30 November 2015 print
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The Northern Ireland released Implementation Plan for Rare Diseases

After much debate, the Northern Ireland Executive Health Minister, launched “Providing High Quality Care for people affected by Rare Diseases – The Northern Ireland Implementation Plan for Rare Diseases”. The Plan reaffirms Northern Ireland’s commitment to effectively implement the 51 Commitments of UK Strategy for Rare Diseases which will be taken forward during the period 2015-2021. These Commitments are set out under five key themes in the UK Strategy and an additional sixth theme which reflect the opportunity to work with their neighbours in the Republic of Ireland to realise the mutual benefits of cross-border collaboration on rare diseases. It aims to ensure that people living with a rare disease have access to "the best evidence-based care and treatment that health and care services, together with charities, research and industry can provide."

The themes committed to by the Department of Health, Social Services and Public Safety in Northern Ireland (DHSSPS) include:

• Empowering those affected by rare diseases and continuing to work with their patient partners, including those in Northern Ireland the Northern Ireland Rare Disease Partnership (NIRDP) and other patient groups.
• Identifying and preventing rare diseases which includes continuing to work with the UK National Screening Committee to ensure appropriate early diagnosis and establish carrier testing approved by the appropriate commissioning bodies, where the associated molecular tests are evaluated and recommended by UK Genetic Testing Network (UKGTN).
• Providing an accurate and timely diagnosis and early intervention by identifying genetic services as a priority for progress to enable all individuals with genetic conditions to access the tests they need to get a diagnosis.
• Coordination of Care by taking steps to facilitate the creation of a Northern Ireland register of rare diseases.
• Emphasising the role of research which includes the announcement of a £3.3 million investment in the establishment of a Genomics Medicine Centre in Northern Ireland, working with Genomics England, and participating in the 100,000 Genomes Project.
• Collaborating and working with the Republic of Ireland to identify areas in which rare disease patients would benefit from cross border collaboration.
Read the Plan

Spotlight on...
PARENT Joint Action Final Event
The PARENT Joint Action held its final event in Valencia on 22-23 October 2015. The event entitled “Patient Registries in a Digital Europe” concluded a successful project that has provided tools and resources to support the long-term perspective on registry interoperability. The PARENT Joint Action was co-funded by the European Commission and 12 Member States to support the development of comparable and interoperable patient registries, thus enabling the use of secondary data for public health and research purposes in cross-organisational and cross-border settings. The EUCERD Joint Action was a member of the Associated Projects Group which provided input and advice, especially in regard to registries for rare diseases. RD-Action was also represented at this final event as the ongoing work on rare disease registries is part of the policy work package in RD-Action.

The main PARENT resources presented at the final event were the Registry of Registries (RoR) – mapping and analysis of existing registries, Methodological Guidelines on Governance of Registries, and the Registry Assessment tool to identify unmet needs/standards, quality, completeness of data and interoperability of patient registries.

As this was the final meeting the discussion centred on how the tools and resources produced in PARENT could be used by other initiatives, such as the EMA Registry initiative, the e-Health network, the JRC, and the new HTA Joint Action (EUnetHTA 3); the discussion also focused on the dissemination of these resources more widely and their ongoing sustainability and updating. It was proposed that this could be achieved through a policy paper with recommendations to encourage collaboration and updating of resources and to strengthen links with the ongoing and future initiatives.

PARENT joint action achievements will contribute to the future joint effort, together with other relevant initiatives, building the interoperability roadmap for rare diseases as part of the policy work of RD-ACTION
Access the website for further information on the PARENT Joint Action


EU Policy News
Commission report on the application of patients’ rights in cross-border healthcare
Directive 2011/24/EU1 on the application of patients’ rights in cross-border healthcare came into force on 24 April 2011. It was due to be transposed by Member States by 25 October 2013. It clarifies the rights of patients to seek reimbursement for healthcare received in another Member State.

This report contains current data on Patient mobility such as Prior authorisation , Reimbursement and administration , Patient flows, National Contact Points and Information to patients, Cross-border cooperation Recognition of Prescriptions, European Referen ce Networks, eHealth, Health Technology Assessment (HTA), Cross-border collaboration under the Directive. It also reports on the use of delegated powers pursuant to Article 17(1) of the Directive, which requires the Commission to report on these by 24 October 2015.
For further information

The European Commission launched in public consultation a new notice on orphan medicinal products
The European Commission is proposing to review the 2003 Communication on orphan medicinal products to streamline the regulatory framework and to adapt the Communication to technical progress.

Stakeholders are invited to comment on the following items which are included in the draft Notice which includes the following:

• Clarification of the definition of "significant benefit"
• Encouraging the development of orphan medicinal products for communicable diseases (e.g. Ebola)
• Simplifying the procedure for the reassessment of orphan criteria when two authorisation application procedures are pending in parallel for two orphan medicinal products.
• Introducing the reassessment of the orphan criteria for a new subset of the condition when a sponsor extends the use of its product after marketing authorisation
• Clarifications on processing the transfer of orphan designations between sponsors.

Read the document for further information

This notice is open for public consultation from 16 November 2015 to 15 February. The EC asks interested parties to submit responses to these public consultations by 15 February 2016 at the latest by e-mail to SANTE-PHARMACEUTICALS-D5@ec.europa.eu.

Access the European Commission website for details on submission

Public consultation on the EMA proposal to enhance early dialogue to facilitate accelerated assessment of priority medicines (PRIME)
The European Medicines Agency (EMA) is developing a scheme for priority medicines (PRIME), to optimise the development and accelerated assessment of medicines of major public health interest. The scheme is based on enhanced interaction and early dialogue with medicine developers. EMA expects to launch PRIME in the first quarter of 2016.

Through the scheme, EMA aims to:
• optimise the development and facilitate the accelerated assessment of new priority medicines to benefit patients as early as possible;
• encourage medicine developers to focus on medicines with a potential significant benefit.

