Editorial
Recommendation on Cross Border Genetic Testing of Rare Diseases in the European Union
On 13th November 2015, the Commission Expert Group on Rare Diseases adopted Recommendations on Cross-Border Genetic Testing of Rare Diseases in the European Union. The Recommendations are addressed to the Member States and the European Commission and focus specifically on the issues of cross-border testing. There is significant variation between EU Member States in terms of the number of genetic tests available in-country for RD – some countries test for fewer than 20 genes, whilst others test for over 2000. Even with the increasing use of Next Generation Sequencing, there will remain a need for countries to conduct some genetic tests for RD on a cross-border basis. Building upon previous expert discussions and workshops, research was conducted under the EUCERD Joint Action by partner Helena Kääriäinen, which explored the volume of cross-border genetic testing for RD and highlighted some of the key challenges involved in the process. Following an expert workshop in December 2014, draft Recommendations were elaborated, with the aim of generating meaningful impact in this area. They emphasise the need to:
• facilitate access to cross-border genetic testing, where appropriate
• collaborate across borders to assess the added-value of genetic testing
• share expertise and collaborate at the European level
• ensure reliable information on laboratories providing genetic testing for RD
Access the report
EC Expert Group
Report on the 6th Commission Expert Group Meeting
The Commission Expert Group on Rare Diseases met for the 6th time on the 12th and 13th of November 2015. Apart from successfully adopting the recommendation on cross-border genetic testing, developed with the support of the EUCERD Joint Action, a number of priorities on the rare diseases agenda were addressed. This included an update on the implementation of the Cross-Border Healthcare Directive of 2011, in particular in the relation to the creation of European Reference Networks in the field of rare diseases: participants were given an update on the recent discussions of the Board of Member States concerning the implementation of these measures, and of the second conference held in Lisbon on the 8-9 October to inform those interested of the timeline for the submission of proposals for ERNs and the procedure to be followed. The members also heard about the advancement of the tender underway to define the services to be rendered by these ERNs.
The participants also had the opportunity to discuss the recommendations elaborated by the EUCERD Joint Action concerning social care for rare disease patients, which will be further worked upon by a drafting group before final discussion at an upcoming meeting in 2016. In addition, the members of the group were given an update on the actions carried out to date in the scope of the new Joint Action on rare diseases RD-Action (www.rd-action.eu/), in particular a number of priorities for work to be undertaken in the coming year by the Expert Group with the support of RD-Action were outlined, which include the creation of a Task Force to examine the question of intereoperability in the context of European Reference Networks. This subject of work will tie in closely with the work to be undertaken by the Joint Research Centre's Platform for Rare Disease Registration, which will hold a number of workshops in the 2016 to examine subjects related to the interoperability of registries, amongst others. The JRC will also be constituting an Advisory Group composed of Expert Group on Rare Diseases members to help guide their actions in the future. The meeting also included a discussion on the adaptive pathways for medicines for rare disease patients, presenting the views from different stakeholders on this innovative approach. Finally, Members were informed of the latest activities concerning the implementation of rare disease national plans/strategies in EU Member States.
Spotlight on...
Now available: European Reference Centre conference report
The report on the 2nd European Reference Networks Conference is now available online. With more than 450 attendees, this highly successful and enlightening conference held in Lisbon on 8 & 9 October was well received by health professionals, researchers, patient organisations and policymakers who gathered for this lively event. The conference featured a full day of presentations and debate, followed by four parallel workshops on the second day, which was also streamed live online.
In anticipation for the first call for ERNs expected in early 2016, the conference not only built on the 2014 conference, but also offered practical guidance to individuals and organisations interested in achieving ERN status.
The first roundtable session explored the timetable and milestones for creating the ERNs as well the approval process including the key players were introduced. The attendees also heard from the health ministries in several Member States offering the much valued political endorsement for this task. Contributions from patient groups – their experiences and insights as well as the challenges observed by the coordinators of existing pilot networks funded under EU programmes was the highlight of the third session. The next session featured presentations on the potential for ERNs to devise and implement clinical guidelines and the fifth session highlighted the importance of interoperability between IT solutions was also highlighted. On the second day practical tips on applying for ERN status was disseminated through four workshops - each examining a different element of building an ERN proposal.
Overall the conference was an excellent opportunity for stakeholders to network, gain information and provide valuable feedback that will be of great value especially for rare disease patients.
Read the ERN conference report
RD-ACTION informal ’matchmaker’ for Rare Disease ERNs
The Call for the first European Reference Networks (ERNs) is anticipated in February 2016. The new Joint Action for Rare Diseases, RD-ACTION, continues the work of the EUCERD Joint Action to support the rare disease (RD) field in conceiving and implementing robust ERNs which will, in time, be able to address the specific needs of all those living and working with RD.
At this critical stage, whilst groups are defining the structure of ERNs in the various disease areas, many clinicians and researchers see value in a means of discovering other colleagues and consortia who might be interested in applying to set-up or join an ERN in the same disease field. Therefore, to facilitate discussions and collaboration between specialists, RD-Action’s Policy WP, led by Newcastle University, is launching an informal ERN ’matchmaking’ exercise.
