14 March 2007 print
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Orphanet celebrates its 10th anniversary at a conference held on 15 February at the French Ministry of Health

Orphanet held a 1-day conference last month to celebrate its 10th birthday, at which its chief collaborators, healthcare professionals and patients organizations presented their accounts, appreciations and comments on the creation of the European database, its evolution and its current place on the international internet scene. The key players in the Orphanet adventure had all convened at the French Ministry of Health: Members of the 1996 Working Group responsible for Orphanet’s conception, key health politicians, geneticists, physicians, scientists, patients and their support groups, as well as the Orphanet team itself. The day was punctuated by presentations from the major institutions which have supported Orphanet over the years: the French Health Ministry (DGS), the French National Institute for Health and Medical Research (INSERM) and the European Commission, represented by John Ryan from the Commission's Directorate of Public Health and Risk Assessment. All were present to retrace and relive the determining events between 1997 and 2007. Their enthusiastic eye witness accounts and presentations also took into account the difficulties related to the challenge faced by many ten years ago.

Within the initial Working Group set up in 1996 to determine the creation of Orphanet, three exceptional ladies were to play a determining role in the Orphanet venture. The first was Simone Veil, former French minister and first woman President of the European Parliament, famous for her active role in European politics. The second, Annie Wolf of the Mission des Médicaments Orphelins, was just back from a fact-finding mission in the USA where the US Orphan Drug Act had already created orphan drug legislation and where she had met key international figures Abbey Meyers, President of NORD and Marlene Haffner of the FDA. The third grande dame is of course the future Director of Orphanet herself, Ségolène Aymé, who had already been singled out for her expertise and energy as an experienced geneticist in the rare disease field. Together, these three women had a remarkable impact on events moving towards the creation of a totally innovatory European database.

Back then in the France of 1996, the first “Internet militants” were gaining momentum and “Accessibility for All!” was the catchphrase as Orphanet started to take shape. The idea was, and still is, to provide a truly accessible, free electronic information on rare diseases for Europe now in 6 European languages. Ten years on, the Orphanet service is widely regarded as a “model” in its field and is the world’s Number One website on rare diseases and orphan drugs. In spite of a unique “avant-garde” approach, the creation of the project was confronted by many obstacles. Internet was at that time reserved for a limited network of specialists and the concept of a database with open access in several languages seemed somewhat crazy. Times have changed since then, but it was noted that doctors at that time were suspicious about posting up serious medical texts on the Net as this was still considered as “dangerous”!

During the birthday conference, Orphanet appeared first and foremost as a centralising force for information capable of breaking the isolation of both patients and healthcare professionals. Representatives of patients and their families were given the opportunity to speak about the importance of information that is precise, objective and transparent especially when on the bumpy road to diagnosis and specific healthcare. Examples were given through personal accounts of isolated patients whose lives were dramatically improved by Orphanet’s services, sometimes in countries such as Reunion Island, where access to reliable medical information can be limited. Orphanet’s 35 European partners were represented in a particularly lively panel discussion. The partners are coordinated from the Paris headquarters, however various political, economical or social contexts in each of the European partner countries had produced a range of obstacles encountered by the local teams. The Swiss coordinator, Loredana d’Amato-Sizonenko, provided an interesting illustration of this in her own country, where for each national decision made, she has to obtain the authorisation of no fewer than 26 cantons used to communicating in three different languages!

This Birthday event drew to a close with a simple but memorable conclusion: if Orphanet has managed to keep pace with its users’ needs over the past 10 years, it is thanks to the meeting of men and women each with his or her own particular contribution, working towards a common aim: helping patients across Europe living with rare diseases.

Read the Report on 10 years of Orphanet activities (in French only - English version to come shortly)

Read the address of the French Minister of Health (in French only)

The conference was filmed and will soon be webcast by the “U medicine” Channel. Further details will be given soon.

Read highlights of the presentations given at Orphanet’s 10th anniversary:

Introduction on Orphanet's services by Ségolène Aymé
Presentation on Orphanet's Orphan Drug services by Annick Dubosq
Presentation on Orphanet's Health services by Ana Rath
Presentation on Orphanet's Patient services by Marc Hanauer
Presentation on Orphanet's Research services by Valérie Thibaudeau



A new Communication from the Commission for scientific information in the digital age

The dissemination of scientific research results and access to the resulting information is central both to research funding policies and to the overall excellence of European research. Following a major consultative process on this subject by the European Commission involving the chief players from major publishing companies and libraries, learned societies and research-funding organisations, a new Communication was adopted on 14 February this year. This has launched a policy process on access and dissemination with regard to scientific information and strategies for the preservation of scientific information across the EU described by the Commission as “the pillar of the research system”. This policy is emerging at a strategic moment in the EC’s research programme, with a €50 billion FP7 research investment over the 2007-2013 period to develop the European Research Area (ERA). Whilst the Communication has no legal clout, it is expected to lead to important future legislation on this subject, taking on the “open access” issue already hotly debated in all quarters of the scientific information sector.