EMA launched a two-month public consultation on 26 October 2015 on the key elements of the scheme, including eligibility criteria, procedural aspects, key features and data requirements.
Read Draft reflection paper on a proposal to enhance early dialogue to facilitate accelerated assessment of priority medicines (PRIME)


National & International Policy Developments
Other European news
Audit reveals the pitfalls of the Cancer Drugs Fund of the United Kingdom as it failed to collect patient outcomes
The Cancer Drugs Fund (CDF) was set up by the United Kingdom Government in 2010 to improve access to cancer drugs that were not routinely available on the the UK Department of Health and National Health Service (NHS) England. 74,380 patients were approved to receive cancer drugs through the CDF between October 2010 and March 2015, at a total cost of £968 million. However, the NHS England have failed to collect data for the outcomes of patients with cancer who received treatment through CDF, according to a report published by the National Audit Office (NAO), which scrutinises public spending for the UK Government.

According to this report clinical outcomes, including patient survival, were not documented, and the NAO are therefore unable to determine the full impact CDF has had in the treatment of cancer patients.

The report comments that CDF had recognised the importance of collecting outcomes when it was set up, but the hospitals were not sanctioned to submit data to the National Chemotherapy Dataset until April 2014. They further acknowledged that in 2014–15, only 7% of records had outcome data. The report concludes that an NHS England consultation is underway, with the aim to implement changes to CDF from April 2016.
Access the report

Interim Report: Review of Innovative Medicines and Medical Technologies
A review has explored the question of the current state of accelerated access of innovative medicines and medical technologies, through four work streams spanning the development pathway and a fifth focusing on patient engagement in all parts of the pathway. In the review each work stream has looked across issues concerning drugs, devices, diagnostics and digital health products. Comments from stakeholders, including patients and carers, the UK Department of Health and National Health Service (NHS) England frontline, researchers and industry (spanning the pharmaceutical, device, diagnostic and digital sectors) were incorporated in the review. This review is the first stage of engagement with stakeholders which has identified a number of factors driving the rapid uptake of innovative products. The review will look to build on as a new accelerated access landscape is developed.

The review presents 5 key propositions distilled from the comments and a number of provisional, high-level conclusions associated with each proposition. The propositions are outlined below, with further detail presented in the report:
• Putting the patient center stage
• A radical approach to accelerate and manage entry into our health system for the innovative products
• Supporting all innovators
• Galvanising the NHS England by making them an active partner in this venture
• Delivering change on a sustainable basis, within a framework of collective agreement to ambitions and goals.
This review is currently open for public consultation.
Read the report

An analysis of discrepancies between cancer research funding and societal burden in the United Kingdom and a comparison with United States
A study published in the Health Research Policy and Systems reports that in the United Kingdom there are discrepancies between cancer research funding allocation and societal burden. The authors estimated the burden using the metric ‘years of life lost’ (YLL), which combines overall mortality and age at death using United Kingdom data from 2010, and compared research funding from the National Cancer Research Institute for 26 types of cancers.

The study revealed that certain cancers are funded at levels far higher than their relative burden such as testicular, leukaemia, Hodgkin’s lymphoma, breast, cervical, ovarian, prostate. They also found that other cancers appear underfunded gallbladder, lung, nasopharyngeal, intestine, stomach, pancreatic, thyroid, oesophageal, liver, kidney, bladder, and brain/central nervous system. The authors have suggested that this may be because during past decade there has been an increase in funding to previously underfunded cancers. This trend, also observed in the United States, is not consistent across all types of cancer.
Read the open access article

Analysis of the clinical evidence submitted to European Medicines Agency for the market authorisation of orphan-designated oncological treatments
An investigation of the implications of small sample sizes on marketing authorisations of orphan medicines an article has been published in the Orphanet Journal of Rare Diseases. The authors analysed the clinical evidence of orphan medicines submitted to the European Medicines Agency (EMA) by sponsors to obtain marketing authorisations of orphan medications in relation to the sample size. The study concentrated on treatments included in the anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs), approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. The authors reported that the longest duration of follow-up was observed in the trial for the osteosarcoma medication -mifamurtide, which ranged from 308 to 2906 patient years. Additionally, the authors note that "of the 37 indications for which clinical trial data were presented, 52 % of the pivotal studies were Phase III trials and RCT data were provided in 57 % of the pivotal studies (which shows that) problems relating to low patient numbers, or other methodological limitations, do not necessarily preclude approval of an orphan product."

From the study the recognise that small sample sizes and inadequate follow is observed in trials for treatments of orphan diseases could be ameliorated by the establishment of rare disease reference networks and patient registries.
Read the Open access article

Other International News
NORD published the State Policy progress report: a state by state analysis
In the United States patient access to health care is increasingly dependent upon state policies. To understand the similarities and differences among the states on rare disease policies, the National Organization for Rare Disorders (NORD) has developed and released the first ever State Progress Report which evaluates how states are serving the 30 million Americans with rare diseases. In its initial release, the State Progress Report focuses on four key policy areas: medical foods coverage, prescription cost sharing requirements, newborn screening, and Medicaid eligibility levels.

The 65 page document contains an executive and national summary, key policy sections, and detailed appendices with state by state breakdowns, maps, contacts and resources. The report is also a toolkit that provides resources for stakeholders to advocate on these issues. This includes NORD’s Rare Action™ Network, its grassroots advocacy community that connects advocates and gives them the tools to support the rare disease community in their state. The progress report offers information on how to sign up for Rare Action and a list of local contacts. The report will launch with a dedicated page on the NORD website with patient stories, downloadable toolkit with action alerts, and maps.
Read the NORD state-by-state progress report

Closing the gap in treating rare disease patients in China
Two short articles showcasing the current scenario of rare diseases in China has been published in the Orphanet Journal of Rare Diseases. The first article titled - Focusing on rare diseases in China: are we there yet – report that the Chinese researchers have made significant progress in studying rare diseases in the recent years. According to the authors the number of research papers and of clinical trials has shown a steady trend of increase. They report that from 2000 to 2014, 269 out of 1892 clinically relevant original research papers published on high impact journals by Chinese institutions, and 2678 out of 6040 clinical trials conducted by Chinese institutions and registered at ClinicalTrial.gov are focused on rare diseases. The authors believe that there is a need for open data access and a nationwide data-sharing platform creating public databases for rare disease as currently most of the data are only available to local researchers. Although creating a public database is a daunting task that requires collaborative efforts by researchers in the Chinese medical research community, the authors believe that it will escalate progress in rare disease and enable multicenter studies.