The approach is based upon the model espoused by the 2015 Addendum of the EUCERD Recommendations on RD ERNs, as this represents the expert opinion of the Commission Expert Group on Rare Diseases. The dedicated webpage provides further details on the process (e.g. how the information will be shared and what respondents can expect to receive.)
This ’matchmaking’ venture will also enable the RD-Action team to generate a summary of the status quo regarding ERNs (e.g. the number of HealthCare providers interested in participating, the distribution of interested participants by Member States, the relative interest from one disease Grouping to another) which should help us move towards the Call with greater clarity and transparency. It is acknowledged that many consortia are already well-developed in terms of their plans to respond to the first ERN Call– this venture is expected to complement such processes, to provide an opportunity to find others whose work may be of interest and relevance to the application.
EU Policy News
EMA
The EMA releases guidance on conducting post-authorisation efficacy studies
The European Medicines Agency (EMA) has released guidance on methods to be used in the design and conduct of post authorisation efficacy studies. The EMA has released a draft scientific guideline that outlines how post-authorisation efficacy studies (PAES) should be designed by companies to support regulatory decision making in the European Union (EU). These studies are conducted within the authorised indication after a medicine has been granted a marketing authorisation, to collect data on aspects of its benefits that can only be or need to be explored once the medicine is marketed. The results of these studies should translate into better labelling and better use of medicines by patients and prescribers in clinical practice. In addition, a guidance that describes the regulatory aspects for the fulfilment of imposed PAES is also published.
For further information
National & International Policy Developments
Other International News
Inborn Errors of Metabolism in the United Arab Emirates
An article published in JIMD Report reports on the inborn errors of metabolism (IEM) detected by the national newborn screening in the United Arab Emirates between 2011 and 2014. The study reports 114 patients diagnosed during this period giving an incidence of 1 in 1,787 citizens. According to the authors Emirati citizens have diverse geo-ethnicities, which include ancestors from the Arabian Peninsula, Persia, Baluchistan, and East Africa whose tribal culture favors consanguineous marriages which has resulted in the relatively high prevalence of IEM. The authors report that biotinidase deficiency, phenylketonuria, 3-methylcrotonyl glycinuria, medium-chain acyl-CoA dehydrogenase deficiency, argininosuccinic aciduria, glutaric aciduria type 1, glutaric aciduria type 2, and methylmalonyl-CoA mutase deficiency account for 80% of the diagnosed disorders with the identification of many clinically significant which could be included in premarital screening. The authors believe that high prevalence of IEM in can be combatted by newborn and premarital screening.
Read the PubMed abstract
The Undiagnosed Diseases Network of the National Health Institute in the United States
A description of the Undiagnosed Disease Network (UDN)- an extension of the Undiagnosed Diseases Program (UDP) set up by the National Institutes of Health (NIH), is published in JAMA. UDP evaluates patients and families for whom medicine has failed to provide a diagnosis. Of the 6000 annual calls to the Genetic and Rare Diseases Information Center, 6% are from persons without a diagnosis, and 15% of patients with rare diseases spend more than 5 years searching for a diagnosis. Participants in the UDP are chosen based on objective signs and symptoms, the unique nature of the problem, and an estimate by the UDP of its ability to make a diagnosis. According to the article comprehensive clinical assessment represents only the beginning and the UDN acts an extension which allows the analysis and sharing of data which enhances the working of UDP. The UDN has an opening of an online patient application portal, called the UDN Gateway, through which patients and their physicians can register and apply.
The authors believe that since sharing enhances the identification of other patients with similar presentations, a powerful tool of the global information age, fostered by social networks that readily connect individuals with shared interests. This also augments the possibility of genetic discovery; if genetically unrelated individuals present with a similar set of signs and both have very rare genetic variants in the same gene, the probability that the gene causes the disease is increased.
Read the Open Access article
Undiagnosed Diseases Network International
A related article published in Molecular Genetics and Metabolism announced the launch the Undiagnosed Diseases Network International (UDNI) modeled in part after the NIH UDP. The article describes the consensus framework of principles of UDNI, best practices and governance. According to the authors the UDNI involves centers with internationally recognised expertise, a Patient Advisory group and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis.
Read the PubMed abstract
Medicare Benefits Scheme Review in Australia
The Australian Government is currently conducting the first review of the entire Medicare Benefits Scheme (MBS) since its inception 30 years back. The MBS is a key component of the Australian Medicare system. It lists Medicare subsidised services provided by health practitioners and private hospitals and sets out the ’Schedule fee’ for each service and the rate/s at which the benefit for that service is to be calculated. The purpose of this review is to ensure it reflects current best clinical practice and promotes the provision of health services that improve health outcomes. It is clinician led and is looking at opportunities for reform of the MBS over the short, medium and longer terms. As well as looking at specific MBS items, the Taskforce will also review the legislation and rules which underpin the MBS. (Full information see Department of Health website). They are calling for public comment through an online survey.
