5 November 2014 print
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Rare Diseases Clinical Research Network in the US awarded $29 million to study more than 200 rare diseases

Earlier last month, the National Institutes of Health (NIH) announced $29 million towards expanding the National Center for Advancing Translational Sciences (NCATS)' collaborative Rare Diseases Clinical Research Network (RDCRN) which is dedicated to furthering translational research and investigating new treatments for patients with rare diseases. Currently comprising of 2600 researchers, the NIH Office of Rare Diseases established RDCRN in 2003. RDCRN is overseen by NCATS to work towards advancing medical research on rare diseases by facilitating collaboration, study enrollment and data sharing.

RDCRN is made up of 22 distinctive consortia and a Data Management and Coordinating Center that work collaboratively to improve availability of rare disease information, treatment, clinical studies, and general awareness for both patients and the medical community. The RDCRN also aims to provide up-to-date information for patients and to assist in connecting patients with advocacy groups, expert doctors, and clinical research opportunities.

This new NIH funding will establish six new RDCRN consortia, including bone diseases, lung diseases, food allergy disorders, and three separate neurological diseases concentration areas— amyotrophic lateral sclerosis and related disorders, autism and intellectual disabilities, and frontotemporal lobar degeneration. NIH said researchers at the 22 RDCRN consortia will conduct a minimum of two multisite clinical studies, including one longitudinal natural history study for a group of at least three related rare diseases. Each consortium will partner with relevant patient advocacy groups. According to the NIH press release this award will result in “physician scientists at 22 consortia collaborat(ing) with representatives of 98 patient advocacy groups to advance clinical research and investigate new treatments for patients with rare diseases”.
Read the NIH press release
Go to the NCATS website

EC Expert Group
OrphaNews International: the newsletter for the rare disease community has grown from strength to strength over the years
OrphaNews International, an electronic newsletter published fortnightly, has been a source of comprehensive information for the rare disease community for over 9 years. This newsletter of the European Commission Expert Group on Rare Diseases (formerly the European Union Committee of Experts on Rare Diseases 2009-2014, the European Commission’s Rare Diseases Task Force 2005-2009) has been instrumental in providing up-to-date political, regulatory and scientific news that affect rare disease stakeholders around the world. While OrphaNews International is in English, you can also subscribe to the French and Italian newsletters.

Launched as OrphaNews Europe on the 15th June 2005, the newsletter has seen an extraordinary growth in popularity, currently reaching over 15200 readers internationally. Over 160 issues of the newsletter have been published with ever-increasing subscription numbers with each publication. The graph above shows the steady increase in subscription numbers this year alone, with readers from all around the world. Due to its international reach, OrphaNews Europe was renamed OrphaNews International earlier this year. OrphaNews is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01) and the French Muscular Dystrophy Association (AFM).

OrphaNews France caters exclusively to the French audience, reaching more than 9200 readers. The articles published in this newsletter are central to the experience of rare disease stakeholders in France. The French newsletter, also supported by French Muscular Dystrophy Association (AFM) telethon, precedes the English version as it debuted in 2003. Since its inception, OrphaNews France has provided compelling knowledge about the scientific and regulatory progress in France, in the field of rare diseases.

OrphaNews International is translated into Italian (OrphaNews Italia) by Orphanet Italy, to benefit the Italian readers. This translated version of OrphaNews International was launched in December 2011 and currently has more than 4400 subscribers.
Subscribe to the newsletter in French
Subscribe to the newsletter in Italian

EU Policy News
Swiss Federal Office of Public Health announces the adoption of its national plan: National Concept on Rare Diseases

The Federal Council of Switzerland has approved the “National Concept Rare Diseases”, which is an equivalent of the countries’ national plan for rare diseases. The plan proposes 19 measures, including the establishment of reference centers designed to ensure a quick and safe diagnosis as well as effective treatment. The implementation of this plan is scheduled for the spring of 2015. A meeting was held at the Swiss Ministry of Health with stakeholders on 21 October 2014 to take the first steps in determining the actions needed to implement the measures outlined in the "concept".

The Federal Council of Switzerland recognises that people who suffer from rare diseases and their families face many challenges which involves delay in diagnosis, improper management as well as major hurdles with hospitals and social insurance. They are also confronted with the uncertainty regarding reimbursement of certain drugs and benefits.

The national plan deliberated by the Federal Council of Switzerland has planned to designate reference centers for disease or group of diseases that require special attention, which includes rare diseases. According to the “concept”, these centres must ensure that patients have access to good treatment throughout the duration of the disease. The plan also makes provisions for health care professionals to pursue education to gain further specialised information in the field of rare diseases. The plan pays particular attention for patients that are transitioning from paediatric to adult medicine.

In addition, the “concept” also recommends the use of coordinators in the townships and hospitals who will guide patients in their administrative procedures as well as provide much needed relief to their relatives. Also included in the “concept” are the current procedures for the refund of benefits for sickness and disability which is currently too complex for patients and health professionals in Switzerland. The Federal Office of Public Health (BAG) has examined how to establish standardised procedures to facilitate collaboration between physicians, medical directors and insurance agencies in order to improve the management of certain drugs and genetic analysis.

Rare disease patients and other stakeholders in Switzerland see the announcement of the “National concept on Rare Diseases” a huge step forward for the better diagnoses and treatment of rare diseases and await its implementation.