One of the interesting facts thrown up by the Communication notes that 2 000 scientific journal publishers worldwide, producing some 1.4 million articles a year, approximately 780 of whom are based in the EU, produce nearly 50% of total journal output and employ 36 000 employees in Europe. This large overall workforce directly concerned by the science information sector represents a substantial part of the world market in the sector. The Communication addresses the major debates in this field, including dissemination and access strategies (notably Open Access), publishing business models such as reader-pay and author-pay as well as science publication and its relation to quality of research. Following a public consultation held over several months last year, a set of recent guidelines entitled a Study on the economic and technical evolution of the scientific publication markets in Europe – Final Report January 2006 has provided some essential background to the Communication. In addition, a Conference at the European Commission in Brussels last month looked further into the issues concerned. A multi-functional web-tool called SINAPSE now provides a platform for the scientific publication system debate, aiming to create closer links between scientific advice and policy-making. One of its immediate tasks is to construct a “Yellow Pages” of European scientific expertise.

Read the European Research Council (ERC) Scientific Council Statement on open access (Dec 2006)

Consult the European Commission webpages on Scientific Publications



DG SANCO launches a new Call for Proposals 2007

As part of its Programme of Community Action in the field of Public Health (2003-2008), DG SANCO has launched a new Call for Proposals on 16 February 2007. Following the adoption of the Public Health Programme’s 2007 Work Plan earlier the same month, the Public Health Executive Agency published a Call for Proposals on 16 February 2007. The programme is based on 3 main objectives: health information, health risks and health determinants.

Submissions deadline: 21 May 2007
Thereafter the Public Health Executive Agency (PHEA) will undertake the evaluation of the submitted proposals. The selection procedure is expected to last until autumn 2007. No information on the evaluation of projects can be provided during the selection procedure.
This year, the call will be focussed on certain key actions taken on previously and on several new fields not previously covered by submitted proposals made following earlier calls. The projects to be financed should be innovatory and should not take place over a period of more than 3 years.

With regard to rare diseases, projects should be concentrated on the following aspects :

  • Development of strategies and mechanisms for exchange of information between patients with a rare disease and action to help improve epidemiological studies, codification, classification and definitions

  • Support to European network centres of reference for rare diseases aiming at developing recommendations of best practice in terms of treatment, sharing of information on diseases and performance evaluation.

  • The total amount of funds given to this call for proposals is estimated at €33 800 000. Given the complementary and motivating effects of Community funding, at least 40% of project costs must be funded by other sources.



    Other European news
    First trans-national Call for Proposals for European research projects on rare diseases

    The ERA-Net for research programmes on rare diseases (E-Rare) has been established to coordinate the research efforts of European countries in the field of rare diseases. Ten partners are taking part in this project which is coordinated by the French Institute for Research on Rare diseases/Inserm. The six E-Rare partners include the National Research Agency (ANR), France; the Federal Ministry of Education and Research (BMBF), Germany; the National Institute of Health (ISS), Italy; the Chief Scientist Office of the Ministry of Health (CSO/MOH), Israel; the Institute of Health Carlos III (ISCIII), Spain; the Scientific and Technological Research Council of Turkey (TÜBITAK), Turkey. These partners have decided to open the first joint Call for funding multilateral trans-national research projects on rare diseases.

    The aim of the Call is to enable scientists in different countries to build an effective collaboration on a common research project based on complementarities and the sharing of expertise. The projects shall involve a group of rare diseases or a single rare disease according to the European definition i.e. a disease affecting not more than 5:10,000 persons in the EU.

    Further information can be obtained from the E-Rare web site

    Steps have been taken to develop a National Plan for Rare Diseases in Spain

    On 21 February, the Spanish Senate unanimously approved a Request to the Government to develop an "Action Plan for Rare Diseases", that will be developed in collaboration with the ministries of Health, Social Services, Education, the appropriate scientific societies and FEDER. This Plan requests that the government set up an integral approach to manage rare disease in terms of medical, educative and social assistance for the 3 million persons in Spain affected with rare diseases. The Senate recommends the creation of an organization for rare diseases (OEER), dependent on the National System of Health that will be in charge of the promotion of research, training and recompilation of information in the field of rare diseases. FEDER (The Spanish Association of Rare Diseases Support Groups) evaluated positively this first step in a long road to a National Plan for RD, and expressed its wishes that this plan be supported by a specific budget to fund it.

    This initiative is intended to reinforce the Royal Decree approved last November, for establishing the procedures to designate and accreditate Centres of Reference in the Spanish National Health System. A commission has been created and a budget approved to evaluate and designate the type of Reference Centers that would be so necessary for the appropriate management of Rare Diseases. To this date, the public health system is still not covering the real needs of patients affected by rare diseases.

    This is one of the 23 conclusions that have been published by the organizers of the "3rd International Congress of Orphan Drugs and Rare Diseases", FEDER and the "Real e Ilustre Colegio Oficial de Farmacéuticos de Sevilla". Some of the conclusions were to propose the creation of a general registry of patients affected by rare diseases, and promote the exchange of information between professionals in primary care and hospital specialists. Several participants in the meeting pointed out the difficulties for clinicians to access orphan drugs and compassionate care, because of their inexperience in the field and because of the administrative problems related to pharmaceutical costs. Much attention was also paid to the creation of centres or reference for a specific group of diseases and the need for help for the families, such as housing the affected people in the cities where the reference centres will be located.

