10 July 2009 print
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Spain joins the growing number of EU countries to define a national strategy for rare diseases

In early June the Spanish Ministry of Health announced the establishment of a national strategy for its estimated 3 million rare disease patients and their families. Not yet officially unveiled, the Spanish plan is primarily a coordination tool based upon seven strategic lines that will encompass the domains of information; prevention and early detection; healthcare coordination; treatment (including advanced medicinal products, orphan drugs, and related materials); social services; research; and training. The elements defined in the Spanish strategy follow the recommendations delineated by the European Council Recommendation on an Action in the Field of Rare Diseases.
Consult the Ministry of Health press release (in Spanish language)

Spotlight on...
How specific legislation for rare diseases and orphan drugs is changing life for some patients in Taiwan

In Taiwan, the Rare Disease and Orphan Drug Act was implemented in 2000 - the fifth such legislation to be adopted worldwide. This legislation offers support and assistance to patients with rare diseases who need medical treatment, encourages rare disease research, and raises public awareness. With the establishment of the Committee for the Review of Rare Diseases and Orphan Drugs, the government has classified 167 diseases under the rare disease category, thereby protecting patients whose ailments are now included in National Health Insurance coverage for major diseases and injuries and whose co-payment can be waived. Furthermore, medicinal products for 81 rare diseases and special nutrient supplements for 40 rare diseases have been reviewed, established, and announced, and additional medical cases to be subsidised have been reviewed.

For the diagnosis, treatment, and drug costs for rare diseases that are not covered under the National Health Insurance Act, Article 33 of the Rare Disease and Orphan Drug Act is followed, and the Bureau of Health Promotion appropriates a budget in the form of subsidies. With the establishment of a logistics centre for rare disease nutrient supplements and drugs, 32 items were supplied in 2008 to 17 hospitals and used for 303 patients with rare diseases. The subsidised budget reached over NT$27.7 million (€600,000). In addition, ten emergency drugs for patients with rare diseases were supplied to hospitals for diagnostics and treatment. In 2008 thirteen patients used these drugs and the budget subsidised was NT$360,000 (€8000).

Providing international medical laboratory referral services for rare disease cases, information in Taiwan concerning the referrals of samples to international laboratories was integrated and established to provide international medical collaboration channels for rare diseases. The government, along with national patient alliance the Taiwan Foundation for Rare Disorders, subsidised 40% of the referral test costs. Between 2000 and 2008, a total of 312 cases were subsidised. In addition, rapid review principles for 12 rare diseases were formulated to shorten the review process for international laboratory referrals.

Construction of complete medical service networks for genetic and other rare diseases is underway via the establishment of a rare disease reporting database and single-window inquiry service. By the end of 2008, a total of 3,314 cases of rare diseases had been reported from hospitals, and genetic consultation centers were established in northern, central, southern, and eastern parts of Taiwan (10 medical centers) to provide necessary assistance.

In order to obtain the benefits offered under the country’s Rare Disease and Orphan Drug Act, patients in Taiwan must submit via their physician or medical facility a rare disorders report sheet (including suspected cases), along with an abstract of the disease, and related medical tests, to the Bureau of Health Promotion, Department of Health, Executive Yuan. Patients officially acknowledged as having a rare condition may then apply for the reimbursement of medical expenses incurred in their local medical centre or one of the country’s regional teaching hospitals. Expenses covered include diagnostics, treatment, medicinal products, and special nutritional supplements. The reimbursement cap is 70% of actual expenses but families who qualify for low-income status can receive reimbursements up to 100% for drugs and nutritional supplements for the patient.

"We can’t take care of our children forever, but a well-established system can." - The Taiwan Foundation for Rare Disorders

The Taiwan Foundation for Rare Disorders – championing the cause
Established in 1999 by two parents of children with rare diseases, the Taiwan Foundation for Rare Disorders (TFRD) championed the adoption of the Rare Disease and Orphan Drug Act. The patient advocacy group has the mission of improving the life of rare disease patients by assisting rare disease patients to receive proper medical treatment and rehabilitation, securing orphan drugs and special nutrients and fulfilling patient needs in terms of education, employment and other activities.

The TFRD undertakes or participates in the provision of patient subsidies; genetic counselling; transferring specimens abroad for diagnosis; providing nutritional counselling; performing workshops; arranging scholarships; organising patient activities and tours; fostering patient groups and formal associations; and holding public and campus advocacy activities. Financed largely by donations from the public and from enterprises, the foundation has established several subsidy funds in order to ease the financial burden placed on the families of rare disease patients. These help compensate in cases where medical insurance is lacking, or can be used to aid in emergency situations, and to assist patients who need adapted in-home and in-center services. Furthermore, for parents who have given birth to a baby with a rare disease and who are planning to have another child, TFRD has available a care assistance subsidy for prenatal examinations. In 2008, TFRD distributed funding for 99 cases of medical aid, 81 cases of livelihood assistance, 43 cases of prenatal services, and 81 cases of in-home and long-term patient care. The total amount of subsidies distributed came to $NT9,366,891 dollars (€204,000).