Read the National Concept Rare Diseases in French
Read the National Concept Rare Diseases in German

EMA stays with DG SANCO
In the beginning of September, President of the European Commission, Jean-Claude Juncker, announced a plan to move the responsibility of the EMA from the directorate general for health and consumers (DG SANCO) to directorate general for enterprise (DG Enterprise). Details of this announcement can be found in a previous issue of OrphaNews. This move was heavily criticised by healthcare advocates, as the primary objective of regulating medicines by EMA is to ensure the safety and efficacy of medicinal products brought into the marketplace due to which DGSANCO oversees the Agency. In all probability, ensuring the patients’ well being would cease to be the Agency’s main responsibility if it became a part of DG enterprise, making it a commercial entity. The opposition to this plan was strong and unanimous, leading to its withdrawal within a month. EMA will continue to be overseen by DG SANCO.
Read more on this topic in OrphaNews
Read more on this topic

EMA announces that the Clinical trial data will be shared: patients prevail
After a lengthy debate over access of clinical trial data, the European Medicines Agency (EMA) have released a press statement confirming that clinical trial data of medicinal products with marketing authorisation in Europe will be made public. This policy will take effect for all products to be submitted after 1 January 2015, while sponsors of previously authorised products will have to release their data by June 2015. Data can be viewed and downloaded to ensure that it can be analysed and re-evaluated as required. Companies may be allowed to suggest redaction of certain proprietary information; however the final decision will remain at the discretion of the EMA. While Europe is the first to implement this landmark decision, it is hoped that other regulatory agencies would follow suit.

Read EMA’s press release on publication of clinical trial data

A revised version of the EMA paediatric investigation plans developed ease the application process
According the guidelines of the paediatric investigation plan laid out by European Paediatric Regulation, “pharmaceutical companies have (had) a legal obligation to develop plans to evaluate medicines in children”. A revised version of the paediatric investigation plan, which was first published in September 2008, has been recently published by the EMA. The revision is aimed to facilitate the application process which will ultimately help pharmaceutical companies bring more and better paediatric medicines into the market. This version introduces further flexibility, incorporates new study concepts, and clarifies compliance requirements.
Read the revised version of the paediatric investigation plans

EMA pledges continual support of Small and Medium sized enterprises during SME week
Several peer reviewed studies, as well as data from the EMA has shown that small and medium sized enterprises (SME) are in the forefront of producing innovative medicines. According the EMA “(these medicines) have the potential to bring significant benefits to patients and address unmet medical needs” especially in the area of rare diseases. The EMA extols the significance of SME’s in generating these innovative medicines and bringing them to the market, which is also an important service to rare disease patients. The EMA have released a press statement reiterating its continual support of SME’s during the SME week, which was from 29 September to 5 October 2014.
Read the EMA press release in support of SME’s


National & International Policy Developments
Other European news
Stamina Foundations’ fraudulent stem cell therapy trial is finally brought to a standstill
A panel of experts appointed by the Italian Ministry of Health concluded that the trial of the so-called Stamina method should not move forward. Astonishingly, this took more than a year, however, this time Italy’s minister of health, Beatrice Lorenzin, declared that the new panel’s October recommendation is final and has vowed to block any trial. Meanwhile, 20 people involved in promoting this controversial therapy, including its leading proponent, are facing allegations of criminal conduct. In April, Italian prosecutors released a report alleging that the group was engaged in fraud by selling the therapy to patients. Prosecutors in Turin have seized vials containing patient cells and tissues from a hospital involved in supporting Stamina Foundations fraudulent therapy.
Rare Cancers Europe recommendations for clinical studies in rare cancers

Rare Cancers Europe (RCE) is a multi-stakeholder initiative representing patient associations, medical societies and industry has recently published a consensus paper with recommendations on conduting clinical trials for rare cancers to try to bring better medications faster into the market. They have also released a press statement “calling both the community of researchers and European authorities to address research methodologies and regulatory criteria that could limit rare cancer patient access to new therapies”. The authors believe that the current methodologies may be discriminating against this rare disease patient population. The recommendations highlight the importance of allowing certain “high risk medications” to come to the market to avoid discriminating against small population of patients suffering from rare cancers and encouraging innovative approaches to treatment. For clinical trials RCE recommends adaptive trial designs and surrogate end points to obtain swift answers to the clinical trial process. Also highlighted in the consensus paper is the significance of “reference networks in Europe, involving Centres of Expertise to improve the quality of care for rare cancers »
Read the Open Access article
Read the RCE press release

Other International News
NIH revises its genomic data sharing policy
The US National Institutes of Health (NIH)’s has issued the data sharing policy replacing the previous Genome-Wide Association Studies (GWAS) data sharing policy, issued in 2007. It will apply to all NIH-funded, large-scale human and non-human projects that generate genomic data beginning with funding applications submitted by January 25, 2015. According to the NIH «The genomic data sharing policy reflects NIH’s commitment to responsible data stewardship and includes a number of provisions to assure the protection of human data”.
Read the NIH genomic data policy

Call for public consultation: WHO Statement on Public Disclosure of Clinical Trial Results
While the EMA announces its policy on the release of clinical trial data (See above), International Clinical Trials Registry Platform (ICTRP) established by the World Health Organisation has released a statement calling for “public consultation on accessibility of clinical trial result data”. ICTRP, which collates information on trials that have been notified in a network of clinical trial registries, are making substantial effort to increase transparency of the clinical trials. Until recently, clinical trial data results are sometimes shrouded in secrecy leading to concerns about the reliability and validity of the product. This is a platform for the voices of the public to be heard to build greater transparency in drug delivery process.
Please download the comment form from the website and enter comments into the Word file. Email completed comment forms to: ictrpinfo@who.int. The deadline for comments is 15/11/2014

Go the International Clinical Trials Registry Platform

Catalyst Pharma plans exorbitant price for rare disease drug in the US
"The Street" has recently published a scathing criticism of Catalyst Pharmaceuticals as they envisage an exorbitant pricetag for the drug Firdapse, which was recently reported to have positive results from a phase III study as a treatment for Lambert-Eaton Myasthenic Syndrome (LEMS), a progressive, muscle-weakening disease. According to "The Street" the company plans to seek Food and Drug Administration approval for Firdapse early next year and believes that the drug will cost upwards of $60,000 to $80,000 per year for a LEMS patient. "The Street" considers this an “unconscionable” price as the active ingredient of the drug - 3,4-diaminopyridine - has been available in compounding pharmacies in the U.S. for more than 20 years to treat the small numbers of LEMS patients and Catalyst has spent next to nothing on its clinical development.
Read the article on The Street