For further information
Guidance Documents and Recommendations
Aplastic anaemia: guidelines for the diagnosis and management
Br J Haematol. ; [Epub ahead of print] ; November 2015
Nodular lymphocyte predominant Hodgkin lymphoma: guidelines for the investigation and management
Br J Haematol. ; [Epub ahead of print] ; November 2015
Bioinformatics, Registries and Data Management
A call for registries independent of the industry for post-authorisation assessment of orphan drugs
The unsustainability of the high cost of orphan drugs along with lack of clarity on its effectiveness has been a concern of many rare disease stakeholders. The authors of a commentary in Lancet believe that the system of post-authorisation assessment for orphan drugs needs to be reformed to address these problems. They illustrate the pitfalls in the post-authorisation studies of agalsidase alfa that is recommended for the treatment of Fabry Disease to explain their case. To change the systems that are currently in place the authors propose the launch of collaborative registries that are independent from the pharmaceutical industry based on the features mentioned below, to promote appropriate use of orphan drugs and management of costs and to conduct adequate post-authorisation assessment of orphan drugs.
a. Disease-centred registries, instead of drug-centred registries
b. Registries supervised by relevant stakeholders, independent of corporate activity
c. Analysis of data by independent statisticians
d. Obligatory data entry for all doctors which include extended trial data and natural history data
e. launched early in the development process
f. key factors needed for cost-effectiveness studies
Read the Open Access article
Utilising the principle of proportionality in genomic data sharing
A comment in Nature Reviews Genetics emphasises the value of the principle of proportionate whilst sharing of genetic data. According to this principle the depth of data has be balanced with the breadth of sharing. According to the authors the depth and scale of genomic data have led to increasing concerns about the potential identifiabil¬ity of anonymised research participants and the harms that might result. However they also state that in the area of rare diseases, where finding a molecular diagnosis is key, an alternative approach that enables broad sharing of individual-level data with limits the depth of the data, is advantageous.
The authors exemplify the usage of a proportionate approach with the Deciphering Developmental Disorders (DDD) Study and as a result have developed a two-tier approach to data sharing. First, anonymised individual-level genomic data with detailed phenotypic descriptions are shared securely with authorised researchers, to enable further research into developmental disorders. Second, a small number of individual variants are shared openly with phenotypic descriptions via the DECIPHER database. The authors suggest that a principle of proportionality should be applied to genomic data, which considers the purpose and risks of data sharing and flexes the depth of data and breadth of sharing to optimize this balance.
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DIDA: a novel database for digenic diseases
An article published in Nucleic Acid Research has described DIDA (DIgenic diseases DAtabase) a novel database that provides for the first time detailed information on genes and associated genetic variants involved in digenic diseases, the simplest form of oligogenic inheritance. The database currently includes 213 digenic combinations involved in 44 different digenic diseases which are composed of 364 distinct variants distributed over 136 distinct genes. According to the authors "next to providing a unique resource for the development of new analysis methods, DIDA gives clinical and molecular geneticists a tool to find the most comprehensive information on the digenic nature of their diseases of interest."
Read the Open Access article
The Exomiser: a tool that goes one step further for variant identification
Whole-exome sequencing (WES) has been enormously successful in the identification of novel Mendelian disease–associated genes. An individual exome typi¬cally harbors over 30,000 variants compared with the genomic ref¬erence sequence, and up to roughly 10,000 of them can be filtered but additional methods are needed to predict the variants that may have serious functional con-sequences. The authors of an article published in Nature Protocol describe a protocol for the Exomiser suite that uses clinical data, model organism phenotype data, as well as random-walk analysis of protein interactome data for novel disease-gene discovery or for differential diagnostics of Mendelian disease.
The Exomiser has been used in a number of projects for disease-gene discovery and diagnostics such as the US National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) as well as PhenomeCentral portal. The inputs to Exomiser are the called variants resulting from exome sequencing are stored using a variant call format (VCF) file. The Exomiser analyzes these VCF files to first filter the variants and then to prioritize the remaining candidates. The article provides a detailed explanation of the data sources utilised by Exomiser, which includes human and animal data sources integrated into algorithm, to prioritise exome sequences
According to the authors, Exomiser requires ~3 GB of RAM and roughly 15–90 s of computing time on a standard desktop computer to analyse a variant call format (VCF) file and can be safely used within hospital firewalls. Exomiser is freely available for academic use from http://www.sanger.ac.uk/science/tools/exomiser.
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Ethical, Legal & Social Issues
Mutlidisciplinary, patient centred facilities a model of care for ultra-rare diseases
Authors of an article published in Orphanet Journal of Rare Diseases analysed the national service for an ultra-rare disease, Alstrom syndrome, and compared the outcome and cost of the service to the standard care. Patients with rare and ultra-rare diseases make heavy demands on the resources of both health and social services, but these resources are often used inefficiently due to delays in diagnosis, poor and fragmented care. The authors undertook a cross-sectional study of the UK Alstrom syndrome patients and their carers by systematically evaluating the national service and compared the quality and cost of care with patients’ previous standard of care. The authors reported that the patients displayed high level of satisfaction in their care describing the highly specialised care facilities as well organised, personalised, holistic, and attentive with high treatment compliance and attendance. The authors valued the clinics at just under £700/patient/annum with a significant reduction in frequency of clinic visits. Additionally, the patients also displayed an enhanced quality of life thus showing that multidisciplinary patient centred facilities are cost-effective in every aspect.