Another article titled - Rare genetic disease in China: a call to improve clinical services – expresses despair that despite dramatic advances in public medicine and genomic research in China, the needs of the rare disease patient population are far from being met. According to the authors a lack of accurate epidemiological data in China means that the true number of patients affected with a rare disease is unknown. The authors believe that the most important priority at present should be to systematically improve the quality and accessibility of services for the diagnosis of rare genetic disease.

The article points out that Ministry of Health does not recognise Clinical Genetics as a medical specialty and no formal training program exists to qualify those personnel who practice in this field. The authors mention other barriers such as distance, cost, fragmented province—based health system and the fact that even though 90% of China’s population are covered under a universal insurance scheme, genetic testing is excluded from coverage making the cost prohibitive to many patients. The authors maintain that while it is now "relatively easy to generate vast quantities of genomic data, skills for phenotyping— essential for the interpretation of genetic tests and in predicting clinical course and mortality in rare disease - are lacking". The authors recommend that regulations around genetic testing need to be simplified and a nationally recognized accreditation scheme for molecular genetic laboratories— be they public or commercial –needs to be introduced.

Costs of genetic testing in Brazil
A study published in Genetics and Molecular Biology identifies and describes the operating costs associated with the molecular diagnosis of genetic diseases, in Brazil. To approximate the costs associated with these tests, data was collected from hospital software and a survey of market prices. The authors identified 2 main factors as the main determinants of the cost values obtained in this study: the use of the available capacity and the techniques used for genetic testing.

The results show that only one genetic technique was not impacted by rising costs due to underutilized capacity while several common techniques were considerably more expensive, including polymerase chain reaction, microsatellite instability analysis, gene rearrangement analysis by multiplex ligation probe amplification, non-labelled sequencing, and quantitation of nucleic acids. The authors believe that the findings of this study suggest that investment of public funds in the establishment of centralised diagnostic research centers would reduce costs to the Public Health System in Brazil.
Read the open access article

Guidance Documents and Recommendations
Mitochondrial disease: consensus statement on diagnosis and management
Consult the Pubmed abstract
Genet Med. ; 17(9):689-701 ; September 2015
Arrhythmogenic right ventricular dysplasia: consensus statement on treatment
Consult the Pubmed abstract
To read more about "Arrhythmogenic right ventricular dysplasia"

Eur Heart J. ; [Epub ahead of print] ; July 2015
Hereditary nonpolyposis colon cancer: guideline on the diagnosis and management
Consult the Pubmed abstracts
To read more about "Lynch syndrome"

Gastroenterology ; 149(3):777-82; 149(3):783-813; 149(3):814-5 ; September 2015

Ethical, Legal & Social Issues
Data sharing in stem cell translational science: policy statement by the International Stem Cell Forum Ethics Working Party
In 2014, the Global Alliance for Genomics and Health (GA4GH) adopted a common Framework for Responsible Sharing of Genomic and Health-Related Data. The GA4GH Framework is applicable to data sharing in the stem cell field, however, adaptation and interpretation is required so as to provide guidance for this specific context. In a paper published in Regenerative Medicine, the International Stem Cell Forum (ISCF) Ethics Working Party discusses those principles that are specific to the aims of translational stem cell science.

Specific policy principles are outlined in this paper (mentioned below) which the authors encourage researchers to integrate into their protocols and professional guidelines. These include:
• Engagement, collaboration and active participation with researchers.
• Maintenance of the highest level of quality assurance and safety.
• Privacy, security and confidentiality explicitly addressed in the consent process.
• Efficient assessment of risk–benefit analysis.
• Sustainability
Read the PubMed abstract


Orphanet News
Orphanet delivers result of user satisfaction survey
Orphanet has published the results of a survey of around 3200 of their users carried out at the end of 2014. This annual survey provides a snapshot of the type of users visiting Orphanet, and their views on the utility of the data and products provided by Orphanet. In the 2014 edition, 47% respondants were health professionals, 26% were patients, their families or patient organisations, 17% were students and 4% were researchers. Most users replying to the survey had found out about Orphanet via Google (nearly 50%). Respondants were mostly regular users (only 25% were visiting for the first time) and were looking for an information related to a specific disease (87% of respondants). Once again, the most useful services to all these different audiences were the texts on rare diseases, and the classifications and lists of rare diseases. OrphaNews was deemed very useful, useful or fairly useful by 90% of respondants who knew of the newsletter. The survey also shows which are the least well known Orphanet services: surprisingly 39% of respondants did not know of OrphaNews, and less surprisingly nearly 50% of respondants did not know of newer services and tools geared specifically to researchers (who were not well represented in the survey sample) such as www.orphadata.org and the Orphanet Ontology of Rare Diseases.

