15 September 2010 print
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Who’s doing what for rare diseases?
A comprehensive new document takes stock of the different initiatives throughout the European Union
Amongst the biggest challenges to addressing rare diseases are fragmentation and duplication. With small, widely-scattered populations of patients suffering from one of over seven thousand heterogeneous rare conditions identified to date, experts have long insisted that organisation and harmonisation are crucial in order to bring real solutions to rare disease patients and their families. Coordination and collaboration are essential for every aspect of disease management – prevention, diagnostics, research, treatment, and social support.

To help reduce fragmentation and duplication of effort and to encourage an organised coordinated response on the European level, the Scientific Secretariat of the Rare Disease Task Force (RDTF) in collaboration with the European Project for Rare Diseases National Plans Development (EUROPLAN) have published the 2009 Report on Initiatives and Incentives in the Field of Rare Diseases. Produced via contracts from the EU Programme of Community Action in the field of health, this surveillance report details all the initiatives and incentives for rare diseases underway at the EU level as well as those taking place in each EU Member State (MS) and four non‐EU European countries. This document will be submitted for endorsement to the newly formed European Union Committee of Experts on Rare Diseases (EUCERD) which will meet for the first time on 9 and 10 December 2010 in Luxembourg.

Working from a variety of sources, including European Commission documents, Rare Disease Task Force publications, the archives of OrphaNews Europe, European Medicines Agency and other orphan drug publications, patient organisations, Orphanet country partners, and a questionnaire developed by the Europlan project, the authors have compiled a comprehensive inventory of the actions and incentives on both the European and MS levels.

At the European level, the report provides a retrospective of the actions undertaken by the Directorate General Enterprise and the European Medicines Agency (EMA), including regulations adopted, committees formed and work programmes developed. A similar assessment was made for the Directorate General Public Health and Consumers (DG Sanco) and the Directorate General Research and a descriptive list of past and ongoing relevant funded projects from both entities is provided. Other Europe-wide actions and initiatives are also listed, including special celebrations, alliances, meetings, calls for proposals and more.

At the country level, utilising the elements identified in the 2009 European Council Recommendation on an action in the field of rare diseases, which calls upon each Member State to develop a strategy for their rare disease patients, the document reports the past and current actions for individual countries in the following areas: Definition of a rare disease; National plan for rare diseases and related actions; Centres of expertise; Registries; Neonatal screening policy; National alliances of patient organisations and patient representation; Sources of information on rare diseases and national help lines; National rare disease events; Hosted rare disease events; Research activities and E‐Rare partnership; Participation in European projects; Orphan drug committees and incentives; Orphan drug availability; and Specialised social services. Similar data is provided, where available, for four other European countries: EU-candidates Croatia and Turkey, as well as Norway and Switzerland.

The report closes with a select bibliography of key publications, including all relevant legislation, and furnishes electronic links whenever available. There is also a list of European research projects on rare diseases, previously or currently funded by the European Commission and the ERA-Net for research programmes on rare diseases (E-Rare), with a recapitulative table giving the total number of projects by country and by funding body.

This sweeping overview of rare disease initiatives in Europe - to be updated annually - presents a powerful tool to illuminate the path for future rare disease strategising.
Consult the 2009 Report on Initiatives and Incentives in the Field of Rare Diseases

EUCERD update
First meeting of the European Committee of Experts on Rare Diseases scheduled
The first meeting for the newly-formed European Union Committee of Experts on Rare Diseases (EUCERD), which replaces the European Commission Rare Disease Task Force, has been scheduled. The meeting will take place on 9-10 December in Luxembourg.


EU Policy News
Today is the last day to respond to the Commission consultation on the in vitro diagnostic directive!
EuroGentest position paper seeks to protect rare disease diagnostics offer
The European Commission in June launched a public consultation on the revision of Directive 98/79 EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices (the IVD Directive).

Council Directive 90/385/EEC relating to active implantable medical devices, Directive 93/42/EEC concerning medical devices and Directive 98/79/EC on in vitro diagnostic medical devices harmonise safety and performance rules for medical devices in the European Union (EU). Due to both technological advances and identified emerging weaknesses identified in the regulatory framework, a public consultation was launched in 2008 on the Recast of the Medical Devices Directives. Responses to this underlined a necessity for the revision of the IVD Directive, which has remained largely unchanged since its adoption in 1998, despite significant technological advancement in the sector.

The IVD Directive sets out the regulations governing the safety and efficacy of diagnostic tests marketed in Europe and creates a single market for in vitro diagnostic devices across the EU. The existing IVD Directive has been criticised for being inflexible and arbitrary in the way it classifies tests. The blanket exemption for tests produced in health institution laboratories is also criticised for being too broad and poorly defined.

