29 October 2008 print
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While we all love Paris in the springtime, the rare disease community also found autumn in Paris pretty fantastic this year!

Rare disease stakeholders undertook a whirlwind of activity as three back-to-back rare disease events were held earlier this month in Paris under the patronage of the French Presidency of the European Union. The first, the European Symposium on Rare Diseases, notably contained an affirmation from French President Nicolas Sarkozy that France would renew its expiring national rare disease plan. The French plan is the sole in the world with a specific budget allocated. Its four year term comes to an end this year. President Sarkozy confirmed that the new plan would enter into action by 2010 at the latest, following a period of reappraisal and reprioritisation. At the European level, the President expressed support for the EC Communication, Rare Diseases: Europe’s Challenges, indicating that under the current patronage of the French EU Presidency the contents of this vital document would receive priority status. The Symposium featured presentations from rare disease experts on the performance of the French rare disease plan – considered a model by many other countries. At the European level, recent advances and perspectives in the field were presented and the benefits of European orphan drug regulation were reviewed. Other sessions of the day-long event emphasised the value of European rare disease and orphan drug research; considered the need for pan-European organisation for managing patient needs; and reiterated the crucial role patient organisations play in forwarding rare disease initiatives.

The next event, European Health at the Service of Patients, took place at the Institut Pasteur in Paris, and featured presentations on improving access to diagnostics and quality healthcare. Invited speaker Terkel Andersen (Eurordis), emphasised that there could be no equal rights for patients without EU-level collaboration. The session also brought home the point that individual Member States need to commit to sharing resources. Shared expertise can foster harmonised standards of care – considered critical in view of the rarity of disorders and the dispersion of expertise. A key discussion considered how the rare disease community could access primary care physicians to furnish them with resources to help determine when and where to refer rare disease patients. Orphanet, with its roster of partners in all 27 EU Member States (and beyond), was evoked as the leading example of successful pan-European collaboration.

Next, it was off to the European Platform for Patients’ Organisations, Science and Industry (EPPOSI ) workshop taking place at the Assemblée Nationale. The workshop, now in its ninth year, was hosted by the French deputies representing the country’s working group for rare diseases within the French government. The theme of the workshop was Partnering along the chain and across the borders: Sharing strategies and tools for access to diagnosis and treatment. Several topics came under fiery debate during the two day event: The first considered whether permissive off-label practices hinder drug development for specific indications. France, for example, under Article 56 of its national social security law that specifies the reimbursement of non-medicinal treatment products (nutritional supplements, special skin creams, et cetera), also allows for reimbursement of the off-label use of medicinal products when no other treatment exists. But in the long-term do these compassionate policies discourage the development of products created and tested for a specific indication currently treated off-label?

Another debate centred on the current procedures for appraising clinical added-value for products that have received marketing authorisation. This procedure, used to determine pricing, presently takes place at the Member-State level and is enormously heterogeneous and often lengthy, resulting in a lack of equitable access between countries. The point was made that the orphan drug regulation was created to boost patient access to treatments, but this bottleneck at the end of the process is hindering treatment availability.

Another pertinent point arose around the transparency of clinical trials. EudraCT , the database of all clinical trials commencing in the EU from May 2004 onwards is inaccessible to the public. It was suggested that Europe needs an open-access model similar to the USA-based ClinicalTrials.gov registry.

The Epposi workshop yielded a bounty of reflections, concerns and some suggestions which, if taken up, give participants some real homework to complete:

Patient groups called for European-level funding for the reimbursement of orphan medicinal products. Eurordis leader Yann Lecam echoed the need for sharing costs equitably at the European level. Assuming costs at the national level is simply not feasible for many MS, and regional-level and hospital-level burden of cost schemes, both of which many countries employ, do not work and hinder equity.

Patient groups also expressed concern for an increasingly cautious policy on the part of regulatory ethics committees looking for “zero risk” scenarios for clinical trials. Patients would like to have more responsibility for determining the risk/benefit ratio for a product under development.

Another suggestion called for financing what is known as the “Death Valley” research area. Whereas basic research (typically conducted in academic settings) has adequate funding, and clinical research has industry resources to work from, there is an empty wind blowing through the critical area of research that translates fundamental findings into clinical applications. Public/private funding collaboration could give a crucial boost to this stage of research.

The recent recommendations of the Pharmaceutical Forum vis-à-vis orphan drugs were greeted with enthusiasm (See the related article in this issue of OrphaNews Europe).

Finally, the value of innovation was evoked. High prices for many orphan medicinal products result from small patient populations for the development and eventual sales of products, but also are caused by the unknowns of the market. Orphan medicinal products are frequently innovative products, produced for markets that are unknown and unshaped. Innovation boosts research for unmet medical needs and thus its rewards are merited.