    EPPOSI calls for closer patient-science-industry collaboration for innovatory developments
    At the recent EPPOSI Conference in Dublin, co-organised with the EC’s DG Enterprise, the EPPOSI co-chairs representing patients, science and industry identified major proposals for improvements in collaboration between the leading players in Europe. The European Platform for Patients’ Organisations, Science and Industry has made the following bids for across-the-board development and innovation through the following actions:

    • Closer clinical collaboration and transparency with increased access to therapies
    • Simplification of the current treatment development procedure
    • Harmonization of reimbursement schemes
    • Improved communication about risk
    • Greater appreciation of science in human terms

    Concerns were expressed about the isolation of industry and regulation often resulting in unnecessary duplication. It was considered that “spectacular savings” could be made if concerted actions were made to avoid duplicated testing and analysis. One of the co-chairs, Erik Tambuyzer, said that clinical development and regulatory approval outgoings were a major source of soaring costs and did not translate into improved benefits for patients. He stressed the importance of “streamlining” the 3 phases of clinical trial to bring costs down and encourage governments and health systems to look more favourably upon new treatments developed.

    Alastair Kent, a fellow EPPOSI co-chair, claimed that currently “only 3 out of 10 drugs pay for themselves”. It was time to encourage the players involved to reassess treatments in order to weed out “poorly used or ineffective treatments” thereby lightening the burden of the European reimbursement schemes. Greater harmonisation involving more working in tandem with EU consensus was important to avoid current scenarios by which poorer EU states from Eastern Europe were found to be paying more than their richer neighbours.

    The Conference identified that the communication of risk information was crucial. It was more important to “educate patients” about the risks involved in order to accept a very small risk with a treatment (eg based on an established 99.5 success rate) and allow them to decide for themselves, since the enormous costs often involved in the very slight improvement of this risk were prohibitive. Finally, the EPPOSI co-chairs highlighted the general need to put Science higher up on the agenda in terms of human investment, rather than in terms of infrastructure only. An example was given of a taxi-driver in Paris being better paid than a fully trained scientist in the same country.

    Read the EPPOSI press release



    New Calls for Proposals at the Brocher Foundation
    The Brocher Foundation is calling for scientific projects to be undertaken during 1-6 month stays in Geneva where it is based. It is inviting submissions from researchers on the following topics:

    • Ethical, legal and social issues relating to genetics
    • Ethical, legal and social issues relating to biotechnologies, biomedical engineering or nanomedicine
    • Health law, healthcare economy, philosophical approaches to healthcare or biotechnologies.

    Deadline: 15 May 2007

    Read the full Brocher Foundation Call for scientific proposals



    New diseases & syndromes
    Anophthalmia associated with malformations of the lungs, the heart, the diaphragm and intellectual deficiency

    Four members of two consanguineous families manifest a malformation syndrome characterized by anophthalmia associated with alveolar capillary dysplasia, congenital cardiac disorders or a hernia of the diaphragm. Some homozygous mutations in the STRA6 gene would appear to be the cause of the pathology. The function of this gene has not yet been fully understood.
    Read the Pubmed abstract

    Am J Hum Genet. ; 80(3):550-60 ; Mar 2007
    Lactic acidosis, hypertrophic cardiomyopathy and muscular hypotonia: a new disorder of the respiratory chain

    Two sisters from a non consanguineous Turkish family were born with lactic acidosis, hypertrophic cardiomyopathy and muscular hypotonia. The two children died before reaching one year of age. Researchers identified a homozygous mutation in the exon 3A of the SLC25A3 gene, encoding a transporter of the mitochondrial membrane. Through alternative splicing, the expression of this exon is limited to the muscular tissues, which explains the selectivity fault of the ATP synthesis.
    Read the Pubmed abstract

    Am J Hum Genet. ; 80(3):478-84 ; Mar 2007
    Severe metabolic disorders associated with a dolichol kinase deficiency in four patients

    Four patients from two consanguineous families manifest variable clinical signs marked, among others, by muscular hypotonia and ichtyosis and associated with early childhood death. Deficiency in dolichol kinase 1 (DK1), an enzyme implicated in neosynthesis of the dolichol phosphate, is the cause of the disease. The mutations, which are identified in DK1 genes, are responsible for a 96 - 98 % diminution of enzyme activity.
    Read the Pubmed abstract

    Am J Hum Genet. ; 80(3):433-40 ; Mar 2007
    Ichtyosis and hypotrichosis are associated in a new autosomal recessive syndrome

    Three members of an Israeli-Arab consanguineous family manifest congenital ichtyosis and an under-developed pilous system. A linkage analysis associated with a candidate gene approach has made it possible to identify a missense mutation in the ST14 gene, encoding maltriptase, a new protease of the trypsin type. Analysis of patients’ skin samples suggests this enzyme plays a role in the desquamation of the epidermis.
    Read the Pubmed abstract

    Am J Hum Genet. ; 80(3):467-77 ; Mar 2007


    New genes
    Mutations in the SPG11 gene are a major cause of spastic paraplegia marked by agenesis of the corpus callosum

    Spastic paraplegia associated with agenesis of the corpus callosum is apparent by learning difficulties from early childhood progressing towards a syndrome of the frontal type over a period of 10 - 20 years. A French team and an Italian team with the help of the Mediterranean clinical network SPATAX, have just identified a SPG11 gene mutation in most familial forms (11 out of 12 families studied). This gene is expressed in the nervous system but, to date, its function is still unknown.

