arachnoiditis
Date: 2-3 July 2010
Venue: Chambéry, France

International health professionals will discuss recent findings on Tarlov and meningeal cysts, Arachnoïditis, Cauda Equina syndrome, and neuropathic pain. Patients will share their experience. Translations available in English, French and Spanish.
For further details

Fifth Eastern European Conference for Rare Diseases and Orphan Drugs and First Russian Conference for Rare Diseases
Date: 2-4 July 2010
Venue: Saint Petersburg, Russia

With sessions on Rare Diseases in the Focus of Personalized Medicine; Best Practice in Field of Rare Diseases and Personalized Medicine; Rare Diseases – Future, Perspectives, Challenges of Health Care; Modern capabilities in diagnostics and treatment of rare diseases; and much more.
For further details

14th International Conference on Behçet Disease
Date: 8-10 July 2010
Venue: London, England

Presenting new developments in basic and clinical science to bear on the specific issues of Behçet Disease (BD). Topics to be covered will include immunology of BD, vasculitis in BD, genetic basis of BD, regional inflammation and paediatric BD. The programme will also include debates on topics of current interest or controversy.
For further details

17th International Paediatric Colorectal Club Meeting
Date: 17-19 July 2010
Venue: Padova, Italy

Topics include anomalies of the bowel, anorectal malformation, Hirschsprung disease and urological aspects.
For further details

2th International Congress on Neuromuscular Diseases
Date: 17-22 July 2010
Venue: Naples, Italy

Offering a variety of sessions including paediatric neuromuscular diseases, genetic testing and diagnosis, pathogenic mechanisms of inherited neuropathies, novel therapeutic targets at the neuromuscular junction, motor neuron diseases, and much more.
For further details

International All Star Vasculitis Symposium
Date: 30 July-1 August 2010
Venue: Long Beach, CA, USA

Topics will cover all the vasculitides and will concentrate on the advances in medical treatments, research and quality of life issues for patients.
For further details

FDA Orphan Drug Workshop
Date: 3-4 August 2010
Venue: Minnesota, USA

Over two days, FDA staff from the Office of Orphan Products Development (OOPD) will provide regulatory assistance to sponsors to find regulatory paths forward. Most of the time will be spent in application writing and individual one-on-one guidance sessions to develop the strongest possible orphan designation application to be submitted at the close of the workshop.
For further details

26th International Congress of Pediatrics
Date: 4-9 August 2010
Venue: Johannesburg, South Africa

Amongst the general programme are symposia on primary immunodeficiency diseases in resource-limited settings, appropriate genetic testing, and a workshop on approaches to the dysmorphic child.
For further details

2nd Congress of the European Society for Paediatric Anaesthesiology
Date: 2-4 September 2010
Venue: Berlin, Germany

Amongst the programme of this congress will be a session entitled “Rare diseases: a common problem!” featuring the anaesthetic management of a child with a rare disease; approaches to rare diseases at the national and European level; and the OrphanAnaesthesia project.
For further details

MEN 2010: 12th International Workshop on Multiple Endocrine Neoplasia
Date: 16-18 September 2010
Venue: Viareggio, Italy

This two-day meeting will provide a forum for educating basic and clinical investigators on the most recent advances in the area of hereditary endocrine tumours.
For further details

Second AnEUploidy Workshop
Date: 17-19 September 2010
Venue: Split, Croatia

AnEUploidy is the acronym of an Integrated Project (IP) funded by the European Commission within its Sixth Framework Programme. This project aims to contribute to the understanding of the molecular basis and pathogenic mechanisms of aneuploidies. This second workshop will allow colleagues to share views, advancements, and ideas.
For further details

International Meeting on Fibrous Dysplasia of Bone/McCune-Albright Syndrome: Best Clinical Practice and Future Research
Date: 3-5 October 2010
Venue: Bethesda, Maryland, USA

This conference will gather experts to develop a consensus on the best current medical and surgical treatment of fibrous dysplasia, MAS and Cherubism, to define areas of focus for future research, and to establish parameters for a registry/bio repository to aid research. Participants in the meeting include paediatric and adult orthopaedic specialists, cranio facial surgery, plastic surgery, endocrinology, and specialists in stem cells, microbiology and pathology from the USA, Israel, Italy, and Taiwan.
For further details

2nd European Rett Syndrome Conference
Date: 7-10 October 2010
Venue: Edinburgh, Scotland

Sessions include clinical and molecular update on MECP2 and Rett Syndrome; non coding RNAs & brain development; lessons from other diseases and other models; treatments and trials; outcome measures, international collaborations; and current perspectives and next steps.
For further details

15th International Congress of World Muscle Society
Date: 12-16 October 2010
Venue: Kumamoto, Japan

The main topics to be addressed include new therapeutic targets for neuromuscular disorders; congenital muscular dystrophies (celebrating the 50th anniversary of Fukuyama congenital muscular dystrophy); and distal myopathies and protein aggregation myopathies.
For further details

26th Annual Meeting of the Histiocyte Society
Date: 18–20 October 2010
Venue: Boston, Massachusetts USA

This year’s scientific programme will feature presentations by several experienced researchers regarding a variety of perspectives on the histiocytic disorders.
For further details


Press & Publications

Genetics in Medicine takes an in-depth look at patents for genetic testing
Genetics in Medicine, the journal of the American College of Medical Genetics, has published a special supplement devoted to the complex, often controversial subject of gene patenting and licensing. The free-access issue examines the case of gene patents and/or licenses for a number of rare disorders – including Tay Sachs and Canavan disease, spinocerebellar ataxia, long QT syndrome, cystic fibrosis, hearing loss, and inherited cancers- and examines various legal, economic, and ethical considerations. Particular attention is paid to how patents can either hinder or facilitate access to both genetic testing and research.
Consult the Genetics in Medicine supplement


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, Raphaël Demonchy, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Charlotte Rodwell, Paloma Tejada, Aurélie Vandeputte
National Contact Point: Till Voigtländer (Austria), Jean Jacques Cassiman (Belgium), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), Andres Metspalu (Estonia), Riitta Salonen (Finland), Manfred Stuhrmann (Germany), Michael Petersen (Greece), János Sándor (Hungary), Andrew Green (Ireland), Judith Melki (Israel), Bruno Dallapiccola and Domenica Taruscio (Italy), Andre Megarbane (Lebanon), Vaidutis Kucinskas (Lithuania), Alfred Cuschieri (Malta), Abdelaziz Sefiani (Morocco), Martina Cornel (Netherlands), Stein Are Aksnes (Norway), Jolanta Sykut-Cegielska (Poland), Jorge Sequeiros (Portugal), Dragica Radojkovic (Serbia), Ludovit Kadasi (Slovakia), Borut Peterlin (Slovenia), Miguel del Campo and Manuel Posada de la Paz (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Habiba Chaabouni-Bouhamed (Tunisia), Fatmahan Atalar and Ugur Ozbek (Turkey), Edmund Jessop and Idoia Gomez-Paramio (United Kingdom)
For more information on the Rare Diseases Task Force
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