The EU-funded Network of Excellence EuroGentest has produced a position paper on the revision of the IVD Directive, which has been adopted as EuroGentest policy. One central proposal of the EuroGentest document is that the exemption from CE-marking for in-house tests manufactured in public health service laboratories should be retained, but that it should be restricted to laboratories accredited to ISO 15189 or equivalent. This would provide a balance between test availability and patient safety. There have been calls for the abolition of the in-house exemption. If this were to occur, however, it would severely limit the scope of testing available - especially for rare diseases. The EuroGentest response to the consultation robustly supports the retention of the exemption, while emphasising that patient safety should be ensured by restricting it to accredited laboratories.

Network of Excellence EuroGentest encourages all national human genetics societies, rare disease groups, rare disease testing laboratories and other interested individuals who have not yet done so to respond swiftly to the consultation and suggests that those submitting responses add data on the numbers of genetic tests carried out in their country/region/laboratory which would no longer be available without the in-house exemption. Respond to the In Vitro Diagnostic Directive Public Consultation

German and UK Europlan conferences for national rare disease strategies seek participants
The European Project for Rare Disease National Plans Development (Europlan) is a three-year project of the Programme of Community Action in the Field of Public Health which launched in April 2008, in order to provide national health authorities with tools for the development and implementation of national strategies for rare diseases following the European Council Recommendation on an Action in the field of Rare Diseases. As part of this initiative, Europlan, working in conjunction with European rare disease patient alliance Eurordis, has organised a series of conferences in over a dozen individual European Union Member States. Upcoming conferences are scheduled to take place in Dubrovnik, Croatia on 18-20 September; Paris, France on 30 September; and Berlin, Germany on 13-14 October. Other conference destinations include Bulgaria, Romania, Hungary, Spain, Sweden, Italy, the United Kingdom, the Netherlands, Denmark, Greece and Ireland. While some conferences are organised on an invitation basis, others – including Germany, Ireland and the UK – encourage interested stakeholders to register for the event taking place in their country. Learn more about the Europlan conferences

National & International Policy Developments
Moving toward a global registry for rare diseases
An article in the journal Contemporary Clinical Trials reports the outcome of a workshop sponsored by the USA’s Office of Rare Diseases Research (ORDR) which includes the launch of an initiative to develop a global patient registry for rare diseases. The workshop Advancing Rare Disease Research: The Intersection of Patient Registries, Biospecimen Repositories, and Clinical Data was held in January 2010 with the objective of discussing “the development of an infrastructure for an internet-based platform with common data elements utilizing a federated rare disease registry able to incorporate existing rare disease registries; patient organizations with no registry looking to establish one; and patients with no affiliation with a support group looking to belong to a registry”. Many of the challenging questions inherent to the development of a global registry were raised – including identifying best practices; standardising terminology; codes and diagnostic recommendations; informatics and technology issues; determining who would control a centralised database; what kind of data should be included; assuring accuracy; updating data; data access; and issues around privacy. The workshop also focused on the possibility of creating a centralised database of biorepositories for rare biospecimens that could link to the global registry. Consult the PubMed abstract
New legislation in the USA seeks to Create Hope for paediatric patients with rare conditions
A new bill has been introduced in the USA that would extend an existing incentive scheme for neglected tropical diseases to rare childhood disorders. S.3697, the Creating Hope Act of 2010, was introduced in August by senators from both the democratic and republican parties. The bill builds upon the 2007 FDA Amendments Act, which established a priority review voucher programme which provides sponsors undertaking drug development for a neglected tropical disease with a “voucher” that allows them an expedited FDA review process for any other product in development –including blockbusters. The Creating Hope Act seeks to extend this scheme to rare paediatric conditions, with the expectation that the new legislation would give pharmaceutical companies more incentive to focus on rare paediatric diseases. The bill has been referred to the senate Committee on Health, Education, Labor, and Pensions.
Consult the bill proposal


EU Project Follow-up
Neuromuscular disease network of excellence TREAT-NMD launches public consultation on future strategies
European Network of Excellence for neuromuscular diseases TREAT-NMD has launched a consultation process on the future direction of the network. Open through 1 October 2010, the public consultation describes the purpose and activities of TREAT-NMD, and outlines the current status. European Commission funding for TREAT-NMD will end in December 2011 and the consultation is designed to help TREAT-NMD define its future activities, strategy and funding sources. Respond to the consultation

Orphanet News
New Texts
New Orphanet Journal of Rare Diseases publications
Interstitial lung diseases in children

