Edition of 17 September 2013

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Germany adopts the National Plan for rare diseases

In keeping with the European Council recommendations, Germany has elaborated and adopted the National Plan for Rare Disease, which will guide and structure actions in rare diseases within their health and social systems. In 2010 the German Federal Ministry of Health (BMG), together with the German Federal Ministry for Education and Research (BMBF) and the Alliance of Chronic Rare Diseases (Allianz Chronisch Seltener Erkrankungen, ACHSE), founded the National Action Coalition for Persons with Rare Diseases (Nationales Aktionsbündnis für Menschen mit Seltenen Erkrankungen, NAMSE). The goal of NAMSE is to improve the quality of life of individuals with a rare disease through a concerted effort. Following a three-year process of coordinating these actions, which involved the commitment of all those involved in the healthcare sector, a total of 52 policy proposals were compiled and included in a National Plan of Action for Persons with Rare Diseases.

The 52 policy proposals in the National plan represent a broad spectrum of tasks to be executed as it addresses the most pressing problems of the patients and their relatives. They include many concrete suggestions on implementing information management, on possible paths to diagnosis, on caretaking structures and on conducting research on rare diseases. The goal of NAMSE is to establish and provide aid to National and European networks of Reference and Expertise Centres that are adapted to the special needs of rare disease patients and make them available to patients and their doctors. This was also highlighted to be in agreement with the cross-border healthcare directive. Adequate funding and certification for these centers will ensure timely diagnoses so patients can receive necessary care. An important goal of the National plan is to intensify the research in the area of rare disease. The National Plan provides vital contribution to the goals of the Framework Program of Healthcare Research presently being pursued by the German Federal Government. Thus funds for research in the field of rare diseases in order to improve diagnosis and treatment are provided in this plan

The successful adoption of this national plan is the result of the hard work and unrelenting engagement of the many experts who participated in the workgroups and of those who were members of the Steering Committee. The publication of the policy proposals is the first big step of the National Action Plan. This will be followed by implementing and monitoring the suggested proposals.
Go to the NAMSE website
For further information

Interview

Orphanews Europe: What motivated you to start this organisation?
Kay Parkinson: Alström Syndrome is a life –limiting disease which in my two children’s case caused childhood blindness, hearing loss, heart failure , diabetes type two, kidney failure, bladder dysfunction and many associated problems. Matthew died aged 25 following heart transplant surgery in 2003 and Charlotte following heart and kidney transplantation in 2010 aged 29.
I founded Alström Syndrome UK charity in 1998 following the late diagnosis of my two children, Matthew was 18 and Charlotte was 15. They had years of mis-diagnosis at my local hospital, before finally being asked to attend Great Ormond Street Hospital as a doctor was looking into their latest diagnosis.

Orphanews Europe: Can you describe the early beginnings of ASUK?
Kay Parkinson: I had studied Law at Exeter University as a mature student, primarily because I was having to fight so many issues for my children and fortunately also specialised in Charity Law.
I informed the Consultant who made the diagnosis that I wanted to start a charity for the condition and she contacted 12 other families she knew with the condition and invited them to our first family conference in 1998. Seven families attended and it soon became clear that even those with a diagnosis were not having all aspects of the disease identified. The following year we invited physicians who were working with my own two children from Torbay Hospital to attend. This was the beginnings of our multi-disciplinary clinics. In a hotel in Brixham, S Devon audiology tests took place in the bedrooms, families gathered round a cardiologist, an endocrinologist and dietician and ad hoc consultations took place wherever they could find a spare room in the hotel. The unmet needs of these families were clear as were the needs of the physicians to see more patients, gain more experience and learn more about the disease. AS UK facilitated and funded this development.
The family conference/clinic progressed on these lines for a number of years. As our numbers grew it became increasingly difficult for families to travel to Torbay and back in a weekend. I was already in touch with Birmingham Children’s Hospital and it was agreed that we could use their facilities at the weekend of our family conference. All was still on an ad hoc voluntary basis with doctors giving freely of their time at the weekends to examine our Alström patients and Alström Syndrome UK charity organising and funding the family conference and the clinic lists.

