15 October 2008 print
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The Eleventh European Health Forum Gastein considers the challenge of managing rare diseases
The eleventh European Health Forum took place in Gastein, Austria, from 1-4 October with sessions devoted especially to rare diseases. The first forum, Meeting the challenge: an opportunity for demonstrating European added value took the form of a panel discussion on several related themes: Integrating European initiatives with national activities reviewed EU-level initiatives for rare diseases, considered Romania as an example of the pertinence of national rare disease plans, and looked at the initiatives within the scope of the French presidency of the European Council. France is the only country in the world that has adopted a rare disease plan with a specific budget. France’s plan was adopted in 2004 with a budget of 100 million euros for a four-year period. Ten strategic objectives were delineated to meet the overriding aim of ensuring equitable access to rare disease diagnostics, care, and treatment: increasing knowledge; recognising rare diseases within the long-term disease framework of care; providing accurate information for patients and professionals; improving training for professionals; implementing a coherent screening policy; ameliorating access to treatment via centres of reference and via the availability of reimbursed orphan drugs; developing new products; meeting the accompanying needs of RD patients by linking various institutions and supporting patient groups; improving RD research by establishing a voluntary research policy; and coordinating partners at both the national and EU levels. France’s plan has been considered a model by several other countries and with France currently assuming the presidency of the European Union and thus extending its patronage to rare disease initiatives at the EU level, this is an ideal time to spotlight rare disease policies and patient needs across Europe. Several events are being held under the patronage of the French EU presidency.

The second forum, The need for patient centred efforts: centres of reference – equal access addressed the difficult issue of how to foster equitable access to rare disease care. Not every country (particularly smaller ones and those with limited resources) can have expertise for every rare disease. The role of European networks of centres of expertise is particularly relevant to rare diseases, as is the role of patient involvement. Improving professional and patient access to information and quality management is being developed by pilot projects such as ECORN-CF. Epidermolysis bullosa was presented as an example of the critical role networks of centres of expertise play in the field of rare diseases. Expert networking combined with skilled fundraising for this devastating rare genetic disorder resulted in a successful gene therapy trial. Recent developments, such as cross-border health care, need to be scrutinised to be rendered most effective for all players. Rare diseases, perhaps more than any other domain, need a collaborative effort between the 27 member states. The EU action in the field of rare diseases is intended to bring together the different elements in order to create an efficient strategy. The adoption of a European Commission Communication and proposal for a Council Recommendation (taking place in November 2008) will then require implementation, including the development of EU guidelines on many different aspects, the classification of diseases, an analysis of orphan drug bottlenecks, and many other actions.

The next subject to be tackled asked How to enforce the development of orphan medical products and how to fund them? Considering the various aspects of value, rarity, risk and pricing, a model developed by the EU High Level Pharmaceutical Forum’s Pricing and Reimbursement Working Group is sustainable because it is ultimately in the best interest of all society. Raising both public and policy maker awareness of the impact rare diseases have on patients and their entourage is critical in order to sustain the principle of solidarity that guides public opinion vis-a-vis orphan medicines.

Stakeholders are considering this year’s European Health Forum a success for that very reason: it enabled those who champion rare disease and orphan drug research, policies and funding to present the concerns and issues facing rare disease patients and professionals to key European health decision-makers.
Consult the European Health Forum rare disease presentations


Spotlight on...
Medting… An interactive online repository for sharing medical images and clinical data

Spain-based Medting is following the growing trend of pooling information and technology in the field of medicine and research to avoid duplication and to share and disseminate expertise internationally. These collaborative efforts are especially critical to the field of rare disease research, an area hampered by the dispersal of both knowledge and patient populations. Medting brings to the table a repository for medical images and clinical cases that can be exchanged freely amongst professionals via a secured website. This unique initiative, founded by Miguel Cabrer, an independent e-health advisor who formerly coordinated e-health for the Balearic Islands Health Service, allows registered clinicians to post their cases along with associated images and videos on the Medting website. The website then allows professionals to view and discuss posted cases, make references to experts in the field, and share their own knowledge in a secure, private and closed community. No personal patient details of clinical cases or images are accepted, assuring privacy and confidentiality. Medting can be used by individual health professionals, hospital teams, or between groups of hospitals. An interesting feature is the potential for non-profit medical services working abroad to use the service, as well as developing countries that may lack expertise in particular fields. The site employs Snomed CT (Systematized Nomenclature of Medicine - Clinical Terms) terminology to ensure uniformity and to allow harmonised translation between different languages. Cases and images/videos are tagged with SNOMED keywords chosen by the clinician that allow for fast search from the repository. Uploaded images can be made available to the whole public or rendered private, accessible to a specific group of persons. A group that seeks to work on a specific illness or procedure can create a private group on Medting, which can also serve as a central coordinating platform to which clinicians post samples while using a general information website (external to Medting) to which those samples could be linked.

