5 December 2007 print
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The latest European conference on rare diseases: the Lisbon strategy
The latest European-level conference on rare diseases took place in Lisbon, Portugal in late November, following close on the heels of the release of the public consultation for the Communication on European Action in the Field of Rare Diseases. The European Conference on Rare Diseases gathered over 400 participants from some 35 countries.

It seems more than ever that Europe is moving forward to coordinate and harmonise efforts to address the needs of rare disease patients and their families across our fair continent. Despite the enormous differences between individual illnesses, united we must stand when it comes to demanding resources for the over 7 000 known rare diseases to date. The Lisbon conference took the momentum one step further with a vigorous programme that included presentations, debates, poster sessions, and a pre-conference workshop.

The first day's sessions addressed the issues of building upon existing European policies, promoting national centres of expertise, and patient mobility in Europe. Enhancing Member State national rare disease plans was an important topic of the day. How can national plans be encouraged throughout the European Union? How can plans be coordinated to facilitate a harmonisation of efforts and a better integration of EU-wide policies? The opening ceremony provided an opportunity for the Director of DG Public Health, Mr Andrzej Rys, to announce a commitment on the part of the EC to continue supporting activities in the field of rare diseases. A representative from the Portuguese minister of health officially launched a public consultation on a national plan for rare diseases to be adopted during the first semester of 2008. Very good news, indeed.

The second day's conference topics included recent advances in quality assessments for patient information, genetic testing, and centres of expertise; patient needs beyond medical care; new initiatives in individual member states; and how to get the most out of European research policy. The conference ended on a forward-thinking note with a session devoted to shaping future policies for orphan medicines and advanced therapies. The issues presented included preparing for the advanced therapies that are starting to appear on the horizon. How can EU policy be best developed to promote the potential of exciting techniques such as gene and cellular therapies that hold so much promise in the realm of rare disease treatment?

Each of the eleven conference sessions was followed by a lively debate during which patient representatives, scientists, government agents, and pharmaceutical stakeholders could voice their concerns and perspectives. The conference ended with recommendations for actions each individual could take back to their respective domain and put into motion to ensure that things keep moving forward across Europe for rare disease patients and their families.


Task Force Update
Mark your calendars for 2008 first quarter
The Rare Diseases Task Force has a series of meetings coming up. Please note that some dates have changed. All interested RDTF members are encouraged to get involved in the various Working Groups. A preliminary response of interest would be very helpful in aiding us to best plan these meetings:

RDTF general meeting (new date):

  • 28 February, 2008 - 9th RDTF meeting in Luxembourg

  • RDTF Working Groups:
  • 06 February, 2008 - Coding and Classification Working Group Meeting in Paris, France
  • 11 March, 2008 - Standards of Care Working Group Meeting in Paris, France
  • 12 March, 2008 - Health Indicators Working Group Meeting in Paris, France
  • 13 March, 2008 - Rare Disease Registries Working Group Meeting in Paris, France


    EU Policy News
    EMEA and FDA adopt a common application for orphan designation
    The European Commission, the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) have announced the adoption of a common application form for sponsors applying for orphan designation status for medicinal products. A common application form allows sponsors to apply to both jurisdictions at the same time and with one application. The initiative is intended to simplify the process of obtaining orphan designation in both jurisdictions. The form has a section for information required by both the EMEA and the FDA, as well as sections for requirements that are unique to each agency. Review of the applications will continue to be conducted independently by each agency. The common form can also be used for sponsors applying uniquely to the EMEA or the FDA for orphan designation. To see the new orphan designation application form