New Syndromes

New familial syndrome combines ptosis, nasal speech, prominent ears, hand anomalies and learning problems
The authors describe a four-generation family in whom five members show the combination of a large head, ptosis, nasal speech that sometimes goes along with a cleft palate, full cheeks, small mouth, prominent ears, and learning problems. Three affected members also had a partial cutaneous syndactyly between the third and fourth fingers, an increased distance between second and third finger, and a decreased sense of smell. Pattern of inheritance is likely to be autosomal dominant.
Read the PubMed abstract

Eur J Med Genet ; 192-196 ; Jul-Aug 2010
Speech delay, seizures and variable corpus callosum thickness with a deletion in the region containing the HNRPU gene
The authors describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them, who share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. The deletion shared by the patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions.
Read the PubMed abstract

Eur J Med Genet ; 179-185 ; Jul-Aug 2010
Agenesis of the corpus callosum and congenital lymphedema: a novel recognisable syndrome?
The authors present double first cousins, a girl and a boy, with the uncommon association of agenesis of the corpus callosum and congenital lymphedema. Other features shared by both include oligohydramnios, similar facial dysmorphism, sacral dimple, developmental delay, and sociable personality. While some of these findings overlap with FG syndrome and Hennekam syndrome, the findings in these patients are sufficiently different to exclude these diagnoses. The authors propose that this is a new syndrome with presumed autosomal recessive inheritance.
Read the PubMed abstract

Am J Med Genet ; 1621-1626 ; July 2010

New Genes

Osteogenesis imperfecta: identification of a frameshift mutation in Osterix in a patient
Osteogenesis imperfecta, or "brittle bone disease," is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. The authors report a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation.
Read the PubMed abstract

To read more about "Osteogenesis imperfecta"

Am J Hum Genet ; 110-114 ; 9 July 2010
Mesomelia-synostoses syndrome: deletion of SULF1 and SLCO5A1 genes
Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterised by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. The authors have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is still unknown.
Read the PubMed abstract

To read more about "8q13 microdeletion syndrome"

Am J Hum Genet ; 95-100 ; 9 July 2010
Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4
Clubfoot is a common musculoskeletal birth defect for which few causative genes have been identified. A recurrent chromosome 17q23.1q23.2 microduplication was identified in 3 of 66 probands with familial isolated clubfoot. The chromosome 17q23.1q23.2 microduplication segregated with autosomal-dominant clubfoot in all three families but with reduced penetrance. Mild short stature was common and one female had developmental hip dysplasia. Subtle skeletal abnormalities consisted of broad and shortened metatarsals and calcanei, small distal tibial epiphyses, and thickened ischia. Several skeletal features were opposite to those described in the reciprocal chromosome 17q23.1q23.2 microdeletion syndrome associated with developmental delay and cardiac and limb abnormalities. The chromosome 17q23.1q23.2 region contains the T-box transcription factor TBX4, a likely target of the bicoid-related transcription factor PITX1 previously implicated in clubfoot aetiology.
Read the PubMed abstract

To read more about "Tibial hemimelia - clubfoot"

Am J Hum Genet ; 154-160 ; 9 July 2010
Paraganglioma: tumour suppressor gene SDHA at cause
The authors identified a heterozygous germline SDHA mutation, p.Arg589Trp, in a woman suffering from catecholamine-secreting abdominal paraganglioma. In vivo and in vitro functional studies demonstrated that the SDHA mutation causes a loss of SDH enzymatic activity in tumour tissue and in the yeast model. Immunohistochemistry and transcriptome analyses established that the SDHA mutation causes pseudo-hypoxia, which leads to a subsequent increase in angiogenesis, as other SDHx gene mutations. Loss of heterozygosity was detected at the SDHA locus in the patient's tumour but was present in only 4.5% of a large series of paragangliomas and pheochromocytomas.
Read the PubMed abstract

To read more about "Hereditary pheochromocytoma-paraganglioma syndrome"

Hum Mol Genet ; 3011-3020 ; 1 August 2010
Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene
Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterised by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. The authors identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter.
Read the PubMed abstract

To read more about "Terminal osseous dysplasia - pigmentary defects"

Am J Hum Genet ; 146-153 ; 9 July 2010
Heterotaxy: recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1)
Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in the left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Although autosomal-recessive inheritance of heterotaxy syndrome is seen in multiple families, underlying gene defects have remained unknown. The authors identified the molecular genetic basis of a kindred with five siblings with RAI. Linkage analysis and positional candidate gene approach showed that the affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene.
Read the PubMed abstract

To read more about "Heterotaxia"

Hum Mol Genet ; 2747-2753 ; 15 July 2010
Mitochondrial myopathy with sideroblastic anemia: YARS2 mutations at cause
Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. The authors identified a pathogenic mutation (c.156C>G [p.F52L]) in YARS2, located at chromosome 12p11.21, in a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). They subsequently identified the same mutation in another unrelated MLASA patient.
Read the PubMed abstract