    To read more about ""

    Nature Genetics published online ; | doi:10.1038/ng1980 ; 18 Feb 2007
    A new X-linked gene associated with the development of Wilms’ tumour

    In children, the Wilms’ tumour is the most common renal cancer. In 5 - 10% of cases, it is associated with the inactivation of two alleles of the tumour suppressor gene WT1. In order to determine the origin of non WT1 mutated tumours, Rivera et al. have researched new genetic alterations. In approximately one third of cases, they have discovered a somatic deletion of the WTX gene, carried by X chromosome. This gene, like WT1, is normally expressed in embryonic kidney. The high incidence of WTX deletions is probably linked to its chromosomal localisation: the inactivation of the only allele carried by the single X chromosome in men or by the active X chromosome in women is sufficient to abolish completely the function of this tumour suppressor.

    To read more about ""

    Science ; 315(5812):642-5 ; Feb 2007
    Mutations of the NDUFA1 gene are responsible for X-linked mitochondrial encephalomyopathy

    The deficiency of the respiratory chain complex I is responsible for a variety of clinical symptoms including neurological disorders, cardiomyopathies and hepatic insufficiency. Mutations in 9 of the genes of this complex have been identified to date, however they only represent a minority of cases observed. In addition, preliminary studies have shown a mainly masculine transmission in certain families. In accordance with these observations, Fernandez-Moreira et al. have just identified in patients with encephalomyopathy, mutations in the NDUFA1 gene carried by X chromosome, which encodes one of the components of complex I respiratory chain. This has the effect of diminishing the quantity of complex normally formed, suggesting a dysfunction of its assembly/joining or stability.

    To read more about ""

    Ann Neurol. ; 61(1):73-83 ; Jan 2007
    Gene mutations in the cohesin complex are responsible for mild forms of Cornelia de Lange syndrome

    The Cornelia de Lange syndrome is a malformative syndrome characterised by dysmorphia and accompanied by mental deficiency of variable severity, major growth anomalies of the extremities and sometimes cardiac or renal malformations. Recently, mutations of the SMC1A gene have been associated with this syndrome. In this study, researchers have for the first time identified a mutation in the SMC3 gene and 14 new SMC1A mutations in patients manifesting mild forms of the disease. SMC1A and SMC3 encode the two sub-units of the cohesin complex which is implicated in the segregation of sister chromatides. The proteins expressed in these patients seem functional but the dynamics of the cohesin complex could be disturbed.
    Read the Pubmed abstract

    To read more about ""

    Am J Hum Genet. ; 80(3):485-94 ; Mar 2007
    ERCC1 mutations associated with the Cerebro-Oculo-Facio-Skeletal Syndrome suggest a new function for this protein

    The nucleotide excision by endonucleases, including the ERCC1-XPF complex, makes it possible to repair certain DNA lesions. In accordance with this function, the XPF deficit can be the cause of syndromes such as progeria or xeroderma pigmentosum. In this study, the researchers have for the first time identified mutations in the ERCC1 gene. Surprisingly, the patient’s cells manifest only a slight hypersensitivity to DNA-modifying agents (mitomycin C ultra-violet rays) and clinical signs are typical of severe forms of the cerebro-oculo-facio-skeletal syndrome. These observations suggest a new role for ERCC1.
    Read the Pubmed abstract

    To read more about ""

    Am J Hum Genet. ; 80(3):457-66 ; Mar 2007
    Deregulation of the TAF1 gene in X-linked dystonia and parkinsonism

    X-linked dystonia and parkinsonism is an endemic movement disorder in the Philippines. Previous studies have associated the locus DYT3 to transmission of the disease. Makino et al. have undertaken a sequence analysis of the locus and expression studies in patients’ cerebral tissue. They thereby identified the insertion of a retrotransposon in an intron of the TAF1 gene which encodes one of the components of the TFIID transcription complex. This results in the caudate nucleus in a diminution of the level of expression of an isoform of TAF1 itself and of the D2 receptor to dopamine.

    To read more about ""

    Am J Hum Genet. ; 80(3):393-406 ; Mar 2007


    New fundamental research
    Neutral polymorphism prevents the deleterious effect of a mutation associated with MCAD deficiency

    MCAD deficiency (medium chain acyl-CoA deshydrogenase) is characterised by episodes of hypoketosic hypoglycemia with hepatomegalia, appearing at times of prolonged fasting or of infections, generally before the child’s second year. Nielsen et al. have analysed the effect of a missense mutation and a polymorphism situated in the exon 5 of the MCAD gene. They have been able to establish that the mutation, associated with the disease’s development, modifies a regulatory splicing sequence and provokes exon 5 skipping and production of a non functional protein. The polymorphism, which affects an antagonist regulatory splicing sequence, does not modify the protein’s structure or fonction. On the other hand, associated with the mutation, it reestablishes the normal splicing and the expression of a functional enzyme. This mechanism, which demonstrates the importance of the context on the deleterious effect of a mutation could, over time, trigger off new therapeutic approaches.