Orphanews Europe: How did you obtain funding for your charity?
Kay Parkinson: Following Alastair’s talk, Torbay Hospital, Birmingham Children’s Hospital and AS UK decided that we would apply for NHS Commissioning to fund the clinical service on a more professional basis. In 2006 the NHS Commissioning Team for Highly Specialised Services agreed to fund 4 clinics for children at the Birmingham Children’s Hospital yearly and 4 adult clinics at Torbay Hospital. Two outreach clinics in Leeds were also arranged. However, the NHS said at that time that they did not fund charities.
Fortunately my legal training equipped me with the skills to challenge this decision and I set about tracking the legal basis to do this. The COMPACT document signed by Tony Blair when Prime Minister laid out the principles of how the public sector should work with the voluntary sector. Reading the document it became clear that there were a number of breaches in our dealings with the NHS. The NCVO had COMPACT officers funded by the Big Lottery who took up our case. When the breaches were pointed out to the NHS Commissioners, AS UK was invited to meet with them. The outcome was that we were to be funded as equal partners with the two hospitals we worked with in delivering the Alström clinical service that we had developed.

Orphanews Europe: How has ASUK developed since then?
Kay Parkinson: The NHS Commissioned clinics have gone from strength to strength since we started, our numbers have doubled since we incorporated an Asian Mentoring Scheme, the Alström gene has found to be present in a number of families in the Leeds, Bradford area. In 2012 we successfully moved the adult clinic from Torbay Hospital to the brand new state of art Queen Elizabeth Hospital in Birmingham. It had become clear that the needs of our adults could not be met at a district hospital, and although thankful to Torbay for their initial help with setting up the clinics it was time to move on.
On the back of the success of the clinics AS UK applied for and were successful in gaining a Big Lottery Medical and Scientific grant to develop research into the condition through taking skin samples from consenting patients and starting a research database. Cambridge University partnered with AS UK and were commissioned to generate pluripotent stem cells that will be differentiated into cell types. Birmingham and Torbay Hospitals were commissioned to take the skin samples and develop a research database.

Orphanews Europe: Can you describe the challenges you faced while developing this database?
Kay Parkinson: Six months prior to the completion of the grant when AS UK were expecting to be able to review the database, Torbay Hospital announced that AS UK could not have access to it for ethical reasons. As we were not NHS “employees” it was unethical for us to have access and as our patient numbers were so small we would still be able to recognise anonymised data. The fact that we see un-anonymised patient information, as part of our role as a partner in the NHS England, National Specialised Commissioned Alström Clinical Service was ignored. The fact that we owned the database was ignored. This information announced at such a late date in the project put the grant and AS UK into jeopardy. If the Big Lottery were to call back in the grant AS UK would be ruined. Our members had believed that when they consented to the database that AS UK would as owners of the database have access to it.
ASUK kept the Lottery closely informed of discussions and an emergency meeting was held between partners.
The outcome was that the Database will move to the Queen Elizabeth Hospital, Birmingham and all patients will be re-consented to the database explicitly stating that they allow AS UK access. AS UK, will now add further consents to the form; allowing the data to be shared, with EU and International databases.
Alström Syndrome is an ultra-rare condition, the vast majority of patients have been found through the infrastructure and services that I have developed over the years. I instigated, pioneered and fought for the first Alström Syndrome multi-disciplinary clinics in the UK and started the first research through the Big Lottery grant.

Orphanews Europe: What advice would you give to associations that are working for rare disease patients.
Kay Parkinson: I hope the above information helps other groups be more prepared for issues which can arise when working with the NHS and the other groups avoid the problems we encountered.
Patient groups have patient interests at heart- the solutions for rare diseases will only come by all parties to their care bringing down the barriers that prevent collaborative working.
With such a complex condition as Alström it is only the patient groups, families and patients who have lived with all the multiple manifestations of the disease and managed them on a daily basis. We cannot “lock out” their valuable experience and expertise. Patient groups deserve and need better recognition.