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New Syndromes
Autism, intellectual disability, basal ganglia dysfunction and epilepsy associated with recessive DEAF1 mutation in a consanguineous family
The authors studied a consanguineous Omani family with three affected children presenting with intellectual disability and autism. Two of three affected siblings also suffered from severe epilepsy. All patients exhibited dyskinesia of the limbs. An autosomal recessive mutation in DEAF1 was found in all affected individuals.
Consult the Pubmed abstract
J Med Genet. ; 52(9):607-11 ; September 2015
Autosomal recessive neurodevelopmental syndrome with learning disability, spasticity and abnormal gait caused by HACE1 deficiency
The authors aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait. In both families, biallelic loss-of-function mutations in HACE1 were identified.
Consult the Pubmed abstract
J Med Genet. ; 52(12):797-803 ; December 2015
A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by a novel mutation in PEX5 in four patients from two independent families
The authors reported a novel type of rhizomelic chondrodysplasia punctata (RCDP5) caused by a novel mutation in PEX5 in four patients from two independent families. They all carried the same novel homozygous frame shift mutation in PEX5.
Consult the Pubmed abstract
Hum Mol Genet. ; 24(20):5845-54 ; October 2015
New syndrome of hypotonia and psychomotor developmental delay due to a mutation in CCDC174
Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. A Bedouin consanguineous kindred was also affected with a similar recessive phenotype. Whole exome sequencing identified a mutation in the CCDC174 gene in all affected individuals.
Consult the Pubmed abstract
Hum Mol Genet. ; 24(22):6485-91 ; November 2015
Novel syndrome of primordial dwarfism associated with a mutation in POC1A in two patients
The authors described a family with two affected patients presenting with primordial dwarfism, dolichocephaly, facial dysmorphism, brachydactyly, nail hypoplasia and pes planus. Using whole-exome sequencing, they identified a novel missense mutation in the POC1A gene.
Consult the Pubmed abstract
Hum Mol Genet. ; 24(19):5378-87 ; October 2015
Tubulinopathy-related dysgyria linked to mutations in TUBA1A, TUBB2B and TUBB3
The authors identified patients with a highly characteristic cerebellar dysplasia but without lissencephaly, pachygyria and polymicrogyria typically associated with tubulin mutations. In seven patients, targeted sequencing revealed mutations in three different tubulin genes (TUBA1A, TUBB2B and TUBB3), occurring de novo or inherited from a mosaic parent. Brain imaging revealed only an irregular pattern of gyri and sulci, for which the authors proposed the term ’tubulinopathy-related dysgyria’.
Consult the Pubmed abstract
Hum Mol Genet. ; 24(18):5313-25 ; September 2015
A novel syndrome of generalised lipodystrophy associated with pilocytic astrocytoma
The authors reported three males who presented with poor weight gain and generalised loss of subcutaneous fat at birth to 3 years of age consistent with generalised lipodystrophy, with subsequent development of pilocytic astrocytoma. Two of them had hypothalamic tumours, and one had a multicentric tumour with a large right parietal mass. The onset of lipodystrophy occurred 2.5 to 7.3 years before the diagnosis of brain tumour, and all of the patients gained body fat or weight after surgical removal and/or chemotherapy. One patient had hepatosplenomegaly and impaired glucose tolerance, and another patient had severe hyperglycemia and hypertriglyceridemia during the course of the disease. Two patients presented with central precocious puberty and advanced bone age at the chronological age of 6 years.
Consult the Pubmed abstract
J Clin Endocrinol Metab. ; 100(10):3603-6 ; October 2015
Undifferentiated thoracic malignancies due to SMARCA4 inactivation
The authors identified 19 cases of compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months linked to the inactivation of SMARCA4. The authors named these malignancies 'SMARCA4-deficient thoracic sarcomas'.