To read more about "Mitochondrial myopathy with sideroblastic anemia"

Am J Hum Genet ; 52-59 ; 9 July 2010

Research in Action

Fundamental Research
Amyotrophic lateral sclerosis-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2
In mutant superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS), accumulation of misfolded mutant SOD1 in spinal cord mitochondria is thought to cause mitochondrial dysfunction. Whether mutant SOD1 is toxic per se or whether it damages the mitochondria through interactions with other mitochondrial proteins is not known. The authors previously identified Bcl-2 as an interacting partner of mutant SOD1 specifically in spinal cord, but not in liver, mitochondria of SOD1 mice and patients. They now show that mutant SOD1 toxicity relies on this interaction. Mutant SOD1 induces mitochondrial morphological changes and compromises mitochondrial membrane integrity leading to release of Cytochrome C only in the presence of Bcl-2. In cells, mouse and human spinal cord with SOD1 mutations, the binding to mutant SOD1 triggers a conformational change in Bcl-2 that results in the uncovering of its toxic BH3 domain and conversion of Bcl-2 into a toxic protein. Bcl-2 carrying a mutagenized, non-toxic BH3 domain fails to support mutant SOD1 mitochondrial toxicity.
Read the PubMed abstract

To read more about "Amyotrophic lateral sclerosis"

Hum Mol Genet ; 2974-2986 ; 1 August 2010
Lafora disease: laforin, the most common mutated protein, regulates autophagy
Lafora disease (LD) is an autosomal recessive, progressive myoclonus epilepsy, which is characterised by the accumulation of polyglucosan inclusion bodies, called Lafora bodies, in the cytoplasm of cells in the central nervous system and in many other organs. However, it is unclear at the moment whether Lafora bodies are the cause of the disease, or whether they are secondary consequences of a primary metabolic alteration. Here the authors describe that the major genetic lesion that causes LD, loss-of-function of the protein laforin, impairs autophagy. Conversely, laforin expression stimulates autophagy. Laforin regulates autophagy via the mammalian target of rapamycin kinase-dependent pathway. The changes in autophagy mediated by laforin regulate the accumulation of diverse autophagy substrates and would be predicted to impact on the Lafora body accumulation and the cell stress seen in this disease that may eventually contribute to cell death.
Read the PubMed abstract

To read more about "Lafora disease"

Hum Mol Genet ; 2867-2876 ; 15 July 2010
Clinical Research
Class II 1q21.1 microdeletions: unreported clavicular pseudoarthrosis, anomalous coronary artery and extra crease of the fifth
More than 40 individuals with distal 1q21.1 deletions have been reported to date. Submicroscopic deletions of two adjacent regions within chromosomal band 1q21.1 were recently associated with two distinct phenotypes: a deleted region of 200-500 kb was found in individuals with Thrombocytopenia Absent Radius syndrome (TAR). Deletion in another region of about 1.25 Mb that is located just telomeric of the TAR region, referred to as distal 1q21.1 region, was found to be associated with a phenotype of cognitive impairment, congenital heart defects and other variable manifestations. A significant proportion of individuals with either of the two deletions did not have phenotypic abnormalities. A proportion of them (9 reported individuals) had larger (>2 Mb) deletions involving both the TAR and the distal 1q21.1 regions, referred to as class II deletions. The authors describe four additional individuals from two families with such class II deletions, who presented with previously unreported manifestations: clavicular pseudoarthrosis and anomalous origin of the coronary artery in the proband of the first family; an extra transverse crease of the fifth finger, segregating in two of the three deletion carriers in the second family. Previously reported features, associated with such microdeletions - absolute or relative microcephaly, cognitive impairment and short stature, were variably observed in the reported individuals. This report expands the phenotypic spectrum associated with class II 1q21.1 deletions, and demonstrates striking phenotypic variability even within the same family.
Read the PubMed abstract

Eur J Med Genet ; 213-216 ; Jul-Aug 2010
Nijmegen breakage syndrome: high prevalence of primary ovarian insufficiency in girls and young women
Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterised by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, whose product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Growth and sexual development, along with hormonal assays, were evaluated in 37 girls and young women with NBS homozygous for c.657_661del5 mutation. Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. These findings emphasise the need for long-term endocrinological and interdisciplinary supervision of these patients.
Read the PubMed abstract

To read more about "Nijmegen breakage syndrome"