French Minister of Health Roselyne Bachelot brought the workshop to an end with an encouraging affirmation of her commitment to renewing the national plan for rare diseases. She also echoed President Sarkozy’s support for European-level action as delineated in the EC Communication.

The next and last official rare disease event taking place under the patronage of the French EU Presidency is the European Conference on National Strategies on Rare Diseases in Europe, "State of the art and sharing experiences: toward EU Recommendations” being held on 18 November 2008 at the French Ministry of Health in Paris.

Task Force Update
Rare Disease Task Force
The tenth Rare Disease Task Force (RDTF) general meeting is scheduled for 13 November 2008 in Luxembourg. Details to follow shortly.

Spotlight on...
Sifap…determining prevalence of Fabry disease in young stroke patients

Following a 2005 study published in the Lancet that described the prevalence of Fabry disease in young cryptogenic stroke patients, the Sifap network (Stroke In Young Fabry Patients) has been designed to provide more data on the association between Fabry disease and stroke in young patients. A preliminary seven month pilot phase involving some 700 patients allowed the research team to establish the proof-of-principle, and the Sifap network, a multicentre study headed by the University of Rostock in Germany, officially launched in January 2008.

Fabry disease is a rare x-linked lipid storage disorder. A deficiency of the enzyme alpha galactosidase A causes globotriaosylceramide to accumulate within tissues and organs, leading to function impairment. The major clinical manifestations are primarily due to progressive small vessel disease pathology with angiokeratoma, autonomic dysfunction including hypohidrosis, and lifelong debilitating pain. Renal failure and vasculopathy of the heart and brain lead to early demise in adulthood. The Sifap network was established with a two-pronged aim: to clarify the prevalence of Fabry disease in young stroke patients, and to characterise stroke rehabilitation in young Fabry patients. To meet these goals, Sifap is divided into two phases: Sifap1 and Sifap2.

Sifap1 seeks to determine prevalence of Fabry disease by analysing samples taken from 5000 unselected stroke patients aged between 18 and 55 years of age (at the time of this publication, almost 2000 patients have been recruited). Some 50 neurological centres from across Europe are participating, including sites in Austria, Belgium, Croatia, Denmark, Finland, France, Germany, Georgia, Italy, Malta, Poland, Portugal, Ireland, Spain, and the United Kingdom. It is hoped that 5000 young stroke patients will be identified by June 2009.

A unique characteristic of Sifap is the “fully automated analysis and storage of specimens in combination with the complete digital and web-based data handling. A pipetting robot extracts DNA from specimens and analyses them for Fabry disease.” A biobank for storing DNA, clinical and MRI samples and data from identified patients has been established at the University of Rostock and will serve as a resource permitting researchers to access a well-defined sample pool in order to conduct further studies on the causes of stroke.

Sifap2, expected to run until mid-2012, seeks to characterise stroke rehabilitation in young patients with Fabry disease. Based on findings from the 2005 Lancet study, it is estimated that some 80-120 patients culled from Sifap1 will be eligible for Sifap2, which will determine the relapse rate of acute cerebrovascular events with clinical relevance in patients undergoing different prophylactic therapeutic approaches. Such approaches are not prescribed, but consist of the local routine of participating centres. Patients with a proven Fabry disease are to be included in Sifap2 for a minimum follow-up of 36 months.

Sifap, funded via an unrestricted educational grant provided by Shire Pharmaceuticals, will ultimately yield knowledge on the prevalence of Fabry disease in stroke and the outcome of Fabry patients following stroke.


EU Policy News
High Level Pharmaceutical Forum creates blueprint for equitable access to orphan drugs in the EU
The European Pharmaceutical Forum has concluded a three-year undertaking that looks at Europe’s competitiveness in the sector and considers three major challenges: providing citizens with reliable information on diseases and treatments; establishing effective assessment procedures; and determining fair and workable pricing and reimbursement strategies for medicinal products. Orphan drugs were at the centre of the discussions. The Forum, co-chaired by European Commission vice president Günter Verheugen and Commissioner for Health Androulla Vassiliou, gathered Member States (MS), Members of Parliament, and various stakeholders, including patient organisations (Eurordis), health professionals, industry representatives, and insurers. Three working groups contributed their expertise to each of the key challenges on which the Forum mandate focused. The final report, released on 2 October, puts forward conclusions and recommendations resulting from a series of discussions, brainstorming, and exchanges of practices for each of the three key areas. The Forum specifically acknowledges that patients have the right to equal access to orphan medicinal products and encourages the development of options that would create equity. In particular, Recommendation 7.3 states that MS and stakeholders are "called upon to take up the appropriate ideas developed in the Working Group Pricing regarding":

  • i) early dialogue on research and development
  • ii) exchange of knowledge on the scientific assessment of the clinical added value
  • iii) specific pricing & reimbursement mechanisms
  • iv) increased awareness on orphan diseases
  • .