This information will help Orphanet to better respond to users' needs and concentrate efforts to communicate more widely on services that are less well known to different audiences. Orphanet wishes to thank all those who took the survey for their valuable time in providing their input which is much appreciated and essential information for us and those who fund Orphanet. Orphanet counts on your continued support for the next survey to be launched at the start of 2016 and would like to hear the opinion of more researchers, Industry and policy makers next year.
Read the survey

Orphanet becomes the French Institute of Bioinformatics' 30th platform
This November, Orphanet officially became the 30th Platform of the French Institute of Bioinformatics (IFB). The IFB is a national bioinformatics infrastructure bringing together platforms from the main players in research in France: CNRS, INRA, INRIA, CEA and the INSERM, as well as the Curie and Paster Institutes and French universities. At the moment, 30 platforms are members, grouped into six regional centres across France. The IFB's primary mission is to provide the basic services and resources in the field of bioinformatics for scientists and engineers working in life sciences. Notably, IFB is the French node of the European research infrastructure ELIXIR. ELIXIR is a distributed infrastructure for life-science information, uniting Europe’s leading life science organisations in managing and safeguarding the massive amounts of data being generated every day by publicly funded research. As a platform of the IFB, Orphanet is also part of this European research infrastructure, offering data and a bioontology of rare diseases to advance research in this field.

Orphanet will, in particular, participate in the ELIXIR pilot use case on rare diseases in the context of the EXCELERATE project that aims to build an ELIXIR registry of data resources and analysis tools critical for the development of rare disease research, implement a technical framework for the comparison and standardisation of services useful for rare-disease communities, and collaborate with rare-disease communities in organising and running training courses, workshops and jamborees. One of the principal goals of ELIXIR is to work towards the sustainability of resources and tools such as those offered by Orphanet, which makes this a strategic step in the right direction for Orphanet's future.Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.


New Syndromes

Syndromic form of intellectual disability with a distinctive behavioural phenotype caused by de novo, heterozygous, loss-of-function mutations in SYNGAP1
The authors reported individuals with a syndromic form of intellectual disability carrying de novo, heterozygous, loss-of-function mutations in SYNGAP1. A distinct behavioural phenotype was observed with aggressive/challenging behaviour and significant sleep problems.
Consult the Pubmed abstract

Am J Med Genet A. ; 167(10):2231-7 ; October 2015
New recognisable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies due to DYRK1A haploinsufficiency
The authors have identified 14 individuals with de novo heterozygous variants of DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals.
Consult the Pubmed abstract

Eur J Hum Genet. ; 23(11):1473-81 ; October 2015
Autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies linked to DPH1 variant
The authors reported four individuals with a homozygous missense variant in DPH1. This gene underlied syndromic intellectual disability with short stature and craniofacial and ectodermal anomalies, reminiscent of, but distinct from, 3C and Sensenbrenner syndromes.
Consult the Pubmed abstract

Hum Mutat. ; 36(10):1015-9 ; October 2015
Novel syndrome including short stature, microcephaly and intellectual disability with or without diabetes caused by mutations in PPP1R15B
A novel syndrome was described in two articles. In a first article, the authors reported a homozygous mutation in the PPP1R15B gene in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. In a second article, the authors reported a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation in PPP1R15B.
Consult the Pubmed abstracts

Diabetes ; 64(11):3951-62 ; November 2015
Hum Mol Genet. ; 24(22):6293-300 ; November 2015
X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia associated with a missense mutation in RPL10 in two cousins
The authors described a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia. Using X-exome resequencing, they identified a novel missense mutation in the RPL10 gene.
Consult the Pubmed abstract

Hum Mutat. ; 36(12):1155-8 ; December 2015
Agenesis of the corpus callosum with intellectual disability and macrocephaly associated with a familial 7q36.3 duplication involving RBM33 and SHH genes
The authors described four individuals from a three-generation family with agenesis of the corpus callosum and a duplication of 7q36.3. The 7q36.3 duplication involved two genes: RBM33 and SHH. Most affected family members had mild intellectual disability or borderline intellectual functioning, macrocephaly, a broad forehead, and widely spaced eyes. Two individuals had a Chiari type I malformation.
Consult the Pubmed abstract

Am J Med Genet A. ; 167A(9):2201-8 ; September 2015
Syndromic form of intellectual disability with facial dysmorphism, speech impairment and motor developmental delay linked to heterozygous MED13L variants
The authors reported eight patients with predominantly novel MED13L variants who lacked complex congenital heart malformations. Rather, they depicted a syndromic form of intellectual disability associated with facial dysmorphism, speech impairment, motor developmental delay and behavioural difficulties.
Consult the Pubmed abstract

Eur J Hum Genet. ; 23(10):1308-17 ; October 2015
Microcytic hypochromic anaemia and increased foetal haemoglobin linked to KLF1 mutation
This study investigated two unrelated male children in China who had refractory anaemia associated with poikilocythemia. These were accompanied by an upregulation of biochemical markers of haemolysis, along with abnormal haemoglobin level and elevated reticulocyte counts. Next-generation sequencing revealed that the patients were compound heterozygotes for a KLF1 frameshift mutation.
Consult the Pubmed abstract

Eur J Hum Genet. ; 23(10):1341-8 ; October 2015
Mild intellectual disability with obesity and symmetrical shortening of the digits and posterior metacarpals caused by PRMT7 variants in two families
The authors described six affected individuals from three families with compound heterozygous variants in PRMT7. The associated clinical phenotype was a phenocopy of pseudohypoparathyroidism. Mild intellectual disability with obesity and symmetrical shortening of the digits and posterior metacarpals and metatarsals were observed.
Consult the Pubmed abstract

Nat Genet. ; 47(11):1363-9 ; November 2015

New Genes

Intellectual disability and abnormality in resting muscle tone linked to HACE1 mutations and heterotaxia due to MMP21
Consult the Pubmed abstract
To read more about "Heterotaxia"

Nat Genet. ; 47(11):1363-9 ; November 2015
Linear nevus sebaceus syndrome caused by a postzygotic NRAS mutation in one patient
Consult the Pubmed abstract
To read more about "Linear nevus sebaceus syndrome"

Am J Med Genet A. ; 167A(9):2223-5 ; September 2015
Pelizaeus-Merzbacher-like disease associated with a homozygous missense mutation in MAG in three siblings
Consult the Pubmed abstract
To read more about "Pelizaeus-Merzbacher-like disease"