Genetic and nutritional counselling
Since 2001, together with the Taiwan Human Genetic Society, the National Taiwan University Hospital, and the Mackay Memorial Hospital, the TFRD has integrated the Human Resources subsidies fund, as provided by the Council of Labor Affairs, Executive Yuan, to conduct a one-year Genetic Counseling Training Program. Graduating students from areas relevant to genetic studies are hired as genetic counsellors. They make clinical rounds at the National Taiwan University Hospital and Mackay Memorial Hospital and receive on-site training by genetic specialists. Additionally, they assist patients and doctors with relevant services, connecting patients and hospital workers. The foundation also set up the “National Rare Diseases Service Center” and plans to promote such cooperative models to the genetic health counselling centers in Taiwan and set up an initial genetic counselling network. To date, eleven genetic counselling centres have been established in various medical centers and teaching hospitals in Taiwan. The Bureau of Health Promotion has evaluated the facilities to assure the quality of the genetic counselling centers.
Read the full article on rare diseases in Taiwan
Contact the Taiwan Foundation for Rare Disorders


EU Policy News
The verdict is in on the impact of the EC Clinical Trials Directive
The Clinical Trials Directive, implemented in 2004, was developed in order to harmonise European regulatory systems pertaining to the clinical research environment, improve the protection of study participants, optimise safety information, and ensure quality and data credibility across Europe. However, the directive came under fire from some scientists who accused the measure of hindering academic research, resulting in fewer new trials initiated with fewer patients enrolled. An increased workload for ethics committees was cited amongst the causes for slowing trial initiation (see OrphaNews Europe 09 April 2006). A one-year project financed by the Seventh Framework Programme to measure and analyse the impact of the directive on clinical research in respect to different stakeholders, the Impact on Clinical Research of European Legislation (ICREL) project involved a longitudinal, retrospective, observational and comparative survey conducted with different stakeholders from each European country – competent authorities, ethics committees, and sponsors (public and private) - in order to assess how the Clinical Trials Directive has impacted the number, size, nature, costs, resources, workload and performance relating to clinical trials. The results of this project have been compiled into a report that was published online in mid-June. The ICREL data suggest that large pharmaceutical companies seem less affected by the new legislation than small- and medium-sized enterprises (SME) and non-commercial sponsors. An increase in workload was identified amongst all the stakeholders. There was also an increase in fees to competent authorities and to ethics committees. The cost of insurance dramatically increased for commercial sponsors, though not for non-commercial sponsors. Furthermore, an increase in clinical trial costs as a result of the Clinical Trials Directive was of particular concern to SMEs, non-commercial sponsors and the sponsors of orphan drug trials. The survey detected a significant increase from 2003 to 2007 in the number of biotechnology product and orphan drug trials, considered to reflect more the new orphan drug regulation as well as scientific and technological progress rather than the implementation of the Clinical Trials Directive. The report ends with a discussion of the findings and a series of conclusions and recommendations.
Consult the ICREL final report

EMEA seeks comments on new transparency policy
The European Medicines Agency (EMEA) has announced that it is inviting comments on the draft of a transparency policy paper that gathers into one document the various initiatives the agency has implemented over the years. Three principal objectives focus on improving transparency in daily operations, strengthening the interchange between the agency and stakeholders, and encouraging a harmonised approach to transparency throughout Europe. In terms of orphan drug decision-making, the draft policy seeks to improve the understanding of the opinion/decision making process by assessing the information presented in the European Public Assessment Reports (EPARS) for orphan drugs, and by exploring how the public might optimally be informed of the review process outcome of the criteria for orphan designation at the time of marketing authorisation.
To consult and/or comment upon the EMEA Transparency Policy draft

EMEA updates list of member state sources for identifying existing authorised medicinal products
The EMEA has updated its list that gathers into one handy document the website address of the source of information and data concerning the status of authorised medicinal products, including the orphan medicinal products, for each European Union and Economic Area country.

National & International Policy Developments
A Canadian province adopts rare disease drug evaluation programme

In the absence of a national orphan drug strategy, Ontario has moved forward to develop an evaluation framework for medicinal products for rare diseases, recognising that an innovative approach is required that will take into account available clinical evidence, patient needs, and the current funding gap.

The Ontario Drugs for Rare Disease (DRD) programme, introduced in January of this year, will allow some rare disease patients to access medicinal products that they previously could not obtain. The programme seeks to identify groups of individuals that may potentially benefit from treatment with a particular drug that the Ontario Public Drug Programs (OPDP) may consider funding. Not all patients will be funded for treatment and there may be instances where the OPDP collaborates with manufacturers to provide funding.

In Canada, a drug must be approved by the country’s health administration (Health Canada) for safety and effectiveness before passing reviews by two other government committees. The first is the Common Drug Review, which analyses costs – both in contrast to existing products and in terms of extended life expectancy the treatment might provide. Next, the provincial drug plans must initiate a cost-effectiveness assessment. In a news article, Ed Koning, vice-president of CORD and president of the Canadian Fabry Association, was quoted as saying of this process that, "It is unreasonable to apply rules designed for common drugs to drugs for rare disorders. The CDR and the provincial drug plans have rejected about 80% of rare and innovative drugs, even though they are available to patients in most other developed countries."

