30 October 2007 print
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The 2007 EPPOSI Workshop Tackles the Reality of Orphan Medicines
The eighth European Platform for Patients' Organisations, Science and Industry (EPPOSI) workshop opened at the Danish Parliament in Copenhagen on 18 October with an ambitious agenda for addressing this year's topic, The Reality of Orphan Medicines.

Over 120 rare disease stakeholders attended the two-day event, which included the special presence of HRH Crown Princess Mary of Denmark on the opening day. Alastair Kent (GIG/EGAN) launched the workshop with a pertinent reminder that patients have no choice over their disease. He evoked two major themes in need of examination: Health Technology Assessment (HTA) and Prevalence. EPPOSI offers a unique and vital opportunity to gather together the various rare disease (RD) players with all the special skills, expertise and knowledge they possess. Birthe B. Holm (COMP/EURORDIS/Rare Disorders Denmark) continued the opening remarks by targeting the topic of orphan drugs (ODs) reaching patients within the legal timeframe delineated by EU-level legislation as an issue in urgent need of examination. Torben Gronneb�k (Rare Disorders Denmark/EURORDIS) concluded the workshop opening by listing four criteria necessary to ensure RD patients a decent quality of life: prompt diagnosis; treatment permitting physical independence; socialisation (schooling, respite care); and coping strategies.

The first workshop session, chaired by Alastair Kent and Andrea Rappagliosi (Merck-Serono) addressed a sometimes thorny topic: How to estimate the value of an orphan drug. In his introductory comments, A. Rappagliosi defined HTA as a tool that could help society better appreciate the value of ODs, and referred to European project EunetHTA's definition of HTAA: A multidisciplinary process that summarises information about the medical, social, economic and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, robust manner.

Christine Lavery (MPS Society/EURORDIS) presented The patient's view on health technology assessment for Orphan Medicines, using the powerful example of MPS diseases, a group of lysosomal storage disorders that need early diagnosis. Although treatments became available in recent years for some of these diseases (ERT for Fabry disease in 2001 and for MPS I in 2003), they were not always accessible to patients due to the restrictive use of HTA by some of the local agencies in charge of funding. A combination of lobbying and legal action resulted in the treatments becoming available from April 2005 via national specialised commissioning in England, but not in Scotland or Wales. The model that is used in England to regulate access to ODs includes strict diagnosis criteria, centres of excellence, registries, treatment guidelines and post-marketing follow up, and may be adaptable to other regions or disease areas.

Finn Borlum Kristensen (Natl Board of Health, Danish Center for Evaluation and EUnetHTA, a large EU project on HTA) next presented: Is HTA an appropriate tool to promote access to Orphan Drugs? The aim of HTA is to inform the formulation of safe, effective, health policies that are patient focused and seek to achieve best value. HTA does not mandate policy. The seventh work package of EU project EUnetHTA (European Network for Health Technology Assessment) is dedicated to monitoring the development of emerging/new technologies and is particularly relevant to ODs. EUnetHTA has 59 partners in 22 EU countries and was created to avoid duplication. HTA monitoring is needed during the developmental, experimental, and real-life stages of product development. Trans-national HTA collaboration does not interfere with national competences for healthcare organisation.

The next session explored OD access in a real-life setting by examining three member state (MS) countries:

Francois Meyer, (HAS) described OD access in France. The French system was held up on numerous occasions throughout the workshop as a model. France has a mechanism (Temporary Utilisation Attribution or ATU) that grants temporary medicine authorisation for severe diseases that have no approved alternative. Over 20 of the first 35 market authorised (MA) OD products were granted ATU availability by the French medicines agency before they received MA and 28/28 ODs evaluated were granted reimbursement.

Wim Goettsch (CVZ) described OD access in the Netherlands, a country that has an independent body serving as a sort of "gate keeper" for the health system. The Netherlands operates "intramural funding". There are currently five hospital-administered ODs for very rare diseases that are all fully reimbursed. In determining added-value, an important determinant to consider is the eventual cost-saving that treatment permits via reduced hospitalisations, for example.

Edmund Jessop (NHS) emphasised three conditions necessary for the UK system to function: very rare diseases need a "separate box"; pricing must be fair; and a moral perspective must be included - public acceptance has value. He queried the rationale behind the pricing of a monoclonal antibody (MAB) product in the UK that is ten times greater in price than other MABs. He called for increased transparency regarding price determination for ODs.

Jens Grueger (Novartis) next presented an industry experience via a case study involving orphan drug Glivec (imatinib). It was uncertain whether HTA could be applied. Could it capture all the dimensions of value of OD drugs, some of which are difficult to quantify?