    To read more about ""

    Am J Hum Genet. ; 80(3):416-32 ; Mar 2007
    An overdose of the cleaved form of prolactin in primitive gravidic myopathy

    Primitive gravidic myopathy is a disease the origin of which is unknown. It is distinguished by a high risk of cardiac insufficiency during pregnancy. Hilfiker-Kleiner et al. have observed a similar phenotype in mice invalidated for the STAT3 transcription factor in cardiomyocytes. In these animals, the loss of STAT3 provokes an increase in the expression and activity of cardiac cathepsin D which is associated with a particular cleavage of hormone prolactin. By analogy, researchers have observed in patients a reduction in STAT3 cardiac level associated with an increase in cathepsin D-cleaved circulating prolactin. Inhibiting the prolactin cleavage could therefore become a new therapeutic strategy in the treatment of primitive gravidic myopathy.

    To read more about ""

    Cell ; 128(3):589-600 ; 9 Feb 2007
    Pycnodysostosis : the role of cathepsine K in bone homeostasis

    Pycnodysostosis is a bone disease caused by a deficit in the lysosomal enzyme, cathepsin K. In order to understand the mechanism of this pathology, researchers have established a mouse strain deficient in cathepsin K which manifest characteristics of the disease. The osteoclasts of these mice proliferate due to an apoptosis and senescence fault. Cathepsin K appears to play a major role in bone homeostasis modulating the regulation of these two processes.
    Read the Pubmed abstract

    To read more about ""

    Human Molecular Genetics ; 16(4):410-23 ; 15 Feb 2007
    Charcot-Marie-Tooth disease type 1A: effects of an anti-progesterone treatment in adult rats

    Charcot-Marie-Tooth disease type 1A is a demyelinisating form of neuropathy caused by the duplication of the Pmp22 gene. A preliminary study has shown that a treatment using anti-progesterone onapristone in young rats has a beneficial effect on the neuropathological phenotype. Researchers have tested the effects of a long-term treatment by onapristone in adult rats representing a better model of the disease. They observed a decrease in the expression of Pmp22 correlating with an improvement in strength and muscular mass. In addition, contrary to the axonal loss, the demyelinisation is not corrected, which suggests that this loss is not due to a myelinisation problem.
    Read the Pubmed abstract

    To read more about ""

    Ann Neurol. ; 61(1):61-72 ; Jan 2007


    New clinical research
    Aneuploidy detected by the analysis of placental RNA or fetal DNA in maternal plasma

    Current prenatal diagnostic methods of aneuploidy, such as amniocentesis, are invasive techniques which are risky for the fetus. Two studies published recently describe the development of screening tests based on the analysis of a maternal blood sample. The approach of Lo et al. relies on the analysis of an RNA messenger transcribed from the chromosome of interest and expressed exclusively in the placenta (in this case PLAC4 on chromosome 21). For a polymorphic heterozygous sequence in the fœtus, the measurement in the maternal plasma of the ratio of alleles expressed in placenta makes it possible to deduct the ploïdy of the chromosome. The approach of Dhallan et al. relies on the analysis of different DNA polymorphisms present in homozygotes form in the two parents. The comparison, for different chromosomes, of the ratio in the maternal plasma between the single allele transmitted by the father and the maternal allele present in the fetal and maternal DNA is a direct indicator to the number of copies of the chromosomal region concerned. None of these tests gives a definitive diagnosis, however they can provide a support to screening tests in pregnant women who wish for this.

    Lancet ; 369(9560):474-81 ; Feb 2007
    Nature ; 13(2):218-223 ; Mar 2007
    Digenic transmission explains the phenotypical variability in families with hypogonadotrophic hypogonadism

    In families affected by idiopathic hypogonadotrophic hypogonadism, an inter- and intra-familial variability in addition to an incomplete penetrance indicate a multifactorial transmission. Pitteloud et al. present a study of two families, one associating a heterozygous mutation of the FGFR1 gene to variable forms of the Kallmann syndrome (hypogonadotrophic hypogonadism associated with an anosmia), and the other where composite heterozygous mutations of the GNRHR gene are linked to hypogonadotrophic hypogonadism. The analysis of other candidate gene sequences has made it possible for them to identify supplementary heterozygous mutations respectively in the NELF and FGFR1 genes. The digenic transmission explains both the phenotypical variability and the severity of the phenotypes sometimes observed.

    To read more about ""
    To read more about ""

    J Clin Invest. ; 117(2):457-463 ; Feb 2007
    Mutations in the KRAS gene associated with extremely variable clinical signs

    The Noonan and Costello syndromes, and the cardio-facio-cutaneous syndrome are developmental disorders marked by congenital anomalies such as cardiac deficiencies. The deregulation in the RAS-MAPK signalisation can cause each of these disorders, which suggests a common pathological mechanism. Zenker et al. have analysed a sequence of the KRAS gene in 260 patients. For the first time, they have been able to associate mutations of this gene to the Costello syndrome. In addition, their study points out a correlation between genotypes and phenotypes: in Noonan syndrome, the patients carrying KRAS mutations and those carrying PTPN11 gene mutations manifest different clinical signs and in the cardio-facio-cutaneous syndrome, clinical differences are noticed between patients carrying KRAS, BRAF or MEK1 mutations.

