14 August 2009 print
Task Force Update
EU Policy News
Nat Pol News
New Syndromes
New Genes
Research in Action
Patient Man & Therapy
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Call for Tender issued to determine newborn screening practices for rare disorders in each Member State of the European Union

The Call for Tender Evaluation of Population Newborn Screening Practices for Rare Disorders in Member States of the European Union has been published in the Official Journal of the European Union. This call seeks to bridge the knowledge gap surrounding the current policies and practices for newborn screening in the Member States (MS). The outcome of the call will be a detailed report on newborn screening practices in the MS that outlines the disorders screened and the rationale behind conditions chosen for inclusion in each MS programme; the number of newborns being screened; the technologies involved; the number of centres involved in newborn screening; and the medical management and follow-up care implemented in the MS. Another related outcome will be a network of experts established to produce a final opinion with recommendations for best practices, a “core panel of … conditions that could be included in all MS practices”, and the development of a matrix for decision making that MS could use to expand or reduce screening practices. The tender offer reflects recommendations outlined in the European Commission Communication Rare Diseases: Europe’s Challenges that specifically address the issue of screening:

It is recommended to encourage cooperation in this area to generate evidence on which decisions should be based at Member States level. An evaluation of current population screening (including neonatal screening) strategies for rare diseases and of potential new ones, will be conducted by the Commission at EU level to provide Member States with the evidence (including ethical aspects) on which to base their political decision. The Commission will consider such support as a priority for action.

The deadline for submitting a Tender for this call is 2 September 2009. For more detailed information, consult the website of the European Agency for Health and Consumers.

Task Force Update
Summer break....

The Rare Disease Task Force and OrphaNews Europe wish all our readers a pleasant summer holiday. The next issue of OrphaNews Europe will be published on 23 September 2009. See you then!


EU Policy News

Alzheimer Communication adopted by EC encompasses rare forms of dementia
The European Commission adopted in late July a Communication on a European initiative for Alzheimer disease and other dementias along with a proposal for a Council Recommendation on measures to combat neurodegenerative diseases through joint programming of research activities. The Communication encompasses rare forms of dementia – which include frontotemporal dementia, Pick disease (lobar atrophy), Binswanger disease, and Lewy-Body dementia. The Communication makes reference to data gleaned from a project conducted by European Union patient platform Alzheimer Europe with the support of the European Commission that identified significant rare forms of dementia. The Communication encourages national and collaborative efforts in four key areas: prevention, the coordination of research across Europe, disseminating best practice for treatment and care, and the development of a common approach to ethical matters concerning the rights, autonomy, and dignity of people with dementia.
European survey of direct-to-consumer genetic test offers finds need for regulation
A European Parliament Science and Technology Options Assessment report examines the growing phenomenon of direct to consumer genetic tests (DCGT) from the perspectives of experts, authorities and the marketplace, and weighs the need for political intervention. The factors fueling the increasing usage of Internet-purchased genetic tests are the same elements that characterise the field of genetic testing in general: growing availability of tests for both common and rare disorders; technical improvements that lower costs; and the viewpoint that genetic testing has an important role to play in preventive medicine. However, sharp differences distinguish DCGT from standard genetic testing – with the crucial role of genetic counselling being largely absent from Internet genetic test offers. While the majority of DCGT offers involve testing for susceptibility toward common disorders, some 20% of the 38 companies surveyed in the report offer tests for monogenic disorders – all of which are rare. One company tests for late-onset Chorea Huntington disease. The report assesses the information provided to consumers, including the qualification of institute and personnel; the accuracy of test data; genetic testing in general and test-specific information; necessity and possible methods of counselling; consequences and actions to be taken; and price of genetic testing. Other points discussed in detail include quality assessment, the need for regulation, and potential policy options. The report concludes that in order to ensure quality, a European system of control and accreditation of laboratories carrying out direct to consumer molecular testing could be established following the guidelines delineated in the recent OECD publication on the subject. A “checklist” for further policy intervention options is discussed.
Consult the report

DG Research
European Commission issues FP7 calls for proposals in several fields... including health
The European Commission has published several calls for proposals in various thematic areas of the Seventh Framework Programme (FP7). Thematic areas under the Cooperation Specific Programme include the Health Theme. All relevant information on these calls can be found here.
European Commission seeking expertise for FP7 evaluation, review and monitoring
A call by the European Commission is open for the establishment of a database of independent experts to assist the Commission’s services for tasks in connection with the Seventh Framework Programme (FP7). Should you wish to express your interest for participating in future FP7 evaluation, review and/or monitoring tasks, registration is now open.