The DRD evaluation framework includes the construction of predictive models based on an in-depth review of what is known of the natural history of the disease and its impact on patients, involving experts to fill in any knowledge gaps, and the potential effects of the drug in question. The predictive model is thus a tool that can help identify groups of patients with similar characteristics. This will greatly assist OPDP in predicting the potential treatment effect of the drug on a specified disease in a specific group of patients. Where the patient is likely to benefit [the type of benefit is different for every drug/disease reviewed] OPDP may consider public funding for the drug. The preliminary working definition of "rare" is 1/100,000 - 1/150,000 (births/ incidence). This definition is for the purposes of a funding policy for DRDs. There is on-going consultation with stakeholders on this definition.

Ontario’s DRD evaluation framework has already reviewed products for the treatment of glycogen storage diseases, including Elaprase for the treatment of Hunter disease, and Myozyme for the treatment of late-onset Pompe disease. The Ministry has provided funding for both these drug therapies in patients who meet reimbursement criteria developed through the DRD evaluation process. The Ministry is currently prioritising which additional drugs/diseases are to be reviewed through the DRD evaluation framework. There will be on-going evaluation of funding decisions made under the evaluation framework. Helen Stevenson, the Executive Officer of the Ontario Public Drug Plan, was honoured by the Canadian Organization for Rare Disorders for her efforts behind the rare disease drug initiative in early June.

Good laboratory practices for molecular testing of heritable disorders: recommendations from the USA
Intended for molecular genetic testing laboratories and for health professionals who evaluate laboratory practices and policies, a set of Recommendations developed by the Centers for Disease Control, the Centers for Medicare & Medicaid Services, and the Clinical Laboratory Improvement Advisory Committee in the USA has been issued as a “resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care”. The recommendations for good laboratory practices for ensuring the quality of molecular testing for heritable diseases and conditions have some specific guidelines for rare conditions:

In terms of samples selected for establishing performance specifications, “laboratories should not set lower standards for rare diseases or rare mutations; samples should be adequate and appropriate for establishing test performance specifications and defining limitations”.

Laboratories must have an alternative mechanism capable of monitoring DNA extraction and the preceding analytic steps…“when testing is performed for a rare disease or rare variants for which no control material is available for the extraction phase".

In the case of molecular genetic tests for which no proficiency testing programme is available, and when inter-laboratory exchange or obtaining external materials is not practical… “(e.g., testing for rare diseases, testing performed by only one laboratory, patented testing, or unstable analytes such as RNA or enzymes), laboratories may consider options such as repeat testing of blinded samples, blind testing of materials with known values, exchange with either a research facility or a laboratory in another country, splitting samples with another instrument or method, or inter-laboratory data comparison”.

The recommendations cover the preanalytic testing phase, the analytic testing phase, the postanalytic testing phase, laboratory responsibilities regarding authorised persons, ensuring confidentiality of patient information, personnel qualifications, responsibilities, and competency assessments, considerations before introducing molecular genetic testing or offering new molecular genetic tests, quality management system approaches for molecular genetic testing, and further education. These recommendations are in harmony with previously published OECD guidelines.
Consult the USA Recommendations


Ethical, Legal & Social Issues
International expert group reiterates need to adhere to guidelines for stem cell clinical applications
In response to the report in PLoS Medicine of a child with ataxia telangiectasia who developed glioneuronal neoplasms in the brain following multiple injections of foetal neural cells at a clinic in Russia, the International Society for Stem Cell Research (ISSCR) has released a statement urging adherence to the set of guidelines that the independent non-profit organisation issued last December. The case of the patient treated in Russia highlights the necessity of preclinical studies for safety and effectiveness for this type of treatment and also underscores the need for full disclosure to patients and their families. The guidance document points out that the patients who seek medical treatment overseas may be particularly vulnerable should they encounter a lack of local regulation and oversight. The ISSCR “condemns the administration of unproven uses of stem cells or their direct derivatives to a large series of patients outside of a clinical trial, particularly when patients are charged for such services”. The international guidelines offer “a roadmap for the responsible development of safe and effective stem cell therapies for patients”. The ISSCR also offers a handbook furnishing useful information to assist both patients and their physicians to evaluate a proposed stem cell treatment. Amongst the rare disorders for which stem cell treatments are presently offered in certain countries are Batten disease, ataxia telangiectasia, amyotrophic lateral sclerosis, and Huntington disease.
Consult the guidelines


Orphanet News
Orphanet Journal of Rare Diseases more than doubles its impact factor in just one year
The latest edition of Journal Citation Reports reveals that the Orphanet Journal of Rare Diseases (OJRD) has more than doubled its impact factor in the last year. The journal impact factor increased from 1.30 in 2007 to 3.14 in 2008.

OJRD is now in the 22nd place out of a total of 82 journals in the "Medicine, Research & Experimental" category of the Journal Citation Reports.

Orphanet expressed gratitude to all the contributors - authors, reviewers and editors - who have worked hard to make the OJRD a quality publication.

“There are many parameters responsible for the increased impact factor, including the quality of the journal contents and the stability of the publication,” commented Dr. Katia Marazova, the OJRD Managing Editor. “The citation can also be interpreted as proof that research on rare diseases has much to contribute to more common illnesses. Furthermore, the review articles serve the entire rare disease community around the world, providing comprehensive, up-to-date information that is hard to obtain elsewhere, and is useful to patients, health professionals, and the scientific and biopharmaceutical community”.