Mathew Parkinson (9-2-1978-11-5-2003) and Charlotte Parkinson (11-4-1981- 29-4-2010). The picture was taken in 1998 shortly after diagnosis by Great Ormond Street Hospital. The family was flying to the USA- the only country at that time with any knowledge of the disease. Local press took the photo as they were about to depart.

EMA

A progress report on rare diseases and orphan drugs policy in Japan

An article published in Expert Opinion Orphan Drugs reports on the current and future policy initiatives on rare diseases in Japan. According to the authors, these initiatives have been an element of the Japanese national health system dated as early as 1972. The authors believe that due to the extensive support from the government, rare disease policy in Japan has witnessed “considerable progress over the past 40 years” which encompasses the orphan drug legislation of 1993.

This legislation not only encouraged research and development of orphan drugs but also brought changes to the pricing and reimbursement systems. The authors contend that this legislation “facilitated access to orphan drugs, specific research programs to promote research on and development of orphan drugs, and a government-supported information centre to promote the understanding of rare diseases”.

In the article, the authors contrast pricing and reimbursement strategies in EU and US, with the Japanese National Health Insurance (NHI) system. Unlike the EU and US, the NHI in Japan “negotiates prices with pharmaceutical companies once a drug is approved for use, allowing a selling price of cost plus 10% for orphan drugs”. Japan has designated130 diseases as intractable or rare diseases, out of which 56 can receive reimbursement of medical expenses. The reimbursement structure allows “30% of expenses paid by insurance companies and the rest paid by national and prefectural governments”.

The authors describe several research programmes that are supported by the Japanese government such as the project establishing ’Bases for Early and Exploratory Clinical Trials in Specific Research Areas’, launched in 2011 “to promote the development of innovative orphan drugs and medical devices from Japan”. The authors also highlight another project ’Enhanced International Information Exchange’ launched this year which will aid in “publicis(ing) the results of limited research on rare diseases and orphan drugs to a broader international audience”.

Finally, the authors illustrate the example of Japan Intractable Disease Information Center – a collaborative effort of the MHLW and the Japan Intractable Diseases Research Foundation – to disseminate information about rare diseases in Japan. The authors highlight that this website gets over 15 million hits per year and is a testament to in spreading knowledge about rare diseases in Japan
Consult the abstract

Other International News

Change is in the air for sequencing grants

Despite of considerable advances in science and technology, sequencing has not generally entered routine clinical care. Up to now, National Institutes for Health (NIH) grants were difficult to obtain for sequencing. The US National Human Genome Research Institute (NHGRI, part of the National Institutes for Health) is trying to change this situation. It has just announced the second round of Clinical Sequencing Exploratory Research (CSER) grant awardees at four institutions around USA. “These grants aim to answer questions about how genomic sequencing might be used in the treatment of several disorders, and to assess how this information is used by doctors and patients. Each research group must also answer questions about how to generate and communicate the sequence data, and how clinicians and patients cope with the psychosocial and ethical dilemmas this information can present.” explains Lucia Hindorff, programme director for CSER at NHGRI.

Katrina Goddard, a genetic epidemiologist at the Kaiser Permanente Center for Health Research, OR, and a new CSER grantee, along with her colleague Benjamin Wilfond, is showing how genomic sequencing can be used even before a person is born. Sequencing data could be used by couples in order to make more informed choices about carrier status and pregnancy risk for inherited disorders.

Richard Myers’ team from Hudson-Alpha Institute for Biotechnology in Huntsville, will sequence the genomes of 500 children diagnosed with a developmental disorder, as well as both of their parents in order to identify genetic markers common to the disorders and speed up the diagnostic process.

Arul Chinnaiyan’s research group at the University of Michigan, will focus on sarcomas and other rare cancers, sequencing the tumour cells to determine any common genetic alterations in these cancers.

The last research group, is located in the University of Washington and includes Gail Jarvik and Wylie Burke. They will build a coordinating centre, weaving together the various strands of everyone’s research into a large tapestry of data.