Medting, which debuted in March 2008, is offered free of charge. Premium users (also a free service) can use Medting to create private cases and conduct Telemedicine. This service could be especially useful for rare disease experts, who could create an expert network and offer second opinions to generalist or non specialised physicians. Development of the initiative was funded by parent company C2C, an organisation specialised in Health IT development, particularly medical imaging integration. Organisations that may want to create their own personal Medting via their intranet, can purchase an Enterprise Partnership License, which also allows online meetings (virtual clinical sessions) to be held. Medting Enterprise is one source of funding for the initiative. Medting is also developing an innovative advertising scheme that would serve to sustain the website but could also benefit non-profit organisations by providing a source of funding. In addition, Medting is seeking investors as a means of sustaining funding and development.

Medting is integrated with PubMed. When reviewing a clinical case or resource (image or video) with keywords assigned, Medting performs a search of PubMed citations. The results of the newest articles are displayed.

Medting receives 1000 visitors per day and presently has 1500 registered users, from an array of countries, including the USA, Switzerland, UK, India, Mexico, Colombia, Argentina, and Spain. Institutions such as the Geneva University Hospital, the Mayo Clinic, and the Catalunya Health Region are amongst users. Medting has been proposed as a base platform for several clinical R&Ds. The repository currently has 1800 cases and 15,000 images and videos posted on the site. Medting is an ideal platform to concentrate rare disease cases for patients searching on the internet and then, through the user profile, to redirect the patient to the appropriate website. All the Medting content related to a specific rare disorder could be shown from an external website (a rare disease association, for example) by using the Medting connectors.

The site has the added value of serving as an educational tool for medical universities and training programmes. Medting aims to help medical students learn about rare cases and expert opinions on such cases.

EU Policy News
Communication guides market exclusivity period review for orphan drugs
The European Medicines Agency has published a communication from the European Commission providing guidance on the application of Article 8(2) of the Orphan Medicinal Products regulation (EC No 141/2000). The guideline reviews the principles that determine the period of market exclusivity granted to orphan medicinal products, in particular the procedures that reduce the period of exclusivity from ten years to six. This may occur when the designation criteria (set out in Article 3 of the Orphan Drug regulation) are no longer met. Orphan medicine products are not systematically reviewed to determine whether market exclusivity is still applicable. Rather, a review is made following the report of information from a Member State (MS) country in the case when a country has evidence that a specific product no longer meets the designation criteria for orphan status. In such circumstances, MS are obliged to inform the EMEA that the product no longer fulfils criteria for orphan designation. Following such an alert by a MS, the COMP undertakes a review of the product and issues an opinion as to whether market exclusivity should be maintained or reduced.

National & International Policy Developments
Vive la France! Sarkozy agrees to renew national rare disease plan
French President Nicolas Sarkozy confirmed the renewal of the country’s rare disease national plan during a European symposium on rare disorders taking place in Paris on 10 October. The Gallic leader stated that the particulars of the plan will be ironed out in 2009 and enter into action by 2010 at the latest. He mentioned continuing funding for the designated rare disease centres of reference, of which France presently has 132. The current rare disease plan, which came into being in 2005, is due to expire at the end of this year. President Sarkozy also declared his support for the EC Communication on rare diseases, considering it a priority under the French presidency of the EU.
German pharmaceutical association deplores second procedure added to orphan drug reimbursement assessment
The German Joint Federal Committee (G-BA) has taken the decision to add an additional procedure for assessing orphan drug reimbursement policy. The German Pharmaceutical Industry Association (BPI) condemns the decision, worried that it will lead to delays in access to medicines. In a news article, a BPI representative expressed concern, evoking the possibility of hospitalised patients treated with orphan medicines losing access upon their release to out-patient status. As many orphan drugs require sustained ongoing treatment, delays or refusals when a patient moves to an out-patient setting could undo any benefits a medicine may have established. The decision was also criticised for the method used to select products for re-assessment.
USA considers impact of expanded newborn screening programme
The 17 August 2007 edition of OrphaNews Europe reported a March of Dimes assessment of newborn screening practices in the USA. The American College of Medical Genetics currently recommends newborn screening for 29 disorders. To date, 21 states and the District of Columbia have fully implemented these recommendations. Other states include varying numbers of disorders in their newborn screening programmes. A recent study published in the Centers for Disease Control Morbidity and Mortality Weekly Report estimates the number of infants who would have been identified with disorders – most of which are rare and have improved outcome when early detection is achieved - if the recommendations were implemented in all US states. The study found that detection would increase by 32% (from 4370 to 6439) and that “these children would have had many rare disorders that require local or regional capacity to deliver expertise in screening, diagnosis, and management. The findings underscore the need for public health …to build or expand the programs required to manage the rare disorders detected through expanded newborn screening, while also continuing programs to address more common disorders.”
Consult the study