The Journal Citation Reports provide a critical evaluation of the leading journals, providing quantifiable statistics based on citation data.

New Texts
New Orphanet publications
Beckwith–Wiedemann syndrome (in association with the European Journal of Human Genetics)
Triple X syndrome: a review of the literature (in association with the European Journal of Human Genetics)
Neurofibromatosis type 2 (NF2): A clinical and molecular review (in the Orphanet Journal of Rare Diseases)


New Syndromes
New autoinflammatory syndrome with neonatal onset has mutations in interleukin-1-receptor antagonist gene
Two articles appearing in the New England Journal of Medicine describe ten newborns presenting an autosomal recessive autoinflammatory syndrome characterised by neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. The authors propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement.
Read the first PubMed abstract
Read the second PubMed abstract

N Engl J Med ; 2426-2437 ; 4 June 2009
N Engl J Med ; 2438-2444 ; 4 June 2009

Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia
The sideroblastic anemias are a heterogeneous group of congenital and acquired hematological disorders whose morphological hallmark is the presence of ringed sideroblasts-bone marrow erythroid precursors containing pathologic iron deposits within mitochondria. Here, by positional cloning, the authors define a previously unknown form of autosomal recessive nonsyndromic congenital sideroblastic anemia, associated with mutations in the gene encoding the erythroid specific mitochondrial carrier family protein SLC25A38, and demonstrate that SLC25A38 is important for the biosynthesis of heme in eukaryotes.
Read the PubMed abstract

Nat Genet ; 651-653 ; June 2009

New Genes

Succinate CoQ reductase deficiency: SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated
The authors report mutations in SDHAF1, encoding a new LYR-motif protein, in two families with infantile leukoencephalopathy with defective succinate dehydrogenase (SDH, complex II). Disruption of the yeast homolog or expression of variants corresponding to human mutants caused SDH deficiency and failure of OXPHOS-dependent growth, whereas SDH activity and amount were restored in mutant fibroblasts proportionally with re-expression of the wild-type gene. SDHAF1 is the first bona fide SDH assembly factor reported in any organism.
Read the PubMed abstract

To read more about "Succinate CoQ reductase deficiency"

Nat Genet ; Epub ahead of print ; 24 May 2009
Familial progressive hyperpigmentation: gain-of-function mutation of KIT ligand on melanin synthesis at cause
Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterised by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. In this study, a six-generation Chinese family with FPH was subjected to a genome-wide scan for linkage analysis. They found a KITLGN36S mutation which has a gain-of-function effect on the melanin synthesis.
Read the PubMed abstract

To read more about "Hyperpigmentation progressive, familial"

Am J Hum Genet ; 672-677 ; May 2009
Cone-rod dystrophy: loss of the metalloprotease ADAM9 leads to the disease in humans as well as retinal degeneration in mice
Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By homozygosity mapping, the authors identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. They also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic.
Read the PubMed abstract

To read more about "Cone rod dystrophy"

Am J Hum Genet ; 683-691 ; May 2009
Sensory/motor neuropathy with ataxia: IFRD1 is a candidate gene
Autosomal-dominant sensory/motor neuropathy with ataxia (SMNA) is a rare neurological disorder whose phenotype encompasses both the central and the peripheral nervous system. The authors identified a nonsynonymous variant in the human interferon-related developmental regulator gene 1 (IFRD1) as a disease-causing candidate. Sequence conservation, animal models, and protein structure evaluation support the involvement of IFRD1 in SMNA. Mutation analysis in additional patients with similar phenotypes is needed for demonstration of causality and further evaluation of IFRD1 importance in neurological diseases.
Read the PubMed abstract

To read more about "Autosomal dominant cerebellar ataxia"

Am J Hum Genet. ; 692-697 ; May 2009
Asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III: DYNC2H1 mutations at cause
Jeune syndrome, also called asphyxiating thoracic dystrophy, is a short-rib dysplasia characterised by a narrow thorax and short limbs. In some cases, postaxial polydactyly may also be present. The narrow thorax may cause respiratory failure, even in the neonatal period, and may be associated with persistent respiratory manifestations. Jeune syndrome is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterised by early prenatal expression and lethality and variable malformations. Studying a consanguineous family from Morocco, the authors identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. DYNC2H1 is directly involved in the generation and maintenance of cilia.
Read the PubMed abstract

To read more about "Jeune syndrome"
To read more about "Short rib-polydactyly syndrome"

Am J Hum Genet ; 706-711 ; May 2009
Coenzyme Q10 deficiency: a nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset
Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. The authors identified a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast saccharomyces cerevisiae abolished respiratory growth.
Read the PubMed abstract

To read more about "Coenzyme Q 10 (CoQ10), deficiency"

Am J Hum Genet ; 558-566 ; May 2009
Premature pubarche: Inactivating PAPSS2 mutations in a patient
The authors identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels.
Read the PubMed abstract