Read the full article

Guidance Documents and Recommendations

Bioinformatics, Registries and Data Management

How rare disease patients/parents are playing different roles to facilitate drug discovery

An interesting article published in “Drug Discovery Today” emphasises the vital role parents and patients are performing in order to fund, discover and develop treatments for rare and ultra-rare diseases. The article highlights the diverse roles they play and also illustrates some of the success stories that their involvement of has brought about. The diverse roles include entrepreneurial, organizational and in some cases, the role of principal investigators to further scientific knowledge leading to drug discovery. Furthermore, the authors stress that these roles are played by the parent/patients sometimes without any formal education. According to the authors patients/parents make a remarkable “to disrupt the usual course of drug discovery” as the current process usually takes years to find appropriate therapy.

The authors describe three ultra-rare disease parent/patient advocate groups who are involved in the fast generation of treatment for the diseases and recommend this approach as an alternative model for pharmaceutical research. Their efforts have been instrumental in drug discovery for rare diseases as well as profitability for companies involved in making these drugs. The authors highlight the “urgent need to accelerate discovery and development for thousands of other rare and ultra-rare diseases”. The authors encourage academic and pharmaceutical scientist to come together with the parent and patient advocates to get and give advice for furthering the cause of generating medications for rare disease sooner. However, the authors also warn that a balance is necessary for the patient/parent involvement on when to get involved and when to allow the experts to lead the course. The authors believe that “the lack of formal scientific or medical training should not hold people back in their search for researching or developing treatments”.
Consult the PubMed abstract

New Research Projects open for Recruitment

Crowdfunding campaign to help patients with Alkaptonuria: donate now!

Alkaptonuria, or AKU for short, was the first genetic disease to be discovered more than 110 years ago. Besides the fact that these patients are often faced with misdiagnosis, a lack of efficient care and a lack of awareness, AKU still has no cure. The medical world remains largely unaware of its existence and impact on everyday life. Now more than 100 years later, the drug nitisinone has been identified as the first potential treatment for AKU. Nitisinone is already licensed as a treatment for another rare disease, but it is yet to be approved for treating AKU. The first clinical trial is now almost complete and AKU patients are being sought to participate in the second longer trial. This four year trial to assess the long-term suitability of nitisinone for use in AKU patients, is estimated to begin in late 2013. The trial will be based at three test centres in Europe: Liverpool (UK), Paris (France) and Piestany (Slovakia).

Help cure Black Bone Disease from bradbell.tv on Vimeo.

However, the rarity of AKU means patients are scattered around the world. This means that patients from across Europe and beyond have to be recruited to run a good clinical trial. A crowdfunding campaign, initiated by Nick Sireau - father of two boys with AKU, who quit his job to devote his time towards helping AKU patients - aims to generate funds for the clinical trial. The clinical trial needs 140 participants and although this may seem like a small number, for rare disease patients this is an uphill task. By donating money to this crowdfunding campaign you will help them to: Bring patients from across the world to the clinical trial centres. Allow patients to bring carers with them. Help them care for the patients properly while they are on the trial. Allow them to organise events across Europe for patients. The deadline to donate is 17 October 2013.
Donate now to make a difference for this community .
Click here to read more about the crowdfunding campaign
If you are interested in participating in this clinical trial or if you would like more information, please visit
www.developakure.eu or email the Clinical Trials Coordinator, Hana Ayoob or call +44 (0) 1223 322897

Clinical Research

Stem Cells

Gene Therapy

Therapeutic Approaches

Diagnostic Approaches

Political and Scientific News

Analysing cost-effectiveness of Orphan Drugs: suggestions for the future

This month in the article published in Applied Health Economics and Health Policy, authors discuss several approaches to tackle the decision of the Dutch Healthcare Insurance Board advice on not reimbursing orphan drugs (enzyme replacement therapy) that target lysosomal storage disorders: agalsidase alfa and agalsidase beta for Fabry disease and alglucosidase alfa for Pompe disease. The Dutch Healthcare Insurance Board concluded this on the basis of the “unfavourable cost effectiveness originated from the limited additional therapeutic value (as a result of the slow progression of the disease) and high costs”. Additionally continued reimbursement of these drugs would lead to limited resources for other drugs which may be more cost-effective.