    National & International Policy Developments
    Portugal develops rare disease plan - now open for national consultation
    Portugal is amongst a growing number of European countries that recognises the need for a strategic approach to furnishing resources for its rare disease patients and their families and has thus taken the initiative to create a plan of action. The Programa Nacional para Doencas Raras has been released for public consultation and is open for comments in Portugal until 31 January 2008. With 46 specific strategies delineated for approaching intervention, information, and education, and a concrete timeline for achieving each strategic action, it is expected that things will quickly move forward toward meeting the needs of Portugal's rare disease community.
    Greek rare disease plan on the wing
    The Greek Alliance for Rare Diseases (GARD) recently held a conference at the Eugenides Foundation in Athens, under the auspices of Mr. Karolos Papoulias, President of the Hellenic Republic. The conference, Orphan Drugs: Access of Rare Disease Patients, was attended by Greek and foreign scientists, along with representatives from patient organisations and government. Aikaterini Karatza, from the Greek Ministry of Health and Public Affairs, made the day a true success by announcing the creation of the Hellenic National Health Plan for Rare Diseases. This plan will be part of the General National Health Plan and is scheduled to be officially launched by the Minister of Health on 29 February, 2008 at a special press conference. Details of the plan are to be developed by a committee consisting of members of the Ministry of Health, the Greek Alliance of Rare Diseases, and other national agents.
    Spain's Ministry of Health to fund rare and paediatric disease clinical trials
    The Spanish Ministry of Health has earmarked some 20 million euros for rare and paediatric disease research, resulting in several, mostly multicentric, clinical trials in development by research groups from various hospitals throughout the country. Williams syndrome, Marfan syndrome, Friedreich ataxia, and neuroblastoma are amongst the rare diseases selected for the new initiative. Funding program for the promotion of independent research sponsored outside of the pharmaceutical industry is launched by the Ministry of Health in collaboration with the General Directorate of Pharmaceutical and Medicinal Products. A total of 98 research proposals have been selected, of which 78 are clinical trials and 20 observational/utilisation drug studies. Amongst the main categories being funded are: rare diseases (18), paediatric drug indications (20), antimicrobial (10), cell/gene therapy (5), comparative or efficacy studies of drugs (36), security of drugs (7) and studies developed with various support groups or scientific societies (13). This is the first time in Spain that clinical trials are being developed under non-profit conditions.
    Heads up! - Protocol registration requirements have changed in the US
    On 27 September, 2007 Public Law 110-85, The Food and Drug Amendment Act of 2007, was enacted. Title VIII of this law expands the types of clinical trials that must be registered in the National Institutes of Health (NIH) ClinicalTrials.gov database. This law also increases the number of data elements required, and requires submission of results data. Penalties can be levied for non-compliance with the law. A fact sheet on the new law is available on the clinicaltrials.gov website. The NIH has issued a guidance for the new requirements.
    Public comment sought for US report on oversight of genetic testing
    The Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) is seeking public comment for a draft report to the Secretary of Health and Human Services on the oversight of genetic testing. SACGHS last year began an in-depth fact-finding process on the oversight roles of Federal, State, and private sector entities. In March of this year, the Office of the Secretary of HHS outlined a specific charge to SACGHS to focus the Committee's inquiry. The charge reads as follows:

    Undertake the development of a comprehensive map of the steps needed for evidence development and oversight for genetic and genomic tests, with improvement of health quality as the primary goal. Consider and address the following questions:

  • What evidence of harm exists regarding genetic tests? Is that harm attributable to analytic validity, clinical validity, or clinical utility of the tests? If evidence does not exist, what threats are not currently being addressed? What public health benefits are not accruing as quickly as they might?
  • What distinguishes genetic tests from other laboratory tests for oversight purposes?
  • What are the existing pathways that examine the analytic validity, clinical validity, and clinical utility of genetic tests? Consider the use of case studies.
  • What organizations are currently involved with each of these aspects, and what are they doing to address these issues? Who should be responsible for each of these aspects?
  • What resources (e.g., standards reagents/materials) are needed to develop proficiency testing kits or protocols for genetic tests? What is currently available in terms of proficiency testing kits or protocols for genetic tests? What information is provided by proficiency testing? Is the current level of proficiency testing for genetic tests adequate and are the results of such laboratory performance assessments sufficiently transparent?
  • What are the potential pathways to communicate clear information to guide test and treatment selection by the provider?
  • What new approaches or models should be considered for private and public-private sector engagement in demonstrating clinical validity and clinical utility for developing effectiveness measures of genetic tests in clinical practice?
  • Would additional or revised Government oversight add value for patients, and if so, how and where?

  • For further information and to read the draft report

    Other European news
    Irish rare disease conference highlights country's need for national plan
    OrphaNews Europe is pleased to present this account of the recent rare disease conference held by the Irish Platform for Patient Organisations, Science and Industry, written by Peter Wrobel, a science journalist and editor based in London:

    Ireland is a paradox. On the face of it, it should be ideally equipped to contribute to the health of people with rare diseases: it has thriving pharmaceuticals and biotech industries, a growing research base, and has been deeply and constructively involved with the operation of the European Union's Orphan Drug Regulation since it came into force in 2000. And yet Irish patients have limited access to the new treatments - many of them life-saving - that have come onto the market since the regulation appeared.

    It was against this background that more than 100 patients, clinicians and doctors, and representatives of industry and the regulators, came together in Dublin on 9 November to see where Ireland stands in the rare disease landscape - and more importantly, to find consensus about what needs to be done. The meeting divided broadly into two topics: patient aspects, and the development and regulation of medicines for rare diseases. In both areas, there was hope, and concern.

    On the one hand, it was clear, as session chair Professor Brendan Buckley from the Irish Medicines Board said in closing the meeting, that the process of orphan drug development has been very successful on both sides of the Atlantic, and that Ireland is catching up. We are now seeing, he said, a flow-through of drugs in Europe, at least in terms of market authorisations. But, he added: "We have a fundamental difficulty in Ireland about living up to the spirit and letter of the Regulation. If you look up the list of incentives and who is doing what, member state by member state, embarrassingly you see almost nothing in Ireland. That is something that is unworthy of us. We put in an enormous effort at the level of regulation, but we are absent at the wider level."