USA passes act requiring current information for parents receiving prenatal and postnatal disorder diagnoses
In the USA, bill S.1810 was passed in late September, requiring health professionals to furnish parents who receive a pre- or post-natal diagnosis for Down syndrome and other disorders with current, evidence-based information. The Prenatally and Postnatally Diagnosed Conditions Awareness Act seeks to “increase patient referrals to providers of key support services for women who have received a positive diagnosis for Down syndrome, or other prenatally or postnatally diagnosed conditions, as well as to provide up-to-date information on the range of outcomes for individuals living with the diagnosed condition, including physical, developmental, educational, and psychosocial outcomes”. Advocacy groups, including the National Down Syndrome Society, lobbied for three years to bring the bill to passage.
Consult bill S.1810

Other European news
Upcoming conference targets rare tumours in Europe
The European Society for Medical Oncology (ESMO) is hosting the conference Rare Tumors in Europe: Challenges and Solutions on 6 November 2008 in Brussels. Keynote speakers include Androulla Vassiliou, EU Commissioner for Health, and Roselyne Bachelot, French Minister of Health. The scientific agenda includes sessions exploring Methodological and Regulatory Challenges, Organisational Challenges, Patient Access Challenges, and Addressing Gaps in Rare Tumor Treatments in Europe. The conference will conclude with a plenary session consisting of panel discussions devoted to the topic of EU action in the field and will include perspectives from industry, patients, and policy makers. For further information

Ethical, Legal & Social Issues
Portuguese recommendations on commercial use of genetic tests now available in English
The 6 August 2008 issue of OrphaNews Europe reported on recommendations developed in Portugal concerning the commercial use of genetic tests, including direct-to-consumer tests. These include the opinion that genetic tests for health-related purposes must not be offered directly to the public. Non-medical applications of genetic testing must follow the same requirements of quality assurance, transparency of claims and loyal advertising, if they are to be sold directly to consumers. The recommendations, developed by the Portuguese National Council of Ethics for the Life Sciences, are now available in English language.
Study of international genetic testing practices concludes that compatible accreditation and OECD guidelines need applying
The recently published study, Molecular genetic testing in the United States: comparison with international practice compares practices between 19 different countries. The study identified differences between professional qualifications, tests on offer, and laboratory settings. However, similarities were also revealed, including adherence to quality standards. The study also documented transborder flow of specimens, usually due to a local lack of test availability. The authors conclude that recently-developed OECD guidelines could be applied and that compatible accreditation programmes would enhance quality and clinical validity.
Read the PubMed abstract

Defining ideal genetic counselling: an international survey
A recently-published article compares international guidelines for genetic counselling and sifts out the most important elements. A survey of some 56 collected documents revealed that appropriately trained professionals, relevant and objective information, mechanisms to assure patient understanding, psychological support, informed consent, confidentiality, and familial implications figured repeatedly amongst the elements contributing to "ideal" genetic counselling.
Read the PubMed abstract


Orphanet News
New Texts
New Orphanet Journal of Rare Diseases Publications
Transposition of the great arteries


New Syndromes
Maternally inherited mental retardation dysmorphism syndrome caused by mutation in the genomically imprinted potassium channel
The authors describe a maternally transmitted genomic-imprinting syndrome of mental retardation, hypotonia, and unique dysmorphism with elongated face. They mapped the disease-associated locus to approximately 7.27 Mb on chromosome 8q24 and demonstrated that the disease is caused by a missense mutation in the maternal copy of KCNK9 within this locus. KCNK9 is maternally transmitted (imprinted with paternal silencing) and encodes a member of the two pore-domain potassium channel subfamily. The mutation fully abolishes the channel currents.
Read the PubMed abstract

Am J Hum Genet ; 193-199 ; August 2008

New Genes
Infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency: FASTKD2 nonsense mutation identified
For two siblings presenting mitochondrial encephalomyopathy, characterised by developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low cytochrome c oxidase (COX) activity in skeletal muscle, the authors identified a homozygous nonsense mutation in the KIAA0971 gene. The corresponding protein, FASTKD2 appears to play a role in mitochondrial apoptosis.
Read the PubMed abstract

Am J Hum Genet ; 415-423 ; September 2008
Spondylocostal Dysostosis: mutation of HES7 at cause
Spondylocostal dysostosis (SCD) is an inherited disorder characterised by the presence of extensive hemivertebrae, truncal shortening, and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites (the precursor tissue of the vertebrae, ribs, and associated tendons and muscles). Previously, three genes causing a subset of autosomal recessive forms of this disease have been identified: DLL3, MESP2, and LFNG. These genes are all important components of the Notch signalling pathway, which has multiple roles in development and disease. Here the authors used autozygosity mapping to identify a mutation in a fourth Notch pathway gene, HES7, in an autosomal recessive SCD family. HES7 encodes a protein that is both a direct target of the Notch signalling pathway, and part of a negative feedback mechanism required to attenuate Notch signalling. A missense mutation was identified in the DNA-binding domain of the HES7 protein.
Read the PubMed abstract