PhRMA renews legal battle over big hospital discounts in the US for orphan drugs
In related news, the Pharmaceutical Research and Manufacturers of America (PhRMA) is suing the federal government of the United States over a rule that allowed some hospitals to get orphan drugs at a steep discount, for the second time. According to the 340b program, which was devised in the US to protect vulnerable patients, pharmaceutical companies must offer a discount of up to 50% for outpatient drugs supplied to hospitals and clinics that serve poor populations. This rule allows these hospitals to obtain orphan drugs at a discount, but only when used to treat non-orphan conditions. However, PhRMA feels that these discounts can add up because several drugs given orphan status have indications to treat much larger populations of patients.

Although the federal court ruled in the favour of PhRMA the first time, the U.S. Health Resources and Services Administration (HRSA) has reissued the rule, compelling PhRMA to sue again.
Read PhRMA press release on the 340b program

Intricacies in the Affordable Care Act of the United States may fail rare disease patients
The advent of the Affordable Care Act (ACA) in US was one of the most promising news for rare disease patients. Before the implementation of this act, rare disease patients in US patients were vulnerable as often they were unable to access these treatments because of high out-of-pocket costs, particularly if they are not already covered under a health insurance. ACA, promised improved access to healthcare for those who have not had access to insurance coverage through existing public and private sources. However, the authors in an article published in “ Journal of Managed Care & Specialty Pharmacy » mentions that this process can be quite cumbersome. A goal of the ACA was to create a market in which choices in insurance products offered could be easily understood and compared by individuals. The act requires everyone to enrol in 1 of the 4 “metal level” plans - bronze, silver, gold, and platinum – bronze being the one that covers the least, while platinum covers 90% of the plan. These metal levels provided the basis for how plans designed their insurance products, including their drug benefits.

Robinson et al., found that the coverage of drugs and other treatment levels for rare disease patients differs considerably based on many factors such as the state that the patient belongs to, the number of drugs that have been approved by the FDA for the rare disease in question as well as utilisation management. Higher cost medications, such as those for rare disease therapies, may be placed on a plan’s higher formulary tiers (gold and platinum) with higher premiums. The authors analysed 7 rare diseases and the available treatments to examine how the insurance agencies would cover patients with the particular disease. They found that bronze plans were far less likely than silver plans to cover the selected products. Select drugs identified as being the only FDA-approved product indicated for a certain rare disease were robustly covered while when several orphan drugs with FDA-approved indications to treat the same rare disease coverage was generally low and potentially more complex.

The copayment rates across the products ranged from as low as $20 to as high as $250. The authors also found that a gold or platinum plan may prove to be more cost-effective in the long term for patients than a bronze plan, with higher premiums potentially being offset by reduced out-of-pocket maximums and better coverage. The authors reiterate the importance for patients with rare diseases seeking coverage in the exchanges to, at minimum, examine plan formularies prior to enrolling in an exchange plan and managed care pharmacists can play an important role in educating rare disease patients on plans.
Consult the Pubmed abstract

Guidance Documents and Recommendations
Special issue of ‘Annals of Oncology’ on European Society for Medical Oncology updated clinical practice guidelines
Read the special issue
Annals of Oncology ; September 2014
Hypertrophic cardiomyopathy: 2014 European Society of Cardiology guidelines on diagnosis and management
Consult the Pubmed abstract
To read more about "Hypertrophic cardiomyopathy"
To read more about "Familial isolated hypertrophic cardiomyopathy"

Eur Heart J. ; 35(39):2733-79 ; October 2014
Cardiofaciocutaneous syndrome: guidelines on clinical features, diagnosis and management
Consult the Pubmed abstract
To read more about "Cardiofaciocutaneous syndrome"

Pediatrics ; 134(4):e1149-e1162 ; October 2014
Bioinformatics, Registries and Data Management
Never before has genome and exome sequencing been as accessible as it is today, making it easier to extract important genomic information. However, analysing the vast amount of data generated by next- generation sequencing to acquire important information and disregard noise is a tricky task. It is also responsible for the bottleneck that is often experienced by patients, researchers and clinicians. In this issue of the newsletter we are highlighting some of the analytical instruments that have been published in the past couple months to ease these impediments.

Algorithm that aids in genetic diagnosis by ranking genes based on the phenotype
Correlating mutated genes with the patient’s phenotype to reach a possible clinical diagnosis is an area of great importance to clinicians and researchers. Masino et al., have published an algorithm that aids in interpreting variant information relative to patient phenotype in BMC Bioinformatics. This algorithm ranks genes by the semantic similarity between patient phenotype features and phenotype features directly associated with each of a patient’s mutated genes. The rank ordered list assigns a score to each gene that indicates the “strength of association” between the gene and the patient’s clinical presentation (or phenotype). When the algorithm presents the ranks of the genes, the ones with very low scores are unlikely to be associated with the patient’s specific phenotype, thus not requiring a detailed review, while the genes that rank highly within the list are likely to aid in a genetic diagnosis.