N Engl J Med ; 2310-2318 ; 28 May 2009
Cutis laxa: an autosomal-recessive form is due to homozygous elastin mutations
Cutis laxa (CL) is a heterogeneous group of connective tissue disorders characterised by loose, sagging skin and variable involvement of other organs. Autosomal-dominant forms are relatively mild, and may be caused by mutations in the elastin gene, whereas the more severe recessive forms have been associated with mutations in the fibulin 4 and fibulin 5 genes, as well as in a vesicular ATPase subunit. The authors describe a previously unreported autosomal-recessive form of CL caused by homozygous recessive mutations in exon 12 of the elastin gene in three patients from two related consanguineous Syrian families. Furthermore, the presence of a polymorphism in the fibulin 5 gene in one of the patients seems to modify the phenotype, producing more severe symptoms.
Read the PubMed abstract

To read more about "Cutis laxa"

J Invest Dermatol ; 1650-1655 ; July 2009
Infantile parkinsonism-dystonia: homozygous loss-of-function mutations in dopamine transporter gene associated
The authors analyzed 2 unrelated consanguineous families with infantile parkinsonism-dystonia (IPD) syndrome and identified homozygous missense loss-of-function SLC6A3 mutations in both families. Loss-of-function SLC6A3 mutations that impair DAT-mediated dopamine transport activity are associated with an early-onset complex movement disorder.
Read the PubMed abstract

J Clin Invest ; 595-603 ; June 2009
Urocanic aciduria: mutations in UROC1 are associated
Urocanase is an enzyme in the histidine pathway encoded by the UROC1 gene. This report describes the first putative mutations in the coding region of the UROC1 gene in a girl with urocanic aciduria presenting with intellectual deficit and intermittent ataxia. Computed predictions, protein expression studies and enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme.
Read the PubMed abstract

J Med Genet ; 407-411 ; June 2009

Research in Action

Fundamental Research
Huntington disease: a striatal specific protein mediates mutant-huntingtin cytotoxicity
Huntington disease (HD) is caused by a polyglutamine repeat in the protein huntingtin (Htt) with mutant Htt (mHtt) expressed throughout the body and similarly in all brain regions. HD neuropathology is largely restricted to the corpus striatum. The authors report that the small guanine nucleotide-binding protein Rhes, which is localised very selectively to the striatum, binds physiologically to mHtt. Using cultured cells, they found Rhes induces sumoylation of mHtt, which leads to cytotoxicity. Thus, Rhes-mHtt interactions can account for the localised neuropathology of HD.
Read the PubMed abstract

To read more about "Huntington disease"

Science ; 1327-1330 ; 5 June 2009
Clinical Research
Partial STAT1 deficiency has predisposition to viral and bacterial infections that respond to treatment
Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here the authors report a recessive form of partial STAT1 deficiency, characterised by impaired but not abolished IFN-alpha/beta and IFN-gamma signalling in two affected siblings suffering from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation. This deficiency should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
Read the PubMed abstract

To read more about "Mendelian susceptibility to atypical mycobacteria"

J Clin Invest ; 1502-1514 ; June 2009
Congenital hypertrichosis terminalis with or without gingival hyperplasia: copy-number mutations identified
Congenital generalised hypertrichosis terminalis (CGHT) is a rare condition characterised by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. The authors describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. They found pathogenic copy-number mutations on 17q24.2-q24.3 responsible for CGHT with or without gingival hyperplasia.
Read the PubMed abstract

To read more about "Gingival fibromatosis - hypertrichosis"

Am J Hum Genet ; 807-813 ; June 2009
Spectrum of childhood tumours caused by mutations in the mismatch repair genes
Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, the authors refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases. The authors analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, they identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. The authors suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability.
Read the PubMed abstract

J Med Genet ; 418-420 ; June 2009
Ciliopathies: a common allele in RPGRIP1L is a modifier of retinal degeneration
Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited in part owing to poorly understood effects of second-site modifiers. Here the authors demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber and Joubert syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes.
Read the PubMed abstract

To read more about "Retinal ciliopathy"

Nat Genet ; Epub ahead of print ; 10 May 2009
Head and neck paragangliomas: VHL and RET mutations are rare
Head and neck paragangliomas (HNPs) occur as sporadic or familial entities, the latter mostly in association with germline mutations of the SDH genes. Heritable non-SDH HNP might occur in von Hippel-Lindau disease (VHL gene), multiple endocrine neoplasia type 2 ( MEN2, RET genes), and neurofibromatosis type 1 (NF1, NF1 gene). Reports of non-SDH HNP presentations are scarce and guidance for genetic testing nonexistent. An international consortium registered patients with HNPs and performed mutation analyses of the SDH, VHL, and RET genes. The observations provide evidence that molecular genetic testing for VHL or RET germline mutations in patients with HNP should be done only if personal and/or family history shows evidence for one of these syndromes.
Read the PubMed abstract

To read more about "Hereditary pheochromocytoma-paraganglioma syndrome"

J Clin Endocrinol Metab ; 1938-1944 ; June 2009
Hereditary diffuse gastric cancer syndrome: quantification of second hits in CDH1 during disease progression
Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumours acquire complete CDH1 inactivation through "second-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). The authors quantified the different second hits in CDH1 occurring in neoplastic lesions from 17 HDGC patients from 15 families. Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed. The authors conclude that second hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumours and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumour initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.
Read the PubMed abstract

To read more about "Gastric cancer, familial"