    To read more about ""
    To read more about ""
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    J Med Genet. ; 44(2):131-5 ; Feb 2007
    Progressive somatic expansion of a GAA triplet-repeat sequence in the ganglia of patients with Friedreich’s ataxia

    Friedreich’s ataxia is due to an expansion of GAA triplet-repeat sequence in the FXN gene. Patients develop an ataxia caused by neurodegeneration of the dorsal root ganglia, particularly sensitive to FXN deficiency. Aiming to explain the progressive nature of the disease,de Biase et al. have analysed the expansion of the triplet-repeat sequence in the dorsal root ganglia in comparison with other patients’ tissue. They have shown a specific accumulation of triplets in the dorsal root ganglia compared to other tissue. The somatic accumulation of GAA triplet-repeat sequence specifically in the ganglia and in an age-dependent manner could therefore contribute to the progress of the disease.

    To read more about ""

    Ann Neurol. ; 61(1):55-60 ; Jan 2007
    A new genetic diagnostic test in Usher syndrome

    Usher syndrome is characterized by a pigmentary retinitis and deafness. It is remarkable for its genetic heterogeneity (twelve independent loci identified to date) which could pose problems for genetic diagnosis. Cremers et al. have developed a DNA microarray making it possible to test 298 alleles known for their association with the syndrome. The already genotyped patients’ DNA indicates a precision detection of mutations which is more than 98%. This method therefore represents an efficient tool for the genetic diagnosis of this disease.

    To read more about ""

    J Med Genet. ; 44(2):153-60. Epub 2006 Sep 8 ; Feb 2007
    Angelman Syndrome: call for patients

    As part of a study on Angelman’s syndrome, two research teams would like to collaborate with patients and their families. The first team is interested by the syndrome’s natural history with the aim of improving the quality of life and longevity of patients. The second team is seeking to evaluate the treatment benefits of Metafolin (L-5-methyltetrahydrofolate), vitamin B12 creatine and betaine in children. The patients and their families can find out more from their family doctor.

    Read the Call for patients



    New therapeutic & diagnostic approaches
    The genetic expression profile of the donor could indicate risks in developing a graft versus host disease

    After an allogeneic transplant of hematopoietic cells, the T-cells of the donor recognize the host’s antigens provoking known complications in the name of graft versus host disease. However, the histoincompatibility does not seem to be the only cause of the disease. Canadian researchers analysed then compared the gene expression profiles of the T-cells of donors for which the receivers have developed the disease. They have thus shown certain common characteristics to all the donors believed to be “dangerous”, for which the host’s complications have been observed. This way, either the expression profile of the genes regulating the signalisation path of the TGF-beta or the cellular proliferation, appear to be an indicator of the risks taken by the receiver.
    Read the Pubmed abstract

    To read more about ""

    PLoS Med. ; 4(1): e23 ; Jan 2007
    New clinical signs in Schimke immuno-osseous dysplasia

    Schimke immuno-osseous dysplasia is an autosomal recessive disorder caused by the loss of function of the SMARCAL1 protein. The autopsy of two patients with a severe form of the disease made it possible to see new clinical signs which should be checked, such as pulmonary hypertension, combined immunodeficiency, sub-cortical ischemic dementia and cardiac anomalies.
    Read the Pubmed abstract

    To read more about ""

    J Med Genet. ; 44(2):122-30 ; Feb 2007


    Genetic testing
    MCAD deficiency screening in England reveals some interesting developments in early detection methods

    The UK Department of Health has announced it is to screen all newborn babies in England for the metabolic disorder Medium Chain Acyl CoA Dehydrogenase (MCAD) deficiency. This rare inherited metabolic disease, which affects between one in 10,000 and one in 20,000 births, reduces the ability to maintain a normal blood sugar level at times of metabolic stress. The disorder can result in death and severe neurological damage in affected children. Early detection plays a key role in reducing the risk of death and disability. The new MCAD deficiency test, due to be introduced by March 2009, will be integrated into the standard Newborn Screening Programme in England , which already tests “heel-prick” bloodspot samples from newborn babies for the genetic diseases phenylketonuria, congenital hypothyroidism, sickle cell disorders and cystic fibrosis.

    The UK National Screening Committee (NSC) has been running a pilot study for MCAD deficiency screening of newborns since 2004, during which time over a million babies have already been screened. The final report was due in 2008 but the screening operation has had sufficiently convincing results for the NSC to recommend that the national screening programme be implemented.

    Read the UK Dept of Health Press Release

    To read more about ""



    The Orphanet Journal of Rare Diseases : 1 year on already!
    Just one year after its creation, the Orphanet Journal of Rare Diseases (OJRD), the first scientific journal entirely dedicated to rare diseases and orphan drugs, has already achieved an impressive track record.

    Of its 73 articles submitted to the Journal’s specialist peer reviewers, 55 have been commissioned (giving an overall acceptance ratio of 3:1). The 60 published articles in its first year include the following types of papers: 1 Editorial, 1 original research paper, 2 case studies, 2 case reports and 54 review articles. The Journal gives researchers and clinicians the opportunity to publish state-of-art developments in the rare disease field enabling them to announce new syndromes, orphan drug events and clinical trial results (including those with negative results). Its 37-member Editorial board of prominent experts orients the Journal in its coverage of rare disease-related issues. The past year’s results and proportion of “Highly accessed” articles suggest that the OJRD attracts a wide range of professionals from all medical specialities as well as researchers from scientific fields such as genetics, biology and pharmacology, with a real demand for these review articles.