Cees Smit (Dutch Genetic Alliance/VSOP) rounded out the afternoon presentations with a perspective of the patient's view, providing a qualitative example of how to estimate the value of an orphan drug through a 2001 survey of over 1000 haemophilia patients. Quality of life components were compared from 1972 to 2001, including time spent in hospital, absenteeism from school/work, inability to work, and life expectancy. The results were dramatically improved post-treatment. This survey could serve as a model for RDs, but required long term follow-up (~20 years) for which it is difficult to find funding. The average cost of all haemophilia treatments (averaging severe and less-severe cases) comes to about 37 000 euros per year. Evidence-based medicine and QALY (quality life-adjusted years) instruments are becoming more economic-focused but overlook certain aspects, such as long-term loss of professional life for a parent caring for a sick child, resulting in lost tax income for the state. Although EU citizens value healthcare and the EU wants to stimulate OD development, many MS have budget problems. This must be resolved.

The ensuing discussion period brought up whether industry was sufficiently transparent, whether development costs are directly linked to patient population size, and the role of biomarkers. As scientific advances in disease understanding and drug development make the unimaginable become imaginable, patient expectations are growing. But budgets have ceilings. Fair, robust, and transparent decision making is needed.

Participants awoke to crisp autumn Copenhagen sunshine on the second day of the EPPOSI workshop. The morning session was entitled, How many orphan drugs - for how many patients?

The recent successes in OD development have created fear in those holding the purse strings. The spectre of a multitude of ODs, each rare and costly, is worrying to Member States hampered by limited budgets. This session thus sought to find strategies to forecast numbers that could possibly reassure MS.

S�gol�ne Aym� (INSERM/Orphanet) discussed the possibility of a forecast for ODs using epidemiology data. Although prevalence is difficult to determine, figures are essential to present to policy makers. How many RDs depends on what is meant by disease. The World Health Organization defines a disease as a recognisable pattern of signs and symptoms. To date, there are some 5200 distinct phenotypes listed in Orphanet. Five to six new syndromes are described in the literature each month. Using a range of 6000 diseases, how many patients does this mean? A literature survey of 2343 diseases found 1642 stated prevalence. The majority had low prevalence and could be considered ultra-rare. However, most scientists are not epidemiologists and this data source is considered weak. Prevalence is often confused with incidence or life-long incidence. The majority of RDs is due to developmental defects for which there is currently not much pharmacological treatment potential, although other elements to alleviate suffering certainly exist. Registries are a rich source for determining prevalence. An example of this comes from Veneto, Italy, where patients must register to obtain reimbursement. Not all RDs are included in the registry, however, nor do all RD patients register. The prevalence rate of 3.5% that literature yields is overestimated, while the registry rate of 1% is underestimated. The number of treatable patients can be determined by taking the number of designated products (distributed by disease category), and comparing it with the prevalence of patients in corresponding categories. This equation reveals that the patients who would potentially need treatment represent 1.6% of the European population - if all the designated products make it to market. However, these patients are not identified and therefore the number of treated patients would be even lower in reality.

Fabrizia Bignami (EURORDIS) presented a Forecast of Orphan Drugs: perspective from modelisation based on US data (because it has long-term hindsight) of 1711 designations and of 306 potential marketing authorisations. Extending this model to European product development, applying a designation rate of 80 per year, a 16% MA success rate, and a three-year developmental period yields a forecast of 90 medicinal products in five years, including the currently approved 40. This model does not indicate disease group, product type, or other specifics.

Tan Nguyen (FDA) spoke on the Forecast of Orphan Drugs from the FDA perspective. Of 200 designation applications for 2007, approximately 70% are granted; those that are not usually have issues pertaining to prevalence, subsetting or lack of scientific rationale. In the US, an average of 14 ODs are authorised each year. 70% of these are chemical products, versus 30% biologics. There is a higher number of biologics developed in Europe. In the US, the median time from designation to authorisation is 2.8 years for chemicals and 4.1 years for biologics. Infectious/parasitic products have the shortest developmental time-span (1-2 years) and nervous system/perinatal products have the longest (over 5 years). Other US statistics include: the number of RD treated is 186+/-. 30% of these have more than one product; 70% have only one. 16% of authorised products (almost 50 products) are for paediatric diseases and conditions. 88% of authorised ODs have a treatment indication; 9% are preventive - a group that is decreasing significantly; and 3% are diagnostic products. Multinational sponsorship is increasing. The median prevalence is 28 000 patients in the US. Of new molecular entities, 38% are OD. More companies are targeting malignancies. Japan has the shortest median time from designation to market.

Paolo Tomasi (EMEA) next presented a Forecast of Orphan Drugs from the EMEA perspective. He reminded the participants that an orphan designation is competitive, i.e. more than one sponsor can obtain designation for the same product and the same condition. An orphan indication may often be broader than the therapeutic indication. The number of withdrawals from the designation/authorisation process is decreasing. Approximately 30% of applications are coming from SMEs. 46% of OD applications in 2006 were for oncological conditions, followed by muscular/skeletal disorders. Sponsors seem to estimate a longer time to MA than the reality shows, but this may reflect a bias in data collection. One factor linked to successful MA is having previously received a MA for another product. Chemical products are easier for sponsors than biologics. In summation, although the road to MA is difficult, approximately two-thirds of MA applications for orphan drugs receive a positive opinion by the CHMP. According to several mathematical models based on the current trend, an increased number of applications for orphan designation, and an increased number of marketing authorisation applications for orphan-designated products can be expected. The magnitude of the increase is difficult ro predict however, as too many factors are involved. Thus the possibility of a smaller increase or a stabilization of the number of applications and authorisations cannot be excluded.