Brain ; 138(Pt 9):2521-36 ; September 2015
Aniridia caused by variants in TRIM44 in patients from a four-generation Chinese pedigree
Consult the Pubmed abstract
To read more about "Aniridia"

Hum Mutat. ; 36(12):1164-7 ; December 2015
Histiocytoid cardiomyopathy linked to a de novo NDUFB11 mutation in three patients
Consult the Pubmed abstract
To read more about "Histiocytoid cardiomyopathy"

Am J Med Genet A. ; 167A(9):2114-21 ; September 2015
Congenital myasthenic syndrome due to mutations in GMPPB
Consult the Pubmed abstract
To read more about "Congenital myasthenic syndrome"

Brain ; 138(Pt 9):2493-504 ; September 2015
Schneckenbecken dysplasia associated with a mutation in INPPL1
Consult the Pubmed abstract
To read more about "Schneckenbecken dysplasia"

Am J Med Genet A. ; 167(10):2470-3 ; October 2015
Progressive pseudorheumatoid arthropathy of childhood and spondyloepiphyseal dysplasia, Stanescu type, caused by a novel COL2A1 variant in three individuals
Consult the Pubmed abstract
To read more about "Progressive pseudorheumatoid arthropathy of childhood"

Hum Mutat. ; 36(10):1004-8 ; October 2015
VACTERL/VATER association might be linked to ZIC3 and FOXF1 mutations
Consult the Pubmed abstract
To read more about "VACTERL/VATER association"

Hum Mutat. ; 36(12):1150-4 ; December 2015
Narcolepsy-cataplexy: EIF3G as a novel susceptibility gene
Consult the Pubmed abstract
To read more about "Narcolepsy-cataplexy"

Eur J Hum Genet. ; 23(11):1573-80 ; October 2015
Peutz-Jeghers syndrome and gastrointestinal ganglioneuroma: SMAD9 as a new susceptibility locus
Consult the Pubmed abstract
To read more about "Peutz-Jeghers syndrome"
To read more about "Ganglioneuroma"

Gastroenterology ; 149(4):886-889.e5 ; October 2015
Hereditary nonpolyposis colon cancer: germline mutations in FAN1 as a risk factor
Consult the Pubmed abstract
To read more about "Lynch syndrome"

Gastroenterology ; 149(3):563-6 ; September 2015

Research in Action

Clinical Research
Glycogen storage disease due to acid maltase deficiency, late-onset: increase in respiratory muscular strength with threshold training combined with enzyme replacement therapy
Consult the abstract
To read more about "Glycogen storage disease due to acid maltase deficiency, late-onset"

Molecular Genetics & Metabolism Reports ; 5(2015):67-71 ; December 2015
Marfan syndrome: mitigated results with losartan treatment
Consult the Pubmed abstract
Consult this study on Orphanet

To read more about "Marfan syndrome"

Eur Heart J. ; 36(32):2160-6 ; August 2015
Mitochondrial neurogastrointestinal encephalomyopathy: allogeneic haematopoietic stem cell transplantation improves clinical manifestations
Consult the Pubmed abstract
To read more about "Mitochondrial neurogastrointestinal encephalomyopathy"

Brain ; 138(Pt 10):2847-58 ; October 2015
Pulmonary arterial hypertension: pharmacological cardioversion and radiofrequency ablation can be applied safely and effectively
Consult the abstract
To read more about "Pulmonary arterial hypertension"

Heart, Lung and Circulation ; [Epub ahead of print] ; 2015
Acquired generalised lipodystrophy: metreleptin therapy reduced insulin resistance and hypertriglyceridemia in three patients
Consult the Pubmed abstract
To read more about "Acquired generalized lipodystrophy"

J Clin Endocrinol Metab. ; 100(11):3967-70 ; November 2015
Takayasu arteritis: efficacy and safety of biological-targeted treatments
Consult the Pubmed abstract
To read more about "Takayasu arteritis"

Circulation ; 132(18):1693-700 ; November 2015
Severe congenital neutropenia: the outcome of allogeneic haematopoietic stem cell transplantation in patients younger than 10 years is acceptable
Consult the Pubmed abstract
To read more about "Severe congenital neutropenia"

Blood ; 126(16):1885-92 ; October 2015
Von Willebrand disease: safety and efficacy of a recombinant von Willebrand factor treatment
Consult the Pubmed abstract
Consult the Spanish study on Orphanet
Consult the Italian study on Orphanet

To read more about "Von Willebrand disease"

Blood ; 126(17):2038-46 ; October 2015
No evidence of transmission of chronic lymphocytic leukaemia through blood transfusion
Consult the Pubmed abstract
To read more about "B-cell chronic lymphocytic leukemia"

Blood ; 126(17):2059-61 ; October 2015
Tetrasomy X: first study reporting on neurodevelopmental findings
Consult the Pubmed abstract
To read more about "Tetrasomy X"

Am J Med Genet A. ; 167(10):2251-9 ; October 2015
Alternating haemiplegia of childhood: faulty cardiac repolarisation reserve as a phenotype extension
Consult the Pubmed abstract
To read more about "Alternating hemiplegia of childhood"

Brain ; 138(Pt 10):2859-74 ; October 2015
Therapeutic Approaches

Charcot-Marie-Tooth disease type 1B: targeting peripheral nerve macrophages by an orally administered inhibitor of CSF1R alleviates two mice models of the disease
Consult the Pubmed abstract
To read more about "Charcot-Marie-Tooth disease type 1B"

Brain ; 138(Pt 11):3193-205 ; November 2015
Mucopolysaccharidosis type 2: high-dose enzyme replacement therapy given to mice of earlier ages may play a role in preventing central nervous system damage
Consult the Pubmed abstract
To read more about "Mucopolysaccharidosis type 2"

Orphanet J Rare Dis. ; 10:141 ; October 2015
Fucosidosis: mitigated results with partial enzyme replacement in a dog model
Consult the Pubmed abstract
To read more about "Fucosidosis"

