Edition of 15 March 2014

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Strategy for Rare Diseases announced in England and Belgium releases their National Rare Disease Plan

NHS England released details of implementation plans for the first UK strategy for rare diseases, which was published by the Department of Health in 2013. In a Statement of Intent, NHS England sets out how it will deliver commitments from the strategy and develop services for rare diseases within the new framework for specialised services.

The UK Strategy for Rare Diseases contained a total of 51 commitments which all four countries have agreed to achieve by 2020. This is the first strategy of its kind, aiming to help build an understanding of rare diseases and boost research in this important area of healthcare.

Key elements of the strategy include:
• Personal care plans for patients, bringing together health and care services, with more support for patients and their families;
• Support for specialist clinical centres offering better care and support;
• Better education and training for health professionals to help ensure earlier diagnosis and access to treatment;
• Promotion of the UK as a world leader in research and development in this field.

The statement confirms increased representation of patients on the Clinical Reference Groups for specialised services, as well as the Rare Disease Advisory Group, where their views will be accounted to “improve and build upon patient involvement in rare disease service provision”. The statement also affirms the commitment of NHS England to providing education and training for health professionals so that they are well equipped to provide faster and accurate diagnosis as well as access to specialised services to patients. This includes “piloting and evaluation of ’expert systems’ to support recognition and diagnosis of rare diseases, such as a computerised prompt service to help GPs to help GPs recognise potential rare disease symptoms”

Additionally, Public Health England (PHE), who are building a national rare disease register with NHS England, have emphasised “the success of the recently expanded NHS Newborn Blood Spot Screening programme in diagnosing the rare metabolic disorder MCADD; potential expansion of the programme to include more rare disorders is being piloted”.

England, Scotland, Wales and Northern Ireland released their plans for implementation of the UK rare diseases strategy by 28 February 2014 and held receptions in partnership with Rare Disease UK. A draft form of the Welsh Implementation Plan for Rare Diseases is currently open for consultation.
Read the Rare Disease Statement of Intent

Belgium, especially Orphanet Belgium, has been actively engaged in creating a Rare Disease Plan for Belgian patients. The plan was made public by the Belgian Minister of Health on the 6th of February 2014. The Belgian Plan for Rare Diseases consists of 20 actions, grouped into four domains, forming a comprehensive framework for managing care plan for patients affected by a rare disease, which include:

- Improved access to diagnostics and information to the patient
- Optimisation of care
- Knowledge and information
- Governance and Sustainability Plan

These actions were developed and selected based on their ability to be implemented as well as maintain a concrete impact on patient care in the field. For the implementation purposes, a total budget of € 15 million is allocated to each action. The plan is patient centric with direct implications for the diagnosis and care for the patient. The plan also includes collection as well as dissemination of knowledge. Since a high amount of quality research ( basic, translational, clinical, sociological ... ) is already being conducted within Belgium and there is a pause to see if international data can be joined together for a common framework, the current plan has no concrete actions recognised for research. Finally, this plan is not perceived as the end for advancing help for rare disease patients. To highlight this, a domain within the plan also outlines the creation of a dedicated team for continuous evaluation and monitoring of the implementation of the various actions. In addition, a separate working group within the Chronic observatory disease has also been established to monitor continuously 'unmet medical needs '
Read the Belgian plan in Dutch
Read the Belgian plan in French

Stephen Groft leaves a legacy of hard work and persistence promoting the cause of rare disease patients

Stephen Groft at the IRDiRC conference in Dublin, Ireland

Stephen C. Groft, Pharm.D., has been a strong voice for rare disease patients for more than 3 decades. He has now retired from his position at NIH after reinvogarating hope for rare disease patients and their families in US as well as providing them a collective voice. Throughout the 1980s, he has served in a variety of leadership roles to help advance the national research and drug development agendas for rare diseases, beginning with his support of the Orphan Drug Act (ODA) in 1983.