    There is much that can be done. Encouragingly, though, there are many positive examples from other countries that Ireland could use to rectify its current deficiencies in research, development, access and care in rare diseases. A number of compelling messages emerged from this meeting of stakeholders, and are detailed in the two main sections of this report, on Patient Aspects and the Development and Regulation of Rare Diseases Ireland. Briefly summarised, the key ones are these:

    1. Ireland needs a national plan for Ireland for orphan medicines, encompassing development, pricing, access and care.
    2. This plan should include the creation of one or more Centres of Excellence for rare diseases.
    3. In formulating a plan, Ireland should study but not necessarily imitate other European countries. In particular, access to treatments for rare diseases should be determined by societal rather than economic values.
    4. With proper incentives and promotion, orphan medicines could be the gateway to the further development of Ireland's knowledge economy.
    5. Patient organisations are central to the process of promoting awareness of and research into rare diseases. They must continue to push for development, and should be supported in their work.
    Read the full IPPOSI report

    UK mutation database platform publishes first newsletters
    In the UK, the Manchester-based National Genetics Reference Laboratory (NGRL) is funded by the Department of Health to develop tools and services useful to the field of genetics and diagnostics. One of their creations, the Diagnostic Mutation Database (DMuDB), provides a confidential repository for UK diagnostic laboratories to share mutation data. UK molecular genetics laboratories analyse hundreds of mutations each year, some of which are very rare, yet data are generally not shared between different laboratories, nor reported in journal publications or added to the online databases that exist. DMuDB provides a venue for diagnostic laboratories to circulate mutation data. Currently, DMuDB has some 3500 gene entries, including those for Lowe syndrome, Sotos syndrome, cystic fibrosis, X-linked retinitis pigmentosa, Alstrom syndrome and CADASIL, for example. Now the first issue of the DMuDB newsletter has been released, designed to keep readers informed of developments such as genes covered, statistics and future targets. Another NGRL project also has its first newsletter: the Universal Browser. Developed to display variant information graphically on a DNA sequence, the Universal Browser was created to be used with DMuDB, but can also accept and present data from other sources, including the UK Gene Testing Network. The first Universal Browser newsletter provides available data, statistics and future targets.
    Other International News
    SNOMED put to the test by US rare disease network
    SNOMED Clinical Terms (SNOMED CT) is a scientifically validated clinical health care terminology and infrastructure developed by the NHS in England and the College of American Pathologists in 1999. With over 357 000 unique concepts, it provides core general terminology for electronic health records and is also applicable to ICU monitoring, medical research studies, clinical trials, disease surveillance, and consumer health information services. It can map to other medical terminologies and classifications systems already in place. Recently, the NIH-funded Rare Disease Clinical Research Network (RDCRN) set out to test the consistency of SNOMED coding amongst professional coders of clinical research concepts by sending them a sample of 319 question/answer pairs from 15 separate case report forms. Unfortunately, the report revealed an overall lack of consistency with "no significant level of agreement among the experts...". The results are published in the Journal of the American Medical Informatics Association.
    Autism update: Researchers release autism genome scan;
    paediatrians call for mass screening and publish guidelines

    Autism spectrum disorders are neuro-developmental disorders and include conditions currently considered rare, such as tuberous sclerosis or fragile X syndrome. The Autism Consortium, a group of clinicians, researchers, and families, recently announced that it has completed the first genome scan for the disorder via high resolution technology of genetic data from more than 3 000 children with ASD and their families, and is making the results available in a database accessible to qualified researchers worldwide. The decision to release the raw genotype/phenotypic data before the consortium's own researchers have fully analysed the material was heralded by the director of the US National Institutes of Mental Health as indicative of the consortium's dedication to advancing research in the field. In other news, the American Academy of Pediatrics (AAP) is now urging two autism screenings for all children before age two. There is no cure for autism, but early intervention can lessen the severity of the disorder, especially for mild cases, which often escape early diagnosis. The AAP has published two autism guidelines on its website: Identification and Evaluation of Children with Autism Spectrum Disorders and Management of Children with Autism Spectrum Disorders. A recent Lancet editorial also endorsed the AAP call for early screening. Elsewhere, a new website debuted in mid-October, featuring video clips that contrast autistic infants and children with their unaffected peers, demonstrating how symptoms manifest in terms of social interaction, communication, regulatory and sensory systems, repetitive behaviours and restricted interests. The AAP recommendations assert that treatment should begin in suspected autism cases even before a formal diagnosis is reached. They also warn parents against special diets and alternative treatments that have no proven efficacy. The AAP in October published Caring for children with Autism Spectrum Disorders: A Resource Toolkit for Clinicians, a CD-ROM that contains screening and surveillance algorithms, example screening tools, management and developmental checklists, and referral forms and tools.