Orphanet J Rare Dis. ; 10(1):143 ; November 2015
Retinitis pigmentosa: long-term rescue of cone photoreceptor degeneration in mice by gene replacement therapy
Consult the Pubmed abstract
To read more about "Retinitis pigmentosa"

Hum Mol Genet. ; 24(22):6446-58 ; November 2015
Congenital stationary night blindness: intravitreal delivery of a novel adeno-associated virus vector restores visual function in a mouse model
Consult the Pubmed abstract
To read more about "Congenital stationary night blindness"

Hum Mol Genet. ; 24(21):6229-39 ; November 2015
Congenital stationary night blindness: a new mouse model
Consult the Pubmed abstract
To read more about "Congenital stationary night blindness"

Hum Mol Genet. ; 24(20):5915-29 ; October 2015
Chronic autoimmune hepatitis: a single dose of depleting mouse anti-CD20 antibody at the peak of liver inflammation induces remission in mice
Consult the Pubmed abstract
To read more about "Chronic autoimmune hepatitis"

Hepatology ; 62(5):1511-23 ; November 2015
Chronic autoimmune hepatitis: a novel ‘humanised mouse’ model
Consult the Pubmed abstract
To read more about "Chronic autoimmune hepatitis"

Hepatology ; 62(5):1536-50 ; November 2015
Adenocarcinoma of aesophagus: APR-246, a reactivator of mutant p53, potently inhibits tumour growth and overcomes chemoresistance in xenograft models
Consult the Pubmed abstract
To read more about "Adenocarcinoma of esophagus"

Gut ; 64(10):1506-16 ; October 2015
Autosomal dominant dopa-responsive dystonia: a new knock-in mouse model
Consult the Pubmed abstract
To read more about "Autosomal dominant dopa-responsive dystonia"

Brain ; 138(Pt 10):2987-3002 ; October 2015
Ataxia-telangiectasia: a novel porcine model
Consult the Pubmed abstract
To read more about "Ataxia-telangiectasia"

Hum Mol Genet. ; 24(22):6473-84 ; November 2015
Ataxia-telangiectasia: a novel mouse model
Consult the Pubmed abstract
To read more about "Ataxia-telangiectasia"

Hum Mol Genet. ; 24(22):6331-49 ; November 2015
Fragile X syndrome: a new rat model
Consult the Pubmed abstract
To read more about "Fragile X syndrome"

Hum Mol Genet. ; 24(21):5977-84 ; November 2015
Diagnostic Approaches

Human leukocyte antigen markers DQ8 and DR53 are associated with lymphocytic hypophysitis and may aid in differential diagnosis
Consult the Pubmed abstract
To read more about "Primary hypophysitis"

J Clin Endocrinol Metab. ; 100(11):4092-7 ; November 2015
Primary hypohysitis: diagnosis in Germany
Consult the Pubmed abstract
To read more about "Primary hypophysitis"

J Clin Endocrinol Metab. ; 100(10):3841-9 ; October 2015
Constitutional mismatch repair deficiency syndrome: microsatellite instability and tolerance to methylation in lymphoblastoid cells are useful for the diagnosis
Consult the Pubmed abstract
To read more about "Constitutional mismatch repair deficiency syndrome"

Gastroenterology ; 149(4):1017-1029 ; October 2015

Patient Management and Therapy
Hypertriglyceridemia: review on novel therapeutic options
Consult the Pubmed abstract
Clin Ther. ; [Epub ahead of print] ; August 2015
Review on immunosuppressive drugs and fertility
Consult the Pubmed abstract
Orphanet J Rare Dis. ; 10:136 ; October 2015
Pulmonary arterial hypertension: review on molecular genetic defects
Consult the Pubmed abstract
To read more about "Pulmonary arterial hypertension"

Hum Mutat. ; 36(12):1113-27 ; December 2015
Hepatocellular carcinoma: review on genetic landscape and biomarkers
Consult the Pubmed abstract
To read more about "Hepatocellular carcinoma"

Gastroenterology ; 149(5):1226-1239 ; October 2015
Pancreatic cancer: review on genetics
Consult the Pubmed abstract
Gastroenterology ; 149(5):1252-1264 ; October 2015
Haemochromatosis: review on genetics and management
Consult the Pubmed abstract
Gastroenterology ; 149(5):1240-1251 ; October 2015
Cranofacial malformations: a review
Consult the Pubmed abstract
Hum Mol Genet. ; 24(R1):R50-9 ; October 2015
HELLP syndrome: a review
Consult the Pubmed abstract
To read more about "HELLP syndrome"

Clin Chim Acta. ; 451(Pt B):117-120 ; December 2015
Autosomal dominant spastic paraplegia type 4: a review
Consult the Pubmed abstract
To read more about "Autosomal dominant spastic paraplegia type 4"

Brain ; 138(Pt 9):2471-84 ; September 2015
One new and four updated GeneReviews published
GeneReviews are expert-authored, peer-reviewed disease descriptions ("chapters") presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions. One new GeneReviews has been published for:
CLCN2-related leukoencephalopathy

Four updated GeneReviews have been published for:
Dopamine beta-hydroxylase deficiency



Medical Research Grant Application Guidelines : Progeria Research Foundation
The foundation is proving several grants such as Innovator Awards, Established Innovator Award, and Specialty Award. Details are provided on their website
AFM Telethon: Call for proposals
Several call for proposals are being made available by AFM Telethon. They have published a call for proposals for Spinal Muscular Atrophy and Collagen VI Call for Projects.
For further information

BMBF Funding initiative: innovative stem cell technologies for personalized medicine
The German Federal Ministry for Education and Research (BMBF) has announced a new funding initiative for the development and use of innovative stem cell technologies. The initiative aims at funding interdisciplinary research collaborations which are geared towards unlocking the full potential of novel reprogramming technologies and iPS cells for practical use. For this, a pooling of expertise from applied basic and clinical research is needed, for example of research groups from the life sciences, medicine, pharmacology and relevant technical disciplines. The funding can be applied for in two modules: "therapy" and "model & test systems". Deadline for applications is 30 November 2015.
More information (in German)