The EMEA issues a report considering the communication of benefit/risk information for medicinal products
The European Medicines Agency (EMEA) recently collaborated with health professionals and patient organisations to investigate the communication of information concerning the benefits and risks of medicinal products. A questionnaire was designed and distributed to obtain the perspectives of regulatory authorities, health care providers and patients on the quality of information concerning the benefits, the risks, and the benefit-risk ratios of medicinal products. The survey, along with a subsequent workshop held in order to discuss the responses, netted some interesting observations that have allowed for the creation of recommendations to help improve benefit/risk information for consumers, health care professionals and regulatory authorities. Responses to the survey revealed the personalised consideration of benefit/risk information from the perspective of patients and health professionals, who consider it imperative that both benefit and risk data be presented as clearly and thoroughly as possible in order to be applied appropriately to the unique circumstances of the individual patient. Benefit-risk information is particularly critical to orphan medicinal products, which are often developed under limited circumstances due to small populations available. The results, gathered from the survey into a report entitled Information on Benefit-Risk of Medicines: Patients’, Consumers’ and Healthcare Professionals’ Expectations also serve to inform the EMEA, which takes into account benefit/risk information as part of its marketing authorisation process. The survey results and discussions have been gathered into a report, now available on the EMEA website.
Consult the report

The COMP appoints new members
The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMEA) in July appointed several new members and re-elected others. Ms Lesley Greene, Ms Birthe Byskov Holm, and Ms Pauline Evers were all nominated by the European Commission to represent patient organisations. Ms. Greene and Ms. Holm are both members of European rare disease patient alliance Eurordis. Meanwhile, Dr David Lyons was nominated by the European Commission based on a recommendation from the Agency, and Prof Dainis Krieviņš joined as the new COMP member from Latvia. The EC Rare Disease Task Force and OrphaNews Europe extend a very warm welcome all around!
View the list of current COMP members


National & International Policy Developments
Other International News
Research network for orphan lung diseases launched in the land down under
The launch of the Australasian Research Network for Orphan Lung Disease (ARNOLD), a joint initiative of the Australian Lung Foundation and the Thoracic Society of Australia and New Zealand, took place recently. Funded by the Australian Lung Foundation and based on the successful British Paediatric Orphan Lung Disease Registry, ARNOLD cites its principal aims as:

  • Raising the profile of rare lung diseases in Australia and New Zealand
  • Gathering prevalence and incidence data on rare lung diseases through electronic reporting of cases
  • Providing information for clinicians and patients/families on rare lung diseases
  • Enabling patients to discuss issues via an on-line forum

  • In a press release, Associate Professor Adam Jaffe, member of the Australian Lung Foundation’s Pulmonary Interstitial Vascular Organisational Taskforce and head of respiratory medicine at Sydney Children’s Hospital commented that “interstitial and orphan lung diseases are uncommon and doctors and patients frequently have difficulty understanding what causes them and what the best treatments are. As a result, patients often experience inequity in service provision compared to those with more common lung diseases.” Meanwhile patient advocate Miriam McLean, consumer representative of the Australian Lung Foundation’s Pulmonary Interstitial Vascular Organisational Taskforce observed that ARNOLD will “sweep rare lung diseases out from under the carpet and raise their profile. It is an important step for patients to know that there is now some interest in conditions that we have felt, for a long time, have been ignored. Hopefully, this will lead to more treatment options and better patient support.”