    EU Project Follow-up
    EuroGentest holds annual general assembly
    European genetic testing Network of Excellence EuroGentest held its annual general assembly in Belgium last month, allowing the network to take stock of its efforts and needs, and permitting the network's working Units to report on the progress each has made in the last year as well as the future endeavours still to be accomplished. In addition to these update reports covering the areas of Quality Management, Information Databases, Public Health, Ethics and Legal, New Technologies and Education, panel discussions were held throughout the three-day event targeting specific topics such as accreditation, counselling and quality assessment. EuroGentest is an EU-funded project that kicked off in December 2004 with the global objectives of harmonising and improving the quality of genetic services throughout the European Union, defining European standards compatible with and complementary to national approaches to offering genetic services. This year's assembly meeting featured "roadshow" presentations that touched upon current topics such as the OECD guidelines on genetic testing that were released earlier this year. Other presentations included contributions from invited speakers representing genetic testing networks, government, and industry stakeholders, and information from DG Research concerning FP6 and FP7 budgets. Two EuroGentest supported projects were presented (Training the trainer - the MCR project and The Mutalyzer project), as well as updates from the two steering committees working on the group's website and sustainability. Power point presentations from the assembly meeting are available on the EuroGentest website.
    Creating standards of care for neuromuscular disease patients
    TREAT-NMD is an EU-funded network of excellence composed of 21 partner organisations throughout 11 European countries working to accelerate treatments for neuromuscular diseases (NMD), many of which are rare disorders. One project of the network is the development of an international consensus for the care and management of patients with neuromuscular diseases. Current standards of care differ within and between countries, and a general consensus has not been developed for NMD patient care to date. However, standards of care can greatly impact a patient's quality of life, and even affect life expectancy. Standardised care and management for NMD patients would make clinical trials easier to conduct, as comparing results would be simpler and more accurate if patients were receiving comparable care.

    Thus, TREAT-NMD is working to develop a European consensus for care and management. The first fruit of this effort is the recently published Consensus Statement for Standard of Care in Spinal Muscular Atrophy, created by an international group of experts, the International Standard of Care Committee for SMA, and appearing in the Journal of Child Neurology. TREAT-NMD would like to hear from patients and clinicians concerning these recommendations and welcomes suggestions for improving them. TREAT-NMD would also like to have the various fact sheets concerning standards of care translated into different European languages, to ensure the widest-reaching user-friendly consensus as possible. Contact the network if you could translate the documents into your language for inclusion on the TREAT-NMD website. The website will feature a range of new documents relating to patient care. Look for new articles continuing to appear in the near future. To contact TREAT-NMD

    EU-funded project deciphers protein membrane with new medicine potential
    The European Commission news service CORDIS reports on advancements made by EU-funded scientists in decoding membrane proteins that hold enormous potential for new medicines. Researchers from the EU FP6 project IMPS, in collaboration with a team from Stanford University in the US and the France-based European synchrotron radiation facility, have determined the structure of a recombinant G protein-coupled receptor. This discovery could eventually lead to future medicines for an array of rare disorders, as well as treatment for more common diseases. In related news, two projects devoted to similar research were selected within the first call of the EU Seventh Research Framework Programme funding scheme: EDICT (European drug initiative on channels and transporters) seeks to characterise the structure of several membrane superfamilies in humans and pathogenic micro-organisms, covering a wide range of human diseases and addressing global health issues. NeuroCypres (Neurotransmitter Cys-loop receptors: structure, function and disease), meanwhile, will focus on Cys-loop receptors, identified as targets for drugs to treat a variety of diseases, including certain forms of epilepsy. The result of the IMPS team's research is published in the journal Nature.

    Orphanet News
    New Texts
    New Orphanet Journal of Rare Diseases publications
    Anophthalmia and microphthalmia

    New Research Projects open for Recruitment
    Study of the Distractibility Syndrome in Patients With Progressive Supranuclear Palsy (in France)

    Randomized Placebo-Controlled Trial of Valproic Acid in Patients With Progressive Supranuclear Palsy (in France)

    Study of Mitochondrial Functions and Oxidative Stress in ALS Patients (in France)

    Phase III study to assess the efficacy and safety of prophylactic use of maribavir for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants (In Sweden)

    Phase III study to assess the efficacy and safety of prophylactic use of maribavir for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants (In Germany)


    New Syndromes
    Muscle glycogen storage disease type 0: cardiomyopathy and exercise intolerance
    The authors describe three siblings with profound muscle and heart glycogen deficiency caused by a homozygous stop mutation in the muscle glycogen synthase gene. The oldest brother died from sudden cardiac arrest at 10 years of age, while the second sibling presented muscular fatigability, hypertrophic cardiomyopathy, and an abnormal heart rate and blood pressure while exercising. A two-year-old sister had no symptoms.
    Read the PubMed abstract