    So what’s next? Recommendation 10.1 counsels MS and the Commission, in cooperation with relevant stakeholders, to review progress in terms of pricing and reimbursement recommendations within the next two years. The Forum also, “invites the Commission to facilitate the reporting from the Members and to engage in a reflection process in 2009 to identify the remaining challenges in these fields”.
    Consult the final report


    National & International Policy Developments
    UK document guides cost-effectiveness decisions for treating rare conditions
    The publication Social Value Judgements: Principles for the Development of NICE Guidance issued a second edition in July of this year, updating the principles guiding National Institute for Health and Clinical Excellence (NICE) policy in the UK. The publication specifically delineates judgements to be applied in making decisions around the theme of cost-effectiveness. The guidance mentions rare conditions in chapter 4, stating that evaluation of products for rare conditions should be the same as for any treatment. However, treatments for “ultra-orphan” disorders (defined by the NHS as conditions or diseases that occur in fewer than 1 in 50,000 of the population) are to be evaluated by “other mechanisms” that the Department of Health has developed. The document also states that the “rule of rescue” is to be weighed against “the needs of present and future patients of the NHS who are anonymous and who do not necessarily have people to argue their case on their behalf”. Consult the NICE publication
    Other European news
    New report from British paediatric surveillance group focuses on 12 rare disorders
    The British Paediatric Surveillance Unit (BPSU ) was established in 1986 to allow paediatricians to contribute to the epidemiological surveillance and further study of rare disorders affecting children. The BPSU has published its latest Scientific Annual Report. This study typically includes 12 rare childhood disorder (or rare complications of common diseases) “of such low incidence or prevalence as to require cases to be ascertained nationally in order to generate sufficient numbers for study”. This year’s report spotlights childhood scleroderma, congenital adrenal hyperplasia, progressive intellectual and neurological deterioration in childhood, and vitamin K deficiency bleeding, amongst other conditions. The report also includes a progress report of the international network of paediatric surveillance units. Following the establishment of the BPSU, other countries have developed similar methodologies, including Australia, Cyprus, Germany, Greece, Latvia, the Netherlands, New Zealand, Portugal, and Switzerland. Argentina, Italy and Poland have also expressed interest in developing units. International-level action over the past two years includes “the surveillance of 70 different rare conditions…covering a child population of over 50 million and involving over 10,000 clinicians”.

    The BPSU is holding a conference in March 2009 that will highlight the rare paediatric surveillance studies it facilitates. The meeting will focus on three themes: infectious disease in childhood; informing policy and practice; and developing partnerships.

    CEMARA: A shared information system for reference centres in France
    Under France’s national rare disease plan, 132 reference centres devoted to different rare diseases or groups of diseases have been officially designated to date. Of these, 25 have decided to share a common information system, dubbed CEMARA (CEntres de MAladies RAres). This database stores information on specific patient cases, including diagnostics, consultation results, treatments, and outcomes, using a common nomenclature and classification provided by rare disease informational portal Orphanet. CEMARA also cooperates with Genatlas for genetic information. With over 11,000 records gathered by more than 300 health professionals, CEMARA provides vital epidemiological information for rare conditions. A description of the database was recently published in the review Studies in health technology and informatics.
    Consult the PubMed abstract

    Second EUROCAT newsletter highlights new findings on congenital screening and prevention
    As was reported in the 13 February 2008 issue of OrphaNews Europe, the European Surveillance of Congenital Anomalies (EUROCAT) developed a newsletter in January of this year to provide news and information concerning the prevalence, risk factors, prevention and screening for congenital disorders. Over 100,000 babies are born with major congenital anomalies each year in the EU. EUROCAT, a network of 41 population-based registries from 20 European countries that surveys over 1.5 million births per year, has just issued its second newsletter, in which it highlights two recent studies: one examines the impact of maternal new generation antiepileptic intake on birth defects; the other presents findings from a European-level survey of screening practices for structural anomalies and Down syndrome.
    View the newsletter


    Orphanet News
    Nosology of rare diseases: Orphanet launches a unique, free-access classification system for rare diseases
    Orphanet is offering a unique new service for those who want to better comprehend a rare disease by pinpointing its scientific and/or clinical classification. Orphanet, the free-access European informational portal for rare diseases, is still completing the ongoing task of providing information for every rare disorder (an average of one or two new rare conditions are reported in the scientific literature each month). However, the non-profit information resource to date counts 5750 clinically distinct entities in its database. Orphanet has now launched the fruits of an ambitious classification project designed to answer the frequent questions the site receives from patients and professionals. Examples of such questions include: “How many rare diseases are seen in a specific medical discipline”? “Is there a list available of all the rare auto-immune diseases?” "What other disorders might be similar to a specific enzyme deficiency or neuro-degenerative condition?”