Consult the Pubmed abstract
Nat Genet. ; 47(10):1200-5 ; October 2015
New Genes
SHORT syndrome due to a new homozygous IGF1R variant
Hum Mutat. ; 36(11):1043-7 ; November 2015
Autosomal recessive non-syndromic intellectual disability associated with mutations in HNMT in two unrelated consanguineous families
Hum Mol Genet. ; 24(20):5697-710 ; October 2015
Joubert syndrome with Jeune asphyxiating thoracic dystrophy caused by biallelic deleterious mutations in KIAA0586 in six children
J Med Genet. ; 52(12):830-9 ; December 2015
Autosomal dominant lentiginous phenotype linked to a SASH1 variant
J Invest Dermatol. ; 135(12):3192-4 ; December 2015
Autosomal recessive keratosis pilaris atrophicans caused by a homozygous missense variant in LRP1 in a large consanguineous Pakistani pedigree
J Med Genet. ; 52(9):599-606 ; September 2015
Multiple symmetric lipomatosis due to homozygous mutations in MFN2
Hum Mol Genet. ; 24(18):5109-14 ; September 2015
Perisylvian polymicrogyria associated with constitutional and mosaic mutations in the PIK3R2 gene
Lancet Neurol. ; 14(12):1182-95 ; December 2015
Myoclonus-dystonia syndrome is not linked to CACNA1B variant
Hum Mol Genet. ; 24(18):5326-9 ; September 2015
Mycosis fungoides and Sézary syndrome due to TNFRSF1B mutations and to CTLA4-CD28 fusion
Nat Genet. ; 47(9):1056-60 ; September 2015
Adult T-cell leukaemia/lymphoma: integrated molecular analysis
Nat Genet. ; 47(11):1304-15 ; November 2015
Juvenile myelomonocytic leukaemia: SETBP1 and JAK3 as modifier genes
Nat Genet. ; 47(11):1326-33 ; November 2014
Cutaneous T cell lymphoma: 17 genes involved in the pathogenesis
Nat Genet. ; 47(9):1011-9 ; September 2015
Brugada syndrome: DSG2 and MYH7 as candidate genes
Hum Mol Genet. ; 24(20):5828-35 ; October 2015
Young-onset Parkinson disease: PTEN, VAPB and ASNA1 as candidate genes
Hum Mol Genet. ; 24(23):6711-20 ; December 2015
Exstrophy-epispadias complex: WNT3 as a candidate gene
Hum Mol Genet. ; 24(18):5069-78 ; September 2015
A high copy number of FAS gene might confer risk for Behçet and Vogt-Koyanagi-Harada diseases
Hum Mutat. ; 36(11):1064-9 ; November 2015
Non-obstructive azoospermia: HIST1H1E, FKBPL and MSH5 as susceptibility genes
Hum Mol Genet. ; 24(19):5628-36 ; October 2015
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies
Nat Genet. ; 47(10):1131-40 ; October 2015
Research in Action
Clinical Research
Cushing syndrome: effectiveness of metyrapone treatment
J Clin Endocrinol Metab. ; 100(11):4146-54 ; November 2015
Fabry disease: agalsidase-beta treatment started at a younger age preserves kidney function
J Med Genet. ; 52(12):860-6 ; December 2015
X-linked hypophosphatemia: conventional therapy in adults may not promote or prevent enthesopathy but may be associated with a lower risk of dental disease
J Clin Endocrinol Metab. ; 100(10):3625-32 ; October 2015
Amyotrophic lateral sclerosis: diaphragm pacing in patients with respiratory insufficiency is associated with decreased survival
Lancet Neurol. ; 14(9):883-92 ; September 2015
Hereditary cerebellar ataxia: riluzole could be a treatment
Lancet Neurol. ; 14(10):985-91 ; October 2015
Chronic immune thrombocytopenic purpura: eltrombopag is a suitable therapeutic option for children
Lancet ; 386(10004):1649-58 ; October 2015
Hypernychthemeral syndrome: daily tasimelteon administration improves sleep in totally blind patients
Lancet ; 386(10005):1754-64 ; October 2015
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A: safety and efficacy of the substitution treatment with cyclic pyranopterin monophosphate
Lancet ; pii: S0140-6736(15)00124-5 ; September 2015
Langerhans cell histiocytosis: a 20 year experience confirms efficacy of polichemotherapy regimen MACOP-B
BMC Cancer. ; 15:879 ; November 2015
Bone disorders: acute adverse events related to zoledronic acid infusion are common in young patients
J Clin Endocrinol Metab. ; 100(11):4163-71 ; November 2015
Ebola haemorrhagic fever: rVSV-ZEBOV vaccine might be highly efficacious and safe
Lancet ; 386(9996):857-66 ; August 2015
Malaria: ferroquine and artesunate treatment is associated with high cure rates and is safe
Lancet Infect Dis. ; 15(12):1409-19 ; December 2015
Doxorubicin does not need to be included in the treatment in some cases of stage II-III intermediate risk nephroblastoma
Lancet ; 386(9999):1156-64 ; September 2015
Differentiated thyroid carcinoma: long-term outcomes following thyroidectomy, postoperative radioiodine and thyroid hormone suppression therapy
J Clin Endocrinol Metab. ; 100(9):3270-9 ; September 2015
Philadelphia chromosome-positive acute lymphoblastic leukaemia: the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions
Lancet Oncol. ; 16(15):1547-55 ; November 2015
Acute promyelocytic leukaemia: mitigated results with all-trans retinoic acid and arsenic trioxide treatment
Lancet Oncol. ; 16(13):1295-305 ; October 2015