In 1995, Stephen Groft realised that scientists studying rare diseases often do so in isolation and unaware of each other’s work. Recognising the need for these researchers to collaborate and share knowledge, Groft and other ORDR staff initiated a scientific conferences program with the 27 Institutes and Centers (ICs) at NIH. Since then, more than 1,200 ORDR-supported research conferences and workshops have taken place. In early 2000, he contributed to research protocols to NIH’s ClinicalTrials.gov as well as collaborated with the National Human Genome Research Institute (NHGRI) to establish the Genetic and Rare Diseases Information Center. In 2003 he led ORDR’s efforts in establishing the Rare Diseases Clinical Research Network (RDCRN), which enabling collaborative, trans-NIH clinical research on causes, prevention, outcomes and treatments of rare diseases. By 2008, Stephen Groft, along with NHGRI, the NIH Clinical Center and other NIH ICs, helped create the trans-NIH, multidisciplinary Undiagnosed Diseases Program. He also led ORDR in joining the International Rare Diseases Research Consortium to encourage international collaboration in rare diseases research in 2012.

Stephen Groft has served as an important supporter of the scientific community working with rare disease patient advocates for over 3 decades. His work is a testament to the amount that can be achieved through sheer hard work and persistence, giving patient advocates the encouragement needed to be engaged in advocacy as well as the scientific process.

Stephen Groft has recently authored an editorial in the Orphanet Journal of Rare Diseases, which was published on the occasion of the 7th Rare Disease Day Celebration. The article titled "A past with uncertainty, a future with hope - rare disease day 2014 from a USA perspective”, reflected on the worldwide research accomplishments, orphan product approvals, and the commitments by the rare diseases community. In the editorial, Stephen Groft affirms “that the global rare diseases community remains strong and responsive to the voices and needs of patients, families, and clinicians awaiting diagnosis and treatment for their disease”.

Other European news

Editorial addressing the achievements of EUCERD and testimonials of past members

An Editorial by Ségolène Aymé and Charlotte Rodwell published in the “Orphanet Journal of Rare Diseases” provides information to the wider community about the activities by the EUCERD and European Commission that have strengthened liaisons at both European and international levels in the field of rare diseases. Following in the footsteps of EUCERD, the European Commission Expert Group on Rare Diseases assures to be a substantial success and for the rare disease community.
Read the Open Access article

At the end of its mandate members of the former EUCERD were proud and enthusiastic about the achievements of the committee and its legacy. In particular they appreciated the multi-stakeholder approach and the impetus this had given to the political process in the field of rare diseases. Below are some of the testimonials from past members of EUCERD

Ségolène Aymé, who chaired the committee during these years, said that she is “proud of what the committee was able to produce despite the wide range of cultural background of its members. What unified people were their consciousness of their responsibility in improving the national healthcare services through exchange of experience and agreement on standards of care.” “We set up a real community of people understanding better the point of view of the other stakeholders. We started to build a Europe for rare disease patients” she said.

Wills Hughes Wilson, an Industry representative, highlighted that the EUCERD was “a truly multi-stakeholder group, with representatives from across Europe, and from all different sectors has been highly constructive and highly productive”. She also underlined the unique opportunity provided by this bringing together of opinion in an area of real European added-value: “There are few areas where the added value of "Europe" can be so well-demonstrated and delivered on, as in the field of rare diseases. The inclusive nature of the EUCERD has meant that we have been able to build robust positions and recommendations that take into account all points of view and the contributions of all of the actors in this sector.” Summing up the experience shared by many of the Members, she stated that “it has been 3 years of hard work, collaboration, friendship and fun - proof that bringing people together with different expertise but a shared cause can truly deliver great results that will make a real difference for rare disease patients across the Union.”