Hum Mol Genet ; Epub ahead of print ; 5 September 2008

Research in Action
Fundamental Research
Chronic lymphocytic leukaemia: a genome-wide association study identifies six susceptibility loci
The authors conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totalling 1,529 cases and 3,115 controls. They identified six previously unreported CLL risk loci. These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.
Read the PubMed abstract

Nat Genet ; 1204-1210 ; October 2008
Huntington disease: phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons
Huntingtin, the protein mutated in Huntington disease, is a positive regulatory factor for vesicular transport whose function is lost in disease. Here, the authors demonstrate that phosphorylation of huntingtin at serine 421 (S421) restores its function in axonal transport. Using a strategy involving RNA interference and re-expression of various constructs, the authors show that polyQ-huntingtin is unable to promote transport of brain-derived neurotrophic factor (BDNF)-containing vesicles, but polyQ-huntingtin constitutively phosphorylated at S421 is as effective as the wild-type as concerns transport of these vesicles. This study also shows that the IGF-1/Akt pathway by promoting huntingtin phosphorylation compensates for the transport defect. This is the first description of a mechanism that restores the huntingtin function altered in disease.
Read the PubMed abstract

Hum Mol Genet ; Epub ahead of print ; 4 September 2008
Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome linked to neuronal complex I defect
Infantile-onset spinocerebellar ataxia (IOSCA) is a severe neurodegenerative disorder caused by the recessive mutation in PEO1, leading to a Y508C change in the mitochondrial helicase Twinkle, in its helicase domain. However, no mitochondrial dysfunction has been found in this disease. The authors studied the consequences of IOSCA for the central nervous system, as well as the in vitro performance of the IOSCA mutant protein. The results of the mtDNA analyses were compared to findings in a similar juvenile or adult-onset ataxia syndrome, mitochondrial recessive ataxia syndrome (MIRAS), caused by the W748S mutation in the mitochondrial DNA polymerase (POLG). The authors show that IOSCA brain does not harbour mtDNA deletions or increased amount of mtDNA point mutations, whereas MIRAS brain shows multiple deletions of mtDNA. However, IOSCA, and to a lesser extent also MIRAS, show mtDNA depletion in the brain and the liver. In both diseases, especially large neurons show respiratory chain complex I deficiency, but also CIV is decreased in IOSCA. Helicase activity, hexamerization and nucleoid structure of the IOSCA mutant were, however, unaffected. The lack of in vitro helicase defect or cell culture phenotype suggest that Twinkle-Y508C dysfunction affects mtDNA maintenance in a highly context and cell-type specific manner. These results indicate that IOSCA is a new member of the mitochondrial DNA depletion syndromes.
Read the PubMed abstract

Hum Mol Genet ; Epub ahead of print ; 5 September 2008
Smith-Lemli-Opitz syndrome: ABCA1 is a potential target for in utero therapy
Patients with Smith-Lemli-Opitz syndrome (SLOS) are born with multiple congenital abnormalities. Postnatal cholesterol supplementation is provided; however, it cannot correct developmental malformations caused by in utero cholesterol deficit. Increased transport of cholesterol from maternal to foetal circulation might attenuate congenital malformations. Treatment of pregnant C57Bl/6 female mice with TO901317, an LXR-agonist, increased maternal-foetal cholesterol transfer to the foetus. In a SLOS mouse model, which is incapable of de novo synthesis of cholesterol, in utero treatment with TO901317 resulted in increased cholesterol content in embryos.
Read the PubMed abstract

Hum Mol Genet ; Epub ahead of print ; 5 September 2008
Down syndrome: DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate
Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are shared between DS individuals and DS mouse models; however, the common underlying molecular pathogenetic mechanisms remain unclear. Using a transchromosomic model of DS, the authors show that a 30%-60% reduced expression of Nrsf/Rest (a key regulator of pluripotency and neuronal differentiation) is an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain and is reproducible across several DS models. Their study reveals that undifferentiated trisomy 21 ES cells show DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping recently reported downstream effects of Rest +/-. These results suggest that deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to DS pathology and new rationales for therapeutic approaches.
Read the PubMed abstract

Am J Hum Genet ; 388-400 ; September 2008
Systemic juvenile idiopathic arthritis: macrophage activation syndrome is associated with MUNC13-4 polymorphisms
Systemic juvenile idiopathic arthritis (JIA) is associated with macrophage activation syndrome. Macrophage activation syndrome bears a close resemblance to familial hemophagocytic lymphohistiocytosis (HLH). The development of familial HLH has been recently associated with mutations in MUNC13-4. This study assessed sequence alterations in MUNC13-4 in 18 patients with systemic JIA/macrophage activation syndrome. The biallelic sequence variants in MUNC13-4 reported in familial HLH were present in 2 of the 18 patients with JIA/macrophage activation syndrome. Further analysis of the MUNC13-4 sequences revealed an identical combination of 12 single-nucleotide polymorphisms (SNPs) in 9 of the remaining 16 patients with systemic JIA/macrophage activation syndrome.
Read the PubMed abstract