Reimbursement of drugs based on cost-effectiveness has been a topic of intense debate due to scientific as well as political challenges. According to the authors, cost-effectiveness concerns of orphan drugs is due to in the inherent uncertainty around its the safety and effectiveness at the time of market launch owing to small number of clinical trial subjects, the lack of randomized controlled trials, and the use of surrogate efficacy measures. The authors believe that the need of times is for proper guidelines on analysing and assessing cost effectiveness of orphan drugs for (ultra-)rare diseases like the National Institute for Health and Clinical Excellence (NICE) who are responsible for assessing orphan drugs in England and Wales from April 2013.

To address the issue of low numbers of patients in the Netherlands, the proposed launch of a “compulsory European wide registry following marketing authorization of an orphan drug” is encouraged by the authors. According to the authors addressing economic evaluation will involve approaches such as “variable cost-effectiveness thresholds (which would set a higher threshold for orphan drugs) or weighted cost-effectiveness ratios (where the health gain in a patient with a rare disease would receive a higher weight)”. They recommend further research to unravel societal values about orphan drugs and then incorporate this in the decision-making process.
Access the article

Review of 11 orphan drugs reveals scope for studying cost-effectiveness

Authors of a study published in Orphanet Journal of Rare Diseases address a question similar to the previous article by systematically reviewing the available evidence on clinical effectiveness, cost-effectiveness and budget impact for orphan drugs. The authors analysed 338 studies recieved on PubMed, Embase, NHS EED and HTA databases for 11 inpatient orphan drugs listed on the Dutch policy rule on orphan drugs. The authors analysed a total of that met the inclusion criteria for this study. According to the authors, 96% of the studies focused on clinical effectiveness of the drug, of which 41% were case studies while 39% observational studies.

However, the authors observed that for all orphan diseases at least one experimental or quasi-experimental study was found, and a randomized clinical trial (RCT) was available for more than half of the orphan drugs studied where eight studies described the cost-effectiveness of an orphan drug and an equal number described an orphan drug’s budget impact. The authors therefore debunk the often heard claim that RCTs are not feasible for orphan drugs, as they found that an RCT was available in 60% of orphan drugs investigated.

The authors highlight that since cost-effectiveness and budget impact analyses for orphan drugs are seldom published, assessing the effectiveness of orphan drugs, policy makers should expect an international interventional study to be available. They also inform policy makers to not expect country-specific RCTs to have been carried out and assessing the cost-effectiveness and budget impact of treatments, policy makers should not expect to find large body of evidence in the literature. The authors recognise that policy makers are restricted to evidence submitted by pharmaceutical companies or to coverage-with-evidence-development schemes and whether the available evidence is considered to be sufficient fully depend on the role of evidence based medicine in reimbursement decisions. The authors strongly urge further research is needed to examine the relation between available evidence and positive reimbursement decisions.
Read the Open Access article

Orphanews International, the newsletter of the European Union Committee of Experts on Rare Diseases
Orphanews International 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
EUCERD Country Representatives: Helmut Hintner (Austria), Pol Gerits (Belgium), Rumen Stefanov (Bulgaria), Ivo Baric (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek Jr. (Czech Republic), Marianne Jespersen (Denmark), Inna Vabamae (Estonia), Helena Kaariainen (Finland), Alain Garcia (France), Birgit Schnieders (Germany), Christos Katamis (Greece), Janos Sandor (Hungary), Thor Thorarinsson (Iceland) , John Devlin (Ireland), Bruno Dallapiccola (Italy), Antra Valdmane (Latvia), Romalda Baranauskiene (Lithuania) , Yolande Wagener (Luxembourg), Miriam Dalmas (Malta), Jolande Huizer (Netherlands), Stein Are Aksnes (Norway), To be nominated (Poland), Alexandre Diniz (Portugal), Emilia Severin (Romania), Borut Peterlin (Slovenia), Frantisek Cisareik (Slovak Republic), Isabel Pena-Rey (Spain), To be nominated (Sweden) , Sabina Gallati (Switzerland), Edmund Jessop (UK)
EUCERD ECDC Representative: Andrew Amato
EUCERD Patient Organisation Representatives: Dorica Dan, Yann Le Cam, Christel Nourissier, Bianca Pizzera
EUCERD Pharmaceutical Industry Representatives: Wills Hughes-Wilson, Kevin William Loth, Samantha Parker, Barbara Valenta
EUCERD Rare Disease Projects under Health Programmes Representatives: Ségolène Aymé, Jean Donadieu, Ester Garne, Domenica Taruscio, Joan Luis Vives Corrons, Thomas Wagner, Susan Webb
EUCERD Rare Diseases Research Projects under Framework Programmes for Research and Technological Development Representatives: Jean-Yves Blay, Kate Bushby, Marc de Baets, Olaf Hiort, Gerard Wagemaker
EUCERD European Commission Participants: Catherine Berens, Iiro Eerola, Jordi Llinares-Garcia (EMA), Georgios Margetidis, Jaroslaw Waligora, Antoni Montserrat Moliner, Michael Huebel, Bruno Sepodes (EMA-COMP)