    NEJM ; 1507-1514 ; October 2007
    A new autosomal dominant syndrome with cardiac anomalies and left isomerism
    The authors describe a three-generation family with nine patients presenting a combination of cardiac abnormalities and left isomerism. The cardiac anomalies include non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. The laterality sequence anomalies include left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia and intestinal malrotation, all compatible with left isomerism. This new syndrome is inherited in an autosomal dominant pattern. A genome-wide linkage analysis suggested linkage to chromosome 6p24.3-21.2 with a maximum LOD score of 2.7 at marker D6S276.
    Read the PubMed abstract

    Hum Genet ; E-pub ahead of print ; October 2007
    Fatal lung fibrosis with immunodeficiency and gonadal dysgenesis in two sisters with normal karyotype
    The authors describe two sisters born to consanguineous parents, presenting immune deficiency, gonadic dysgenesis and fatal lung fibrosis. Both have a normal karyotype (46,XX). Comparative genome hybridization and analysis of genes known to be associated with severe immune defects in infancy or gonadal dysgenesis showed no abnormality.
    Read the PubMed abstract

    Am J Med Genet ; E-pub ahead of print ; October 2007
    A new entity of anaplastic sarcoma of the kidney with polyphenotypic features
    The authors describe 20 patients, aged between 10 months and 41 years, presenting anaplastic kidney sarcomas. The characteristics of the tumours differ from those seen in anaplastic Wilms tumor, primary renal synovial sarcoma, malignant mesenchymoma, ectomesenchymoma, and mesenchymal chondrosarcomas.
    Read the PubMed abstract

    Am J Surg Pathol ; 459-468 ; October 2007

    New Genes
    Autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy linked to TOPORS mutations
    Retinitis pigmentosa is a hereditary dystrophy of the retina caused by a loss of photoreceptors and characterised by visible pigment deposits at the back of the eye. By using a positional-cloning approach, together with the use of bioinformatics, the authors identified mutations in TOPORS gene in patients with autosomal dominant retinitis pigmentosa. A distinct phenotype is noted at the earlier stages of the disease, with an unusual perivascular cuff of retinal pigment epithelium atrophy, found surrounding the superior and inferior arcades in the retina. TOPORS is a RING domain-containing E3 ubiquitin ligase. The ubiquitous nature of TOPORS expression and a lack of mutant protein in patients are highly suggestive of haploinsufficiency, rather than a dominant negative effect. Rescue of the clinical phenotype could therefore be amenable to somatic gene therapy.
    Read the PubMed abstract

    Am J Hum Genet ; 1098-1103 ; November 2007
    Lethal osteosclerotic bone dysplasia is caused by mutations in FAM20C, crucial to bone development
    Lethal osteosclerotic bone dysplasia, or Raine syndrome, is an autosomal recessive disorder characterised by generalised osteosclerosis with periosteal bone formation and a distinctive facial phenotype. Affected individuals survive only days or weeks, due to respiratory insufficiency caused by thoracic malformation. The authors have identified mutations in two alleles of FAM20C in seven patients. FAM20C is a member of the FAM20 family of secreted proteins, and its mouse orthologue has demonstrated calcium-binding properties.
    Read the PubMed abstract

    Am J Hum Genet ; 906-912 ; November 2007
    Some congenital heart defects stem from GDF1 gene mutations
    Most congenital heart defects are considered to arise from multifactorial influences, including environmental and genetic components, as well as from less common syndromic forms. The authors hypothesised that disturbances in left-right patterning could contribute to the pathogenesis of selected cardiac defects by interfering with the extrinsic cues leading to the proper looping and vessel remodelling of the normally asymmetrically developed heart and vessels. In this study, they showed that heterozygous loss-of-function mutations in the human GDF1 gene, already known to be involved in left-right patterning, contribute to cardiac defects ranging from tetralogy of Fallot to transposition of the great arteries. These findings implicate perturbations of the TGF- beta signalling pathway in the causation of a major subclass of human congenital heart defects.
    Read the PubMed abstract

    Am J Hum Genet ; 987-994 ; November 2007
    Arrhythmogenic right ventricular cardiomyopathy: a dominant mutation in the gene encoding plakoglobin identified
    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder associated with arrhythmias and sudden death. A recessive mutation in the gene encoding plakoglobin has been shown to cause Naxos disease, a cardiocutaneous syndrome characterised by ARVC and abnormalities of hair and skin. Now, the authors report a dominant mutation in the gene encoding plakoglobin in a German family with arrhythmogenic right ventricular cardiomyopathy, but no cutaneous abnormalities.
    Read the PubMed abstract

    Am J Hum Genet ; 964-973 ; November 2007
    Walker-Warburg syndrome caused by intragenic deletion in the LARGE gene
    Walker-Warburg syndrome is a rare form of congenital muscular dystrophy characterised by severe structural brain and eye malformations. Compound heterozygous LARGE mutations have previously been reported in a single human patient manifesting with mild congenital muscular dystrophy and severe mental retardation. Now, in a family with this syndrome, the authors have identified a 63-kb homozygous intragenic deletion in the LARGE gene that encodes a putative alpha-dystroglycan glycosyltransferase.
    Read the PubMed abstract