Gastroenterology ; 2137-2148 ; June 2009
The spectrum of ocular phenotypes caused by mutations in the BEST1 gene
Two articles appearing in Progress in Retinal and Eye Research describe the ocular anomalies associated with mutations affecting bestrophin-1, an integral membrane protein encoded by the BEST1 gene, which appears to play a role in ocular development. Over 120 different human BEST1 mutations have been described to date, associated with a broad range of ocular phenotypes including Best vitelliform macular dystrophy and adult-onset foveomacular vitelliform dystrophy, autosomal dominant vitreoretinochoroidopathy, the MRCS (microcornea, rod-cone dystrophy, cataract, posterior staphyloma) syndrome, and autosomal recessive bestrophinopathy.
Read the first PubMed abstract
Read the second PubMed abstract

Prog Retin Eye Res ; 187-205 ; May 2009
Prog Retin Eye Res ; 206-226 ; May 2009

Microtia: a review of the anomaly and related disorders
Microtia is a congenital anomaly, characterised by a small, abnormally shaped auricle (pinna). It is usually accompanied by a narrow, blocked or absent ear canal. Microtia can occur as the only clinical abnormality or as part of a syndrome. Microtia can have a genetic or environmental predisposition. In this article, the authors review the epidemiological characteristics of microtia - the genetic aspects and environmental causes involved. The clinical aspects of various disorders involving microtia are also discussed in relation to the genes that cause them.
Read the PubMed abstract

To read more about "Microtia"

J Med Genet ; 361-369 ; June 2009
Stem Cells
Induced pluripotent stem cells offer new approach to thalassemia and sickle cell anemia and in prenatal diagnosis
In this study, the authors reprogrammed the skin fibroblasts of a patient with homozygous beta(0) thalassemia into induced pluripotent stem (iPS) cells, and showed that the iPS cells could be differentiated into hematopoietic cells that synthesized hemoglobin. Prenatal diagnosis has been effective in decreasing the number of beta-thalassemia births in some countries that have instituted carrier screening and genetic counseling. To make use of the cells from the amniotic fluid or chorionic villus sampling that are used for prenatal diagnosis, the authors also showed that these cells could be reprogrammed into iPS cells. This raises the possibility of providing a new option following prenatal diagnosis of a fetus affected by a severe illness. The cells for prenatal diagnosis can be converted into iPS cells for treatment in the perinatal periods. Early treatment has the advantage of requiring much fewer cells than adult treatment and can also prevent organ damage in those diseases in which damage can begin in utero or at an early age.
Read the PubMed abstract

PNAS ; 9826-30 ; 16 June 2009
Gene Therapy
Wiskott-Aldrich syndrome: evidence for long-term efficacy and safety of gene therapy in preclinical models
Wiskott-Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterised by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic option for patients lacking a suitable bone marrow (BM) donor. The authors analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of was(null) mice. They demonstrated stable and full donor engraftment and Wiskott-Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages up to 12 months after gene therapy. Importantly, they observed a selective advantage for T and B lymphocytes expressing transgenic WASP. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.
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Mol Ther ; 1073-1082 ; June 2009
Therapeutic Approaches
Pompe disease: two studies improve treatment in mouse models
Pompe disease, also known as glycogen storage disease type II, is a lysosomal storage disease caused by acid alpha-1,4-glucosidase deficiency. Two separate studies demonstrate the possibility of improving treatment by ameliorating the muscular absorption of the enzyme in mouse models of the disease. The first study demonstrates that chemical conjugation of a synthetic oligosaccharide harboring mannose 6-phosphate (M6P) residues onto recombinant human acid alpha-glucosidase (rhGAA) via oxime chemistry significantly improved its affinity for the cation-independent mannose 6-phosphate receptor (CI-MPR) and subsequent uptake by muscle cells. The second study improves efficacy by using a pharmacological chaperone.
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Mol Ther ; 954-63 ; June 2009
Mol Ther ; 964-971 ; June 2009

Diagnostic Approaches
Zellweger syndrome: a diagnostic strategy
Zellweger syndrome spectrum (ZSS) comprises a clinically and genetically heterogeneous disease entity, which is caused by mutations in any of the 12 different human PEX genes leading to impaired biogenesis of the peroxisome. Published reports on diagnostic procedures for ZSS patients are restricted either to biochemical markers or to defined mutations in a subset of PEX genes. Clarification of the primary genetic defect in an affected patient is crucial for genetic counselling, carrier testing or prenatal diagnosis. In this study, the authors present a rational diagnostic strategy for patients suspected of ZSS. By combining cell biology and molecular genetic methods in an appropriate sequence, they were able to detect the underlying mutation in various PEX genes within adequate time and cost. Furthermore, this strategy will extend the knowledge on genotype-phenotype correlation in various PEX genes.
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Eur J Hum Genet ; 741-748 ; June 2009