Geoff McDonough (Genzyme) was the last speaker of the morning with an industry perspective on OD forecast. Genzyme has several RD registries, considered the property of the patients and treating physicians. When contemplating product development, it is important to remember that life-changing therapies carry a global, lifelong responsibility. Determining the number of patients for a disease includes a consideration of theoretical prevalence, actual prevalence, diagnosed patients, and treatment-eligible patients, each time diminishing the number involved. For diseases such as lysosomal storage disorders, which Genzyme treats, prevalence models can only provide "guestimates". Newborn screening is the only way to accurately understand prevalence. Taiwan has completed a pilot screening with some 135 000 subjects, from which 4 cases emerged. It is difficult to leverage prior experience for RDs, due to their complexity.

The ensuing discussion period raised several points:

  • Registries are underused as a source of information for RD research and drug development. They are also crucial for reimbursement appraisal. When registries are being created, the data to include must be considered carefully. The FDA recently issued guidelines for capturing data. European-level guidelines would be very helpful. Funding for registries needs to be considered. France, under its national RD plan, has established a working group for RD registries. Prioritising for funding proved very difficult. RDs with treatments were given priority. Registries for ultra RDs should be established at the European level because of the rarity of the underlying disease. Payers should be included in the discussions at the time registries are designed.
  • How will generic products change the OD landscape? They will save money but also present particular challenges.
  • What about gene therapy? It is currently lagging behind, representing only 20% of designated products, most of which are in early development.
  • The Clinical Trials Directive is resulting in clinical trials being conducted outside Europe. On the other hand, it offers adequate guidelines to certain countries that are missing them.

  • In the conclusion to the morning session, it was noted that forecasts must include costs. OD costs are not additive and budgets must be calculated to reflect this.

    The final workshop session, How to communicate about orphan drugs in the real life setting? was chaired by Terkel Andersen (Haemophilia Denmark/EURORDIS) and Bert Leufkens (Dutch Steering Committee on Orphan Drugs).

    Yann Le Cam (EURORDIS) presented Patient Access to Orphan Drugs in the EU: a EURORDIS survey. This survey reviewed the availability of 22 ODs in 28 European countries. Sources included MA holders, COMP, NCAs direct contacts and patient groups. Despite current legislation that requires OD availability within 180 days after MA, several countries surveyed have few or even zero of the ODs accessible. Some general reflections this survey fostered: It is harder for RD patients in smaller countries. In general, the rarer the disease, the higher the price of the product. Lack of transparency is a problem - why are some companies reluctant to divulge information concerning product distribution?

    B. Leufkens discussed Orphan Drugs today: what are the communication challenges? Evoking the history of the seven previous EPPOSI workshop topics, he defined three phases of OD development, the current one being tinged with scepticism due to issues of cost and bottlenecks. He referred to a recent news article appearing in the Economist that explored the end of the blockbuster model, a trend that will be helpful to OD development, factoring in better phenotyping, disease characterisation, personalised medicine and political pressure. Communicating the true value of registries is needed so they are not viewed sceptically as marketing gadgets that invade privacy.

    Erik Tambuyzer (EBE/Genzyme Europe) presented Industry's communication about orphan drugs. Industry is heterogeneous. It is difficult to offer a unified voice. There are many misconceptions concerning industry: it is too profit-oriented; only positive trial results are communicated; patents are over-protected. These views can be challenged by other perspectives: industry innovates for unmet needs; industry is a major source of healthcare products. Models of success generate interest in the field. Market exclusivity does not equate monopoly. The "spirit" of OD legislation is important to keep in mind. Rare diseases are part of the continuum from common diseases. Complexity of development increases with rarity. Shareholder expectations play a significant role. Financial sustainability is important for industry, but also for patients. Discussion between stakeholders is invaluable. Controversial issues will not just disappear, but need to be addressed head on. It is important to engage personally.

    Some important points were raised during the following discussion period:

  • Eastern European countries in particular depend upon clear, present communication to establish access. What window of diversity is acceptable for ODs across Europe, taking into account the diversity of economic wealth?
  • The sustainability of registries must be considered at the time of development, along with potential changes in data requirements.
  • Industry does not divulge information because it does not always have the time to do so. Some data is confidential.

  • As the workshop drew to a close, Birthe B. Holm offered the final words. She focused on a few conclusions harvested from each of the three sessions:
    HTA is an important tool that must be put into the context of each country. HTA alone is not sufficient for decision making.
    Improved data is needed for decision making. The data presented at this workshop need publishing.
    Communication is needed to fill gaps. Should a united European HTA be developed?