    Hum Genet ; 685-690 ; July 2007

    Research in Action
    Clinical Research
    In Turner syndrome, aortic dilatation precedes dissection
    Turner syndrome is a chromosomal disease linked to a complete or partial absence of one X chromosome. Patients have small stature and frequently present ovarian insufficiency. They are also at increased risk for aortic dissection. In this study, the authors show that aortic dilatation precedes dissection. Because of their small size, the classic criteria for aortic dilatation cannot be applied to Turner syndrome patients. Thus, individuals with a dilated ascending aorta defined as aortic size index > 2.0 cm/m2 require close cardiovascular surveillance, while those with aortic size index > or = 2.5 cm/m2 are at highest risk for aortic dissection.
    Read the PubMed abstract

    Circulation ; 1663-1670 ; October 2007
    ATR-X syndrome caused by partial duplications in the ATRX gene
    ATR-X syndrome is an X-linked alpha thalassemia with mental retardation, characterised by developmental growth delay, facial dysmorphia, genital anomalies, and alpha thalassemia. This recessive syndrome is caused by ATRX gene mutations. For the first time, the authors have observed intragenic duplications in this gene, leading to an absence of ATRX mRNA and of the protein. These findings underscore the need for including quantitative analyses to mutation analysis of the ATRX gene.
    Read the PubMed abstract

    Eur J Hum Genet ; 1094-1097 ; October 2007
    Gitelman syndrome: the presence of a non-functional mutation caused a severe phenotype
    Gitelman syndrome is an autosomal recessive disorder, characterized by hypokalemic alkalosis in combination with significant hypomagnesemia and low urinary calcium, caused by mutations in gene SLC12A3 that encodes the sodium-chloride co-transporter. The authors studied the phenotype-genotype correlation by extensive mutational analysis in 27 patients. They observed a sub-group of patients presenting a severe form of the syndrome characterised by precocious onset and growth delay. The mutations that were associated with this severe presentation were at least for one allele, a missplicing resulting in a truncated transcript that was downregulated by nonsense-mediated decay or a nonfunctional, cell surface-absent mutant. The most recurrent mutation on the second allele was a newly described mutant that affected the functional properties of the co-transporter.
    Read the PubMed abstract

    J Am Soc Nephrol ; 1271-1283 ; April 2007
    Therapeutic Approaches
    Hypohidrotic ectodermal dysplasia: recombinant ectodysplasin A shows promise in dog models
    X-linked hypohidrotic ectodermal dysplasia (XLHED) is a condition characterised by sparse hair, inability to sweat, decreased lacrimation, frequent pulmonary infections, and missing and malformed teeth, caused by defective ectodysplasin (EDA). In canine models of XLHED, the authors studied the developmental impact of EDA on secondary dentition. Administering soluble recombinant EDA intraveineously to newborn dogs, the authors observed the normalisation of adult teeth in four of five cases. The treatment also restored lacrimation and resistance to eye and airway infections and improved sweating ability.
    Read the PubMed abstract

    Am J Hum Gen ; 1050-1056 ; November 2007
    Diagnostic Approaches
    Pseudoachondroplasia: COMP serum/plasma levels as diagnostic marker
    Pseudoachondroplasia (PSACH) is an autosomal-dominant osteochondrodysplasia due to mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Clinical diagnosis of PSACH is based primarily on family history, physical examination, and radiographic evaluation, and is sometimes extremely difficult, particularly in adult patients. Genetic diagnosis based on DNA sequencing, on the other hand, can be expensive and time-consuming because COMP mutations may be scattered throughout the gene. However, there is evidence that decreased plasma COMP concentration may serve as a diagnostic marker in PSACH, particularly in adult patients. Here, the authors report the serum and/or plasma COMP concentration-based differential diagnosis of a family with affected adult members. The mean serum and/or plasma COMP concentrations of the three affected family members were significantly lower than those of an age-compatible control group of 21 adults. Thus, serum and/or plasma COMP concentration may be suggested as an additional diagnostic marker in suspected cases of PSACH.
    Read the PubMed abstract

    Eur J Hum Genet ; 1023-1028 ; October 2007

    Patient Management and Therapy
    Fabry disease: equal doses of alpha and beta agalsidase have the same efficacy
    Fabry disease is an X-linked autosomal recessive metabolic disease caused by a deficit of lysosomal enzyme alpha-galactosidase A. In 2001, the EMEA bestowed marketing authorisation on two recombinant enzymes to treat the disorder: Agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). The first product has an indication of 0.2 mg/kg once every two weeks, while the second is administered 1.0 mg/kg at the same interval. The annual cost for these treatments is almost identical for the doses indicated, although agalsidase alfa is around five times more expensive per protein milligram than agalsidase beta. The authors compared the efficacy and tolerance of the two enzymes administered at the same dosage (0.2 mg/kg once every two weeks) in an open randomised clinical trial. Thirty-four patients were followed for 12 then 24 months. Similar effects between the two treatments were observed for the clinical parameters monitored (cardiac hypertrophy, glomerular filtration level) and in the urinary and plasma levels of globotriasylceramide. Moreover, in the two groups, a failure of treatment was observed in older patients with severe illness. The authors suggest that early enzyme treatment can prevent long-term complications.
    Read the PubMed abstract