Arthritis Rheum ; 2892-2896 ; September 2008
Clinical Research
Cutaneous adult T-cell leukemia/lymphoma: should cutaneous and smoldering types be considered as distinct entities?
Adult T-cell leukemia/lymphoma (ATLL) has been divided into four subtypes up to now: (i) acute; (ii) lymphoma; (iii) chronic; and (iv) smoldering. Skin lesion(s) may be present and the cases showing less than 5% abnormal T-lymphocytes in peripheral blood without involvement of other organs, have been classified as smoldering ATLL. However, this type of ATLL with skin manifestations had a worse prognosis than that without skin lesions. This study aimed to define and distinguish cutaneous ATLL lacking nodal lymphoma and leukemic change from smoldering ATLL. Blood samples were collected from 41 HTLV-1-infected patients, 21 asymptomatic carriers, 16 patients with cutaneous ATLL and four patients with smoldering ATLL. HTLV-1 proviral loads, soluble interleukin-2 receptors and other parameters were examined in each case. HTLV-1 proviral DNA loads in smoldering ATLL group are significantly higher than those in asymptomatic carrier and cutaneous ATLL group. Cutaneous ATLL may be a distinct entity that should be separated from smoldering ATLL clinically and virologically.
Read the PubMed abstract

J Dermatol ; 270-275 ; May 2008
Hereditary cystatin C amyloid angiopathy: a drastic reduction in the life span of Icelandic carriers due to life-style changes
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, characterised by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in cystatin C, with contemporary carriers reaching an average age of only 30 years. Here, the authors report that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born from 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period.
Read the PubMed abstract

PLoS Genet ; e1000099 ; 20 June 2008
Cerebro-oculo-facio-skeletal syndrome: 3 more cases with CSB mutations and new diagnostic criteria
Cerebro-oculo-facio-skeletal syndrome (COFS syndrome) is an autosomal recessive disorder initially described in a specific aboriginal population from Manitoba. In recent years, COFS syndrome has been linked in this original population to a defective DNA repair pathway and to a homozygous mutation in the major gene underlying Cockayne syndrome (CSB ). However, most reports of suspected COFS syndrome outside this population have not been confirmed at the molecular level, leading to considerable heterogeneity within the syndrome and confusing overlaps between COFS syndrome and other eye and brain disorders. The authors report the exhaustive clinical, cellular and molecular data of three unrelated COFS patients with mutations in the CSB gene. All three patients present the cardinal features of COFS syndrome including extreme microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. They also exhibit a predominantly postnatal growth failure, a severe psychomotor retardation, axial hypotonia and peripheral hypertonia, and neonatal feeding difficulties. Fibroblasts from the patients show the same DNA repair defect which can be complemented by transfection of the CSB wild-type cDNA. Five new mutations in the CSB gene have been identified in these patients. These data indicate that COFS syndrome represents the most severe end of the Cockayne spectrum. New diagnostic criteria for COFS syndrome are proposed.
Read the PubMed abstract

J Med Genet ; 564-571 ; September 2008
The QT syndromes: the long and short of them
This text provides most recent information about the congenital long and short QT syndromes, emphasising the varied genotype-phenotype association in the ten different long QT syndromes and the five different short QT syndromes. Although uncommon, these syndromes serve as a Rosetta stone for the understanding of inherited ion-channel disorders leading to life-threatening cardiac arrhythmias. Ionic abnormal changes mainly affecting K(+), Na(+), or Ca(2+) currents, which either prolong or shorten ventricular repolarisation, can create a substrate of electrophysiological heterogeneity that predisposes to the development of ventricular tachyarrhythmias and sudden death. The understanding of the genetic basis of the syndromes is hoped to lead to genetic therapy that can restore repolarisation. Presently, symptomatic individuals are generally best treated with an implantable cardioverter defibrillator. Clinicians should be aware of these syndromes and realise that drugs, ischaemia, exercise, and emotions can precipitate sudden death in susceptible individuals.
Read the PubMed abstract

Lancet ; 750-763 ; 30 August 2008
Brugada syndrome: recent advances and controversies
The Brugada syndrome, first described as a new clinical entity in 1992, is widely recognized today as a form of inherited sudden cardiac arrest. The past 16 years witnessed a progressive increase in the number of reported cases and a dramatic proliferation of articles serving to define the clinical, genetic, cellular, ionic, and molecular aspects of the disease. This article provides a brief overview of recent advances in understanding of the clinical presentation and molecular and cellular mechanisms and an update of existing controversies.
Read the PubMed abstract

Curr Cardiol Rep ; 376-383 ; September 2008
Gene Therapy
Late infantile neuronal ceroid lipofuscinosis: survival advantage of neonatal CNS gene transfer
Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). In this study, the authors administered AAVrh.10hCLN2 to the neonatal brain. Results showed markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk-treated mice, 168 days for 7 wk-treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.
Read the PubMed abstract