Mandibular hypoplasia-deafness-progeroid syndrome: phenotype extension
Hum Mutat. ; 36(11):1070-9 ; November 2015
Therapeutic Approaches
Down syndrome: therapy using the DYRK1A inhibitor epigallocatechin-3-gallate improves mice skeletal phenotype
Hum Mol Genet. ; 24(20):5687-96 ; October 2015
Stargardt disease: improved dual adeno-associated viral vectors with reduced expression of truncated proteins are safe and effective in the retina of a mouse model
Hum Mol Genet. ; 24(23):6811-25 ; December 2015
Mitochondrial myopathy: cyclosporine A treatment is an efficient therapeutic strategy to slow the development of the disease in a mouse model
Hum Mol Genet. ; 24(23):6580-7 ; December 2015
Diastrophic dwarfism: N-acetylcysteine treatment ameliorates the skeletal phenotype of a mouse model
Hum Mol Genet. ; 24(19):5570-80 ; October 2015
Recessive dystrophic epidermolysis bullosa: intravenously administered recombinant human type VII collagen reverses the disease phenotype in mice
J Invest Dermatol. ; 135(12):3060-7 ; December 2015
Duchenne muscular dystrophy: systemic adeno-associated virus gene transfer is safe and efficient in young adult dogs
Hum Mol Genet. ; 24(20):5880-90 ; October 2015
Retinitis pigmentosa: gene therapy halts degeneration and rescues function for at least one year at early, mid or late disease stages in mice
J Clin Invest. ; 125(9):3704-13 ; September 2015
Developmental epilepsies: review on early rescue of interneuron disease trajectory in rodent models
Curr Opin Neurobiol. ; 36:82-88 ; October 2015
Laron syndrome: generation of a miniature pig disease model
Sci Rep. ; 5:15603 ; October 2015
Spinocerebellar ataxia with axonal neuropathy type 2: new induced pluripotent stem cell model to study neurodegeneration
Hum Mol Genet. ; 24(20):5759-74 ; October 2015
Glycogen storage disease due to glycogen branching enzyme deficiency: a novel mouse model
Hum Mol Genet. ; 24(23):6801-10 ; December 2015
Diagnostic Approaches
Cushing syndrome: measuring urinary free cortisol achieves the best accuracy in diagnosis among patients presenting with suspected hypercortisolism
J Clin Endocrinol Metab. ; 100(10):3856-61 ; October 2015
Juvenile idiopathic arthritis: S100 proteins as specific diagnostic biomarkers in children with fever
Pediatr Res. ; 78(5):554-9 ; November 2015
Ebola haemorrhagic fever: ReEBOV rapid diagnostic test has 100% sensitivity and 92% specificity in both point-of-care and reference laboratory testing
Lancet ; 386(9996):867-74 ; August 2015
Kawasaki disease: development of an eight-biomarker panel to improve the recognition of the disease
Pediatr Res. ; 78(5):547-53 ; November 2015
Patient Management and Therapy
Huntington disease: treatments targeted to peripheral organs can improve the quality of life
Lancet Neurol. ; 14(11):1135-42 ; November 2015<br/>Lancet Neurol. ; 14(11):1135-42 ; November 2015
Mucopolysaccharidosis type 6: review on diagnostic and treatment strategies
Appl Clin Genet. ; 8:245-255 ; October 2015
Cushing syndrome: a review
Lancet ; 386(9996):913-27 ; August 2015
Primary biliary cirrhosis: a review
Lancet ; 386(10003):1565-75 ; October 2015
Laminopathy-associated premature aging: review on skin diseases
J Invest Dermatol. ; 135(11):2577-83 ; November 2015
Middle East respiratory syndrome: two reviews
Lancet ; 386(9997):995-1007 ; September 2015<br/><br/>JAMA ; 314(8):771-2 ; August 2015
Myasthenia gravis: review on therapeutic strategies
Lancet Neurol. ; 14(10):1023-36 ; October 2015
Left ventricular noncompaction: a review
Lancet ; 386(9995):813-25 ; August 2015
American trypanosomiasis: a review
Lancet Infect Dis. ; 15(11):1347-56 ; November 2015
Sparganosis: a review
Lancet Infect Dis. ; 15(10):1226-35 ; October 2015
Pheochromocytoma and paraganglioma: review on genetics, diagnosis and treatment
Hematol Oncol Clin North Am. ; 30(1):135-50 ; February 2016
One new and eight 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:
Baraitser-Winter syndrome
Eight updated GeneReviews have been published for:
Multiple epiphyseal dysplasia, autosomal dominant
Ocular albinism, X-linked
Retinoblastoma
Sotos syndrome
Vascular Ehlers-Danlos syndrome
1q21.1 recurrent microdeletion
Optic atrophy type 1
Spinocerebellar ataxia type 2
Orphan Drugs
In Australia: Expert Reference Group for eculizumab and application process for patients and clinicians
The Australian Government has invested $63 million to cover eculizumab (Soliris ), the most expensive medicine in the world at a cost of $500,000 per patient per year, on the Pharmaceutical Benefits Scheme (PBS), for the treatment of atypical Haemolytic Uraemia Syndrome. According to the Australian government, it is important that they listens to expert advice when listing (subsidising) a medicine like eculizumab that has a high toxicity, so that patients are not unnecessarily exposed to long term side effects.