    Finally, a recipe for success was offered. The ingredients include:
  • Shared knowledge
  • A well-informed public
  • Transparency
  • Open dialogue between stakeholders
  • Brave politicians to make the right decisions

  • While this year's workshop addressed many outstanding questions, it has ironically produced even more. B. Holm left the participants with two: Will society one day believe it can no longer afford Orphan Drugs?
    How can the tremendous display of willingness witnessed during the last two days be translated into action?

    The Eighth EPPOSI workshop served immediately to fulfil one of the "ingredients" listed in B. Holm's recipe: Due in no small part to the gracious presence of HRH Crown Princess Mary, two newspaper articles concerning rare disease patients appeared Friday in the Danish press.

    Thus, an immediate benefit of the EPPOSI workshop: A public already better informed of rare disease issues in at least one European country. The next EPPOSI workshop will take place in Paris in October 2008.

    National & International Policy Developments
    A bill for mandatory free neonatal rare disease screening in Italy
    In Italy, a bill has been proposed to Parliament concerning mandatory free-of-charge neonatal screening for certain conditions that can be treated by pharmacological or dietary intervention, including rare genetic diseases phenylketonuria, galactosemia, cystic fibrosis and hypothyroidism. Put forward by Dorina Bianchi, vice-president of the Social Affairs Commission and member of the Commission for Childhood, the bill, entitled Dispositions in favour of research on Rare Diseases, their prevention, the diffusion of the obligatory neonatal screening and their treatment, is based on recommendations from the Dossetti Association.
    The Netherlands contemplates implementing preconception programme
    A relatively high trend of perinatal mortality has prompted the Health Council of the Netherlands to recommend preconception care measures in an effort to reduce premature birth, miscarriage, and congenital anomalies as well as perinatal mortality. Measures typically introduced eight weeks into pregnancy, such as folic acid intake, can improve the chances of a healthy pregnancy when introduced pre-pregnancy. Some of the measures would target all women of child-bearing age, while others would be aimed strictly at prospective parents. The programme would take into account food, drink, tobacco and drug use, working conditions, illness and medication, and genetic factors. A pilot programme has already been successfully undertaken in the country.
    France legally recognises genetic counselling as a profession
    A long-awaited decree was published on 3 October modifying the existing public health code to bestow official recognition to the profession of genetic counselling. Decree 2007-1429 validates the legitimacy of the genetic counselling profession “exercising with a medical prescription issued from a physician qualified in genetics.” The genetic counsellor works in contact with patients and their families to evaluate and communicate genetic risks, and the profession integrates social, psychological, cultural, legal and ethical dimensions. France has given much reflection to the issue of recognising the medical genetic professions. Training, however, has been underway in recent years for genetic counselling in anticipation of obtaining official recognition, with recruitment already taking place in rare disease centres of reference and genetics clinics.
    Other European news
    Austria has top health system, with Holland and France close behind
    Sweden-based Health Consumer Powerhouse, a leading provider of consumer health information in Europe, has released its 2007 “report card” on the consumer-friendliness of 29 healthcare systems across Europe. Austria surpassed 2005 winner Holland and 2006 winner France to emerge in first place this year. No country scored the full 100% however - all are in need of reforms in one area or another. Twenty-seven indicators, grouped into five main categories (patient rights and information; waiting time for treatment; outcomes; “generosity”; and pharmaceuticals) were used to evaluate the twenty-seven EU member countries, plus Switzerland and Norway. A set of recommendations for each country has been published alongside the Euro Health Consumer Index report.
    Foetal alcohol syndrome guidelines issued for professionals
    Foetal alcohol syndrome disorders (FASD) are completely preventable mental and physical birth defects resulting from maternal alcohol consumption during pregnancy. Prevalence varies according to geographic location and is generally difficult to determine. FASD are lifelong conditions that can severely impact the life of the sufferer as well as their entourage. Now the British Medical Association has released a guide for healthcare professionals, geared toward increasing awareness of FASD by presenting information on the incidence, cause and outcomes of disorders linked to alcohol consumption during pregnancy. Going further, the document delineates the responsibility of the healthcare professional and the medical community in reducing the incidence of these disorders. FASD diagnosis and clinical management is addressed and the report includes case studies of FASD patients, including first-person testimonies that clearly describe the difficulties of living with these disorders. It is hoped that this document will contribute toward making FASD an ultra-rare disorder in the foreseeable future.
    Expanded Human Gene Mutation Database released
    An updated version of the University of Cardiff’s Institute of Medical Genetics Human Gene Mutation Database (HGMD) was released this summer and now incorporates over 70,000 mutation entries. HGMD has been publicly available via the internet since April 1996 and has grown considerably since its debut: from 10,000 mutation entries in 1996 to over 70,000 entries to date. HGMD is available as a free service to academic/non-profit institutions.
    Other International News
    Rare disease proponents amongst new NIH neurology council members
    The US National Institute of Neurological Disorders and Stroke (NINDS) has announced the appointment of five new members to its Council, an advisory body that meets three times per year to review applications for financial support from researchers working in the area of brain and nervous system disorders. The Council, composed of scientists, physicians and public representatives, also gives advice on the planning and priorities for research programmes. Amongst the new members, Cindy Parseghian is founder and president of a non-profit funding organisation for Niemann-Pick type C disease that has expanded the number of laboratories working with the rare fatal genetic disorder from less than five in 1994 to more than 55 worldwide to date. Vicky Holets Whittemore is vice president and director of science for the Tuberous Sclerosis Alliance, as well as a member of the CETT Review panel for the NIH Office of Rare Disorders, and vice-chair of the National Coalition for Health Professional Education in Genetics. Luis F. Parada is a past member of the Rett Syndrome Research Foundation Board whose area of research interests includes charting nerve cell signalling disorders. The new appointees will serve four-year terms with the 18-member council.