The authors utilised the Human Phenotype Ontology (HPO) to assist in providing the phenotypic descriptor terms, while the information content within the terms aided in providing semantic similarity. The authors tested their algorithm on four actual clinical cases with hearing impairment, which led to ranking a gene that was previously missed by other eminent physicians and researchers. The authors acknowledge that their method is similar to Phenomizer, but while Phenomizer gene-rank is based on HPO term-to-disease annotations, the method presented in this paper provides gene ranks based on HPO term-to-gene annotations. According to the authors, “phenotype rank combined with variant analysis provides significant improvement over the individual approaches (and) expect that a combined prioritisation approach may increase accuracy and decrease effort for clinical genetic diagnosis». The algorithm source code and the resulting data is publicly available at https://github.com/cbmi/phenomantics.
Consult the Pubmed abstract

Disease Manifestation Network: a novel phenotype network database
To add to our understanding of the causative aspects of rare disease, a group from Case Western Reserve University has published the creation of a disease phenotype network that aids in linking complex clinical phenotypes. This article, published in Journal of Biomedical Informatics, describes a novel method of creating phenotype network database which does not rely on mining textual phenotype descriptions, but on the usage of highly accurate disease-manifestation semantic relationships from Unified Medical Language System (UMLS). Chen et al., have called this database Disease Manifestation Network (DMN) and made it available publicly at nlp/case.edu/public/data/DMN.

According to the authors the usage of 50,543 highly accurate disease-manifestation semantic relationships UMLS helped capture major aspects of disease phenotypes which can successfully predict disease causes. A salient feature of this phenotype network database included that DMN not only contained existing knowledge but also some novel insights which the authors found by comparing DMN and mimMiner (a phenotype network database constructed through text mining). The authors also found that DMN partially correlated with the genetic network database - Human Disease Network (HDN) - based on Online Mendelian Inheritance in Man (OMIM) and Genome-Wide Association Studies (GWAS). Finally, using the example of Marfan Syndrome the authors found that DMN has the potential to provide “new leads to discover unknown causes of Marfan Syndrome”, thus concluding that a combinatorial approach where mimMiner and DMN disease is used would be an excellent method for gene discovery and drug.
Consult the Pubmed abstract

A free web-based system for Sanger sequencing-based genetic testing data analysis
Most laboratories use Sanger sequencing for reaching a molecular diagnosis for genetic diseases, especially in cases of rare diseases. However, Sanger sequencing produces an enormous amount of data that has to be carefully examined and annotated. All this has to be done within a short amount of time as patients eagerly wait for the verdict. Usually, the data analysis process holds up the entire testing process because it involves manual inspection of raw data. To address this bottleneck, the authors of an article published in Methods developed an online bioinformatics platform that can automate the process, called the Online Diagnosis System (ODS).

ODS is a freely available webserver“that seamlessly integrates base calling, single nucleotide variation (SNV) identification, and SNV annotation into one single platform” and also allows manual inspection of the quality of the identified SNVs. The authors believe that ODS can significantly reduce data analysis time, hence allowing Sanger sequencing-based genetic testing to be finished in a timely manner. One of the most salient feature of ODS is it highly independent nature, as a web-based system, ODS does not require any installation procedure thereby being operable by mobile devices as one can simply upload the sequencing and download the results. ODS is freely available at Please note that the link provided in the article (http://sunlab.lihs.cuhk.edu.hk/ODS/) for ODS is no longer available.
Consult the Pubmed abstract

Creation of a mitochondrial dysfunction transcriptome using publicly shared data
An article published in Methods have tackled the problem of lack of clinical samples and low research funding to study rare diseases by utilising currently available transcriptome data and performing an integrative analysis on it to reveal novel information of mitochondrial disease. Zhang et al., created the Transcriptome of mitochondrial dysfunction (ToMD) from publicly shared data archive including 30 independent data sets and about 500 biological samples collected from human tissue and cell lines, worm, fruit fly and mouse. In each dataset the authors included a comparison of samples with primary mitochondrial dysfunction - caused by pathogenic gene mutations in patients, knockdown/knockout of key mitochondrial genes in cultured cells or model animals, or exposure to chemicals such as Rotenone and Rapamycin - to those with normal or rescued mitochondrial function. The authors then describe the bioinformatics methods they utilised to “evaluate data quality, standardize gene annotation, and perform integrative analysis”, which according to them was mostly automated but needed some human supervision to ensure data quality and sample labeling.

Not only did the analysis of the transcriptome derived from various sources highlight the central players of mitochondrial dysfunction, but also provided novel information on therapeutic targets. The authors believe that this study provides a method by which researchers can “integrate transcriptome data sets sharing a common link to a rare disease, but generated from different platforms, cell types, and even species” with limited resources. All data sets and analysis results within ToMD are freely available at https://mseqdr.org/data/tomd/.
Consult the Pubmed abstract


Ethical, Legal & Social Issues
Research agenda discrepancy in dystrophic epidermolysis bullosa affects patients’ wellbeing
A letter to the Editor of the Journal of the American Academy of Dermatology addressed growing concerns about the mismatch between current research in dystrophic epidermolysis bullosa (DEB) and the needs of patients and clinicians.

To accentuate this point, authors of the letter searched for all clinical trials of DEB registered in the International Clinical Trials Registry Platform (World Health Organization) and in ClinicalTrials.gov (US National Institutes of Health).They found 26 registered studies of DEB therapy most of which is focused on trying to obtain a cure for DEB using gene transfer, protein-based, or stem-cell therapy, which may not become a clinical reality for a while. The authors highlights a lack of clinical research in areas relevant to patients and clinicians which are more likely to provide answers soon as they believe that the research agenda led by researchers favours a high-risk approach where curative long-term therapies are explored. The authors believe that when patients and clinicians together set the research agenda, they opt for a lower-risk approach that concentrates on solving everyday problems, which however comes at the price of being less innovative.
Access the letter

Use of the DISCERN tool for evaluating web searches in childhood epilepsy.
Since an increasing number of parents or caregivers use the Internet as a source of health information concerning symptoms, therapy, and prognosis of rare diseases, high-quality websites are necessary to satisfy this request. DISCERN is an online resource designed as an instrument to help users of health advice judge the quality of written information about treatment choices. DISCERN is able to judge the reliability of a website as a source of information about treatment choices or to assess whether the sources of evidence are explicit but not the scientific quality or accuracy of the evidence.