    Thus three years ago, Orphanet began the extensive process of gathering all relevant expert classification papers published for rare diseases. When no published documents existed, authorities in the field were located and pressed to contribute their expertise. The fruit of all this labour is now online. Each rare disease in the Orphanet database is assigned to one or more classifications depending on the number of clinical manifestations requiring specialised medical expertise. Certain classifications are based on disease mechanism or aetiology. The body of information has been given a common nomenclature for rare disorders. Classifications will be updated regularly as knowledge becomes available.

    The classifications are accessed from the Orphanet homepage by clicking on the “rare disease” tab, then on the new “classifications” sub-tab. Next, type the name of the disease being searched. A list of the classifications to which the disease is assigned appears on the screen. From this list it is possible to then select each item to view specifically how the disease is classified. It is also possible to search the classification database by disease group (rather than a specific condition).

    This new service, unique in the world, is intended to provide a vital service to medical professionals, researchers, education, the biopharmacutical industry, and also patient groups, who will now be able to find other conditions that resemble their own – a frequent request. The classification system is also available to those working on data gathering for rare diseases; by contacting Orphanet such experts can receive the total database of classification information.

    Orphanet’s new classification feature is the result of a partnership between numerous experts, to whom Orphanet extends its gratitude, particularly the French CEMARA network and two Orphanet professionals – Marie Georget and Ana Rath – who were able to develop the classification database with funding from the French Health Authorities (under the national rare disease plan) and the European Commision (RDPortal contract). The Orphanet informatics team also deserves special mention for their mobilised effort to create a Classifications feature that is pleasantly user-friendly - hats off to Bruno Urbero, Marc Hanauer, Céline Rousselot and Vincent Benoît.

    The EC Rare Disease Task Force Working Group on Coding and Classification meeting on 14 November will examine how Orphanet’s classification system can shape the eleventh WHO International Classification of Diseases currently under development.

    New Texts
    New Orphanet Journal of Rare Diseases Publications
    Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome)


    New Syndromes
    An autosomal recessive syndrome with severe intellectual impairment, cataract, coloboma and kyphosis mapping to chromosome 4
    The authors report on three siblings with a novel intellectual impairment syndrome born to distantly-related Iranian parents. The clinical manifestations comprise severe intellectual impairment, cataracts with onset in late adolescence, kyphosis, contractures of large joints, bulbous nose with broad nasal bridge, and thick lips. Two patients also had uni- or bilateral iris coloboma. Linkage analysis revealed a single 10.4 Mb interval of homozygosity with significant LOD score in the pericentromeric region of chromosome 4.
    Read the PubMed abstract

    Eur J Hum Genet ; Epub ahead of print ; 10 September 2008
    Autosomal recessive neurocutaneous syndrome caused by missense mutation in ALDH18A1
    There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many remains unknown. A consanguineous New Zealand Maori family has been characterised with an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome screen identified a locus at 10q23 . One gene within the candidate interval, ALDH18A1, was considered a plausible candidate since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family.
    Read the PubMed abstract

    Eur J Hum Genet ; 1176-1186 ; October 2008
    Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and overgrowth in six patients
    The authors report on six patients with clinical findings consisting of capillary malformation of the lower lip; lymphatic malformation of the face/neck; asymmetry of face and limbs; and partial/generalized overgrowth. This constellation of findings has been observed in six unrelated patients, constituting a likely new syndrome/association.
    Read the PubMed abstract

    Am J Med Genet A ; 2583-2588 ; 15 October 2008

    New Genes
    Early infantile epileptic encephalopathy: de novo mutations in the gene encoding STXBP1 (MUNC18-1)
    Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, the authors found a de novo microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1).
    Read the PubMed abstract

    Nat Genet ; 782-788 ; June 2008

    Research in Action
    Fundamental Research
    Friedreich ataxia: mitochondrial ferritin could play protective role
    Friedreich ataxia is characterised by difficulties to coordinate movements, associated with neurological signs (dysarthria, loss of reflexes, decrease of deep sensation, pes cavus and scoliosis), cardiomyopathy and sometimes diabetes mellitus. The disease is due to a frataxin deficiency, which affects the mitochondrial function and the energetic metabolism of the cell. The authors studied the role of the protein mitochondrial ferritin, finding a possible protective function in cells characterised by defective iron homeostasis and respiration, as in Friedreich ataxia.
    Read the PubMed abstract

    Hum Mol Genet ; Epub ahead of print ; 24 September 2008
    Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation
    Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive pleiotropic disorder caused by mutations in SMARCAL1, encoding an enzyme with homology to the SNF2 chromatin remodeling proteins. To assess the affect of SMARCAL1 mutations associated with SIOD on SMARCAL1 expression and function, the authors characterised the effects of various mutations on mRNA and protein expression in patient tissues and cell lines, and the ATPase activity, subcellular localization, and chromatin binding of SMARCAL1 missense mutants. Their results show for the first time that SMARCAL1 binds chromatin in vivo and that SIOD arises from impairment of diverse SMARCAL1 functions.
    Read the PubMed abstract