Exp Neurol ; 18-27 ; September 2008
Therapeutic Approaches
Burkitt lymphoma: a study of dose-modified CODOX-M/IVAC in patients defined using cytogenetic and immunophenotypic criteria
This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma, applicable to routine practice, and to evaluate the efficacy of dose-modified CODOX-M/IVAC in 128 patients diagnosed using these criteria.
Read the PubMed abstract

Blood ; 2248-2260 ; 15 September 2008
Cystic fibrosis: effectiveness of PTC124 treatment in cases caused by nonsense mutations
In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.
Read the PubMed abstract

Lancet ; 719-727 ; 30 August 2008
Paediatric acute lymphoblastic leukaemia: bone-marrow relapse
Marrow relapse is the major obstacle to cure for 10-15% of young patients with acute lymphoblastic leukaemia (ALL). Recent investigations into the biology of minimal residual disease indicate that many early relapses derive from residual cells present at first diagnosis, but some late relapses might represent new mutations in leukaemic cells not eliminated by conventional therapy. Treatment of marrow relapse involves higher doses and more intensive schedules of the drugs used for initial therapy with or without haemopoietic stem cell transplantation. In most reports, transplantation is better than continuation chemotherapy in early marrow relapse, but its role in later relapse is less clear. Current therapy cures 10% of patients with early marrow relapses and 50% of those with late relapses, but outcomes have changed little in the past two decades. Understanding the molecular biology of ALL underlies development of improved risk stratification and new therapies. Although better drugs are needed, introduction of new agents into clinical trials in paediatric disease has been difficult. Innovative trial designs and use of valid surrogate endpoints may expedite this process.
Read the PubMed abstract

Lancet Oncol ; 873-883 ; September 2008
Diagnostic Approaches
Lynch syndrome: comparison of predictive models, clinical criteria and molecular tumour screening in a population-based cohort
Hereditary nonpolyposis colorectal cancer (HNPCC) (also known as Lynch syndrome) is the most frequent form of hereditary colorectal cancer. Several models have recently been developed to predict mismatch repair (MMR) gene mutations. Their comparative performance with clinical criteria or universal molecular screening in a population based colorectal cancer (CRC) cohort has not been assessed. In this study, all 1222 CRC from the EPICOLON cohort underwent tumour MMR testing and those with MMR deficiency underwent MLH1/MSH2 germline testing. Sensitivity, specificity and positive predictive value of the PREMM(1,2) and the Barnetson models for identification of MLH1/MSH2 mutation carriers were evaluated and compared with the revised Bethesda guidelines (RBG), Amsterdam II criteria, and tumour analysis for MMR deficiency. The PREMM(1,2) and the Barnetson models offer a quantitative systematic approach to select CRC patients for identification of MLH1/MSH2 mutation carriers with a similar performance to the RBG.
Read the PubMed abstract

J Med Genet ; 557-563 ; September 2008
Pompe disease: newborn screening by measuring acid alpha-glucosidase activity using tandem mass spectrometry
Pompe disease, caused by the deficiency of acid alpha-glucosidase (GAA), is a lysosomal storage disorder that manifests itself in its most severe form within the first months of life. Early detection by newborn screening may be considered, since prompt initiation of enzyme replacement therapy may improve morbidity and mortality. The authors evaluated a tandem mass spectrometry (MS/MS) method to measure GAA activity for newborn screening for Pompe disease. They found that the measurement of GAA activities in dry blood spots using MS/MS is suitable for high-throughput analysis and newborn screening for Pompe disease.
Read the PubMed abstract

Clin Chem ; 1624-1629 ; October 2008
Noonan syndrome: PTPN11 analysis for prenatal diagnosis in foetuses with abnormal ultrasound findings
Noonan syndrome (NS) is an autosomal dominant disorder characterised by short stature, congenital heart defects and distinctive facies. The disorder is genetically heterogeneous with approximately 50% of patients having PTPN11 mutations. Prenatally, the diagnosis of NS is suspected following certain ultrasound findings, such as cystic hygroma, increased nuchal translucency (NT) and hydrops fetalis. A retrospective review was performed to assess the utility of PTPN11 testing based on prenatal sonographic findings. The most commonly reported indications for testing were increased NT and cystic hygroma. Analysis showed heterozygous missense mutations in 12 foetuses, corresponding to a positive test rate of 9%. PTPN11 mutations were identified in 16% and 2% of foetuses with cystic hygroma and increased NT, respectively. Among foetuses with isolated cystic hygroma, PTPN11 mutation prevalence was 11%. Prenatal PTPN11 testing has diagnostic and possible prognostic properties that can aid in risk assessment and genetic counselling.
Read the PubMed abstract