    PLoS One ; e598 ; July 2007
    For Marfan syndrome perindopril reduces aortic stiffness
    Marfan syndrome is an autosomal domininat disease of the conjunctive tissues, due to mutations in the gene encoding fibrillin 1. Patients have increased aortic stiffness, contributing to dilatation and dissection. In a randomised, double-blind, placebo-controlled trial of 17 patients being treated with beta blockers, ten patients received 10mg/day of perindopril, an angiotensin-converting enzyme inhibitor (seven patients received a placebo). Perindopril reduced arterial stiffness and aortic root diameter. The authors specify that larger clinical trials are needed to assess the clinical benefit of this type of inhibitor.
    Read the PubMed abstract

    JAMA ; 1539-1547 ; October 2007
    Huntington disease: riluzole does not show beneficial effects
    Huntington disease is a neurodegenerative illness of the central nervous system. The authors conducted a randomised double-blind clinical trial to test anti-excitotoxic agent riluzole on the progression of the disease. In 379 patients who participated in the study, no neuroprotector effects were found.
    Read the PubMed abstract

    Ann Neurol ; 262-272 ; September 2007
    Juvenile idiopathic arthritis: sulfasalazine produces long-term effects
    Juvenile idiopathic arthritis is a heterogeneous group of chronic inflammatory arthritis, with the first symptoms appearing before age 16. In a 24-week randomised clinical trial, anti-inflammatory sulfasalazine already demonstrated positive results in patients presenting oligo- and poly-articular onset juvenile idiopathic arthritis. The authors followed up patients who participated in this study for a period of 7-10 years. They showed that early sulfazalazine treatment has beneficial effects that last for several years.
    Read the PubMed abstract

    Ann Rheum Dis ; 1518-1524 ; November 2007
    For pulmonary arterial hypertension associated with connective tissue disease, sitaxsentan appears efficacious
    Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the endothelin A receptor, in a cohort of patients with PAH and CTD. In a 12 week randomised double-blind clinical trial, the authors showed beneficial effects of this drug on physical capacity (6 minute walk) and haemodynamic parameters.
    Read the PubMed abstract

    Ann Rheum Dis ; 1467-1472 ; November 2007
    Evaluation of genetic test information for patients in seven European countries
    The authors evaluated the quality of written genetic test documentation for five different conditions intended for patients and their families in seven European countries. The majority of information addressed the effects of the illness, treatment, and genetic risks. Only half the information addressed ways to best obtain further information and support. Less than half of the documentation addressed post testing follow-up, patient rights, and decision taking by families and health professionals. Pre-written leaflets tended to provide a more comprehensive discussion of the issues surrounding genetic testing than personal letters did and should therefore routinely be available to patients alongside personal letters. Written information should include risks and limitations of testing as well as discussion of the psychological and social aspects of genetic testing.
    Read the PubMed abstract

    Eur J Hum Genet ; 1012-1022 ; October 2007
    A bibliographic review of genetic information communication within the family
    The communication of risk is a central activity in clinical genetics, with genetic health professionals encouraging the dissemination of relevant information by individuals to their at-risk family members. To understand the process by which communication occurs as well as its outcomes, a systematic review of actual communication in families about genetic risk was conducted. Findings from 29 papers meeting the inclusion criteria were summarised and presented narratively. Family communication about genetic risk is described as a deliberative process, in which: sense is made of personal risk; the vulnerability and receptivity of the family member is assessed; decisions are made about what will be conveyed; and the right time to disclose is selected. The communication strategy adopted will depend on these factors and varies within families as well as between families. Inherent in these processes are conflicting senses of responsibility: to provide potentially valuable information and to prevent harm that may arise from this knowledge. The authors summarise that there is a lack of information addressing the development of techniques designed to facilitate better communication.
    Read the PubMed abstract

    Eur J Hum Genet ; 999-1011 ; October 2007

    Orphan Drugs
    Amicus and Shire strike a deal over Fabry, Gaucher and Pompe drugs
    Amicus Therapeutics, Inc. and Shire Human Genetic Therapies, Inc. have announced a collaboration to develop three compounds for lysosomal storage disorders. Shire will receive the rights to commercialise the products outside of the United States, while Amicus will retain all commercial rights within the US. The medicines concerned are Amigal (migalastat hydrochloride), currently in Phase 2 clinical trials for the treatment of Fabry disease, Plicera (isofagomine tartrate) currently in Phase 2 clinical trials for the treatment of Gaucher disease, and AT2220 (deoxynojirimycin), which Amicus is studying in Phase 1 clinical trials for the treatment of Pompe disease.