    J Med Genet ; Epub ahead of print ; 19 September 2008
    Astrocytomas: BRAF gene duplication constitutes a mechanism of MAPK pathway activation
    The molecular pathogenesis of paediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumuors, the authors performed a genome-wide analysis of DNA copy number aberrations in paediatric low-grade astrocytomas. Duplication of the BRAF protooncogene was the most frequent genomic aberration and the implication of aberrant activation of the MAPK pathway due to BRAF gene duplication or mutation as a molecular mechanism of pathogenesis in low-grade astrocytomas suggests inhibition of the MAPK pathway could be a potential treatment.
    Read the PubMed abstract

    J Clin Invest ; 1739-1749 ; May 2008
    Clinical Research
    Huntington disease: Decreasing uptake of predictive testing in a German centre over a 12 year period
    The authors examined changes in decision-making for and against the predictive genetic test for Huntington disease, including 478 persons at risk who had undergone genetic counselling in one centre in Germany between 1993 and 2004. At the outset of the counselling procedure the majority of subjects (71%) wanted to make use of the test, yet the actual demand of the predictive test result declined from 67% to 38% over the years. Further studies are necessary to investigate whether changes of test demand rates are a general phenomenon.
    Read the PubMed abstract

    Eur J Hum Genet ; Epub ahead of print ; 10 September 2008
    Turner syndrome: a study of mortality amongst female patients in the UK
    Turner syndrome is characterised by complete or partial X chromosome monosomy. It is associated with substantial morbidity, but mortality risks and causes of death are not well described. The authors followed a cohort of 3,439 women diagnosed with Turner syndrome between 1959-2002. They found mortality in women with Turner syndrome is threefold higher than in the general population, and is raised at all ages, with the greatest excess mortality in older adulthood. These risks need consideration in follow-up and counselling of patients, and add to reasons for continued follow-up and preventive measures in adult, not just paediatric, care.
    Read the PubMed abstract

    J Clin Endocrinol Metab ; Epub ahead of print ; 23 September 2008
    FG Syndrome: clinical experience in the evaluation of 30 patients with a prior diagnosis
    FG syndrome (FGS) is an X-linked disorder characterised by intellectual impairment, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families. The phenotype was highly consistent in all the R961W-positive patients. To determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. This illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.
    Read the PubMed abstract

    J Med Genet ; Epub ahead of print ; 19 September 2008
    Waldenström macroglobulinemia following chronic immune stimulation
    Certain autoimmune and infectious conditions are associated with increased risks of subtypes of non-Hodgkin lymphoma. A few previous studies suggest that chronic inflammation may particularly elevate risk of the distinct non-Hodgkin lymphoma subtype Waldenström macroglobulinemia (WM).The authors assessed WM risk in relation to a variety of chronic immune stimulatory conditions in 4 million US veterans. They found a 2- to 3-fold elevated risk of WM in persons with a personal history of autoimmune diseases with auto-antibodies and notably elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis.
    Read the PubMed abstract

    Arch Intern Med ; 1903-1909 ; 22 September 2008
    Metachromatic leukodystrophy: mutation analysis provides further evidence of genotype-phenotype correlation
    Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder resulting from the inherited deficiency of the arylsulfatase A (ARSA) enzyme. Currently, no valid therapeutic options are available for affected patients. The described correlation between genotype and clinical presentation proved helpful in predicting patient prognosis only in the minority of MLD patients harbouring common mutations. Molecular characterization of a cohort of 26 MLD patients identified 18 mutations, excluding the common 0 and R alleles, 10 of which are rare and 8 are novel. By categorizing the rare mutations, the authors were able to confirm a correlation between ARSA gene mutations, age at onset and patterns of disease progression, not only in those patients bearing common mutations, but also in those carrying rare mutant alleles.
    Read the PubMed abstract

    Clin Genet ; 349-357 ; October 2008
    Cystic fibrosis: disruption of the CFTR gene produces a disease model in newborn pigs
    Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with cystic fibrosis. The pig model may provide opportunities to address persistent questions about the disease pathogenesis and accelerate discovery of strategies for prevention and treatment.
    Read the PubMed abstract