Using the DISCERN tool, the authors of an article published in Epilepsy & Behavior evaluated online information on childhood epilepsy provided by the first 50 links displayed on the Google search engine. The evaluations were performed by a team of paediatric neurologists and by a lay subject. Alarmingly, they found that only 4 of the 42 websites that the paediatric neurologist analysed showed good reliability, while 28 websites were either partially or completely biased. The authors thus warn that there is increasing use of the Internet to get information concerning both common and rare diseases and health problems but there is also a substantial number of the websites that do not provide adequate information. From the analysis conducted, the authors concluded that it is more and more necessary to have websites with clear, easy, and satisfying contents, thereby allowing anyone to surf them for both personal and professional purposes. This study highlights that accurate information is not currently available easily on the internet, making the increasing reliance on the web for understanding of a disease greatly distressing.
Consult the abstract


New Syndromes

New syndrome of enterocolitis and autoinflammation caused by mutations in NLRC4
Two articles described a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of auto-inflammation in two families. The disease is caused by a de novo gain-of-function mutation in NLRC4 in one family (three patients), and by a de novo missense mutation in NLRC4 in the other family (one patient).
Consult the Pubmed abstracts

Nat Genet. ; 46(10):1135-9, 1140-6 ; October 2014
Novel syndrome of CTLA4 haploinsufficiency with autoimmune infiltration disease in four unrelated families
The authors identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Patients exhibited lymphocytic infiltration of target organs as well as progressive loss of circulating B cells.
Consult the Pubmed abstract

Science ; 345(6204):1623-7 ; September 2014
Two new syndromes of developmental delay linked to haploinsufficiency of SETBP1 and truncations of ZMYND11
The authors identified new clinical subtypes of pediatric disease and the genes responsible. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features.
Consult the Pubmed abstract

Nat Genet. ; 46(10):1063-71 ; October 2014
Microcephalic primordial dwarfism compatible with Seckel syndrome caused by mutations in CENPE in two siblings
The authors described novel compound heterozygous variants in CENPE in two siblings who exhibit a profound microcephalic primordial dwarfism associated with developmental delay, simplified gyri and other isolated abnormalities.
Consult the Pubmed abstract

Hum Genet. ; 133(8):1023-39 ; August 2014
Intrauterine growth restriction, short stature, and early-adulthood-onset diabetes associated with a variant in CDKN1C
The authors investigated a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. Whole exome sequencing of 15 affected and 26 unaffected DNA samples from a six-generation pedigree revealed a novel mutation in CDKN1C.
Consult the Pubmed abstract

J Clin Endocrinol Metab. ; 99(10):E2117-22 ; October 2014
Novel autosomal recessive intellectual disability syndrome identified in six patients from northern Finland
The authors identified six patients presenting with a strikingly similar clinical phenotype of profound syndromic intellectual disability of unknown etiology. All patients lived in the same village. Extensive genealogical work revealed that the healthy parents of the patients were all distantly related to a common ancestor from the 17th century, suggesting autosomal recessive inheritance. In addition to intellectual disability, the clinical features included hypotonia, strabismus, difficulty to fix the eyes to an object, planovalgus in the feet, mild contractures in elbow joints, interphalangeal joint hypermobility and coarse facial features that develop gradually during childhood. The clinical phenotype did not fit any known syndrome. Further studies are needed to unambiguously identify the underlying genetic defect.
Consult the Pubmed abstract

Eur J Med Genet. ; 57(10):543-51 ; October 2014
A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX
Pierre Robin sequence is an etiologically distinct subgroup of cleft palate. The authors defined a region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of Pierre Robin sequence. Commonly associated anomalies were talipes equinovarus, finger contractures and crumpled ear helices. The strongest candidate genes were FBN2 and PHAX.
Consult the Pubmed abstract

Eur J Med Genet. ; 57(10):587-95 ; October 2014

New Genes

Early-onset epileptic encephalopathies caused by de novo mutations in synaptic transmission genes including DNM1
Consult the Pubmed abstract
Am J Hum Genet. ; 95(4):360-70 ; October 2014
Early-onset antibody-negative diabetes due to novel recessive mutations in PCBD1 in a consanguineous family
Consult the Pubmed abstract
To read more about "Limb-girdle muscular dystrophy"

Diabetes ; 63(10):3557-64 ; October 2014
Increased susceptibility to childhood acute lymphoblastic leukemia and elevated risk for late relapses associated with KIR ligand C2
Consult the Pubmed abstract
To read more about "Precursor B-cell acute lymphoblastic leukemia"
To read more about "Acute lymphoblastic leukemia"

Blood ; 124(14):2248-51 ; October 2014
Autosomal recessive primary ovarian failure linked to SYCE1 nonsense homozygous mutation in an Israeli Arab family with a consanguineous pedigree
Consult the Pubmed abstract
To read more about "Primary ovarian failure"

J Clin Endocrinol Metab. ; 99(10):E2129-32 ; October 2014

Research in Action

Clinical Research
Childhood-onset, complicated, frequently relapsing nephrotic syndrome: rituximab is an effective and safe treatment
Consult the Pubmed abstract
To read more about "Idiopathic nephrotic syndrome"

Lancet ; 384(9950):1273-81 ; October 2014
Advanced gastric cancer: the combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel
Consult the Pubmed abstract
Consult this study on Orphanet
Consult this study on Orphanet

To read more about "Gastric cancer"

Lancet Oncol. ; 15(11):1224-35 ; October 2014
Osteogenesis imperfecta: two years denosumab treatment demonstrates long term benefit and safety
Consult the Pubmed abstract
To read more about "Osteogenesis imperfecta type 3"

Orphanet J Rare Dis. ; 9(1):145 ; September 2014
Granulomatosis with polyangiitis: rituximab is an effective remission-inducing agent, and the addition of a conventional maintenance agent decreased the incidence of relapse
Consult the Pubmed abstract
To read more about "Granulomatosis with polyangiitis"