Olaf Hiort, an expert representative, also praised the “enthusiasm” and “exceptional variety” of the members of the EUCERD which proved to be “a very valuable committee to bring together various aspects of structuring care for people with rare diseases”. He stressed the effective leadership of the Committee by Ségolène Aymé as one of the factors behind the “very constructive outcomes” of the work to date. Indeed, the Member State representatives from Germany took the opportunity to praise “the great support and excellent efficiency of the whole team of the scientific secretariat” in rendering the achievements of the EUCERD possible over the past few years.

Yann Le Cam, Vice-Chair of the EUCERD and Patient Representative, summing up the legacy of the Committee stated that “the EUCERD’s Recommendations on Quality Criteria for Centres of Expertise on Rare Diseases, on European Reference Networks and on Registries for Rare Diseases as well as on the Clinical Added Value for Orphan Medicinal Products have set the foundations to contribute to innovative, efficient and sustainable health systems so to address the shortages of human and financial resources while improving patients’ health outcomes.” Indeed, with so much achieved by the former EUCERD in a relatively short space of time, it is hoped that the Commission of Expert Group on Rare Diseases will be as efficient and productive in their new mandate. The EUCERD has laid down the foundations, but much more work is needed in the future so as to continue to advance in the key areas that have been identified as of importance for the rare disease community at large.

Other International News

A new opportunity for the diagnosis and therapy of rare diseases affecting the Central Nervous System in Germany

On 1 January 2014, a new specialised Centre for Rare Diseases was inaugurated in Wiesbaden, Hessen, Germany at the Horst Schmidt Klinik (HSK). This new opportunity is for patients affected by Rare Diseases, in particular those affecting the Central Nervous System. Located 30 km far from Frankfurt, the HSK offers all assessments needed to take adequate care for patients with multi-systemic diseases. The Center is part of the Children’s Hospital of the HSK and works in collaboration with all other Clinics of the HSK that are needed for the management of multi-systemic and progressive diseases. Besides organising a multidisciplinary rare disease team, the Center is aimed to facilitate speedy diagnosis, management and treatment for national and international rare disease patients. A major goal of this Center is to improve the quality of life of patients’ and their families as well as to be a meeting point for stakeholders. Furthermore, the Institute will host a basic and clinical research unit for neurological diseases such as neurometabolic and neurodegenerative disorders, inborn malformations and epileptic encephalopathies.

This Center will be integrated with the Brains For Brain Clinical Research Institute, and work as a joint venture with the Brains For Brain Foundation (www.brains4brain.eu) (B4B). The B4B Clinical Research Institute at the HSK will be the site for basic and applied research projects, organisation of clinical trials and educational programmes concerning Rare Diseases including presentations, seminars, meetings, journal clubs, scientific evenings etc. to increase awareness knowledge and interest in rare diseases. The Center also collaborates with the Network for rare diseases at the University of Magdeburg in order to follow the recommendations of the National Action Plan for Rare Diseases in Germany (published August 2013) for establishing a structure of certified centers. The network with other hospitals and the sharing of different expertise in the field of Rare Diseases will lead to a better and more specialized care of rare disease patients.

The HSK Center for Rare Disease and the Brains For Brain Clinical Research Institute represent an excellent of collaboration of expertise to create the critical mass needed to improve the management and the quality of life of rare patients. For more information please contact Prof. Maurizio Scarpa and/or Dr. Christina Lampe

Guidance Documents and Recommendations

Bioinformatics, Registries and Data Management

The Moroccan Genetic Disease Database

In an article published in European Journal of Human Genetics, the authors introduce the Moroccan Genetic Disease Database (MGDD), that is a comprehensive genetic database of the diseases identified in the Moroccan population. The authors report that this “database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language” in a user-friendly interface. To catalogue the molecular data of inherited disorders found in the Moroccan population, the authors perused articles published in PubMed, Web of Science and Google Scholar until April 2013 to add to the database. Among the 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases recorded in the database, the authors report that “most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance and affect endocrine, nutritional and metabolic physiology”.