    Science ; 1837-1841 ; 26 September 2008
    Harlequin ichthyosis: a mouse model delineates a key role for Abca12 in lipid homeostasis
    Harlequin ichthyosis (HI) is a severe and often lethal hyperkeratotic skin disease caused by mutations in the ABCA12 transport protein. In keratinocytes, ABCA12 is thought to regulate the transfer of lipids into small intracellular trafficking vesicles known as lamellar bodies. The authors have identified and characterised a mousel model of HI and showed that it displays many of the hallmarks of the disease including hyperkeratosis, loss of barrier function, and defects in lipid homeostasis. They used this model to follow disease progression in utero and present evidence that loss of Abca12 function leads to premature differentiation of basal keratinocytes. A comprehensive analysis of lipid levels in mutant epidermis demonstrated profound defects in lipid homeostasis, illustrating for the first time the extent to which Abca12 plays a pivotal role in maintaining lipid balance in the skin.
    Read the PubMed abstract

    PLoS Genet ; e1000192 ; 19 September 2008
    Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy
    Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here the authors report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation. Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.
    Read the PubMed abstract

    Nature ; Epub ahead of print ; 17 September 2008
    Rare diseases: an automated communication system for identifying and recruiting clinical research participants
    Strategies for study recruitment are useful in clinical research network settings. The authors describe a registry of individuals with one of a multiplicity of rare diseases, and who express a willingness to be contacted regarding possible enrollment in clinical research studies. A web-based automated system generates periodic and customized communications to notify registrants of relevant studies in the NIH Rare Diseases Clinical Research Network (RDCRN). The majority of these communications are sent by email. A comparison of the characteristics of those enrolled in the registry with the characteristics of participants enrolled in sampled RDCRN studies shows that automated notifications can facilitate consistent, customized, and timely communication of relevant protocol information to potential research subjects.
    Read the PubMed abstract

    Contemp Clin Trials ; Epub ahead of print ; 7 September 2008
    Rare disease services: monitoring clinical quality in England
    After some well-publicised problems with paediatric cardiac surgery, there has been great interest in England in monitoring clinical quality in specialised medical services. The National Commissioning Group plans, funds and monitors a set of highly specialised services for the National Health Service in England. The authors have developed systems for monitoring clinical quality that perform two interrelated but distinct functions: performance measurement and performance improvement. The aim is to collect information on all patients seen during each year. There are a number of problems in interpreting, and acting on, outcome data for rare conditions and treatments. These problems include statistical problems due to small numbers, the need to risk adjust data and coding problems.
    Read the PubMed abstract

    Orphanet J Rare Dis ; 15 September 2008
    Stem Cells
    Haemophilia A: transplantation of haematopoietic stem cells modified to express factor VIII restores hemostasis in disease mous
    Although genetic induction of factor VIII (FVIII) expression in platelets can restore haemostasis in haemophilia A mice, this approach has not been studied in the clinical setting of pre-existing FVIII inhibitory antibodies to determine whether such antibodies would affect therapeutic engraftment. The authors generated a line of transgenic mice (2bF8) that express FVIII only in platelets using the platelet-specific alphaIIb promoter and bred this 2bF8 transgene into a FVIII(null) background. Bone marrow (BM) from heterozygous 2bF8 transgenic mice was transplanted into immunized FVIII(null) mice after lethal or sublethal irradiation. After BM reconstitution, 85% of recipients survived tail clipping when the 1100-cGy (myeloablative) regimen was used, 85.7% of recipients survived when 660-cGy (nonmyeloablative) regimens were used, and 60% of recipients survived when the recipients were conditioned with 440 cGy. These results demonstrate that the presence of FVIII-specific immunity in recipients does not negate engraftment of 2bF8 genetically modified haematopoietic stem cells.
    Read the PubMed abstract

    Blood ; 2713-2721 ; 1 October 2008
    Haemophilia B: erythroid-specific human factor IX delivery from hematopoietic stem cells in disease mouse models
    The authors have developed a lentiviral vector system for human factor IX (hFIX) gene transfer in hematopoietic stem cells (HSCs) that provides erythroid cell-derived systemic protein delivery following nonmyeloablative conditioning and in vivo methylguanine methyltransferase (MGMT) drug selection. After bone marrow transplantation, the initial hFIX expression in the chimeras was minimally detectable. However, the hFIX levels rose sharply following in vivo MGMT-drug selection and eventually reached a level that is considered curative in haemophilia B therapy. The rise of hFIX levels was proportional to the increase in vector copy (VC) number in peripheral blood cells. Importantly, high-level hFIX expression by erythroid cells did not result in anaemia or adversely affect red blood cell counts.
    Read the PubMed abstract