Patient Management and Therapy

Cryopyrin-associated periodic syndrome: canakinumab associated with rapid remission of symptoms
The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab is a human anti-interleukin-1beta monoclonal antibody. The authors performed a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS. They found that treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS.
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N Engl J Med ; 2416-2425 ; 4 June 2009
Bullous pemphigoid: a comparison of two regimens of topical corticosteroids
Superpotent topical corticosteroids (CS) have been demonstrated to improve bullous pemphigoid (BP) patient survival. The authors assessed whether a mild regimen using lower doses of topical CS and a shorter duration could improve the outcome of BP patients even more. Three hundred and twelve BP patients were included in a multicentre randomised controlled trial and stratified depending on the extent of BP as moderate or extensive. A strong beneficial effect of the mild regimen was observed in patients with moderate BP, with an almost twofold decrease in the risk of death or life-threatening adverse events relative to the standard regimen. This mild regimen allows a 70% reduction of the cumulative doses of CS and improves BP patient outcome.
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J Invest Dermatol ; 1681-1687 ; July 2009
Pulmonary arterial hypertension: Tadalafil therapy improves quality of life
Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. Tadalafil was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.
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Circulation ; 2894-2903 ; 9 June 2009
Wegener granulomatosis: deoxyspergualin achieves high rate of disease remission
Conventional therapy of Wegener granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing or refractory disease. Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener granulomatosis. Adverse events were common but rarely led to treatment discontinuation.
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Ann Rheum Di ; 1125-1130 ; July 2009
Neurofibromatosis type 2: from pathogenesis to treatment
Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25,000 live births and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with the disorder. The authors review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis type 2.
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Lancet ; 1974-1986 ; 6 June 2009

Orphan Drugs
Priority guidelines released in response to shortages of Cerezyme and Fabrazyme
In response to the closure of a Genzyme production site manufacturing Cerezyme (imiglucerase) for the treatment of Gaucher disease and Fabrazyme (agalsidase beta) for the treatment of Fabry disease, the European Medicines Agency (EMEA) has issued a press release recommending priority access for patients most in need of treatment. Genzyme’s Allston Landing site in the USA closed due to viral contamination, resulting in the halt of production of rare disease treatment products Cerezyme and Fabrazyme. In response to this, the EMEA agrees to the following changes: for Cerezyme, priority is to be given to infants, children and adolescents, and adults with active disease progression. These patients can continue to receive Cerezyme at the standard dosage schedule of one infusion every two weeks. For adult patients with no clinical evidence of active disease progression, Cerezyme should be administered at a reduced dose of half a dose once every two weeks or at a reduced infusion frequency of once a month at the current dose. For Fabrazyme, priority is given to children and adolescents, and adult male patients, who should continue to receive Fabrazyme as one infusion every two weeks. However, adult female patients, in whom the disease is less severe, may receive Fabrazyme at a reduced dose. The EMEA states that these are temporary recommendations that do not alter the approved Product Information for either Cerezyme or Fabrazyme. These changes in dosage administration are expected to continue until the end of the year. A question and answer document accompanying the press release provides further information. The Genzyme website is also providing regular updates of the situation.

What's on Where?
Crafting a Plan for Rare Disease Drug Development
Date: 17 July 2009
Venue: Maryland, USA

This workshop will focus on solutions to the specific limiting problems of rare disease drug development, with a deliverable, milestone, and results-oriented approach.
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Cornelia de Lange Syndrome World Conference
Date: 23 July 2009
Venue: Brighton, UK

This event is part of the Cornelia de Lange Syndrome World Conference and is aimed at teachers, support staff and health professionals who work with children and adults with intellectual disability, autism spectrum disorder and genetic syndromes. The focus is on identifying and responding to the critical personal and family issues that affect the day to day quality of life of all people with intellectual disability. Cornelia de Lange syndrome will be highlighted.
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Treatment Options in Phenylketonuria and Related Pediatric Neurotransmitter Disorders
Date: 29 August 2009
Venue: San Diego, California USA

Key Topics include challenges in the pharmaceutical treatment of PKU and treatment of paediatric neurotransmitter disorders.
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14th International World Muscle Congress
Date: 9-12 September 2009
Venue: Geneva, Switzerland

New methods for assessing disease progression in neuromuscular disorders; the extracellular matrix in normal and diseased muscle (including collagen and glycosylation disorders, fibrosis, patterning and cell grafting); advances in treatment of neuromuscular disorders. A satellite teaching course will also be held from 8-9 September 2009.
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Rare neurometabolic and neurogenetic disease in adults: a joint French-Italian workshop
Date: 10-11 September 2009
Venue: Siena, Italy

A satellite meeting of the 13th European Federation of Neurological Societies congress. Featuring an overview of rare diseases and updates on mitochondrial encephaloneuromyophaties, spinocerebellar ataxias, small vessel diseases, late onset leukodystrophies, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, dysimmune chronic neuropathies, and treatable neurometabolic genetic diseases.
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Genetics and Genomics of Vascular Disease Workshop
Date: 13-16 September 2009
Venue: Hyannis, MA

The programme will present cutting edge research in areas like genome wide association studies in human populations, mouse QTL mapping of vascular phenotypes, and pathogenesis of vascular and developmental diseases using human patients and mouse models.
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European Working Group on Rett Syndrome – 2009 Meeting
Date: 17-18 September 2009
Venue: Stresa, Italy

An opportunity to discuss Rett syndrome-related science, to find collaborators for grant applications, and to exchange reagents and ideas. Moreover, the close contact with the parents associations should also help to focus better on the scientific problems that need to be resolved to find a cure for patients.
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British Paediatric Neurology Association: Rare Disorders Symposium
Date: 29 September 2009
Venue: Harrogate, England