    New Syndromes
    Congenital spastic tetraplegia: a genetic model for congenital cerebral palsy
    Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. The authors describe an autosomal-recessive type of tetraplegic cerebral palsy with intellectual deficit, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. This disease entity, which the authors refer to as congenital spastic tetraplegia, is caused by mutations in the AP4M1 gene and offers a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.
    Read the PubMed abstract

    Am J Hum Genet ; 40-52 ; July 2009
    Severe growth retardation and multiple malformations caused by loss-of-function mutation in the dioxygenase-encoding FTO gene
    FTO is a nuclear protein belonging to the AlkB-related non-haem iron- and 2-oxoglutarate-dependent dioxygenase family. The authors show that a mutation inactivating FTO enzymatic activity is responsible for an autosomal-recessive lethal syndrome. Eight children born in a consanguineous family presented severe pyschomotor retardation, growth retardation, intellectual deficit, microcephaly, and characteristic facies. Certain members also present structural cerebral malfomations, cardiac anomalies, or genital anomalies.
    Read the PubMed abstract

    Am J Hum Genet ; 106-11 ; July 2009

    New Genes

    Acanthosis nigricans and postprandial hyperinsulinemia: a truncation mutation in TBC1D4
    Acanthosis nigricans (AN) is a skin disorder characterised by hyperpigmentation and hyperkeratosis of the skin of the entire body, particularly in flexural areas, such as the neck and axillae. AN may be benign or associated with an underlying malignant pathology. The authors describe a female presenting at age 11 years with AN and extreme postprandial hyperinsulinemia who was heterozygous for a premature stop mutation in the gene TBC1D4. Two overweight family members with the mutation manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.
    Read the PubMed abstract

    To read more about "Acanthosis nigricans"

    PNAS USA ; 9350-9355 ; 9 June 2009
    Intellectual deficit and nonsyndromic epilepsy: de novo STXBP1 mutations
    The authors identified de novo mutations in STXBP1 in two patients with severe intellectual deficit and nonsyndromic epilepsy suggesting that STXBP1 disruption is associated with autosomal dominant intellectual deficit and nonsyndromic epilepsy.
    Read the PubMed abstract

    Ann Neurol ; 748-753 ; 18 March 2009
    Multiple synostoses: a missense mutation in exon 2 of the FGF9 gene identified
    Multiple synostoses is characterised by premature joint ankylosis. The authors report a missense mutation in exon 2 of the FGF9 gene in 12 patients with multiple synostoses in a large Chinese family. These data demonstrate a previously uncharacterised mutation in FGF9 as one of the causes of multiple synostoses, implicating an important role of FGF9 in normal joint development.
    Read the PubMed abstract

    To read more about "Multiple synostoses"

    Am J Hum Genet ; 53-63 ; July 2009
    Nonsyndromic hearing loss: noncoding mutations of HGF are associated
    A gene causing autosomal-recessive, nonsyndromic hearing loss, DFNB39, was previously mapped to an 18 Mb interval on chromosome 7q11.22-q21.12. The authors mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss to the DFNB39 locus and found three mutations in the hepatocyte growth factor gene (HGF). HGF is involved in a wide variety of signalling pathways in many different tissues, yet these putative regulatory mutations cause a surprisingly specific phenotype, which is nonsyndromic hearing loss.
    Read the PubMed abstract

    To read more about "Deafness, autosomal recessive, nonsyndromic, sensorineural, type DFNB"

    Am J Hum Genet ; 25-39 ; July 2009
    Congenital disorders of glycosylation and the dystroglycanopathies: DPM3 deficiency bridges the disorders
    In a patient with a moderate muscular dystrophy associated with a dilated cardiomyopathy, the authors identified a homozygous point mutation in gene DPM3, implicated in the process of protein glycosylation. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the endoplasmic reticulum revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies.
    Read the PubMed abstract