J Clin Endocrinol Metab ; 3133-3140 ; July 2010
Gene Therapy
Pompe disease: lentiviral gene therapy of murine hematopoietic stem cells ameliorates disease phenotype
Pompe disease (acid alpha-glucosidase deficiency) is a lysosomal glycogen storage disorder characterised in its most severe early-onset form by rapidly progressive muscle weakness and mortality within the first year of life due to cardiac and respiratory failure. Enzyme replacement therapy prolongs the life of affected infants and supports the condition of older children and adults but entails lifelong treatment and can be counteracted by immune responses to the recombinant enzyme. The authors have explored the potential of lentiviral vector-mediated expression of human acid alpha-glucosidase in hematopoietic stem cells (HSCs) in a Pompe mouse model. After mild conditioning, transplantation of genetically engineered HSCs resulted in stable chimerism of approximately 35% hematopoietic cells that overexpress acid alpha-glucosidase and in major clearance of glycogen in heart, diaphragm, spleen, and liver. Cardiac remodelling was reversed, and respiratory function, skeletal muscle strength, and motor performance improved. Overexpression of acid alpha-glucosidase did not affect overall hematopoietic cell function and led to immune tolerance as shown by challenge with the human recombinant protein.
Read the PubMed abstract

To read more about "Glycogen storage disease type 2"

Blood ; 5329-5337 ; 1 July 2010
Congenital Leber amaurosis: self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration
To test whether fast-acting, self-complementary, adeno-associated virus-mediated RPE65 expression prevents cone degeneration and/or restores cone function, the authors studied two mouse lines: the Rpe65-deficient rd12 mouse and the Rpe65-deficient, rhodopsin null Rpe65(-/-)::Rho(-/-) mouse. This work establishes that a self-complementary AAV5 vector can restore substantial visual function in two genetically distinct models of Rpe65 deficiency within 4 days of treatment. In addition, this therapy prevents cone degeneration but only if administered before extensive cone degeneration, thus supporting continuation of current congenital Leber amaurosis-2 clinical trials with an added emphasis on cone subtype analysis and early intervention.
Read the PubMed abstract

To read more about "Congenital Leber amaurosis"

Gene Ther ; 815-826 ; July 2010

Patient Management and Therapy

Interstitial lung disease secondary to systemic sclerosis: randomised, prospective, placebo-controlled trial of bosentan
Endothelin is implicated as a participatory pathway in systemic sclerosis (Ssc). The authors tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). Among the 163 patients, 77 were randomised to receive bosentan, and 86 were randomized to receive placebo. No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.
Read the PubMed abstract

To read more about "Systemic sclerosis"

Arthritis Rheum ; 2101-2108 ; July 2010
Acute lymphoblastic leukaemia and lymphoblastic non-Hodgkin lymphoma: improved outcome with vincristine and corticosteroid
A trial for children with acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomised questions, including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED, 201 to DEX, and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival rate was 90.6%. The effect of pulses was similar in the PRED and DEX groups but more pronounced in girls than in boys. Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster-based protocols, pulses should become a standard component of therapy.
Read the PubMed abstract

To read more about "Acute lymphoblastic leukemia"
To read more about "Non-Hodgkin lymphoma"

Blood ; 36-44 ; 8 July 2010
Cartilage hair hypoplasia: outcome of hematopoietic stem cell transplantation
Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disease caused by mutations in the RMRP gene. Beside dwarfism, CHH has a wide spectrum of clinical manifestations including variable grades of combined immunodeficiency, autoimmune complications, and malignancies. Previous reports in single CHH patients with significant immunodeficiencies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for the severe immunodeficiency, while growth failure remains unaffected. The authors performed a European collaborative survey reporting on 16 patients with CHH and immunodeficiency who underwent HSCT. Immune dysregulation, lymphoid malignancy, and autoimmunity were important features in this cohort. Thirteen patients were transplanted in early childhood. The other 3 patients were transplanted at adolescent age. Of 16 patients, 10 were long-term survivors, with a median follow-up of 7 years. T-lymphocyte numbers and function have normalised, and autoimmunity has resolved in all survivors. HSCT should be considered in CHH patients with severe immunodeficiency/autoimmunity, before the development of severe infections, major organ damage, or malignancy might jeopardise the outcome of HSCT and the quality of life in these patients.
Read the PubMed abstract

To read more about "Cartilage-hair hypoplasia"

Blood ; 27-35 ; 8 July 2010
Acromegaly: a consensus on criteria for a cure
The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarised.
Read the PubMed abstract

To read more about "Acromegaly"