A stand-alone satellite symposium on rare disorders will take place as part of the 8th Paediatric Neurology Conference, exploring a number of themes relating to rare disorders.
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Fourth International Conference on Birth Defects and Disabilities in the Developing World
Date: 4-7 October 2009
Venue: New Delhi, India

The theme of the Fourth International Conference is "Translating Research into Cost-effective Services for the Care and Prevention of Birth Defects, Preterm Birth and Consequent Disabilities".
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EPPOSI: 10th Workshop on Partnering for Rare Disease Therapy Development
Date: 26-27 October 2009
Venue: Brussels, Belgium

The topic of this year’s workshop of the European Platform for Patients’ Organisations, Science and Industry is “10 years after the adoption of the EU Orphan Medicines Regulation: Where do we go? Three key themes will be addressed: “What is the impact of the economic crisis on the field of rare diseases – and what is the vision on further progress in R&D, diagnosis and patient care? Building on the public policy base of the last 10 years: how to advance policies in the next five years? Rare cancers: specific challenges within rare diseases.
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European Society for Phenylketonuria Annual Conference 2009
Date: 30 October – 1 November 2009
Venue: Antalya, Turkey

The conference offers the opportunity to exchange the latest experiences via workshops and presentations. Delegates of member associations will discuss the situation regarding European health politics and European networks. An industry exhibition will inform on the latest product developments.
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TREAT-NMD/NIH International Conference
Date: 17-19 November 2009
Venue: Brussels, Belgium

The aim of the meeting is to share progress in the area of translational medicine in inherited neuromuscular diseases and set the future collaborative agenda. This conference will build on achievements of the NIH and TREAT-NMD. It will be a highly interactive meeting with a strong focus on the key issues surrounding "trial readiness" in the neuromuscular field.
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OI in motion: Rehabilitation and Physiotherapy in Osteogenesis Imperfecta
Date: 20-22 November 2009
Venue: Rheinsberg, Germany

Topics include rehabilitation of children; rehabilitation of adults; assessments of motor functions; orthoses/mobility aids; and international experiences.
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ESF-UB Conference in Biomedicine: Rare Diseases II: Hearing and Sight Loss
Date: 22-27 November 2009
Venue: Sant Feliu de Guixols, Spain

A conference of the European Science Foundation. The meeting will bring together experts in sensory neuroscience, developmental biology, genetics, cell biology, modelling, translational research and therapy. It aims at promoting exchanges between the scientists of the two fields and beyond, at stimulating the emergence of new research projects at the interface between disciplines and at training young researchers in this interdisciplinary field.
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18th International Workshop on Vascular Anomalies
Date: 21-24 April 2010
Venue: Brussels, Belgium
The programme for this workshop will be available soon.

5th European Conference on Rare Diseases 2010
Date: 13-15 May 2010
Venue: Crakow, Poland
Details will be available soon.


Press & Publications

A new Spanish-language publication from CIBERER describes hereditary metabolic diseases
Spanish rare disease biomedical research network CIBERER together with the Hereditary Metabolic Diseases Unit from the Sant Joan de Déu Hospital in Barcelona, have published a book and a compact disc entitled Congenital errors in metabolism: An Educational guide. Written in Spanish language and destined for patients, relatives, and health professionals, the book explains clearly and simply the main hereditary metabolic diseases that the hospital unit headed by Dr. Rafael Artuch encounter in their daily work. The book is freely available on the CIBERER website.
Myasthenia Gravis and Related Disorders - a second edition updates and expands material
Author: Kaminski, Henry J. -Ed.
Publisher: Humana Press
ISBN: 978-1-58829-852-2

Advances in the study of myasthenia gravis have led to the second edition of this work that provides the clinician and scientist with a common resource for understanding this complex disorder. Includes discussions of neuromuscular junction structure and function and updated chapters covering a wide range of topics, such as the acetylcholine receptor, clinical presentation, diagnostic evaluation, and treatment. New supplemental chapters discuss rigorous clinical assessments of patients for research trials and the epidemiology and genetics of myasthenia gravis.
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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, Olaf Bodamer, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Manuel Posada de la Paz, Charlotte Rodwell, Claire Scharf-Kroener, Paloma Tejada, Aurélie Vandeputte
National Contact Point: Jean Jacques Cassiman (Belgium), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), Andres Metspalu (Estonia), Riitta Salonen (Finland), Manfred Stuhrmann (Germany), Michael Petersen (Greece), János Sándor (Hungary), Andrew Green (Ireland), Judith Melki (Israel), Bruno Dallapiccola and Domenica Taruscio (Italy), Andre Megarbane (Lebanon), Vaidutis Kucinskas (Lithuania), Alfred Cuschieri (Malta), Abdelaziz Sefiani (Morocco), Martina Cornel (Netherlands), Stein Are Aksnes (Norway), Jolanta Sykut-Cegielska (Poland), Jorge Sequeiros (Portugal), Dragica Radojkovic (Serbia), Ludovit Kadasi (Slovakia), Borut Peterlin (Slovenia), Miguel del Campo and Manuel Posada de la Paz (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Habiba Chaabouni-Bouhamed (Tunisia), Fatmahan Atalar and Ugur Ozbek (Turkey), Edmund Jessop and Idoia Gomez-Paramio (United Kingdom)
For more information on the Rare Diseases Task Force
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