    EU Project Follow-up
    AnEUploidy seeks patients for two projects
    The FP6 AnEUploidy project seeks patients with partial trisomy 21, partial monosomy 21, or any of the following syndromes: Ohdo syndrome, Baraitser-Winter syndrome, Coffin Siris syndrome, Hallermann-Streiff syndrome, Malpuech syndrome, Schinzel Giedion syndrome, Floating Harbor syndrome, IFAP (ichthyosis follicularis, alopecia and photophobia), Aase-Smith syndrome, and Bohring syndrome. These patients will be phenotyped according to a standardized phenotypic list and genotyped with a 250K SNP array. The project is open to suggestions of interesting syndromes.

    If you have diagnosed a patient with a partial trisomy 21 or monosomy 21 or have a patient with one of the clinically defined syndromes and you would appreciate further study with SNP array (at no cost) do not hesitate to contact Bregje van Bon.


    Orphanet News
    Orphanet a temporary victim of its own success
    The Orphanet server was temporarily inaccessible in mid-October due to a steadily increasing volume of user traffic that overloaded the system. The Orphanet team quickly mobilised to solve the problem, ensuring that the website could sustain the growing activity that is occurring due to an increasing awareness of the resources Orphanet offers.
    New Texts
    New Orphanet Journal of Rare Diseases publications
    Mowat-Wilson syndrome
    Alström Syndrome (published in the European Journal of Human Genetics, in association with Orphanet)

    New Research Projects open for Recruitment

    New Syndromes
    Developmental delay and intellectual deficiency in two children with 14q11.2 deletions
    Two patients with a de novo deletion in 14q11.2 region present developmental delay, intellectual deficit and dysmorphia including widely-spaced eyes and a short, flat nose. The deleted region contains two genes, both candidates for this phenotype.
    Read the PubMed abstract

    J Med Genet ; 556-561 ; September 2007

    New Genes
    Mutations in a member of the nonsense-mediated mRNA decay complex cause X-linked syndromic and nonsyndromic mental retardation
    By performing sequence analysis of 737 genes located on the X chromosome in 250 families with X-linked mental retardation, the authors identified mutations in gene UPF3B. Two mutations are linked to Lujan-Fryns syndrome, one to FG syndrome, and another to a non-syndromic intellectual deficit. The UPF3B protein is implicated in the nonsense-mediated mRNA decay, a mechanism used by all the cells of the organism for controlling the production of abnormally truncated proteins. The authors suggest that the number of organs affected in the patients is due to a functional redundancy of the gene in certain tissues.
    Read the PubMed abstract

    Nature Genetics ; 1127-1133 ; September 2007
    Severe tumoral calcinosis can be due to a homozygous missense mutation in KLOTHO
    Familial tumoral calcinosis is an autosomal recessive metabolic disease characterised by ectopic calcifications and hyperphosphatemia due to inactivating mutations in FGF23 or GALNT3. FGF23 is a hormone necessary for the renal excretion of phosphate, while GALNT is an enzyme contributing to the maturation and secretion of FGF23. In this study, the authors have identified a homozygous mutation in KLOTHO gene in a 13-year old girl. KLOTHO encodes a secreted protein necessary to the transmission of the signal emitted by FGF23 toward its receptors.
    Read the PubMed abstract

    Journal of Clinical Investigation ; 2684-2691 ; September 2007
    Two C syndrome patients have mutations in an immunoglobulin superfamily gene
    C syndrome is characterised by mental retardation and multiple congenital anomalies. The authors identified mutations in gene CD96 in two patients. This gene encodes a protein of the immunoglobulin superfamily. In vitro, these mutations alter cellular adhesion and growth, two mechanisms potentially at the origin of C syndrome.
    Read the PubMed abstract