J Clin Endocrinol Metab ; 3141-3148 ; July 2010

Orphan Drugs

One study compares orphan drug markets between six European countries…
An article appearing in Health Policy compares the regulatory features of rare disease and orphan drug markets between six European countries, using an analysis of existing literature and legal texts as well as a qualitative questionnaire completed by governmental and regulatory agency representatives, rare disease and orphan drug national task forces, patient organisations, health insurance funds and members of the International Network of Agencies for Health Technology Assessment. The findings demonstrate that amongst the countries studied - Belgium, France, Italy, the Netherlands, Sweden and the United Kingdom – there are a variety of operational approaches taken toward the pricing, reimbursement, distribution and prescribing of orphan drug products for rare diseases. Based on their findings, the authors, identify a need to “define priorities for research on rare diseases and orphan drugs at the European level …set up disease and patient registries with a view to investigating the long-term effectiveness and cost-effectiveness of orphan drugs at national level … assess the profitability of orphan drugs over their lifecycle, and … take into account societal considerations in addition to cost-effectiveness and budget impact when evaluating orphan drugs at national level”.
Consult the PubMed abstract

While another study from the same authors considers the issues surrounding orphan disease and orphan drug policies in Europe
A second article by the same authors – an opinion piece appearing in the journal Applied Health Economics and Health Policy – discusses some issues relevant to orphan drugs in Europe. Particular points touched upon include multiple indications for orphan drugs. The authors point out that the “…current legislation allows for one product to have multiple orphan indications and the prevalence across indications is not added up”. Thus, “low prevalence of a certain indication does not equal a low return on investment for the drug across its indications”. Other points emphasised include the lack of quality evidence for the clinical added value at the time of marketing authorisation and the need for balance between various ethical and economic concerns. The authors also join the growing ranks of stakeholders insisting on the need for a standardised approach to registries, which can provide vital information not only for orphan drug pricing and reimbursement issues, but also for the fields of epidemiology, research, prevention, diagnostics, and social agencies for rare disease patients and their families. The article compares some of the advantages and problems of orphan drug, disease or patient-based registries.
Consult the PubMed abstract



FDA Office of Orphan Products Development grants available for 2012-2013
The Food and Drug Administration’s (FDA) Office of Orphan Products Development (OOPD) has announced the availability of funds for fiscal year (FY) 2012 and FY 2013 grant awards to support clinical trials on the safety and effectiveness of products for rare diseases and conditions. Contingent on availability of FY 2012 and 2013 funds, it is anticipated that approximately $14.1 million will be available for new applications, competing awards, and noncompeting continuation awards.

These studies are intended to provide acceptable data to the FDA that will substantially contribute to the approval of new products, or new indications for already marketed products. In the FDA OOPD grant programme, products for rare diseases and conditions (orphan products) are defined as drugs, biologics, medical devices, and medical foods indicated to treat or diagnose a rare disease or condition with a prevalence of fewer than 200,000 people in the United States. The next due date for receipt of FY 2012 grant applications is 2 February, 2011 and for FY 2013, 1 February, 2012. Applicants may submit a re-submission application, but such application must include an introduction addressing the most recent peer review critique.
Learn more


Courses & Educational Initiatives

4th Inborn Errors in Neonatology Course
Date: 21-23 October 2010
Venue: Dubrovnik, Croatia

This practical course is run by an experienced team of paediatricians, neonatologists, molecular biologists and biochemists specialised in metabolic medicine, who already contributed substantially to the understanding of metabolic disorders in childhood. The two and a half days course includes lectures and seminars for 35 participants. The course is aimed at paediatricians with about 2-3 years clinical experience in the neonatology field.

The Orphan Europe Academy provides healthcare professionals with the opportunity to increase knowledge, develop new ideas and strengthen scientific collaboration by offering training and educational activities for healthcare professionals involved in the diagnosis and management of patients affected by rare diseases.
For further details

European Advanced Postgraduate Course in Classical and Molecular Cytogenetics
This ten-day course held in February/March each year is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification. The students will be trained to identify genetic abnormalities for diagnosis and prognosis, and for fundamental and applied research using both classical and molecular cytogenetic techniques. The course is co-organised by the European Cytogeneticists Association and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training. For further details
EuroGentest Quality Management and Accreditation/Certification of Genetic Testing Workshops
The European network of excellence for all aspects of genetic testing, EuroGentest, under its Quality Management and Accreditation/Certification of Genetic testing Workgroup, has several training workshops available around Europe in coming months that focus on accreditation and quality assurance.
For further details


What's on Where?