    Am J Hum Genet ; 76-86 ; July 2009
    Odonto-onycho-dermal dysplasia: mutations cause broad spectrum of ectodermal dysplasias with sex-biased pattern
    Odonto-onycho-dermal dysplasia (OODD), a rare autosomal-recessive inherited form of ectodermal dysplasia including severe oligodontia, nail dystrophy, palmoplantar hyperkeratosis, and hyperhidrosis, was recently shown to be caused by a homozygous nonsense WNT10A mutation. Here, the authors report on 12 patients, from 11 unrelated families, with ectodermal dysplasia caused by five previously undescribed WNT10A mutations. They show that WNT10A mutations also cause other forms of ectodermal dysplasia, from apparently monosymptomatic severe oligodontia to Schöpf-Schulz-Passarge syndrome. WNT10A mutations are a frequent cause of ectodermal dysplasia. About half of the heterozygotes show a phenotype manifestation, including mainly tooth and nail anomalies. Heterozygotes show a sex-biased manifestation pattern, with a significantly higher proportion of tooth anomalies in males than in females.
    Read the PubMed abstract

    To read more about "Odonto-onycho-dermal dysplasia"

    Am J Hum Genet ; 97-105 ; July 2009
    Cutis laxa type 2: mutation in pyrroline-5-carboxylate reductase 1 gene identified
    Autosomal-recessive cutis laxa type 2 is a multisystem disorder characterised by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. The authors identified mutations in the PYCR1 gene, which plays a critical role in proline biosynthesis.
    Read the PubMed abstract

    To read more about "Cutis laxa, recessive type 2"

    Am J Hum Genet ; 120-129 ; July 2009
    Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency
    The authors describe a patient with recurrent infections who was homozygous for an FCN3 frameshift mutation, and who had undetectable serum levels of ficolin-3, and a deficiency in ficolin-3-dependent complement activation. Ficolin-3, encoded by the FCN3 gene and expressed in the lung and liver, is a recognition molecule in the lectin pathway of the complement system.
    Read the PubMed abstract

    N Engl J Med ; 2637-2644 ; 18 June 2009

    Research in Action

    Fundamental Research
    Gardner syndrome is a cilia-related disorder
    Familial adenomatous polyposis (FAP) is an autosomal dominant form of intestinal polyposis and colorectal cancer caused by germ-line mutations in the adenomatous polyposis coli gene (APC). The term Gardner syndrome is used to describe extracolonic manifestations, such as osteomas, skin cysts, congenital hypertrophy of the retinal pigmented epithelium (CHRPE), and desmoid tumours (aggressive fibromatosis), that are especially prominent in families with FAP. The authors demonstrate that a ciliary dysfunction is the underlying pathogenetic mechanism of extraintestinal manifestations in patients with FAP, based on the presence of common clinical manifestations in Gardner syndrome and cilia-related disorder and that both APC and the cilia have degradation of beta-catenin as the common downstream target in the Wnt-signalling pathway.
    Read the PubMed abstract

    To read more about "Gardner syndrome"

    Lancet Oncol ; 727-735 ; July 2009
    Clinical Research
    If-pathies: a large disease spectrum caused by intermediate filament anomalies
    Intermediate filaments (IFs) are encoded by the largest gene family among the three major cytoskeletal protein groups. Unique IF compliments are expressed in selective cell types and this expression is reflected in their involvement, upon mutation, as a cause of or predisposition to more than 80 human tissue-specific diseases. A review series published in the Journal of Clinical Investigation covers diseases and functional and structural aspects pertaining to IFs and highlights the molecular and functional consequences of IF-associated diseases (IF-pathies). Exciting challenges and opportunities face the IF field, including developing both a better understanding of the pathogenesis of IF-pathies and targeted therapeutic approaches.
    Consult the open-access online journal

    17q21.31 microdeletion syndrome: phenotypic expansion and further characterisation
    The recognition of the 17q21.31 microdeletion syndrome has been facilitated by high resolution microarray technology. Recent clinical delineation of this condition emphasises a typical facial appearance, cardiac and renal defects, and speech delay in addition to intellectual disability, hypotonia and seizures. The authors describe 11 previously unreported patients expanding the phenotypic spectrum to include aortic root dilatation, recurrent joint subluxation, conductive hearing loss due to chronic otitis media, dental anomalies, and persistence of foetal fingertip pads. Molecular analysis of the deletions demonstrates a critical region involving either partially or wholly five genes. These data have significant implications for the clinical diagnosis and management of other individuals with 17q21.31 deletions.
    Read the PubMed abstract