Clin Genet ; Epub ahead of print ; 26 August 2008

Patient Management and Therapy
Primary aldosteronism: detection, diagnosis, and treatment
The authors of this review article recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia, by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. They also recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. Furthermore, they recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. Finally, they recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.
Read the PubMed abstract

J Clin Endocrinol Metab ; 3266-3281 ; September 2008
Diamond Blackfan anaemia: diagnostics and treatment recommendations from an international clinical consensus conference
Diamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are reviewed in this article. Evidence-based conclusions are made when possible. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.
Read the PubMed abstract

Br J Haematol ; Epub ahead of print ; 30 July 2008

Orphan Drugs
Positive CHMP opinion for Kuvan (sapropterin dihydrochloride) for hyperphenylalaninaemia in adults and children with PKU
The Committee for Medicinal Products for Human Use (CHMP ) has recommended marketing authorisation for Kuvan (sapropterin dihydrochloride), from Merck KGaA, for the treatment of hyperphenylalaninaemia in adult and paediatric patients of 4 years of age and over with phenylketonuria (PKU). Kuvan is also indicated for the treatment of hyperphenylalaninaemia in adult and paediatric patients with tetrahydrobiopterin deficiency. Kuvan is the 49th orphan medicine to receive a positive opinion by the CHMP. EMEA review began on 23 November 2007 with an active review time of 200 days.
Obtaining optimal sample sizes in rare disease clinical trials
A recent article in the Journal of Clinical Epidemiology provides design options for obtaining statistically valid results in paediatric clinical trials limited by the rarity of certain conditions as well as ethical considerations. The authors of this study conclude that well-designed research can optimise the number of subjects in a trial involving vulnerable populations and that several possibilities to do so exist. Read the PubMed abstract

First Myotubular Trust call for proposals now open
The Myotubular Trust was founded as a charity in 2006 to raise money for research toward a cure and/or treatment for myotubular myopathy. There are three genetically distinct forms of myotubular myopathy. The most common and severe form is x-linked. It usually presents in the newborn period and is characterised by breathing and swallowing difficulties in addition to general muscle weakness. The other forms, either dominant or recessive in inheritance, are usually milder and vary widely.
The Myotubular Trust announces its first call for proposals for research projects focusing on research that would not generally be funded by public or industrial funding sources. This call will be open to European research bodies only. Applications may be made for:

1. Project grants - Applications will be considered from the Principal Investigator for projects of 2-3 years duration to be carried out by a Post Doctoral researcher, or PHD student
2. A Myotubular Trust fellowship, non-clinical - Applicants will have identified a host institution and will be undertaking a basic science project of 3-4 years duration

The Trust may be willing to fund the continuation of an existing research project (not a project that is already being funded by another body). Completed applications are due 19 December 2008. Awards will be made in April 2009.
For further information
For email enquiries


Partnersearch, Job Opportunities
Medical doctor specialised in molecular genetics
The Molecular Genetic Center of the Hospital-University of Montpellier (France) has an opening for a physician specialised in molecular genetics with a strong background in human genetics including laboratory diagnosis and research. The selected candidate will receive a contract of at least one year that may be followed by a permanent position. The selected candidate will be proficient in English and French (or capable of attaining proficiency in French with reasonable notice). For more information or to submit applications (CV, cover letter, references) contact Pr. Mireille Claustres
UCL Institute for Child Health - Dubowitz Neuromuscular Centre has several positions available
The Dubowitz Neuromuscular Centre (part of the UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust) provides a multidisciplinary service as a leading clinical and research centre specialising in neuromuscular disorders affecting children, including clinical trials, basic research focusing on understanding the cause of neuromuscular diseases in childhood and identifying novel therapeutic intervention. The Centre, commissioned to provide national specialist diagnostic and assessment service for congenital muscular dystrophies and congenital myopathies, has the following openings:

Clinical Scientist – muscle pathology: This is a tenured position to complement the diagnostic activities of the centre and promote research and development projects, mainly in the area of the diagnostic work commissioned by the National Commissioning Group, on congenital muscular dystrophies and congenital myopathies.
Clinical trial coordinator: In collaboration with the adult centre for neuromuscular disorders, at the Institute of Neurology, a nurse trial coordinator is needed to support ongoing clinical trial activities. This position is for 3 years and available immediately.
Research physiotherapist: In collaboration with the Institute of Neurology, a research physiotherapist position is available immediately for a 3-year period.
Postdoctoral position – genetic basis of congenital myopathies: This is an 18 month project – the position is available immediately.
For formal enquiries please contact Pr. Francesco Muntoni or Ms Janet Nicholas


What's on Where?
First Congress of the African Society for Immunodeficiencies
Date: 30 October-1 November 2008
Venue: Casablanca, Morocco

Organised by the African Society for Primary Immunodeficiencies in conjunction with the Moroccan Societies for Paediatrics and for Haematologies, themes to be explored during this congress include primary immunodeficiencies (PIDS) and the skin; PIDs and the lungs; PIDs and the adult patient; PIDS and lymphomas; PIDs and nutrition; and PIDs and vaccines.
For further information