International Data Sharing Conference
Date: 20-22 September 2010
Venue: Oxford, UK

This international three day conference is organised by the Centre for Health, Law and Emerging Technologies at the University of Oxford. It will address the implications of data sharing in research and how it should be effectively governed. The conference will bring together a wide range of voices to discuss and think more deeply about the technological, legal, ethical, and social challenges raised by research data sharing. There will be a satellite workshop on ethical and philosophical issues arising from data sharing.
For further details

2nd Conference on Clinical Research for Rare Diseases
Date: 21 September 2010
Venue: Bethesda, MD, USA

Sponsored by the Rare Diseases Clinical Research Network and the Clinical and Translational Science Awards, this unique conference will focus on research methodology for rare diseases and should be of particular interest to trainees and junior faculty engaged in research in rare diseases.
For further details

EFGCP Children’s Medicines Working Party and DIA Europe Second Joint Paediatric Conference
Date: 28-29 September 2010
Venue: London, UK

The European Forum for Good Clinical Practice (EFGCP) Children’s Medicines Working Party and DIA Europe are pleased to announce their second joint paediatric conference. Traditional paediatric meetings of both societies in the past and the joint meeting in 2009 have attracted top level speakers from the European Medicines Agency (EMA), FDA, national authorities, WHO, academia, pharmaceutical industry and parents & patients’ organisations. This second joint program will again offer the opportunity for intensive discussion among stakeholders in different topics relevant for paediatric medicines: visions, daily challenges and ways forward in paediatric drug development.
For further details

Brain, Blood and Iron: Joint International Symposium on Neuroacanthocytosis and Neurodegeneration with Brain Iron Accumulation
Date: 1-2 October 2010
Venue: Bethesda, Maryland, USA

Including sessions on Observations from the clinic; the fate of red blood cells mitochondria, iron, and neurodegeneration; cellular CoA defects; autophagy in neurodegenerative disease; future directions; and developing a research strategy.
For further details

Progress in Paediatric Neurology Research Conference
Date: 1-2 October 2010
Venue: Leuven, Belgium

The Scientific Committee of the European Society for Paediatric Neurology is launching the second Research Meeting on ongoing research related to Paediatric Neurology. The goal of this meeting is to present and discuss clinical and fundamental research work in progress within the field of Paediatric Neurology and related disciplines, such as neonatology, neurometabolics, epilepsy, neurogenetics and neuroimaging.
For further details

First European Conference on Lymphangioleiomyomathosis (LAM)
Date: 1-3 October 2010
Venue: Udine, Italy

This conference provides an unprecedented experience to learn about scientific updates across various fields and the latest results on recent drug trials. In addition, representatives from many LAM associations across the world will attend to learn from each others’ experiences on how to gather patients, promote involvement in the LAM community and raise awareness.
For further details

International Meeting on Fibrous Dysplasia of Bone/McCune-Albright Syndrome: Best Clinical Practice and Future Research
Date: 3-5 October 2010
Venue: Bethesda, Maryland, USA

This conference will gather experts to develop a consensus on the best current medical and surgical treatment of fibrous dysplasia, MAS and Cherubism, to define areas of focus for future research, and to establish parameters for a registry/bio repository to aid research. Participants in the meeting include paediatric and adult orthopaedic specialists, cranio facial surgery, plastic surgery, endocrinology, and specialists in stem cells, microbiology and pathology from the USA, Israel, Italy, and Taiwan.
For further details

XIV Meeting of the European Society for Immunodeficiencies and IX Meeting of the Int’l Nursing Group for Immunodeficiencies
Date: 6-9 October 2010
Venue: Istanbul, Turkey

Featuring an interesting scientific programme of clinical, laboratory and molecular findings, diagnosis, prevention and treatment for common and rare primary immunodeficiencies. Held in tandem with the XIth Meeting of the International Patient Organisation for Primary Immunodeficiencies.
For further details

Sixth International Network of Paediatric Surveillance Units (INoPSU) Meeting
Date: 7 October 2010
Venue: Dublin, Ireland

The INoPSU joins 12 diverse countries with a common purpose - to conduct surveillance of uncommon conditions of childhood. The member units span the globe - from Canada to New Zealand. This year’s keynote address will be from Orphanet.
For further details

2nd European Rett Syndrome Conference
Date: 7-10 October 2010
Venue: Edinburgh, Scotland

Sessions include clinical and molecular update on MECP2 and Rett Syndrome; non coding RNAs & brain development; lessons from other diseases and other models; treatments and trials; outcome measures, international collaborations; and current perspectives and next steps.
For further details

15th International Congress of World Muscle Society
Date: 12-16 October 2010
Venue: Kumamoto, Japan

The main topics to be addressed include new therapeutic targets for neuromuscular disorders; congenital muscular dystrophies (celebrating the 50th anniversary of Fukuyama congenital muscular dystrophy); and distal myopathies and protein aggregation myopathies.
For further details

26th Annual Meeting of the Histiocyte Society
Date: 18–20 October 2010
Venue: Boston, Massachusetts USA

This year’s scientific programme will feature presentations by several experienced researchers regarding a variety of perspectives on the histiocytic disorders.
For further details

Future Direction for Orphan Drugs in Europe
Date: 3 November 2010
Venue: Le Mesnil Amelot (Paris region), France