    To read more about "Monosomy 17q21.31"

    J Med Genet ; 480-489 ; July 2009
    Ehlers-Danlos syndrome: neuromuscular involvement in various types of the disease
    Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterised by joint hypermobility, skin hyperextensibility, and tissue fragility. Muscle involvement is plausible based on recently discovered interactions between muscle cells and extracellular matrix molecules; however, muscle symptoms are only sporadically reported. The authors conducted a cross-sectional study to determine whether neuromuscular features are part of EDS. They found mild-to-moderate neuromuscular involvement is common in various types of EDS. The findings should increase awareness of neuromuscular symptoms in EDS patients and improve clinical care. They also point to a role of the extracellular matrix in muscle and peripheral nerve function.
    Read the PubMed abstract

    To read more about "Classic Ehlers-Danlos syndrome"

    Ann Neurol ; 687-697 ; 19 March 2009
    Haemochromatosis in the Asian community
    Hereditary haemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 haemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile haemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene. Haemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassaemia. The authors provide a comprehensive report of haemochromatosis in a group of patients of Asian origin. They identified novel mutations in HJV, HAMP and SLC40A1 in countries not normally associated with hereditary haemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). These family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries with large immigrant populations from these regions.
    Read the PubMed abstract

    To read more about "Hemochromatosis"

    Blood ; 20-25 ; 2 July 2009
    Neurofibromatosis 1: unravelling the genetic basis of variable clinical expression
    Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that displays considerable inter- and intra-familial variability in phenotypic expression. To evaluate the genetic component of variable expressivity in NF1, the authors examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families. Twelve NF1-related clinical features, including five quantitative traits and seven binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. These results provide evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease.
    Read the PubMed abstract

    To read more about "Neurofibromatosis type 1"

    Hum Mol Genet ; 2768-2778 ; 1 August 2009
    Lymphangioleiomyomatosis and tuberous sclerosis complex: phenotype differences between TSC1 and TSC2 mutations
    Lymphangioleiomyomatosis (LAM) is a prominent finding in the setting of tuberous sclerosis complex (TSC). The authors compared cystic lung changes consistent with LAM in patients with a TSC1 disease-causing mutation, TSC2 disease-causing mutation, or no mutation identified (NMI). Their findings suggest a higher rate of LAM in TSC1 than previously recognised, as well as a fundamental difference in chest computed tomography presentation between TSC1 and TSC2.
    Read the PubMed abstract

    To read more about "Lymphangioleiomyomatosis"
    To read more about "Tuberous sclerosis"

    J Med Genet ; 465-468 ; July 2009
    Stem Cells
    Fanconi anaemia: disease-corrected haematopoietic progenitors from induced pluripotent stem cells
    Patient-specific iPS cells are thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here the authors show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, the authors show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.
    Read the PubMed abstract

    To read more about "Fanconi anemia"

    Nature ; 53-59 ; 2 July 2009
    Therapeutic Approaches
    Ewing sarcoma: a small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth
    Ewing sarcoma family tumours contain a characteristic translocation leading to expression of the oncogenic fusion protein EWS-FLI1, a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. The authors identified a compound that binds EWS-FLI1 and block its interaction with RHA. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumour-specific anticancer agents.
    Read the PubMed abstract

    To read more about "Ewing sarcoma"

    Nat Med ; 750-756 ; July 2009
    Diagnostic Approaches
    Free sialic acid storage disease without sialuria
    The authors performed high-resolution in vitro proton nuclear magnetic resonance spectroscopy on cerebrospinal fluid and urine samples of 44 patients with leukodystrophies of unknown cause. Free sialic acid concentration was increased in cerebrospinal fluid of two siblings with intellectual deficit and mild hypomyelination. By contrast, urinary excretion of free sialic acid in urine was normal on repeated testing by two independent methods. Both patients were homozygous for a mutation in SLC17A5, the gene responsible for the free sialic acid storage diseases. These findings demonstrate that mutations in the SLC17A5 gene have to be considered in patients with hypomyelination, even in the absence of sialuria.
    Read the PubMed abstract