Therefore, in order to reinitiate treatment beyond the initial 12 months an application will have to be placed to an Expert Reference Group who will review applications to ensure there is an additional level of clinical support to ensure the correct decisions are made regarding an individual patient’s circumstances for applications seeking continuation and reinitiation of treatment beyond 1 December 2015.
For further information
Narcolepsy treatment recommended for approval by the EMA
The European Medicines Agency (EMA) has recommended granting a marketing authorisation for Wakix (pitolisant) for the treatment of narcolepsy with or without cataplexy (sudden severe muscle weakness or loss of muscle control). Wakix was designated as an orphan medicinal product on 10 July 2007.
Narcolepsy is a rare, long-term sleep disorder which affects the brain’s ability to regulate the normal sleep-wake cycle which leads to excessive daytime sleepiness including the sudden urge to sleep, and disturbed night-time sleep. These symptoms can be very severe and some patients may experience sudden episodes of a related condition, cataplexy, potentially causing dangerous falls and increasing the risks of accidents, including car accidents. Wakix a first-in-class medicine that acts on histamine H3 receptors in the brain will add to the available treatment options for narcolepsy. It increases histamine release in the brain, thereby enhancing wakefulness and alertness. Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
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FDA approves Ninlaro, new oral medication to treat multiple myeloma
U.S. Food and Drug Administration granted approval for Ninlaro (ixazomib) in combination with two other therapies to treat people with multiple myeloma who have received at least one prior therapy. Ninlaro is a a proteasome inhibitor and works by blocking enzymes from multiple myeloma cells, hindering their ability to grow and survive. Ninlaro is the first oral proteasome inhibitor and is approved in combination with another FDA approved treatment for multiple myeloma called Revlimid (lenalidomide) and dexamethasone (a type of corticosteroid).
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FDA approves Strensiq for hypophosphatasia
U.S. Food and Drug Administration approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile onset hypophosphatasia (HPP). HPP is a rare, genetic, progressive, metabolic disease characterised by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities as well as devastating effects on multiple systems of the body. It leads to severe disability and life threatening complications. Strensiq works by replacing the enzyme in tissue non-specific alkaline phosphatase responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.
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FDA approves Empliciti to treat multiple myeloma
The U.S. Food and Drug Administration (FDA) has approved marketing authorisation for Empliciti (elotuzumab), in combination with two other therapies - Revlimid (lenalidomide) and dexamethasone (a type of corticosteroid), to treat people with multiple myeloma who have received one to three prior medications. Multiple myeloma is a form of blood cancer that occurs in infection fighting plasma cells (a type of white blood cell) found in the bone marrow. Empliciti activates the body’s immune system to attack and kill multiple myeloma cells. The FDA granted breakthrough therapy, priority review and orphan drug designations to Empliciti which allowed for its expedited entry into the market.
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Regulatory News
Drug Development Under the Animal Rule Guidance for Industry by the FDA
The U.S. Food and Drug Administration (FDA) has provided information and recommendations to the industry on drug and biological product development when human efficacy studies are not ethical or feasible. According the Animal Rule of the FDA, drugs for serious or life-threatening conditions developed when human efficacy studies are not ethical or feasible, may be granted marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans. The FDA has published further guidance to sponsors who intend to submit applications for marketing authorisation based on the Animal Rule. This document provides guidance on elements related to etiologic or challenge agent-induced disease or condition as well as selecting an effective dose in humans. The Animal Rule states that the FDA will rely on evidence from animal studies to provide substantial evidence of effectiveness only when all of the following four criteria delineated in the document are met. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm399217.pdf
Positive opinions recommending orphan designation at the COMP meeting
The European Medicines Agency Committee for Orphan Medicinal Products (COMP) adopted seventeen positive opinions issued at the November 2015 COMP meeting for:
- prevention of graft-versus-host disease
- treatment of acute myeloid leukaemia
- treatment of neurotrophic keratitis
- treatment of gastro-enteropancreatic neuroendocrine tumours
- treatment of beta-thalassaemia intermedia and major
- treatment of primary sclerosing cholangitis
- treatment of Charcot-Marie-Tooth disease
- for treatment of pseudohypoaldosteronism type 1B
- treatment of haemophilia B
- treatment of partial deep dermal and full thickness burns
- treatment of neonatal diabetes
- treatment of myelofibrosis
- treatment of osteosarcoma
- treatment of malignant mesothelioma
- treatment of Merkel cell carcinoma
- treatment of acute myeloid leukaemia
- treatment of pseudohypoaldosteronism type 1B
The European Medicines Agency Committee for Orphan Medicinal Products (COMP) adopted seventeen positive opinions issued at the December 2015 COMP meeting for:
- treatment of pancreatic cancer
- treatment of hyperargininaemia
- treatment of arginosuccinic aciduria
- treatment of pancreatic cancer
- treatment of acute radiation syndrome
- treatment of anal cancer
- treatment of congenital alpha-1 antitrypsin deficiency
- treatment of soft tissue sarcoma
Consult the European Register of Designated Orphan Medicinal Products
Consult the Orphanet list of orphan drugs authorised for marketing in Europe
Political and Scientific News
snSMART trial design for use in rare disease research
An article published in Contemporary Clinical Trials has described a small n sequential multiple assignment randomised trial (snSMART) design for Phase 2 clinical trials. According to the authors, this trial design is especially beneficial to test treatments for a rare disease due to the limited number of patients available with each disorder. The authors illustrates the design, sample size estimation and operating characteristics of an snSMART trial design. They demonstrate that using this design in small sample sizes increases the statistical power for these trials compared to traditional trial designs. The authors believe that the snSMART is an effective and practical design strategy in the rare disease setting and hope that other researchers will find the design useful. The authors specify that the first trial using this design will be for a trial in patients sharing a rare form of vasculitis.