This first conference on orphan drugs from the neutral, non-profit, global, professional Drug Information Association will reflect on the experience gained in the first 10 years of the European Orphan Medicinal Products Regulation. It will review current developments in orphan drug research, look at points of collaboration between regulatory and HTA bodies and provide an outlook on future developments.
For further details

Pemphigus & Pemphigoid: From the Bench to the Bedside
Date: 5-6 November 2010
Venue: Bethesda, Maryland, USA

The meeting will bring together physicians and scientists interested in these diseases to meet face-to-face and facilitate interactions. The goal is to identify areas of research opportunity that will promote understanding of the causes and provide experimental and clinical justification for novel treatments of pemphigus and pemphigoid.
For further details

Optimising Orphan Drug Development
Date: 15-16 November 2010
Venue: Brussels, Belgium

Key topics include: Exploring the regulatory landscape for orphan drug development; Reviewing the different reimbursement processes in the EU to achieve better market access; Overcoming developmental challenges in orphan drugs; Examining the post phase 4 and market authorisation challenges; Assessing the opportunities for orphan drug development for “big pharma”.
For further details

3rd European Symposium on Rare Anaemias and 1st Spanish Thalassemia meeting for Patients and Professionals
Date: 19-20 November 2010
Venue: Madrid, Spain

The 3rd European Symposium on Rare Anaemias is an activity of the ENERCA project, which aims to stimulate interest and inform colleagues on the subject of congenital and rare anaemias. The programme will address prevention, diagnosis, treatment and includes an interactive workshop with patient panellists and doctors, focusing not only on clinical management but also on prevention and social action for thalassaemia and haemoglobinopathies.
For further details

11th EPPOSI Workshop on Rare Disease Therapy Development Workshop
Date: 29-30 November 2010
Venue: Prague, Czech Republic

The topics of this year’s European Platform for Patients’ Organizations, Science and Industry workshop will include: Science - the determinants of rare disease research in Europe: understanding the current and future European Research and Development challenges and opportunities; Regulation - Europe and beyond: developing future regulations and policies for better rare disease therapies; and Sustainable Access - the reality we face to improve access to and affordability of orphan drugs.
For further details

4th International Meeting on the Congenital Disorders of Glycosylation and Related Disorders
Date: 13-14 January 2011
Venue: Leuven, Belgium

The meeting will cover all aspects of these disorders, including the discovery of novel types, the study of fundamental aspects of glycosylation, analytical procedures and diagnostic methods and the analysis of models for the disease. The meeting is organised by EUROGLYCANET, a European network for the advancement of research, diagnosis and treatment of a growing group of rare disorders. Deadline for abstract submission: 30 September 2010.
For further details

VII International Conference on Rare Diseases and Orphan Drugs (ICORD 2011)
Date: 21-23 May 2011
Venue: Tokyo, Japan

A global meeting on international cooperation and public health policies focussing on research, diagnosis, development of and access to treatment and care for rare diseases. The programme for this conference will be available shortly.
For further details

Eighth European Cytogenetics Conference
Date: 2-5 July 2011
Venue: Porto, Portugal

This meeting will provide the participants with an opportunity for not only contributing their knowledge and experience, but also for interacting with each other. Deadline for abstract submission: 28 February 2011.
For further details

Treat-NMD Global Conference
Date: 8-11 November 2011
Venue: Geneva, Switzerland

The conference will comprise a range of sessions addressing the challenges in the neuromuscular field, including: Delivery of future therapies; Biomarkers; Care considerations; Neuromuscular diseases and society; and Regulatory issues, orphan drugs and the rare disease field.
For further details


Press & Publications
Rare diseases featured in the mass media
Rare diseases, which are traditionally the domain of specialised medical and scientific journals, caught the interest of a popular general interest publication – Time magazine. The article, Is It Time We Paid More Attention to Rare Diseases? appears in the 21 August issue of the top-selling weekly news magazine. Possibly generated by the recent widely publicised bid of Sanofi-Aventis to purchase orphan drug specialist firm Genzyme, the article brings public attention to the struggle rare disease patients and their families face over the high prices of treatments. It also exposes the recent call for a global-wide registry for rare diseases, which would be useful not only to patients and drug manufacturers, but also for researchers, health professionals, and policy makers (see the related article in this issue of OrphaNews Europe).
Consult the Time magazine article


Orphanews Europe, the newsletter of the European Union Committee of Experts on Rare Diseases
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, Raphaël Demonchy, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Charlotte Rodwell, Paloma Tejada, Aurélie Vandeputte
National Contact Point: Till Voigtländer (Austria), 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 European Union Committee of Experts on Rare Diseases
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