The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. It can benefit the human genetics researchers, clinicians and health professionals interested in a particular genetic disorder or gene to gather an overview of mutations reported in the Moroccan population as well as help designing the diagnostic tests to detect mutations in molecular diagnostic services, as well as the implementation of epidemiological approaches for estimating the prevalence of genetic diseases in the Moroccan or more general Arab population. Additionally, polymorphism data will be useful for the optimisation and design of genetic association studies. The MGDD provides relevant information not only to the local scientific community in Morocco but also to researchers in countries with similar ethnic backgrounds. The authors assure that the database will be continually updated with additional data from online submissions and literature searches, which can be publicly accessed at http://mgdd.pasteur.ma.
Consult the Pubmed abstract

Clinical Research

Stem Cells

Gene Therapy

Therapeutic Approaches

Diagnostic Approaches

Regulatory News

Political and Scientific News

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, Kate Bushby, Catherine Berens, Barbara Cagniard, Virginie Hivert, Helena Kaariainen, Odile Kremp, Yann Le Cam, Jordi Llinares-Garcia, Antoni Montserrat, Charlotte Rodwell, Jaroslaw Waligora

INTERNATIONAL CORRESPONDENTS
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), Zsuzsanna Lengyel (Hungary), Andrew Green (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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Strategy for Rare Diseases announced in England and Belgium releases their National Rare Disease Plan

Stephen Groft leaves a legacy of hard work and persistence promoting the cause of rare disease patients

Other European news

English version of German Rare Disease Plan now available

The Leibniz University of Hannover sets up a portal for rare diseases

Editorial addressing the achievements of EUCERD and testimonials of past members

Other International News

A report on the 5th Pan Arab Human Genetics Conference Genomics into Healthcare

A new opportunity for the diagnosis and therapy of rare diseases affecting the Central Nervous System in Germany

Guidance Documents and Recommendations

Waldenström macroglobulinemia: guidelines on the diagnosis and management

Hereditary breast and ovarian cancer syndrome: three articles on the U.S. preventive services task force recommendation statement

Bioinformatics, Registries and Data Management

Lessons on data sharing from ENGAGE, a large research consortia

Two articles published on the needs of rare disease registries with EPIRARE as a model

EU Pancreas: an integrated approach for combating pancreatic cancer

The Moroccan Genetic Disease Database

Understanding informed consent by parents of children enrolled in a genetic biobank

Evidence-based practice in Behçet’s disease: identifying areas of unmet need for 2014

Free diagnostic exome sequencing for 30 rare disease patients in US

Genes for childhood heritable diseases: past, present and future

Orphanet collaborates with START to enrich its encyclopedia with information on cancers

New syndrome of severe encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor

West syndrome associated with hyperphosphatasia and intellectual disability due to mutations in PIGW

Novel form of primordial dwarfism with distinct facies caused by homozygous truncating mutations in CRIPT

A new syndrome of congenital heart defects, brachydactyly, and mild intellectual disability is associated with de novo deletions in 14q24.1q24.3 in three patients

A newly recognised microdeletion syndrome caused by 9q31.1q31.3 deletion

Midline cleft of the upper and lower lip in a consanguineous family due to a homozygous deletion at 1p31

Bilateral perisylvian polymicrogyria: a deletion mutation in GPR56 selectively disrupts human cortex surrounding the Sylvian fissure

X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures caused by AP1S2 mutation

Attenuated familial adenomatous polyposis associated with a novel AXIN2 germline variant

Benign adult familial myoclonic epilepsy due to ADRA2B in two Italian families

West syndrome associated with de novo mutations in GRIN2B in two individuals

Hereditary sensory and autonomic neuropathy type 1 with bone destruction caused by a mutation in ATL3

Familial Parkinson disease associated with DNAJC13 mutations

Congenital myasthenic syndromes due to LRP4 mutations

Fatal multiple mitochondrial dysfunction syndrome linked to heterozygous missense mutations in LIPT1 in one patient