    The American Journal of Human Genetics ; 835-841 ; October 2007
    Wolfram syndrome type 2 has ERIS mutation
    Type 2 Wolfram syndrome is an autosomal recessive neurodegenerative disease characterised by neonatal insulin-dependent diabetes, optic atrophy and a propensity for bleeding due to a defective platelet aggregation. In this study, the authors identified a homozygous mutation in ZCD2, encoding ERIS, a zinc finger protein, in three consanguineous Jordanian families. As with wolframine, whose gene is mutated in Wolfram syndrome type 1, ERIS localises to the endoplasmic reticulum and plays a role in calcium homeostasis.
    Read the PubMed abstract

    The American Journal of Human Genetics ; 673-683 ; October 2007
    A Kabuki syndrome patient with a partial deletion in gene C20orf133
    Kabuki syndrome is characterised by mental retardation, growth delay and cardiac, renal and vertebral malformations. In one patient, the authors have identified a de novo deletion in C20orf133, a gene of unknown function.
    Read the PubMed abstract

    Journal of Medical Genetics ; 562-569 ; September 2007

    Research in Action
    Clinical Research
    Long arm interstitial deletions in chromosome 18 are linked to language delays
    The authors describe five patients presenting interstitial deletions in the long arm of chromosome 18 (between 18q12.3 and 18q21.1). These patients present developmental delays and language difficulties. This may represent a previously underappreciated syndrome since these children do not have the typical clinical abnormalities that would lead to a chromosome analysis.
    Read the PubMed abstract

    Am J Med Genet A ; 1181-1190 ; June 2007
    Luteinizing hormone beta mutation causes sterility in women
    Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism. The authors describe a woman born into a consanguineous family with a homozygous mutation in the gene encoding this subunit. After a normal puberty, this patient presented secondary amenorrhea and infertility.
    Read the PubMed abstract

    NEJM ; 897-904 ; August 2007
    DAX1 could be behind isolated 46,XY gonadal dysgenesis
    Gonadal dysgenesis linked to a 46,XY karyotype leads to a female phenotype usually including intellectual deficit and/or malformations. It is due, in some 15% of cases to mutations in gene SRY. In this study, the authors describe two sisters presenting isolated gonadal dysgenesis, an apparently normal 46,XY karyotype, without SRY mutation. They identified a duplication at Xp21.2, containing DAX1. This gene, known for its role in sex determination, is an important candidate for 46,XY gonadal dysgenesis.
    Read the PubMed abstract

    J Clin Endocrinol Metab ; 3305-3313 ; August 2007
    Aicardi-Goutières syndrome clinical and molecular phenotypes
    Aicardi-Goutières syndrome is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. An international study authored by over 100 researchers and including 127 children offers a complete clinical and molecular description of this phenotype. They observed biallelic mutations in genes TREX1, RNASEH2A, RNASEH2B and RNASEH2C in 31, 3, 47 and 18 families, respectively. In five families, a monoallelic mutation of RNASEH2A or RNASEH2B is present, while no mutation could be identified in 22 families. Furthermore, it appeared that neonatal forms, strongly reminiscent of a congenital infection, are principally due to mutations in TREX1 gene, while later forms of the disease are linked to mutations in RNASEH2B. Mortality is higher in patients with TREX1, RNASEH2A and RNASEH2C gene mutations versus RNASEH2B gene mutations (34.3% v. 8%).
    Read the PubMed abstract

    The American Journal of Human Genetics ; 713-725 ; October 2007
    Therapeutic Approaches
    Inhibition of MAPKinases signalling reduces craniostenosis in Apert syndrome mouse models
    Apert syndrome is characterised by the association of faciocraniosynostosis and osseous and membranous syndactyly of the four extremities. It is essentially caused by mutations in the gene encoding fibroblast growth factor receptor 2. In mouse models of the disease, the authors succeeded in restoring a normal phenotype by reducing expression of the mutated allele via an interfering RNA. Restoration of the phenotype was accompanied by a reduction of activity in MAPKinases pathway signalling. Consequently, the authors administered an inhibitor of this pathway in mouse models and observed a significant inhibition of craniostenosis. Thus MAPKinases signalling represents a potential therapeutic target for Apert syndrome treatment.
    Read the PubMed abstract

    Nature Genetics ; 1145-1150 ; September 2007

    Patient Management and Therapy
    Cushing syndrome diagnostic tests for paediatric patients
    Cushing syndrome is a group of clinical manifestations resulting from chronic hypercortisolism. Diagnostic criteria have generally been derived from adult patients despite significant differences in both the physiology of the hypothalamic-pituitary-adrenal axis and the epidemiology of Cushing syndrome in childhood. The authors conducted a retrospective study of 125 patients to identify the tests that most reliably and efficiently diagnose pituitary or adrenal tumours in a large cohort of paediatric patients with Cushing syndrome. For children referred for the evaluation of possible Cushing syndrome, a single cortisol value at midnight followed by overnight high-dosage dexamethasone test led to rapid and accurate confirmation and diagnostic differentiation, respectively, of hypercortisolemia caused by pituitary and adrenal tumours.
    Read the PubMed abstract