    Mol Ther ; 1745-1752 ; October 2008
    Junctional epidermolysis bullosa: correction of Laminin-5 deficiency in human epidermal stem cells
    Deficiency of the basement membrane component laminin-5 (LAM5) causes junctional epidermolysis bullosa (JEB), a severe and often fatal skin adhesion defect. Autologous transplantation of epidermal stem cells genetically corrected with a Moloney leukaemia virus (MLV)-derived retroviral vector reconstitutes LAM5 synthesis, and corrects the adhesion defect in JEB patients. However, MLV-derived vectors have genotoxic characteristics, and are unable to reproduce the physiological, basal layer-restricted expression of LAM5 chains. The authors have developed an alternative gene transfer strategy based on self-inactivating (SIN) or long terminal repeat (LTR)-modified lentiviral vectors, in which transgene expression is under the control of different combinations of promoter-enhancer elements derived from the keratin-14 (K14) gene. Transcriptionally targeted lentiviral vectors efficiently transduced clonogenic stem/progenitor cells derived from a skin biopsy of a JEB patient, restored normal synthesis of LAM5 in cultured keratinocytes, and reconstituted normal adhesion properties in human skin equivalents transplanted onto immunodeficient mice.
    Read the PubMed abstract

    Mol Ther ; Epub ahead of print ; 23 September 2008
    Gene Therapy
    Stargardt disease: correction of the disease phenotype in a mouse model by lentiviral gene therapy
    Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy caused by mutations in the ABCA4 (ABCR) gene. The disease phenotype that is most recognized in STGD1 patients, and also in the Abca4-/- mouse (a disease model), is lipofuscin accumulation in retinal pigment epithelium. Here, the authors tested whether delivery of the normal (wt) human ABCA4 gene to the subretinal space of the Abca4 -/- mice via lentiviral vectors would correct the disease phenotype; that is, reduce accumulation of the lipofuscin pigment A2E. Although extrapolation to humans requires caution, the high transduction efficiency of both rod and cone photoreceptors and the statistically significant reduction of A2E accumulation in the mouse model of STGD1 suggest that lentiviral gene therapy is a potentially efficient tool for treating ABCA4-associated diseases.
    Read the PubMed abstract

    Gene Ther ; 1311-1320 ; October 2008
    Familial amyloid polyneuropathy: anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model
    Tauroursodeoxycholic acid (TUDCA) is a unique natural compound that acts as a potent anti-apoptotic and anti-oxidant agent, reducing cytotoxicity in several neurodegenerative diseases. Since oxidative stress, apoptosis and inflammation are associated with transthyretin (TTR) deposition in familial amyloid polyneuropathy (FAP), the authors investigated the possible TUDCA therapeutic application in this disease. They show that administration of TUDCA to a transgenic mouse model of FAP decreased apoptotic and oxidative biomarkers usually associated with TTR deposition. Most important, TUDCA treatment significantly reduced TTR toxic aggregates by as much as 75%.
    Read the PubMed abstract

    Biochim Biophys Acta ; 517-522 ; September 2008
    Therapeutic Approaches
    Leigh syndrome: successful application of preimplantation genetic diagnosis
    The authors report the first case of successful preimplantation genetic diagnosis of a SURF1 gene mutation for Leigh syndrome, resulting in delivery of a healthy newborn.
    Read the PubMed abstract

    Fertil Steril ; Epub ahead of print ; 6 September 2008
    Diagnostic Approaches
    Chronic graft-versus-host disease: a phase 2 study of extracorporeal photopheresis
    Chronic (cGVHD) is a major limitation of successful hematopoietic cell transplantation. The safety and efficacy of extracorporeal photopheresis (ECP) for 12 to 24 weeks together with standard therapy was compared with standard therapy alone in patients with cutaneous manifestations of cGVHD that could not be adequately controlled by corticosteroid treatment. The primary efficacy end point was a blinded quantitative comparison of percent change from baseline in Total Skin Score (TSS) of 10 body regions at week 12. The median percentage improvement in TSS at week 12 was 14.5% for the ECP arm and 8.5% for the control arm. The proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease from baseline in TSS was 8.3% in the ECP arm at week 12 and 0% in the control arm. These results suggest that ECP may have a steroid-sparing effect in the treatment of cGVHD.
    Read the PubMed abstract

    Blood ; 2667-2674 ; 1 October 2008

    Patient Management and Therapy
    Wilson disease in acute liver failure: a comparison of currently available diagnostic tests
    Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. The results of this study found that conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels is less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.
    Read the PubMed abstract

    Hepatology ; 1167-1174 ; October 2008
    Lymphangioleiomyomatosis: lung transplantation as therapeutic option
    Lymphangioleiomyomatosis (LAM) is a rare disease, leading in some cases to end-stage respiratory failure. Lung transplantation (LT) represents a therapeutic option in advanced pulmonary LAM. The authors conducted a retrospective multicentre study of 44 patients who underwent LT for LAM at 9 centres in France between 1988 and 2006. All patients were women with a mean age of 41+/-10 years at LT. Despite a high morbidity mainly caused by previous surgical interventions and disease-related complications, LT is a satisfactory therapeutic option for end-stage respiratory failure in LAM.
    Read the PubMed abstract