Arthritis Rheumatol. ; 66(10):2862-70 ; October 2014
long-term efficacy and safety of pegvisomant in combination with somatostatin analogs
Consult the Pubmed abstract
To read more about "Acromegaly"

J Clin Endocrinol Metab. ; 99(10):3644-52 ; October 2014
Facioscapulohumeral dystrophy: vitamin E, vitamin C, zinc and selenium supplementation may improve skeletal muscle function
Consult the Pubmed abstract
To read more about "Facioscapulohumeral dystrophy"

Free Radic Biol Med. ; [Epub ahead of print] ; September 2014
Autism spectrum disorders and intellectual disability: the frequency and the penetrance of SHANK3 mutations warrant its consideration for mutation screening in clinical practice
Consult the Pubmed abstract
PLoS Genet. ; 10(9):e1004580 ; September 2014
Typical and atypical rolandic epilepsy: 16p11.2 duplications represent a significant genetic risk factor
Consult the Pubmed abstract
To read more about "Rolandic epilepsy"

Hum Mol Genet. ; 23(22):6069-80 ; November 2014
Therapeutic Approaches

Ebola hemorrhagic fever: reversion of advanced disease in rhesus macaques with ZMapp, a combination of monoclonal antibodies
Consult the Pubmed abstract
To read more about "Ebola hemorrhagic fever"

Nature ; 514(7520):47-53 ; October 2014
FGFR3 skeletal dysplasia: statin treatment rescues patient-specific induced pluripotent stem cell models and a mouse model
Consult the Pubmed abstract
To read more about "Thanatophoric dysplasia type 1"
To read more about "Achondroplasia"

Nature ; 513(7519):507-11 ; September 2014
Kabuki syndrome: AR-42, a histone deacetylase inhibitor, rescues structural and functional brain deficits in a mouse model
Consult the Pubmed abstract
To read more about "Kabuki syndrome"

Sci Transl Med. ; 6(256):256ra135 ; October 2014
Dystrophic epidermolysis bullosa: aminoglycosides restore full-length type VII collagen by overcoming premature termination codons
Consult the Pubmed abstract
To read more about "Dystrophic epidermolysis bullosa"

Mol Ther. ; 22(10):1741-52 ; October 2014
Amyloidosis: chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in a model mouse
Consult the Pubmed abstract
To read more about "Familial amyloidosis, Finnish type"
To read more about ""

Mol Ther. ; 22(10):1768-78 ; October 2014

Patient Management and Therapy
Adult T-cell leukemia/lymphoma: a review
Consult the Pubmed abstract
To read more about "Adult T-cell leukemia/lymphoma"

Lancet Oncol. ; 15(11):e517-e526 ; October 2014
Cytomegalovirus retinitis: review on current and future treatments
Consult the abstract
To read more about "Cytomegalovirus disease in patients with impaired cell mediated immunity deemed at risk"

Expert Opinon on Orphan Drugs ; 2(10):999-1013 ; October 2014
Sturge-Weber syndrome: overview of current and future treatment options
Consult the abstract
To read more about "Sturge-Weber syndrome"

Expert Opinon on Orphan Drugs ; 2(10):1015-1025 ; October 2014
Desmoid tumor: review on clinical management
Consult the abstract
To read more about "Desmoid tumor"

Expert Opinon on Orphan Drugs ; 2(10):1027-1036 ; October 2014
Alport syndrome: review on genetic and biological therapies
Consult the abstract
To read more about "Alport syndrome"

Expert Opinon on Orphan Drugs ; 2(10):1037-1047 ; October 2014
Marfan syndrome: review on diagnosis and genetics
Consult the abstract
To read more about "Marfan syndrome"

Expert Opinon on Orphan Drugs ; 2(10):1049-1062 ; October 2014
Pulmonary lymphangioleiomyomatosis: review on therapeutic strategies
Consult the abstract
To read more about "Lymphangioleiomyomatosis"

Expert Opinon on Orphan Drugs ; 2(10):1063-1074 ; October 2014
Lymphangioleiomyomatosis: all patients should be screened for angiomyolipoma at diagnosis of lung disease
Consult the Pubmed abstract
To read more about "Lymphangioleiomyomatosis"

Orphanet J Rare Dis. ; 9(1):151 ; October 2014
Turner syndrome: review on management in adult life
Consult the abstract
To read more about "Turner syndrome"

Maturitas ; [Epub ahead of print] ; September 2014
Acute myeloid leukemia: review on daunorubicin for the treatment
Consult the abstract
To read more about "Acute myeloid leukemia"

Expert Opinon on Orphan Drugs ; 2(10):1075-1087 ; October 2014
Multiple myeloma: review on pomalidomide for the treatment
Consult the abstract
To read more about "Multiple myeloma"

Expert Opinon on Orphan Drugs ; 2(10):1089-1108 ; October 2014
Hemophilia A: review on recombinant factor VIII Fc for the treatment
Consult the abstract
To read more about "Hemophilia A"

Expert Opinon on Orphan Drugs ; 2(10):1109-1116 ; October 2014
Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
Consult the abstract
To read more about "Systemic-onset juvenile idiopathic arthritis"

Arthritis Rheumatol. ; 66(10):2871-80 ; October 2014
Non-transfusion-dependent thalassemia: review on identification and diagnosis
Consult the abstract
To read more about "Hemoglobin H disease"
To read more about "Beta-thalassemia intermedia"
To read more about "Hemoglobin E - beta-thalassemia"

Orphanet J Rare Dis. ; 9(1):131 ; September 2014
Pleuropulmonary blastoma: a review
Consult the abstract
To read more about "Pleuropulmonary blastoma"