    Some key OJRD statistics:

  • 20% of Review articles written by invited experts have been labelled as “highly accessed”

  • The OJRD's "Top 10" most highly accessed articles have each been read by 2,000 - 4,700 readers and have already attracted a total 27,000 readers

  • OJRD’s latest published articles:

    Further phenotypic delineation of subtelomeric (terminal) 4q deletion with emphasis on intracranial and reproductive anatomy (Case Study)
    Health status of adults with Short Stature: A comparison with the normal population and one well-known chronic disease (Rheumatoid Arthritis) (Research)
    Cardiac tumours in children (Review)
    Neonatal diabetes mellitus: a disease linked to multiple mechanisms (Review)

    Published in the European Journal of Human Genetics, in association with Orphanet: Sotos syndrome



    Is your project feeling lonely?... Von-Hipple Lindau disease
    Hashemi Soteh from the Sari Medical faculty and Thalassemia Research Center in Mazandaran, Iran, would like to hear from anybody interested in mutation detection on VHL genes in patients with Von-Hipple Lindau disease from Iran.

    Contact Dr Soteh

    To read more about ""



    Seven new positive opinions for orphan designations in February 2007

    At its 6 - 7 February meeting, the COMP (Committee for Orphan Medicinal Products) awarded a positive opinion for the orphan designation of seven medicinal products for the following indications:

    - Treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
    - Treatment of diffuse large B cell Lymphoma
    - Treatment of adrenal insufficiency
    - Treatment of Duchenne muscular dystrophy
    - Treatment of congenital alpha-1 anti-trypsin deficiency
    - Treatment of cryopyrine-associated periodic syndromes
    - Treatment of peripheral T-cell lymphoma

    Read the COMP report for February 2007
    Consult the European Register of Designated Orphan Medicinal Products

    Results of phase III positive results for Phenoptin®

    The results of a phase III study, carried out in double blind and controled with a placebo, indicate the efficiency and good tolerance profile of Phenoptin® (sapropterin dihydrochloride) used in association with an alimentary diet in 4-12-year-old children affected by phenylketonuria. The treatment by Phenoptin® has significantly increased tolerance to phenylalanine and reduces the amino acid blood concentration levels. Patients were able to double their phenylalanine intake over a period of 10 weeks on average while stabilising their blood amino acid concentration. Phenoptin® will enable patients to follow a less strict alimentary diet and reduce their need of complimentary aliments. BioMarin and Serono are ready to make their requests for approval in the USA and Europe for Phenoptin® in phenylketonuria respectively during the 2nd and 3rd terms in 2007.

    Alphanate® is approved for Willebrand’s disease in the USA

    The FDA has announced that it has just given marketing approval to Alphanate® for the treatment of Willebrand’s disease for use by patients undergoing surgery and other invasive procedures.
    Read the FDA’s press release

    To read more about ""



    New designations & authorisations in Europe
    The 35th OMP to receive a positive CHMP opinion: Cystadane
    The CHMP recommended marketing authorisation on 15 December 2006. Authorisation was acquired by Orphan Europe SARL. Cystadane® (betaine anhydrous) is indicated for the treatment of homocystinuria. The drug already has marketing authorisation in the US, Canada, Australia and Israel. On 15 February 2007, Orphan Europe received marketing authorization for Cystadane® in Europe.
    Read more about homocystinuria



    New ISSCR Guidelines for Human Embryonic Stem Cell Research
    The International Society for Stem Cell Research (ISSCR) has brought out a set of Guidelines for human embryonic stem cell (HESC) research. These include the major principles believed to be essential for guiding ethical stem cell research practices. The guidelines were formulated by a task force convened by the ISSCR and the texts were written by scientists, experts in ethics and legal affairs from 14 countries worldwide. They reflect the values put forth by the Committee on Guidelines for HESC Research of the US National Academy of Sciences (US NAS) and the Regulations of the California Institute for Regenerative Medicine. The Guidelines also acknowledge advanced governmental regulations already in use in other countries, including that of the Human Fertilisation and Embryology Authority of the UK. The ISSCR is the main scientific organisation representing stem cell scientists and transcends all other boundaries including geographical and political ones.

    The ISSCR Guidelines apply essentially to research relevant to derivation and use of pluripotent human stem cell lines and are not intended to take in adult stem cell research or human embryo of fetal tissue research. Instead, they aim to make international partnerships easier and encourage investigators and institutions to apply uniform practices. Furthermore, they are subservient to all laws and regulations of the country or region in which the research takes place.

    A cord stem cell storage bank looks likely to open in a UK public-private venture
    The UK’s Virgin Group has recently announced its intention to open Britain’s first umbilical cord stem cell storage bank, which it claims could save lives by treating conditions such as leukaemia and certain high-risk medical conditions. The technique will enable parents to store cells from their child’s umbilical cord for at least 20 years. This public-private venture differs from private bloodbank schemes in that only 20% of its biological samples will be kept for the family’s treatment of diseases in the future. The remaining 80% will be donated to public stem cell transplant authorities for immediate use if need be. Apart from a fee of approximately 2,250 euros paid by parents wishing to store the blood, no charge will be made to anyone requiring cellular treatment and able to find a sample providing a match. Virgin undertakes to invest half of all resulting profits to public stem cell research.