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)
For more information on the European Union Committee of Experts on Rare Diseases
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Photo credit : Serimedis http://www.serimedis.inserm.fr/ (unless otherwise stated)

Germany adopts the National Plan for rare diseases

Kay Parkinson-Director and Founder of Alström Syndrome UK (ASUK)

Interview

Call for expressions of interest as Commission appointees to the Commission expert group on rare diseases

Petition requesting amendments to the draft on Data Protection Regulation

EMA

European Medicines Agency releases for public consultation its draft policy on the publication and access to clinical-trial data

A progress report on rare diseases and orphan drugs policy in Japan

Other International News

Change is in the air for sequencing grants

Guidance Documents and Recommendations

FIGO COMMITTEE REPORT: Ethical issues in the management of severe congenital anomalies

Beta-thalassemia major: an American Heart Association (AHA) consensus statement on cardiovascular function and disease treatment

Inherited primary arrhythmia syndromes: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients

Chronic myeloid leukemia: European LeukemiaNet recommendations for 2013

Pediatric systemic lupus erythematosus: international consensus for provisions of quality-driven care

Bioinformatics, Registries and Data Management

Study documents shortcomings of the current International Disease Classifications ICD-10 and SNOMED-CT

ODIN – ORCID and DataCite Interoperability Network

How rare disease patients/parents are playing different roles to facilitate drug discovery

Study offers a practical approach to management of rare neurological diseases

IDEAL: international project to explore new methods for design and analysis of clinical studies in rare diseases

The Orphanet Mobile app: six months after its release

New Research Projects open for Recruitment

Crowdfunding campaign to help patients with Alkaptonuria: donate now!

First description of two siblings homozygous for a 2p21 deletion with a phenotype close to hypotonia-cystinuria syndrome

Unique TM4SF20 ancestral deletion in 15 unrelated Southeast Asian families with a paediatric disorder of early language delay and cerebral white matter hyper-intensities

SBF1 mutations cause a novel subtype of autosomal recessive demyelinating Charcot-Marie Tooth disease type 4B

New likely MED13L haploinsufficiency syndrome found in two patients with hypotonia, heart defect and intellectual disability

Severe type of autosomal-recessive infantile encephalopathy with epilepsy and dysmorphic corpus callosum caused by biallelic SZT2 mutations in two unrelated children

Mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance due to FBXL4 mutations

Rare isolated severe myopia in humans is associated with mutations in LRPAP1 and in SCO2

Autosomal-dominant diffuse non-epidermolytic palmoplantar keratoderma is caused by missense mutations in AQP5

Primary ciliary dyskinesia: ARMC4, ZMYND10, and DYX1C1 mutations found responsible in cases with classic disease, and RSPH1 in 11 families without laterality defects

Medullary cystic kidney disease including cardiovascular abnormalities, liver fibrosis and situ inversus is associated with ANKS6 mutations in six families

Autosomal-recessive retinitis pigmentosa caused by ARL2BP homozygous mutations

Fatal infantile hypertrophic cardiomyopathy due to mitochondrial complex I deficiency associated with mutations in ELAC2 in five individuals

Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell

Autosomal dominant Dandy-Walker malformation and occipital cephaloceles: identification of mutations in extracellular matrix genes NID1 and LAMC1