Cancer ; [Epub ahead of print] ; September 2014
One updated Clinical Utility Gene Card published in the European Journal of Human Genetics
EuroGentest, the EU-funded Network of Excellence for genetic testing, has developed disease-specific points to consider regarding clinical indications for genetic testing - the Clinical Utility Gene Cards (CUGCs). These documents provide clinicians and clinical geneticists with guidance on genetic testing for specific conditions in real settings of clinical genetic services. Published in the European Journal of Human Genetics and also available on the Orphanet website, the CUGCs focus on Mendelian diseases.
The European Journal of Human Genetics has published one updated Clinical Utility Gene Card for:
Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP)

Two new and six 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. Two new GeneReviews have been published for:
Cantú syndrome and related disorders
Perrault syndrome

Six updated GeneReviews have been published for:
Congenital cataracts, facial dysmorphism, and neuropathy
Lenz microphthalmia syndrome
Dent disease
Hereditary neuropathy with liability to pressure palsies
Milroy disease
ZAP70-related severe combined immunodeficiency


Orphan Drugs
Political and Scientific News
Article illustrates treatment of advice on adaptive clinical trial designs by the EMA
Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. Both the European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. In addition the EMA also offers a key service of scientific advice and protocol assistance, which sponsors of medicines, can avail early in the marketing authorisation process.

Whether this service proves to be vital for sponsors is discussed in an article publishes in Trials where Elsäßer et al., analysed 59 scientific advices that address adaptive study designs in Phase II and III clinical trials and discussed 3 case studies submitted to the EMA and analysed by the CHMP/SAWP. The authors found that “most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment”. The authors report an increase in submissions in 2011 and while many of the trials were on a rare disease, not all of them had an orphan designation. Promisingly, the authors found that a majority of proposals were accepted “as is” or with conditions attached, however they also reported that Type I error were more frequent than expected. The case studies presented in this paper illustrated how advice on sample size reassessment, interim dose selection and post-hoc adaptations were handled by the CHMP. Although the authors discuss the case studies and the numbers in a fair amount of detail, it is difficult to draw conclusions on marketing authorisation based on them, as the CHMP views applications as a whole. However, the article gives a flavour of how the CHMP tackles issues relating to adaptive clinical trial and what questions the sponsors could ask while planning such a trial.
Consult the Pubmed abstract



Collagen VI Alliance Call for Projects 2015
A new international alliance has been established by AFM-Téléthon, the Muscular Dystrophy Campaign, Muscular Dystrophy Ireland, Cure CMD and the Swiss Foundation for Research on Muscle Diseases to fund research into collagen VI deficiencies that will further the development of therapeutic approaches and/or demonstrate a strong translational impact in this research field. In order to drive the development of treatments for these conditions forward, AFM-Téléthon and the Muscular Dystrophy Campaign have joined forces to launch a Call for Projects dedicated to collagen VI deficiencies with a particular focus on Ullrich muscular dystrophy and Bethlem myopathy.
The research will be funded by the members of the Collagen VI Alliance. The call will be coordinated by the Muscular Dystrophy Campaign.

Application deadline: 20 November, 2014

For further details

Research on Eosinophil Associated Disorders (R01) and (R21)
These two NIH grants are open to non-US entities. Areas of interest include, but are not limited to, the following topics
Research on the fundamental immuno-biologic and mechanistic roles of human eosinophils in Eosinophil-Associated Disorders
Development of predictive biomarkers and clinical outcomes for Eosinophil-Associated Disorders Development of novel therapeutic targets for use in Eosinophil-Associated Disorders
Preclinical evaluation of existing therapeutic agents for use in Eosinophil-Associated Disorders
Identification and improvement of novel invasive and non-invasive techniques for the diagnosis and clinical monitoring of Eosinophil-Associated Disorders
Improvement of diagnostic criteria that delineate differential phenotypes within Eosinophil- Associated Disorders
Development of novel animal models with improved predictive value for human Eosinophilic- Associated Disorders
Earliest Submission Date for the R01 grant : 5 January 2015
Earliest Submission Date for the R21 grant : 16 January 2015

For further details on the R01 grant
For further details on the R21 grant


Courses & Educational Initiatives

ESH-ENERCA Training course on haemoglobin disorders: laboratory diagnosis and clinical management
Date: 23-24 January, 2015
Venue: Barcelona, Spain

The course will cover the following topics: Epidemiology in practice, Clinical aspects of thalassaemia, Trends in biological aspects of thalassaemia, Abnormal haemoglobins and Complications and treatments of thalassaemia and sickle cell disease.
Participants are encouraged to submit clinical cases or abstracts for presentation and discussion during the meeting. Submit your detailed clinical case(s) online
Deadline for clinical cases and abstracts: 24 November, 2014
For further information


What's on Where?

2nd International Rare Diseases Research Consortium (IRDiRC) Conference
Date: 7-9 November, 2014
Venue: Shenzhen, China

The second conference is organised by the International Rare Diseases Research Consortium (IRDiRC), in collaboration with the BGI. The conference will gather top scientists from Europe, North America and Asia-Pacific for dynamic exchanges on knowledge and expertise. The event will also include an educational track. The ambition of this conference is to provide researchers with opportunities to establish new collaborations and confront different cultural approaches to the challenges posed by rare diseases.
For further information

4th Pan-European Conference on Haemoglobulinopathies and Rare Anaemias
Date: 7-9 November, 2014
Venue: Athens, Greece

The 4th Pan-European Conference on Haemoglobinopathies and Rare Anaemias aims to educate and empower patients, develop European expert collaborative networks and improve multidisciplinary interaction concerning policy decision making.
For further information

Third International Symposium on Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)
Date: 12-13 November, 2014
Venue: Montreal, Canada

The Montreal Neurological Institute and Hospital will host the 3rd International Symposium focusing on advances in understanding ARSACS (Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay) in the larger context of mitochondrial dysfunction in neurodegeneration. This two day symposium will bring together clinical, ataxia, and mitochondrial experts, as well as drug developers, to discuss how to accelerate the discovery of treatments for ARSACS.
For further information