    Cord blood is rich in haematopoietic stem cells capable of growing and adapting to replace diseased or damaged cells. Bone marrow transplants are increasingly being replaced by cord blood, especially for treating leukaemia, since unlike adult bone marrow, it is untainted by exposure to infection or illness. Scientists claim that blood stem cells will be useful in the treatment of what is becoming known as “regenerative medicine” for diabetes, Parkinson’s disease and cancer but its future is still uncertain at this stage. The procedure is also advised to parents affected by rare and high-risk medical conditions, such as Fanconi anaemia, which may be treated with a transplant. The scheme has been cautiously applauded by the Lancet medical journal and the UK’s Royal College of Obstetricians and Gynaecologists (RCOG), the latter of which has published a RCOG Scientific Advisory Committee Opinion Paper on Cord Blood Banking. However, the RCOG has warned against resulting interference to mother and baby care through the collection of cord blood extracted from the placenta immediately following the birth, at “a critical time”.

    This still controversial procedure has found a degree of acceptance in the USA within the private sector. However earlier this year, the American Academy of Pediatrics issued a policy statement on cord blood banking, including recommendations on appropriate ethical and operational standards which are critical of this procedure, in particular when run by private ventures.



    Sanfilippo Alliance publishes a White Paper

    The French association, Alliance Sanfilippo, has published a white paper giving a critical in-depth status report on research currently being carried out worldwide on the Sanfilippo syndrome. This lysosomal storage disease, also known as mucopolysaccharidosis type III (MPS III), is characterized by severe and rapid intellectual deterioration. The paper presents a complete analysis of the disease, accompanied by research and therapeutic approaches which are currently available: genetic therapy, enzyme replacement therapy, as well as innovatory therapies such as substrate privation or use of antibiotics to “suppress” the reading of a premature “STOP” codon. Karen Aiach, who chairs the Alliance, points out that the chief objectives of this project are to identify the teams involved in the most promising research as well as their need to go “faster and further” in their work, to inform the families and rare disease community and finally make a contribution to research funding campaigns based on excellence, in science as well as in medicine.

    Read the White Paper

    Call for Patients: Angelman Syndrome
    To read the Call for Patients, go to Research in Action - Call for Patients


    New books
    It is MY life - A new Revolution - Patient Power
    Author: Simon Rozendaal
    Publisher: Uitgeverij Aspekt
    Price: 16€

    This book features a series of 12 interviews by patients from a variety of countries in Europe and elsewhere, about their contribution to research into rare diseases. Based on the author's personal experience, the contributors relate their own life story, their personal recipe for coping with a rare disease, and their resulting accomplishments in founding associations and contributing to the development of treatment for their particular disease. These portraits show how a patient’s involvement with a rare disease followed by close contacts with national and (increasingly) international medical and political forces can shape the person into an “expert patient” uniquely equipped to make a committed and proactive contribution in this field.

    Read more about this book



    Post Doc Position in Songbird Neurology at the University of Antwerp
    A Post Doc position in reporter gene imaging in songbird neurology will be available from April 2007 in the Bio Imaging Laboratory at the University of Antwerp in Belgium.

    Read more

    The Genetic Interest Group (GIG) is seeking a Senior Policy and Research Manager, UK
    The Genetic Interest Group (GIG) is recruiting a Senior Policy and Research Manager based in London, UK.

    Read more



    In March
    5th International Conference of the European Chromosome 11q Network
    Date: 22-25 March 2007
    Venue: Pforzheim-Hohenwart, Germany
    More details

    European Down Syndrome Association Gala Concert
    Date: 23 March 2007 (International Down Syndrome Day)
    Venue: Jussieu University Paris, France
    More details (in French only)

    European Conference on Down Syndrome
    Date: 23 - 24 March 2007
    Venue: Paris, France
    More details



    In May
    EURORDIS 10th Anniversary, Annual membership meeting & Workshop: gaining access to rare disease research resources
    Date: 4-5 May 2007
    Venue: Institut Pasteur, Paris, France
    More details

    6th International IPWSO Conference (Prader Willi International)
    Date: 17-20 May 2007
    Venue: Cologne, Germany
    More details



    In June
    Eurochromnet Meeting
    Venue: Copenhagen-Oslo ferry cruise
    Date: 1-3 June 2007
    More details

    European Human Genetics Conference 2007
    Date: 16-19 June 2007
    Venue: Nice, France
    More details



    In July
    8th Meeting of the International Skeletal Dysplasia Society
    9-22 July 2007
    Toulouse Lautrec Museum, Albi, France
    More details Conference Programme



    In September
    European Conference on Rare Disease Research
    Date: 13 September 2007
    Venue: Charlemagne building- Brussels, Belgium
    Web details to follow shortly

    16th ESGLD - European Study Group on Lysosomal Diseases
    Date: 27-30 September 2007
    Venue: Perugia, Italy
    More details



    In October
    8th EPPOSI Partnering Workshop on Orphan Drugs
    Date: 18-19 October 2007
    Venue: Copenhagen
    More details will follow shortly

    30th Annual meeting of the Society of Craniofacial Genetics
    Date: 23 October 2007
    Venue: San Diego, California, USA
    More details



    In November
    4th European Conference on Rare Diseases (ECRD 2007)
    Date: 27-28 November 2007
    Venue: Lisbon, Portugal
    More details coming shortly


    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, 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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