Read the PubMed abstract
Grants
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
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
Call for Applications for Research Grants on Angelman Syndrome
The Angelman Syndrome Alliance (ASA) supports research on Angelman syndrome with up to 300,000 Euros to be awarded at the next International Angelman Syndrome Scientific Conference. Researchers of any country are invited to apply for research grants covering preclinical (basic) research as well as translational research such as mechanism based controlled trials.
Applications for behavioural therapies are not eligible at this point.
Proposals addressing new ideas/concepts about the pathogenesis of Angelman Syndrome are particularly invited. (Deadline 24th of January 2016).
For further information
Congenital Central Hypoventilation Syndrome Family Network
The Congenital Central Hypoventilation Syndrome (CCHS) pilot grant award represents a collaborative effort between the CCHS Family Network and the CCHS Foundation to encourage and support basic, clinical, translational, or epidemiological research to impact the lives of patients with CCHS.
The grant provides up to $30,000 over 1 year for expenses related to the research project, which may include research laboratory supplies, equipment, publication charges for manuscripts that pertain directly to the funded project, and other research expenses. Application Deadline: 29 February, 2016
Courses & Educational Initiatives
Training Course on Diagnosis and Management of Very Rare Red Cell and Iron Disorders
Date: 29-30 January, 2016
Venue: Lisbon, Portugal
Detailed course on diagnosis and management of these disorders for researchers, doctors and patients.
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: 10-12 February, 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
Courses offered by Recordati Rare Diseases Foundation
The Recordati Rare Diseases Foundation is offering five courses planned for next year. For further information, please contact Cecilia Kellquist, Coordinator and member of the board, ckellquist@rrdfoundation.org/www.rrdfoundation.org.
Homocystinurias and defects of folate and methylation metabolism: practical approaches to diagnosis and treatment Date: 29 February – 2 March, 2016
Venue: Prague, Czech Republic
2nd Asia Pacific course: paediatric neurometabolic and movement Disorders Date: 10- 12 June, 2016
Venue: Taipei, Taiwan
Metabolic myopathies course Date: 3-5 November, 2016
Venue: Paris, France
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.
Genomics of Rare Diseases: Beyond the Exome
Date: 13-15 April, 2016
Venue: Cambridge, United Kingdom
Genomics of Rare Disease: Beyond the Exome will present an exciting blend of genomic science and clinical medicine. This conference provides an excellent forum for clinicians and scientists interested in human genomic variation and the mechanisms by which it exerts its phenotypic effects.
For further information
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
MEET Symposium 2016
Date: 29-30 January, 2016
Venue: Nijmegen, The Netherlands
The Mitochondrial European Educational Training (MEET) Network presents: From bench to bedside, and back: Patients MEET Researchers.
For further information
Linking Life Science Data: Design to Implementation, and Beyond
Date: 18-19 February, 2016
Venue: Vienna, Austria
Open PHACTS will be hosting a two day conference which will include a variety of expert speakers and open discussions on linking data in the life sciences domain.
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
FEPS 2016
Date: 13-14 July, 2016
Venue: Bonn, Germany
The symposium will be a privileged moment to demonstrate through various examples and discuss the pivotal role of Physiological sciences in the discoveries related to rare inherited diseases.
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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.
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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
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
Media, Press & Publications
Orphan: The Quest to Save Children with Rare Genetic Disorders
In a book entitled Orphan, Phillip Reilly paints a picture of several rare diseases and the quest to find treatments for them. This book described the advances for some of the rare diseases, the heroes (parents, scientists, clinicians, companies) behind these advances, and the work left to be done. The author brings a broad and unique perspective on these disorders to his book. He paints a vivid picture of families affected with rare diseases such as phenylketonuria (PKU), dystrophic epidermolysis bullosa and X-linked adrenoleukodystrophy. He narrates the heroic work of physicians and scientists who focus on a rare disorder and make it their career to seek a treatment. The book acknowledges the societal, ethical, and financial considerations in this era of huge progress in rare disease research and treatment.