    Courses & Educational Initiatives
    Orphan Europe Academy 2008 programme focuses on inborn errors of metabolism
    The Orphan Europe Academy 2008 rare disease education programme is now available. The 2008 programme focuses on inborn errors of metabolism with specific courses in neonatology, liver glycogen storage disorders, and paediatric and adult metabolic disorders.
    For further details and to register


    What's on Where?
    East Meets West in Rare Diseases
    Date: 6-7 December 2007
    Venue: Soesterberg, Netherlands

    This workshop, hosted by the Dutch Steering Committe on Orphan Drugs, facilitates an exchange of expertise on rare disease care, cure and research topics between Eastern and Western European stakeholders.
    For further information

    Lowe Syndrome Second International Symposium
    Date: 7 December 2007
    Venue: London, England

    Molecular and clinical advances in Lowe syndrome.
    More details

    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.
    More details

    Rare Diseases: Channels and Transporters
    Date: 8-12 March 2008
    Venue: Sant Feliu de Guixols, Spain

    The conference is devoted to channels and transporters involved in rare inherited diseases. Specifically TRP and CLC channels, connexins, mitochondrial transporters, heteromeric amino acid transporters, neurotransmitter transporters, ABC transporters and related diseases will be covered.
    For further details

    ICORD 4th International Conference on Rare Diseases and Orphan Drugs
    Date: 20-22 May 2008
    Venue: Washington, DC US
    For further details

    14th International Conference on Prenatal Diagnosis and Therapy
    Date: 1-4 June 2008
    Venue: Vancouver, Canada

    Conference sessions will include foetal imaging, cytogenetics, foetal DNA/RNA, PGD, screening, teratology, and legal aspects of prenatal diagnostics and therapy. The deadline to submit an abstract for this conference is 4 February 2008.
    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

    Genetic Alliance Annual Conference 2008
    Date: 11-13 July 2008
    Venue: Bethesda, MD, US

    Brings advocates, health professionals, policy makers, industry representatives, researchers, and community leaders together for workshops and discussions. The deadline for submitting abstracts for this conference is 30 November 2007.
    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
    18-country OECD genetic testing survey results now available
    The 14 June 2007 Editorial of OrphaNews Europe reported on the issuance of Organisation for Economic Cooperation and Development (OECD) quality assurance guidelines for international genetic testing. These were developed from an in-depth survey of over 800 genetic test laboratories in 18 OECD countries. Now, the OECD has published the results of this survey, providing the first detailed overview of the availability and extent of molecular genetic testing across OECD member countries. Chapters cover a variety of topics including: Quality Assurance in Molecular Genetic Testing: Results of a Survey of 18 Countries; Transborder Flow and Rare Diseases; Consent, Storage and Confidentiality; Licensing, Accreditation, Certification and Proficiency Testing/External Quality Assessment; Education and Training and finishes with Conclusions and Recommendations. Genetic Testing: A Survey of Quality Assurance and Proficiency Standards is available from the OECD online bookshop.
    Article outlines rare disease initiatives at national and European level
    Networking for rare diseases: a necessity for Europe, appearing in German medical review Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, outlines the national and European-level rare disease and orphan drug initiatives taken to date in the areas of scientific and biomedical research, drug research and development, industry policy, information and training, social benefits, hospitalisation and outpatient care, and presents the rationale behind such initiatives.
    Bulgarian medical journal article calls for more national rare disease plans
    Bulgarian review Folia Medica (Plovdiv) has published an article considering the state of rare disease policies across Europe and calling for more member state national rare disease plans in order to better harmonise European-wide efforts to meet the needs of rare disease patients and their families. Tackling rare diseases at European level: why do we need a harmonized framework? cites the importance of employing a strategic approach toward rare diseases.
    Official 2007 EPPOSI workshop report now available
    EPPOSI, the patient-led EU partnership of patients, academic science and industry, has released the official report of its Eighth Workshop on Partnering for Rare Disease Therapy Development. Founded in 1994 to facilitate the exchange of information and ideas between the various stakeholders, EPPOSI focuses on building dialogue, consensus positions and policy recommendations. This latest rare disease workshop, entitled The Reality of Orphan Medicines, contributes to the ongoing effort of assuring equitable rare disease health care and services across the European Union. The workshop report is available on the EPPOSI website.

    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, Laura Fregonese, Edmund Jessop, Matthieu Levi-Strauss, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Manuel Posada de la Paz, Ewa Pronicka, Claire Scharf-Kroener, Janos Sandor, Domenica Taruscio, Paloma Tejada, T.O.F. Wagner
    For more information on the Rare Diseases Task Force
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