8th Call for SMA research proposals
This Call is open to any research project aimed at finding a therapy for Spinal Muscular Atrophy (SMA) or elucidating the basic pathophysiological processes of the disease. SMA‐Europe aims to help the international scientific and medical community in its search for therapies for SMA. Preferences will be given to projects with the greatest potential to overcome barriers to translate science into effective treatments.
Two types of research grants will be awarded for up to two years:
1. Operating Grants
2. Postdoctoral Fellowship
Application deadline: 9 December 2015
For further information

Call for Myotonic Dystrophy research
AFM-Téléthon is pleased to announce a new international Call for Myotonic Dystrophy research projects aimed at developing innovative therapeutic approaches in this field. Application deadline is December 18, 2015. Please follow the proposal instructions on the AFM-Téléthon website via this link
CCG Funding Opportunities
The National Cancer Institute (NCI) has published three companion Funding Opportunity Announcements (FOAs) for Genomic Data Analysis Network Centers to support programs of the Center for Cancer Genomics (CCG). The FOAs are managed by CCG and solicit applications for a Processing Genomic Data Center, aVisualization Genomic Data Center, and a Specialized Genomic Data Center.
Access each of the solicitationshere


Courses & Educational Initiatives

2nd International Course: Rare Best practices
Date: 3-4 December, 2015
Venue: Rome, Italy

The course intends to promote guideline quality standards and RAREBestpractices’ outputs across European Member States and to support the upcoming European Reference Networks and Centres of Expertise in the development of their capacity to produce and use health care guidelines on rare diseases.

The course will provide participants with the opportunity to acquire skills necessary to appraise health care guidelines for rare diseases by using AGREE II, the international tool to assess the quality and reporting of health care guidelines, also actively involving them in the appraisal work foreseen in the project.
For Further information
Visit the Rare Best Practices website

EMA workshop on: demonstrating significant benefit of orphan medicines
Date: 7 December, 2015
Venue: London, United Kingdom

The European Medicines Agency (EMA) is organising a workshop on 7 December 2015 to discuss the approach that should be followed by medicine developers to demonstrate the significant benefit of an orphan medicine over existing treatments. Demonstrating a significant benefit is one of the criteria medicines that treat rare diseases must fulfil to benefit from 10 years of market exclusivity once they have been authorised.

The workshop will bring together medicine developers, regulators, healthcare professionals, academia, patients, health technology assessment bodies and healthcare payers who need to register by 31 October 2015 if they wish to participate. The workshop will also be broadcast live.
For further information

European Cytogenetesists Association
Date: February/March of each year
Venue: Nimes, France

This course 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-organized by E.C.A. 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. An application for CME points will also be made for 2016.
For further information

Course for health care guidelines developers on treatment of rare diseases
Date: February 10-12, 2016
Venue: Istituto Mario Negri, Milan Italy

The course is part of the capacity building activities of the project RARE-Bestpractices and will provide participants with the opportunity to acquire skills necessary to produce health care guidelines on treatments of rare diseases.
For further information
Visit the Rare Best Practices website

EMA workshop on pre-licencing activities
Date: 9 March, 2016
Venue: Barcelona, Spain

In collaboration with EMA, E-Rare will organize a workshop dedicated to Interactions between EMA and RD researchers on pre-licensing activities. The workshop will take place from 09:00 to 16:00 on the 9 of March 2015 in Barcelona, before the official start of the RE(ACT) meeting. It will be open to all researchers and interested stakeholders.

The places for Face-to-face meetings with EMA officers are limited! If you would like to participate, please send an email to juliane.halftermeyer@agencerecherche.fr for further instructions.

ExPRESS 2016 Expert Patient and Researcher EURORDIS Summer School
Date: 6-10 June, 2016
Venue: Barcelona, Spain

Patients are taking on ever increasing roles in advocating for medicines development, equal access to treatments across Europe and ensuring that medical information is clear, accurate and comprehensible. In order to help preparing them for these roles and as part of its commitment to empowering people living with rare diseases, EURORDIS launched its own training programme for expert patients in 2008.

The programme has online and face-to face components. The face-to-face portion trains 40 expert patients annually as part of an intensive 4.5 day course.
For further information


What's on Where?

CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference
Date: 20-21 January, 2016
Venue: Brussels, Belgium

This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers.
For further information

BPSU Rare Disease Conference 2016
Date: 23 February, 2016
Venue: Birmingham, United Kingdom

The conference will explore the theme ‘Rare disease in paediatrics – from birth to transition’. It will centre on the child's journey from diagnosis through transition and end of life care.
For further information

Clinical Innovation & Outsourcing
Date: 9-10 March, 2016
Venue: London, UK

Clinical Outsourcing & Partnering World is the largest industry event focusing on the strategic and operational considerations in clinical outsourcing. It is a place where serious business contacts are made. Attended by senior decision makers, it's a platform which facilitates meetings between your sales force and prospects and it's a cost effective sponsorship package with year round advantage.
For further information

The RE(ACT) Congress
Date: 9-10 March, 2016
Venue: Barcelona, Spain

The congress aims to bring together world leaders and young scientist from a variety of breaking through scientific field to present cutting edge research, to discuss results and to exchange ideas. Moreover, many patients and patient organization, which are committed in research, will be present to share their experience.
For further information

MYOLOGY 2016 Fifth International Congress of Myology
Date: 14-18 March, 2016
Venue: Lyon, France

Held for the first time in 2000, MYOLOGY has become a unique opportunity for international experts in the field to exchange and confront the emerging therapeutic approaches, but also to share the first clinical results. The science and medicine of muscle have reached a new milestone. In Myology 2016, no doubt there will be new results, new breakthroughs to share all together.
For further information