    Pediatrics ; e575-586 ; September 2007
    Turner syndrome growth hormone treatment normalises height in infants and toddlers
    Growth delays are observed from the prenatal period onward in Turner syndrome patients. A prospective, randomised controlled, open-label multicentre clinical trial involving 88 girls from nine months to four years of age aimed to determine whether growth hormone treatment initiated before age four could prevent subsequent growth failure. The outcome showed that early growth hormone treatment can correct growth failure and normalise height in Turner syndrome infants and toddlers.
    Read the PubMed abstract

    J Clin Endocrinol Metab ; 3406-3416 ; September 2007
    Long-QT syndrome type 3 mexiletine response predictive test developed
    Congenital long-QT syndrome is a cardiac pathology characterised by an abnormally long QT space, indicating a repolarisation anomaly. The type 3 of this syndrome is due to mutations in gene SCN5A, encoding the alpha subunit of the sodium cardiac channel. Mexiletine can be administered to carriers of this mutation to shorten QT. The authors analysed the in vitro effect of mexiletine on the cells expressing mutated forms of the sodium channel. They then compared the results obtained with the response to treatment of patients with the same mutations. They thus established an in vitro test that predicts the response of patients to mexiletine treatment.
    Read the PubMed abstract

    Circulation ; 1137-1144 ; September 2007
    Juvenile dermatomyositis patients can benefit from rituximab
    Juvenile dermatomyositis (DM) is a chronic inflammatory myopathy of childhood primarily affecting the muscles and skin. Treatment for juvenile DM is often difficult, and conventional therapies include corticosteroids and other immune suppressants. The authors studied the effects of rituximab, a monoclonal antibody targeting the CD20 of B lymphocytes, in four young patients. Three patients had a regression of the disease, while the fourth had an aggravation following administration. Although additional data is needed, this study demonstrates the therapeutic potential of anti-B cell therapies in the treatment of juvenile dermatomyositis.
    Read the PubMed abstract

    Arthritis and Rheumatism ; 3107-3111 ; August 2007

    Orphan Drugs
    Italy-based pharmaceutical Recordati purchases Orphan Europe
    Orphan Europe, a European pharmaceutical group specialising in rare diseases, is being bought by Recordati SpA for the sum of 135 million euros, according to a Recordati press release. Orphan Europe, headquartered in Paris, is dedicated to developing, registering, marketing and distributing unique drugs for the treatment of rare and orphan diseases. The company has brought ten medicinal products to market since its debut in 1990. With 120 employees and subsidiaries in nine European countries and the United Arab Emirates, Orphan Europe reported sales of 40 million euros for 2006. In a recent press release, Recordati founder and CEO Giovanni Recordati stated, “We believe that the market for drugs that treat rare diseases will grow significantly as a result of the identification of a constantly increasing number of rare diseases and the growing awareness which leads to more patients being diagnosed and treated.... Continuous scientific advances will result in an increase in available therapies.” Recordati was established in 1926 and has operations all over Europe, with a total staff of more than 2200. Headquartered in Milan, it is listed on the Italian stock exchange. The purchase of Orphan Europe is expected to conclude before the year’s end.
    Sixteen EMEA orphan drug designations for October

    The COMP (Committee for Orphan Medicinal Products) adopted the following 16 positive opinions on orphan medicinal product designation at its October meeting for the treatment of:

    - Gaucher disease
    - tuberculosis
    - malignant gastrointestinal stromal tumours
    - spinal cord injury
    - malaria
    - acute myeloid leukaemia
    - Castleman's disease
    - glioma (two products)
    - Crigler-Najjar syndrome
    - ovarian cancer
    - small cell lung cancer
    - acute lung injury
    - retinitis pigmentosa
    - prevention of recurrent hepatitis C virus induced liver disease in liver transplant recipients
    - pulmonary arterial hypertension

    Consult the European Registry for Orphan designations
    Consult the Orphanet list of orphan drugs authorised for marketing in Europe

    Negative opinion adopted for extension of miglustat to treat Niemann-Pick type C
    The CHMP adopted a negative opinion for an application to extend the indication of Zavesca (miglustat) to treat neurological manifestations in patients with Niemann-Pick type C disease, an inherited neurodegenerative disease of childhood and adolescence. Zavesca, produced by Actelion Ltd, is an orphan medicinal product currently approved for the oral treatment of mild to moderate type 1 Gaucher disease. A separate question-and-answer document explaining the rationale for the negative opinion for the extension of indication is available on the EMEA website.