ESF-UB Conference in Biomedicine: Biobanks
Date: 1-6 November 2008
Venue: Sant Feliu de Guixols, Spain

The ESF-UB Conference on Biobanks will be focused on providing an open forum of discussion on all aspects involved in the governance, management and use of human biobanks, technical solutions, ethical, legal, and social aspects, also providing participants with a broad overview of the existing models of biobanks and the international initiatives on population-based and disease-oriented biobanks. A limited number of grants are available for young researchers to cover the conference fee and possibly part of the travel costs.
For further details

Rare Tumors in Europe: Challenges and Solutions
Date: 6 November 2008
Venue: Brussels, Belgium

The European Society for Medical Oncology (ESMO) is hosting Rare Tumors in Europe: Challenges and Solutions. The scientific agenda includes sessions exploring Methodological and Regulatory Challenges, Organisational Challenges, Patient Access Challenges, and Addressing Gaps in Rare Tumor Treatments in Europe. The conference will conclude with a plenary session consisting of panel discussions devoted to the topic of EU action in the field and will include perspectives from industry, patients, and policy makers.
For further details

The Ethics of Gene Therapy of Inherited Diseases
Date: 13 November 2008
enue: Brugges, Belgium

Considers ethical perspectives of gene therapy and risk management, amongst other related topics .
For further details

International Symposium on Rare Diseases: Inherited Neuromuscular Disease - Translation from Pathomechanisms to Therapies
Date: 16-18 November 2008
Venue: Valencia, Spain

The symposium will permit exploration of the state-of–the-art of neuromuscular diseases as a whole, including muscular dystrophies, mitochondrial disorders, peripheral neuropathies, spinal muscular atrophy, motoneurone disease and Friedreich ataxia, and will explore pathogenic mechanisms and molecular targets for the different diseases, as a forum for discussion of the rational basis of the new therapeutic approaches.
For further details

Strategies and National Plans for Rare Diseases in Europe: Towards Common Recommendations
Date: 18 November 2008
Venue: Paris, France

Mark your agenda for this important conference, taking place under the French presidency of the European Union, and examining the initiatives of individual member states and the EU Council recommendations for national rare disease plan development.
Details to follow shortly.

From Cardiac Remodelling to Biotherapies: Homage to Ketty Schwartz
Date: 29 November 2008
Venue: Paris, France

The programme will include cardiac phenotype and remodelling in cardiopathies; genetics and pathophysiology of cardiac diseases; and therapies of cardiac and skeletal muscle diseases.
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

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
Good news for German readers…rare diseases once more the focus of German-language publication
A series of articles considering rare diseases and orphan drugs has been published in German-language review Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz (Federal health sheet, Health research, Health protection). Rare disease in professional health care considers the aspect of uncertainty in diagnosing and treating patients with uncommon disorders, particularly as it impacts the risk/benefit ratio of treatments. The article reviews how Germany’s Federal Social Court and Federal Court of Justice assess medicinal products with small trial populations. European incentives for orphan medicinal products delineates the criteria for obtaining orphan designation and reviews issues linked to pricing for orphan drugs. Registries for rare diseases. Compliance and data protection evaluates registries in Germany and discusses efficient ways to establish registries and research networks for rare diseases within the framework of data protection regulations. Rare diseases. Funding programs in Germany and Europe presents an overview of rare disease funding schemes in Germany, provides examples of schemes of other countries within Europe and the European Commission, as well as research networks. The article demonstrates similarities and differences between funding programs. Most funded research takes a bottom up approach. The translation of basic knowledge into clinical benefit is slow. Low prevalence and geographic dispersion lead to infrastructural deficits. While France, Germany, Italy and Spain have implemented specific rare disease research programs that support networking of scarce resources and to stimulate interdisciplinary collaborations, other countries fund rare disease research within the context of general programs. Another article, Quality of life of young patients with haemophilia in Europe describes clinical aspects of haemophilia as well as the assessment of quality of life and proceeds to introduce two recent studies on quality of life of children and adolescents with haemophilia in Europe. Finally, the article, Rare infectious diseases in Germany. Obligatory notification results evaluates the current system of registering rare infectious diseases in the country. This series offers a unique window to consider rare disease and orphan drug policies in Germany.
New books
Providing an overview of recent findings on the neurofibromatoses, including genetics and molecular biology findings, clinical features, diagnostics and treatment.
Author: Dieter Kaufmann, -ed.
Publisher: S. Karger, AG
ISBN: 978-3-8055-8520-0

Stem Cells and Regenerative Medicine
Considers the latest advances in stem cell biology.
Author: Walter C. Low and Catherine M. Verfaillie, -eds.
Publisher: World Scientific Publishing Co.
ISBN: 978-981-277-576-4


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, Lucile Abdennaji, Catherine Berens, Olaf Bodamer, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, 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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