13th International Congress of Human Genetics (ICHG) 2016
Date: 3-7 April, 2016
Venue: Kyoto, Japan

Hosted by the East-Asian Union of Human Genetic Societies (EAUHGS) and the Japan Society of Human Genetics, the 13th ICHG will focus on progress in genome analysis technologies and big data in order to explore disease mechanisms and treatment opportunities. Registrations open in 2015.
For further information

5th International Conference on Myelodysplastic Syndromes
Date: 14-16 April, 2016
Venue: Estoril, Portugal

For further information
8th Alstrom Syndrome International Conference
Date: 12-16 May, 2016
Venue: Massachusetts, USA

This international conference will have a scientific symposium for clinicians and researchers as well as sessions for parents, caretakers and patient organisations.
For further information

17th EMSOS Nurse and Allied professional Group Meeting
Date: 12-16 May, 2016
Venue: Massachusetts, USA

The meeting will be focussing on Ewing sarcoma, margins, pelvic tumours, targeted therapy; open sessions will offer the opportunity to report and discuss the latest results in all fields.
For further information

ECRD 2016 : The European Conference on Rare Diseases & Orphan Products
Date: 26-28 May, 2016
Venue: Edinburgh, United Kingdom

The ECRD is the only event which, from its small beginnings, has united all rare disease stakeholders from all European nations- patients and patient representatives, healthcare professionals and researchers, industry, payers, regulators and policy makers alike- in the fight against rare diseases. The ECRD now brings together over 80 speakers and more than 800 participants, covering six themes of content over two days: from the latest research, to developments in new treatments, to innovations in healthcare, social care and support at the European, national and regional levels.
For further information

14th MPS Symposium
Date: 13-14 July, 2016
Venue: Bonn, Germany

In this symposium you get informed about the latest developments in research on the metabolic disease MPS and related lysosomal storage diseases. It is a great forum for discovering what is new in the field of metabolic diseases research.
For further information

European Association of Centres of Medical Ethics Conference
Date: 8 -10 September, 2016
Venue: Leuven, Belgium

The focus of this year’s conference is on a variety of highly relevant ethical issues in health care:
 Organizational Ethics in Health Care: Principles, Cases and Practical Solutions
 Ethical Issues in Care for Older Persons
 Ethical, Legal and Social Developments in Human Genomics
 Ethics and Integrity in Research
For further information

2nd International Conference on New Concepts in B Cell Malignancies
Date: 9-11 September, 2016
Venue: Estoril, Portugal

This conference aims at improving the understanding of the:
• principles and current developments of molecular pathogenesis of Bcell disorders
• the range of prognostic markers and their impact in specific clinical situations
• evolution of treatment principles in Bcell malignancies
• development of promising new agents targeting disease biology
• to improve understanding of key pathways driving expansion of normal vs. neoplastic Bcells
For further information

9th ISNS International meeting/10th ISNS European Regional meeting
Date: 11-14 September, 2016
Venue: The Hague, the Netherlands

The conference will aid the sharing of neonatal screening experiences for congenital metabolic disorders, its clinical diagnostics and follow-up, and will facilitate learning from other experiences. The programme will consist of plenary lectures, oral presentations and poster sessions and will be attractive for professionals, patient/advocacy groups, policy makers and industrial partners. The programme will include evaluation of performance of neonatal screening systems and strategies for improvement.
For further information

Rare metabolic disorders: detection, research, management and treatment
Date: 20-22 September, 2016
Venue: London, United Kingdom

This conference will discuss rare metabolic disorders, their detection, current research, disease management and treatment.
For further information

5th World Congress of Clinical Safety
Date: 21-23 September, 2016
Venue: Massachusetts, USA

The Boston Congress is organized by IARMM to improve and promote high advanced safe and clean science and technology. The congress covers a wide range of safety topics, such as clinical safety (patient safety, medication safety, medical device safety), infectious disease outbreak, disaster healthcare, clinical crisis governance, environmental helth & safety, food safety, and other related safety subjects.
For further information

ESID European Society for Immunodeficiencies: Biennial meeting
Date: 21-24 September, 2016
Venue: Barcelona, Spain

Sessions at this meeting will be devoted to understanding primary immunodeficiencies and their clinical aspects.
For further information


OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews is supported by the European Commission's DG SANTE (RD-ACTION Joint Action N° 677024) and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Kate Bushby, Ana Rath
Editor: Divya Unni
Editors for Scientific Content: Sophie Höhn
Contact Us
Editorial Board: Valentina Bottarelli, Victoria Hedley, Yann LeCam, Stephen Lynn, Charlotte Rodwell, Domenica Taruscio, Ariane Weinmann Valentina Bottarelli, Victoria Hedley, Yann LeCam, Stephen Lynn, Charlotte Rodwell, Domenica Taruscio, Ariane Weinmann

Advisory Editorial Board: Ségolène Aymé, Anna Bucsics, Paul Boom, Bruno Dallapiccola, Jordi Llinares-Garcia, Adam Heathfield, Alastair Kent, Dominique Péton-Klein, Milan Macek, Till Voigtländer

Orphanet Partner Country Representatives: Romi Armando (Argentina), Kristine Hovhannesyan (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Micheil Innes (Canada), Ingeborg Barisic (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Sirpa Ala-Mello (Finland), Joerg Schmidtke (Germany), Eileen Treacy (Ireland), Annick Raas-Rothschild (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Vaidutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Jorge Sequeiros (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Borut Peterlin (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Dorra H'mida (Tunisia), Ugur Ozbek (Turkey), Dian Donnai (UK)
Orphanet - All rights reserved
Disclaimer : This presentation is part of the project / joint action N° 677024 / RD-ACTION' which has received funding from the European Union's Health Programme (2014-2020).

Photo credit : Serimedis http://www.serimedis.inserm.fr/ (unless otherwise stated)