    What's on Where?
    International Conference on Rare Diseases and Orphan Drugs
    Date: 5-8 November 2007
    Venue: Rome, Italy

    The aims of the conference are to illustrate national and international rare disease and orphan drug activities and promote new Italian advances within a European context.
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    Medicines For Rare Diseases: An Opportunity for Patients, Science and Industry
    Date: 9 November 2007
    Venue: Dublin, Ireland

    The Irish Medicines Board, in conjunction with the Irish Platform for Patients Organisations, Science and Industry, will host this information conference addressing the development and regulation of orphan medicines.
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    Euro-Ataxia AGM 2007
    Date: 9-10 November 2007
    Venue: Paris, France

    Topics include advances in fundamental and clinical research, and promoting awareness in medicine, science and society.
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    Second World Congress on Hypospadias and Disorders of Sex Development
    Date: 16-18 November 2007
    Venue: Rome, Italy

    Topics include new insights in sex determination and differentiation; genes and sexual differentiation; gender assignment; medical management of DSD in the infant, child and adolescent; surgical approaches; and psychosocial management.
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    2nd Pan Arab Human Genetics Conference
    Date: 20-22 November 2007
    Venue: Dubai, United Arab Emirates

    Topics include ethical perspectives as well as a scientific programme including newborn screening, genetic disorders in Arab populations, complex and recessive disorders, premarital genetic screening, mutation detection, and establishing databases.
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    First Egyptian-German Workshop on Disorders of Sex Development
    Date: 24-25 November 2007
    Venue: Cairo, Egypt

    Topics include epidemiology, cytogenetic and biochemical analyses, molecular basis, diagnostic and therapeutic surgery, cultural and religious perspectives, and clinical managements.
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    4th European Conference on Rare Diseases (ECRD 2007)
    Date: 27-28 November 2007
    Venue: Lisbon, Portugal

    This important rare disease conference will be held in English and simultaneously translated into French, German, Portuguese and Spanish. Several satellite meetings are being organised the day before the conference, including a Workshop on Rare Disease Help Lines. To register for the workshop.
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    15th Annual Meeting, Int'l ALS/MND Associations Alliance & 18th ALS/MND Int'l Symposium
    Date: 1-3 December 2007
    Venue: Toronto, Canada
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    Lowe Syndrome Second International Symposium
    Date: 7 December 2007
    Venue: London, England

    Molecular and clinical advances in Lowe syndrome.
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    EuroGentest Workshop: Towards Accreditation-Managing the Human Side of Change
    Date: 7-8 February 2008
    Venue: Nice, France

    Within the context of introducing quality management leading toward accreditation, this workshop addresses overall insights into the ‘human, behavioural’ side of change with techniques to manage this part of the change process, using case studies and role play to help apply these insights and techniques to real life situations.
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    9th European Congress of Neuropathology
    Date: 8-10 May 2008
    Venue: Athens, Greece

    Neuropathological topics, including tumours of the central nervous system and epilepsy.
    For further details

    Fourth International Neuroacanthocytosis Symposium: Bridging Clinical and Basic Aspects
    Date: 1-2 July 2008
    Venue: Oxford and London, England

    Including clinical aspects of chorea acanthocytosis and McLeod syndrome, muscle and nerve neuropathology and syndromes related to NA.
    For further details

    6th World Rett Syndrome Congress
    Date: 10-13 October 2008
    Venue: Paris, France

    Various aspects of Rett syndrome and MECP2 functioning, including fundamental, clinical and management topics.
    For further details


    Press & Publications
    An epidemiologic survey of rare diseases in disabled children
    The Archives of Disease in Childhood has published a survey striving to determine the percentage of rare diseases in severely impaired school-aged children. Impairments included mental, sensorial, neuromuscular, skeletal and movement-related disorders. The survey found 26% of the impairments related to rare diseases, while another 36% had an undetermined origin. The proportion of rare disease implication varied according to type of impairment. Improved survival has lead to an increase in prevalence over time.
    Aging with haemophilia
    Therapeutic intervention has resulted in a significantly increased life expectancy for haemophiliac patients. However, longevity in patients who grew up during a time of limited treatment presents special challenges of comorbidity alongside the common diseases linked to aging. A new book, Aging with Haemophilia - Medical and Psychosocial Impact addresses medical and social issues related to the aging haemophiliac population. The book addresses specific diseases in relation to haemophilia, explores how to avoid complications, and includes a summary of recommendations, as well as a chapter on perspectives and practical advice. Authors: EP Mauser-Bunschoten, A de Knecht-van Eekelen, C Smit
    Publisher: Van Creveldkliniek-Haematology, Utrecht, 2007


    Orphanews Europe, the newsletter of the Rare Diseases Task Force
    Orphanews Europe is supported by the European Commission's DG SANCO
    and the French Muscular Dystrophy Association (AFM)
    Editor-in-chief: Ségolène Aymé
    Editor: Louise Taylor
    Contact Us
    Editorial Board: Ségolène Aymé, Catherine Berens, Helen Dolk, Anders Fasth, Edmund Jessop, Matthieu Levi-Strauss, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Claire Scharf-Kroener, Janos Sandor, Arrigo Schieppati, Rumen Stefanov, Domenica Taruscio, Joan Luis Vives Corrons
    For more information on the Rare Diseases Task Force
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