Isolated succinate-CoQ reductase deficiency: first case due to recessive SDHD germline mutations

Microphthalmia, Lenz type caused by a splice donor mutation in NAA10 which results in the dysregulation of the retinoic acid signalling pathway

Hypertrophic cardiomyopathy is associated with a novel homoplasmic mitochondrial 16S rRNA 2336T>C mutation in maternal members of a Chinese family

Non-syndromic retinitis pigmentosa caused by compound heterozygous mutations in MVK

Early-onset ovarian epithelial tumors: INHBA and INHA mutations contribute to the determinism

Retinal dystrophy is associated with a homozygous mutation in the TUB gene

Supratentorial ependydomas contain oncogenic fusions between RELA and C11orf95

Fibrolamellar hepatocellular carcinoma linked to a recurrent DNAJB1-PRKACA chimeric transcript

Neural tube defect could be associated with missense mutations in LRP6

Isolated Hirschsprung disease: contribution of the mutations within SOX10 enhancers

Congenital diaphragmatic hernia: contribution of mutations in GATA6, previously associated with pancreatic agenesis and congenital heart disease

Distal Xq28 microduplication syndrome: increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients

Clinical Research

Cerebral arteriovenous malformation: medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke

Glioblastoma: first-line use of bevacizumab or in association to radiotherapy-temozolomide did not improve overall survival in patients

Clear cell renal carcinoma: dovitinib activity was no better than that of sorafenib

Esophageal carcinoma: chemoradiotherapy with FOLFOX did not increase progression-free survival

Multiple system atrophy: rifampicin does not slow or halt the disease progression

Skeletal muscle fatty acid oxidation disorders: bezafibrate does not improve clinical symptoms or fatty acid oxidation during exercise

Sézary syndrome and classical mycosis fungoides: lenalidomide therapy demonstrated activity in refractory cutaneous T-cell lymphomas, along with acceptable toxicity

Chronic granulomatous disease: anakinra treatment resulted in a rapid and sustained improvement in colitis

Melioidosis: trimethoprim-sulfamethoxazole (TMP-SMX) is not inferior to TMP-SMX plus doxycycline for the oral phase and is safer

Acromegaly: pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option

Paroxysmal nocturnal hemoglobinuria: poor response to eculizumab

Kawasaki disease: low rate of adverse cardiovascular events through age 21

Stem Cells

Gene Therapy

Hurler syndrome: platelets are efficient and protective depots for storage, distribution, and delivery of lysosomal enzyme in mice model

Amyotrophic lateral sclerosis: immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment

Charcot-Marie-Tooth disease type 1A: rAAV1.NT-3 therapy resulted in improvement in motor function, histopathology and electrophysiology in model mice

Spinocerebellar ataxia type 1: broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei

Hemophilia B: integration-deficient lentiviral vectors carrying an improved human FIX cDNA safely and efficiently cure the disease in a mouse model

Hepatocellular carcinoma: human allogeneic suicide gene-modified killer cells therapy demonstrates a marked, rapid, and sustained regression of the disease in mice

Therapeutic Approaches

Retinitis pigmentosa: DENAQ restored visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells

Retinal degeneration: suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models

Epidermolysis bullosa simplex with muscular dystrophy: treatment with 4-phenylbutyrate ameliorates the pathological phenotypes in plectin-deficient myotubes and mice

Amyotrophic lateral sclerosis: LDN/OSU-0212320, a pyridazine derivative, delayed motor function decline and extended lifespan in mice model

Late infantile neuronal ceroid lipofuscinosis: intravenous administration of TPP1 increases lifespan and improves neurological function in a mouse model

Glioblastoma: stage-specific embryonic antigen-4 as a potential therapeutic target in mice

CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo

Precursor T-cell acute lymphoblastic leukemia: c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

New syndrome of severe encephalitis with refractory seizures, status epilepticus, and antibodies to the GABA_A receptor