    To read more about "Free sialic acid storage disease"

    Ann Neurol ; 753-757 ; 18 March 2009

    Patient Management and Therapy

    Placental-site trophoblastic tumours: prognostic markers and long-term outcome
    Placental-site trophoblastic tumours are a rare form of gestational trophoblastic disease and consequently information about optimum management or prognostic factors is restricted. The authors aimed to assess the long-term outcome of stage-adapted management by surgery, chemotherapy, or both for patients with the disorder. Via a retrospective observational study, they found that stage-adapted management with surgery for stage I disease, and combined surgery and chemotherapy for stage II, III, and IV disease could improve the effectiveness of treatment for placental-site trophoblastic tumours. Use of 48 months since antecedent pregnancy as a prognostic indicator of survival could help select patients for risk-adapted treatment.
    Read the PubMed abstract

    To read more about "Placental site trophoblastic tumor"

    Lancet ; 48-55 ; 4 July 2009
    Inherited erythromelalgia: a novel Na(v)1.7 mutation produces a carbamazepine-responsive form of the disease
    Human and animal studies have shown that Na(v)1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia has been linked to gain-of-function mutations of Na(v)1.7. The authors report a novel mutation in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ) and demonstrate a normalising effect of CBZ on mutant Na(v)1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia.
    Read the PubMed abstract

    To read more about "Primary erythermalgia"

    Ann Neurol ; 733-741 ; 23 March 2009
    Allogeneic hematopoietic cell transplantation and subsequent quality of life
    High-dose therapy with allogeneic hematopoietic cell transplantation (HCT) offers effective control and potential cure of hematopoietic malignancies, but with the cost of associated morbidity that includes adverse effects on quality of life (QOL). A growing body of literature has characterised this impact. Longitudinal studies suggest early moderate impairments that largely return to pretransplantation levels by day 100; the majority of studies suggest that greater than 60% of patients report good to excellent QOL in years 1 to 4 after HCT. Comparisons of allogeneic HCT with autologous HCT and standard-dose chemotherapy suggest impairments in QOL and a different trajectory of recovery in allogeneic HCT, but these conclusions are limited by confounding variables. Acute and chronic graft-versus-host disease are significant threats to QOL. Behavioral interventions show promise to maintain or improve quality of life after allogeneic HCT. The review concludes with recommendations to investigators and clinicians as the state of this research advances.
    Read the PubMed abstract

    Blood ; 7-19 ; 2 July 2009
    Noonan syndrome: patterns of growth and puberty in patients treated with growth hormone
    Noonan syndrome (NS) is a heterogeneous genetic disorder characterised by short stature, typical facial dysmorphism and congenital heart defects. In a study involving prepubertal and pubertal children with NS, the authors found that Delta height sd score (SDS) significantly improved with rhGH for children with NS at near-adult height (NAH). Duration of prepubertal rhGH and height SDS at puberty were important contributors to NAH. These data suggest that greater growth optimisation is possible with earlier initiation of therapy.
    Read the PubMed abstract

    To read more about "Noonan syndrome"

    J Clin Endocrinol Metab ; 2338-2344 ; July 2009
    Griscelli syndrome type 2: hematopoietic stem cell transplantation is beneficial but needs improvement
    Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for Griscelli syndrome type 2, an inherited immune disorder causing fatal hemophagocytic lymphohistiocytosis (HLH). The authors retrospectively analysed the outcome for 10 patients who underwent HSCT between 1996 and 2008. Seven patients were cured of the primary immune defect, 4 of them without neurologic sequelae. In the 3 deceased patients, death occurred within 110 days of HSCT and was probably due to adverse reaction to HSCT in 2 patients and to HLH relapse in one patient. One patient received 2 transplants because of graft failure. Clinical events included veno-occlusive disease, graft-versus-host disease, and Epstein-Barr virus-induced lymphoproliferative disease. These results demonstrate the efficacy of HSCT in curing the immune disorder but also show that neurologic HLH before HSCT is a major factor, given the neurologic sequelae after otherwise successful HSCT. Additional studies are required to improve treatment.
    Read the PubMed abstract