Pilocytic astrocytoma: whole-genome sequencing identified recurrent somatic alterations of FGFR1 and NTRK2

ACTH-independent macronodular adrenal hyperplasia: somatic mutation in EDNRA could be implicated

Idiopathic and/or familial pulmonary arterial hypertension: novel heterozygous missense variant in KCNK3 as a disease-causing candidate gene

Isolated CoQ-cytochrome C reductase deficiency caused by mutations in CYC1 in two unrelated children

Familial thoracic aortic aneurysm and aortic dissection: identification of the same rare variant PRKG1 in four families

Short rib-polydactyly syndrome and Jeune syndrome associated with heterozygous mutations in WDR60

A vascular-anomaly syndrome with phenotypic overlap with Rendu-Osler-Weber disease caused by BMP9 mutations in three unrelated individuals

Oral-facial-digital syndrome: exome-sequencing revealed a different homozygous variant in DDX59 in two multiplex consanguineous Arab families

Early infantile epileptic encephalopathy: de novo heterozygous mutations identified in GNAO1 in four individuals

Autosomal-recessive hypocomplementemic urticarial vasculitis associated with DNASE1L3 mutations in two families

Isolated spina bifida: potential role of NKX2-8 as a genetic component of neural tube defects

Wegener granulomatosis: HLA-DP and SEMA6A identified as contributors to risk for the disease

Clinical Research

Fragile X syndrome: high MMP-9 activity levels were lowered by minocycline and a majority of children were improved by a 3-month minocycline treatment

Patients with Loeys-Dietz syndrome type 1 present increased fracture risk and low bone mineral density

Pulmonary hypertension: modest improvements with riociguat in exercise capacity and pulmonary vascular resistance

Wegener granulomatosis and microscopic polyangiitis: a single course of rituximab is as effective as continuous conventional immunosuppressive therapy

Mantle cell lymphoma: ibrutinib shows durable single-agent efficacy in relapsed or refractory disease

Patients with high-risk hepatoblastoma: SIOPEL-4 treatment regimen (cisplatin and surgery) is feasible and efficacious for complete remission at the end of treatment

Glioblastoma: adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir does not improve overall survival

Refractory or recurrent non-testicular malignant germ-cell tumor: a multimodal strategy integrating regional deep hyperthermia might be a successful treatment option

Cornelia de Lange syndrome: identification of high frequency of antibody deficiency

Women who conceived after a diagnosis of vasculitis had a higher rate of pregnancy loss than those who conceived prior to diagnosis

Pregnancy in patients with Behcet disease does not appear to be associated with an increased rate of pregnancy-related complications

Stem Cells

Congenital stationary night blindness: photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina

Gene Therapy

Mucopolysaccharidosis type 3: intracerebrospinal fluid gene therapy corrects both central nervous system and somatic pathology in a mouse model

βSickle cell anemia: -globin gene transfer improves physiological parameters

Argininemia: AAV-based gene therapy prevents neuropathology and results in normal cognitive development in the hyperargininemic mouse

Usher syndrome type 1: MYO7A therapy with AAV2 or AAV5 single vectors is efficacious

Idiopathic and/or familial pulmonary arterial hypertension: therapeutic efficacy of AAV1.SERCA2a in a rat model

Therapeutic Approaches

Glioblastoma: multifaceted oncolytic virus therapy in an immunocompetent cancer stem cell murine model

Correction of classical homocystinuria in mice by treatment with proteasome inhibitors

X-linked adrenoleukodystrophy: pioglitazone halts axonal degeneration in a mouse model

Rett syndrome: statin drugs improve systemic perturbations of lipid metabolism, alleviate motor symptoms and confer increased longevity in Mecp2 mutant mice

Frontotemporal dementia and amyotrophic lateral sclerosis: CDC7 as a novel therapeutic target for TDP-43 proteinopathies

Proximal spinal muscular atrophy: celecoxib increases SMN and survival in a mouse model via p38 pathway activation

Idiopathic and/or familial pulmonary arterial hypertension: low-dose FK506 (tacrolimus) could be useful in the treatment of this disease