Ataxia Telangiectasia Clinical Research Conference 2014
Date: 13-15 November, 2014
Venue: Nijmegen, The Netherlands

The bi-annual A-T Clinical Research Conference 2014 brings together leading figures from the fields of clinical science and translational research in Ataxia-Telangiectasia. The objective of the conference is to share knowledge and map progress in the fields of current research and help identify priorities for future research and opportunities for collaboration. The programme includes lectures, presentation of selected abstracts, a poster session, four workshops, a ‘best poster prize’ and a social programme.
For further information

Cilia 2014
Date: 18-21 November, 2014
Venue: Paris, France

Cilia 2014 will focus on (but not be limited to) recent advances in cilia structure and function, including trafficking, cilia and development, cilia in human genetic disease and cilia in infectious microorganisms. The event is organised by four European cilia networks: GDR CIL (France), the Ciliopathy Alliance, the Nordic Cilia & Centrosome Network (Scandinavia) and the EU-FP7 SYSCILIA programme.
For further information

European Williams Syndrome Conference
Date: 21-23 November, 2014
Venue: Budapest, Hungary

The European Federation of Williams Syndrome (FEWS) organises, with the Hungarian Williams Syndrome Association (HWSA), this conference to raise awareness, increase interaction between stakeholders and establish international cooperation.
The focus is to share good practice and knowledge on the disease between European Countries with a good expertise and other European Countries with lesser experience on the syndrome. The ultimate goal is to improve patient care and contribute to EU policy on rare diseases.
The conference targets healthcare professionals, caregivers, politicians, patient organisations, researchers and academics, national authorities, medical societies, health industry, media, etc., as well as professionals from countries with limited knowledge about the syndrome, in order to spread awareness.
For further information

22nd René Touraine Foundation for Dermatology Scientific Meeting
Date: 5 December, 2014
Venue: Paris, France

Every year, the Scientific Meetings go over any acquired knowledge on one skin cell. Mornings are reserved for fundamental approaches, while afternoons are devoted to approaches applied to physiopathology, pharmacology and therapeutic. These are multi-subject meetings. Each presentation starts with a general overview of the terminology used, and continues with the speaker’s own research.
For further information

6th International Meeting on Pulmonary Rare Diseases and Orphan Drugs
Date: 27-28 February, 2015
Venue: Milan, Italy

The International Meeting on Pulmonary Rare Diseases and Orphan Drugs is the only European event dedicated to different types of rare pulmonary diseases affecting both parenchymal and vascular structures. The meeting will be an opportunity to exchange and disseminate knowledge among experts in different areas of clinical and basic research in respiratory medicine, in efforts to provide new insights into science and clinical care, thus helping patients and supporting doctors.
For further information

2nd International GENCODYS Conference on Integrative Networks in Intellectual Disabilities
Date: 27-29 April, 2015
Venue: Crete, Greece

European funded research consortium GENCODYS exploits a multilevel approach to resolve the integrative networks in intellectual disabilities. The conference will bring together about 150 top researchers, medical doctors and patient representatives in the field of Cognitive Research and related activities.
Talks and submissions for talks have to be related to studies of cognitive dysfunction but can include other fields, namely genetics, cellular, molecular and physiological studies, genomics and epigenomics and bioinformatics.
For further information

Trisomy 21 Research Society (T21RS) International Conference
Date: 4-6 June, 2015
Venue: Paris, France

T21RS promotes research on Down syndrome and stimulates collaboration between researchers worldwide. The first edition of the T21RS International Conference will be held at the site of the Hôpital de la Pitié-Salpêtrière in Paris. More details will be announced in due course.
For further information

7th International Conference on Children’s Bone Health
Date: 27-30 June, 2015
Venue: Salzburg, Austria

The International Conference on Children’s Bone Health (ICCBH) meetings provide an international forum for the presentation and discussion of current basic and clinical science in the field of bone metabolism and bone mass in children, adolescents and young adults.
The call for abstracts opens in September 2014.
Abstract deadline: 6 February 2015.
For further information

2nd International Primary Immunodeficiencies Congress (IPIC)
Date: 5-6 November, 2015
Venue: Budapest, Hungary

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the Second International Primary Immunodeficiencies Congress (IPIC). This event will build on the successful outcomes of the first IPIC, attended by 400 participants. The congress will consist of a two-day programme and is open to all stakeholders with an interest in clinical management of primary immunodeficiencies (PIDs).
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


Commercial events

3rd annual World Biosimilar Congress
Date: 11-12 November, 2014
Venue: Geneva, Switzerland

The 3rd annual World Biosimilar Congress offers keynotes, case studies and roundtables covering topics relating to process, production, regulation and marketing strategies for biosimilars. Speakers and attendees include industry executives, middle managers, academics, key influencers and end-users.
For further information

The World Orphan Drug Congress Europe 2014
Date: 12-14 November, 2014
Venue: Brussels, Belgium

The World Orphan Drug Congress Europe offers partnering opportunities in the orphan and rare disease field. Key networking platforms include: Dedicated networking functions; Privately hosted meeting areas; Online partnering portal and access to free smartphone app; Personal networking managers to assist in meeting scheduling.
For further information


OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01)
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Divya Unni
Editors for Scientific Content: Catherine Pouzat, Sophie Höhn
Contact Us
Editorial Board: Ségolène Aymé, Paul Boom, Anna Bucsics, Kate Bushby, Barbara Cagniard, Lorenzo Dagna, Adam Heathfield, Lilian Lau, Yann Le Cam, Jordi Llinares-Garcia, Antoni Monserrat, Charlotte Rodwell, Gerhard Steffes, Till Voigtländer, Jaroslaw Waligora

Orphanet Partner Country Representatives: Kristine Hovhannesyan (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Riitta Salonen (Finland), Joerg Schmidtke (Germany), Helen Michelakakis (Greece), 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), Ugur Ozbek (Turkey), Dian Donnai (UK)
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