    Transplantation ; 515-520 ; 27 August 2008

    Orphan Drugs
    Fourteen EMEA orphan drug designations for October

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

    - soft tissue sarcoma
    - acute myeloid leukaemia (2 products)
    - Duchenne muscular dystrophy (2 products)
    - chronic lymphocytic leukaemia
    - glioma
    - anaplastic large cell lymphoma
    - Hodgkin lymphoma
    - hairy cell leukaemia
    - multiple myeloma
    - thrombotic thrombocytopenic purpura
    - hypophosphatasia
    - gastro-enteropancreatic neuroendocrine tumours
    Consult the European Registry for Orphan designations
    Consult the Orphanet list of orphan drugs authorised for marketing in Europe

    FDA licenses Kogenate FS to prevent joint damage in children with haemophilia A
    The U.S. Food and Drug Administration has approved Kogenate FS, a genetically engineered version of factor VIII, to reduce the frequency of bleeding episodes and prevent joint damage in children with the most severe form of haemophilia. Kogenate FS is manufactured by Bayer Healthcare LLC.
    FDA approves C1-esterase inhibitor Cinryze for prevention of hereditary angioedema
    The U.S. Food and Drug Administration has licensed for marketing the first product in the United States intended to protect people with hereditary angioedema (HAE), a rare and potentially life-threatening genetic disease. Cinryze, a C1-esterase inhibitor product, is licensed for the prevention of HAE attacks, which can occur spontaneously or during stress, surgery, or infection in patients diagnosed with the disease. Cinryze is manufactured by in the US by Lev Pharmaceuticals through a contract manufacturing agreement with Sanquin Blood Supply Foundation in the Netherlands.

    Partnersearch, Job Opportunities
    Engineer for Preclinical Imaging - Auvergne University, France
    The position is linked to the project "Development of new heteroaromatic halogenated radiotracers for PET imaging and targeted radionuclide therapy of melanoma" designated by the “cancéropôle CLARA” in the programme "Proof of concept" 2008. It concerns in vivo preclinical imaging and pharmacology studies for the selection of compounds and the protocols optimization to clinical transfer in imaging and therapy. Engineer or doctor (imaging, oncology or pharmacology) training required, with expertise desired in the following areas:in vivo preclinical imaging, in vivo experiments on animals, manipulation of radionuclides, practice in imaging techniques, practice in imaging signal analysis.
    To apply send CV and letter of motivation
    For more information: + 33 4 73 15 08 14.


    News from the Patients' Associations
    Unique rare chromosome disorders booklet now available in Spanish and Italian

    UK-based international organisation for rare chromosomal disorders Unique has been offering an array of information and resources for patients, parents, and professionals for more than 20 years. The organisation has 6200 member families, representing nearly 7000 individuals affected by a rare chromosome disorder, from 76 countries worldwide. Membership is currently increasing at the rate of some 800 new families per year. Their Little Yellow Book provides parents with a comprehensive, intelligently-written overview of the chromosomes and related rare disorders. Already available in English, Norwegian and Finnish, two new languages have now been added to the repertoire: Italian and Spanish. The association also publishes Unique Tales, a cartoon-strip guide for brothers and sisters of those with a rare chromosome disorder, which is currently being translated into Italian. The group also has a series of informational leaflets available for individual disorders and in a variety of languages, including Dutch, English, French, and German.


    What's on Where?
    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
    Venue: Bruges, Belgium

    Considers ethical perspectives of gene therapy and risk management, amongst other related topics. The cases of individual conditions are examined (SCID-X1, Wiskott Aldrich syndrome, epidermolysis bullosa).
    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

    This important conference, taking place under the French presidency of the European Union, will examine the initiatives of individual member states and the EU Council recommendations for national rare disease plan development.
    Consult the programme

    IPPOSI Meeting: Access to Medicines and New Technologies in the era of Health Technology Assessments in Ireland
    Date: 24 November 2008
    Venue: Dublin, Ireland

    This meeting, organised by the Irish Platform for Patients’ Organisations, Science and Industry (IPPOSI), will discuss what is currently happening in Ireland and what has happened in the UK and Netherlands in terms of Health Technology Assessments and access to medicines.

    For further details

    First Eastern European CF Conference: What’s New in the Diagnosis, Treatment and Prevention of Cystic Fibrosis?
    Date: 28-30 November 2008
    Venue: Zagreb, Croatia

    The aim of this conference is to stimulate, encourage and help to develop programmes for professionals working in the field of CF in non EU and EU countries, particularly those of Eastern Europe in the hope that such a meeting will promote close ties between CF specialists in Eastern Europe, bring new experts from Eastern Europe into this community and develop collaborations with CF experts in Western Europe.
    For further information

    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

    Conference on the Impact on Clinical Research of European Legislation
    Date: 2 December 2008
    Venue: Brussels, Belgium

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

    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

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

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

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

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

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

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

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

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

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

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


    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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