    To read more about "Griscelli syndrome, type 2"

    Blood ; 211-218 ; 2 July 2009
    Neuroblastoma: predicting outcomes for children using a multigene-expression signature
    The authors sought to develop and validate a gene-expression signature to improve outcome prediction. 59 genes were selected using an innovative data-mining strategy and were profiled in the largest neuroblastoma patient series to date. A multigene-expression signature was built using 30 training samples, tested on 313 test samples, and subsequently validated in a blind study on an independent set of 236 tumours. The authors found the 59-gene expression signature to be an accurate predictor of outcome in patients with neuroblastoma. The signature is an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical-risk groups.
    Read the PubMed abstract

    To read more about "Neuroblastoma"

    Lancet Oncol ; 663-671 ; July 2009

    Orphan Drugs
    Rare disease medicine Soliris again a prize winner
    Alexion Pharma France and Alexion Pharmaceuticals were awarded the 2009 Prix Galien France for Soliris (eculizumab) in the category of “Medicines for Rare Diseases”. The prestigious award acknowledges the innovative achievement of the complement-inhibition technology of Soliris, and the impact the drug is having on the lives of patients with paroxysmal nocturnal hemoglobinuria, a rare, debilitating and life-threatening acquired clonal hematopoietic stem cell disorder characterised by corpuscular hemolytic anaemia, bone marrow failure and frequent thrombotic events. As was reported in the 26 November 2008 edition of OrphaNews Europe, Soliris won the Prix Galien USA for 2008 under the category of Best Biotechnology Agent. The Prix Galien, originating in France in 1970 in order to promote innovation in pharmaceutical research, honours innovative biopharmaceutical drugs and devices “that have made a deep impact on the quality of human life”. It has since been inaugurated across Europe and Canada and is now considered the most prestigious award of its kind in 11 countries. Soliris was the first medicinal product for human use to be evaluated by the European Medicines Agency under the accelerated assessment practice introduced by EU pharmaceutical legislation in November 2005. Soliris was also the first product submitted by a company benefiting from specific incentives for small- and medium-sized enterprises (SMEs) to receive a positive opinion from the EMEA.

    Commentary depicts gloomy picture of orphan drug development in Europe
    A commentary appearing in the British Journal of Clinical Pharmacology presents some sobering statistics concerning the development of medicinal products for rare diseases in Europe. Orphan Drug Development Is Not Taking Off asserts that although rare diseases, taken collectively, present a major public health issue, the development of medicinal products for these illnesses is faltering. Is it the fragmented market that continues to discourage the development and marketing of new products, despite robust incentive mechanisms available since the year 2000 under orphan drug regulation 141/2000? Between 2000 and 2007, only 45 products were approved for marketing authorisation from a total of 528 orphan indications relating to 400 products. This rate of 8.5% of successful orphan drug authorisation pales in comparisn to the 70.7% rate for non-orphan drugs during the same period. State the authors:

    The epidemiological magnitude of rare diseases (7000) is possibly reflected by the number of orphan drug designations (528) but not by their approvals (44), and even less so by their availability on the market (only 26 in the Italian market, driven by a fairly generous national health service).

    The authors ponder the possible causes for the current state of affairs:

    It is a cause for concern that in spite of an ad hoc law, after 8 years orphan drugs in the EU are still few and poorly studied.… It is not clear what discourages the pharmaceutical industry from developing so few orphan drugs out of the many designated, in spite of the market exclusivity, methodological facilities, and the willingness of the European health systems to pay the high costs and endure the possible low cost-effectiveness of these products. Stakeholders need to reflect on these findings to foster new measures to provide an answer to this largely neglected clinical and social issue.
    Consult the free-access article


    What's on Where?

    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.
    For further details

    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.
    For further details

    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, treatable neurometabolic genetic diseases.
    For further details

    ESH Eleventh International Conference – Chronic Myeloid Leukaemia
    Date: 11-13 September 2009
    Venue: Bordeaux, France

    Held in association with the International CML Foundation, this conference will consider the biological basis of therapy.
    For further details

    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.
    For further details

    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 patient associations should also help to focus better on the scientific problems that need to be resolved to find a cure for patients.
    For further details

    Adaptive Immunity and the Pathogenesis of Rheumatic Diseases – A Translational Research in Paediatric Rheumatology Conference
    Date: 24–27 September 2009
    Venue: Genoa, Italy

    This third Translational Research in Paediatric Rheumatology conference will showcase the growing body of evidence that the regulation of central and peripheral B and T cell development plays a pivotal role in the pathogenesis of autoimmune diseases, highlighting the molecular and cellular mechanisms involved in the activation of the effector functions of adaptive immunity, their involvement in the pathogenesis of chronic rheumatic diseases, and the potential identification of targets to modulate the activity of the adaptive immune system.
    For further details

    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.
    For further details

    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".
    For further details

    XXth Congress of International Society of Haematology - European and African Division
    Date: 10-13 October 2009
    Venue: Cairo, Egypt

    Including up to date knowledge and the most recent scientific achievements in the field.
    For further details

    ESH Conference on Myelodysplastic Syndromes
    Date: 22-25 October 2009
    Venue: Mandelieu, France

    Covering diagnostics, overlapping syndromes, treatment approaches and more. Deadline for scholarships and abstracts: 15 September 2009
    For further details

    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.
    For further details

    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 industrial exhibition will inform on the latest product developments.
    For further details

    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.
    For further details

    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.
    For further details

    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.
    For further details

    International Conference on Myasthenia
    Date: 1-2 December 2009
    Venue: Paris, France

    The conference will bring together research scientists and clinicians from around the world who specialise in myasthenia, to review the latest developments, exchange experiences and ideas, and broaden knowledge and understanding of this rare disease. A session dedicated to the interaction between clinicians, scientists, and patient associations is also scheduled.
    For further details

    2nd Pan-European Conference on Haemoglobinopathies
    Date: 13-14 March 2010
    Venue: Berlin, Germany

    This conference aims to further strengthen the national and regional support networks for thalassaemia patients in Europe, and increase awareness among European medical professionals and national health authorities of the disorder, its proper management and prevention.
    For further details

    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

    Gene Patents and Collaborative Licensing Models: Patent Pools, Clearinghouses, Open Source Models and Liability Regimes
    Authors Geertrui Van Overwalle –Ed
    Publisher: Cambridge University Press; July 2009
    ISBN-10: 0521896738

    The cost of patent licenses needed to design a new genetic test or treatment may ultimately prevent research projects getting started, as individual components are protected by different patent owners. The essays in this book explore models designed to render patented genetic inventions accessible for further use in research, diagnosis or treatment. The models include patent pools, clearing house mechanisms, open source structures and liability regimes. This book examines legal measures which might be used to solve the problem of fragmentation of patents in genetics. With the vast majority of rare disorders genetic in origin, this book makes for relevant reading.

    Molecular Basis of Pulmonary Disease: Insights from Rare Lung Disorders
    Authors: Francis McCormack–Ed., Bruce Trapnell–Ed., Ralph J. Panos–Ed.
    Publisher: Humana Press, November 2009
    ISBN-10: 1588299635

    This new text demonstrates how study of rare lung disorders enhances understanding of common pulmonary diseases and disease mechanisms such as fibrosis and emphysema. For example, the finding that the mutations in the alveolar type II cell specific protein, SP-C, can lead to pulmonary fibrosis is prima facie evidence that the alveolar epithelium plays a critical role in fibrogenesis. Similiarly, development of premature emphysema in patients with alpha one antitrypsin deficiency provides strong support for the theory of protease/protease inhibitior balance in the pathogenesis of alveolar destruction. A second equally important premise is that the science in rare lung disease is inherently interesting and can often change with surprising speed. This is partly related to the fact that the genetic basis of many rare lung diseases is now available, providing a unique vantage point for framing research questions.


    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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