15 March 2013 print
EUCERD update
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Rare disease day: Growing larger every day.
The International Rare Disease Day celebrated its sixth anniversary this year and like every year, since its beginning on the 29th of February 2008, a rare day in itself, an ever growing number of people from around the globe joined in activities, to be a part of the annual observance aimed to raise awareness for rare diseases. This year more than 70 countries were involved in observing this special occasion making it the largest Rare Disease Day till date. New countries on board this year included Bahrain, Iceland, Israel, Palestine and Singapore. People from several countries created and uploaded remarkably informative and heart-warming videos to spread awareness about rare disease and its toll.

The social media was ablaze with participation that exceeded expectations. People from all walks of life: caretakers, patient organisations, industries as well as policy makers from all over the world sent in their pictures confirming that they are all in it together to make a difference. Learn more

Rare Disease Day celebrated in Algiers

Policy makers on Rare Disease Day organised by Swiss Alliance of Patients ProRaris

Show of hands for Rare Disease Day from Australia

Show of hands for Rare Disease Day from the Committee for Orphan Medicinal Products at European Medicines Agency

Show of hands in Columbia: more than 600 participants from over 15 organisations

This year’s slogan “Rare Disorders without Borders” emphasises the need for international collaboration for research, treatment as well as availability of experts in the field of rare diseases, all of which remains dispersed in individual countries. This is in line with the recent global initiative taken by the European Commission and the National Institutes of Health in building and developing the International Rare Diseases Research Consortium (IRDiRC) which has already rallied the support of numerous countries. To foster international collaboration, IRDiRC has announced its first conference in Dublin Ireland on 15-17 April. This conference will bring together stakeholders in rare disease from the international arena to discern what advances can be made together.
The highlights of Rare Disease Day included the symposium in Brussels organised between EURORDIS (European Organization for Rare Diseases) and the Members of the European Parliament “to examine how policy measures can help improve access to therapies for rare disease patients” (Further Details)and the setting up of radiz- Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich- to encourage collaboration between researchers and clinicians (Further Details). This year also marks 30 years of the Orphan Drug Act and the National Organization of Rare Diseases (NORD) in the U.S., who have several activities planned through the year to commemorate this landmark.
Photo courtesy: Rare Disease Day, Eurordis, Flickr

EUCERD update
Executive Summary of the 7th Meeting of the EUCERD now online

The public executive summary of the 7th meeting of the European Union Committee of Experts on Rare Diseases, held on 31 January 2013 – 1 February 2013 is now available online (Read the summary ). As reported previously, the meeting saw the unanimous adoption of the EUCERD Recommendations on European Reference Networks for Rare Diseases, which will feed into the work of the Cross-Border Healthcare Expert Group, currently in the process of aiding the European Commission implement the Cross-Border Healthcare Directive, adopted on 28 February 2011. One of the main topics of discussion was the area of registries in the field of rare diseases. Members had a chance to discuss the first draft of the EUCERD Recommendations on Common Principles and Consensus on Patient Registries and Data Collection for Rare Diseases which will be further refined and discussed at a workshop foreseen in the scope of the EPIRARE /EUCERD Joint Action workshop on 22-23 April 2013 in Brussels. This workshop will also be aimed at working on a technical document of possible policy scenarios for rare disease patient registration concerning the direction the proposed European registry platform to be based at the EC’s Joint Research Centre in Ispra could take. Members were also provided with an update on the EUCERD Joint Action activities after one year. In particular an update was given on the activities in the field of the coding and classification of rare diseases, the work being carried out on specialised social services, and work on the elaboration of an EUCERD Recommendation on Indicators for National Plans/Strategies for Rare Diseases. Other topics discussed included newborn screening, the outcomes of an expert workshop held at the Joint Research Centre in Ispra with the collaboration of Eurogentest and the EUCERD on the genetic testing offer in Europe, and progress in the Member States to elaborate, adopt and implement rare disease plans/strategies before the end of 2013.

Spotlight on...

A ray of hope for rare disease patients: 144 million Euros for rare disease projects
A big moment for Rare Disease Day was the announcement of 144 million Euros earmarked by the European Commission to fund rare disease projects. Twenty-six new collaborative projects that will help combat rare diseases have been funded under the scheme across Europe. The awards will benefit an array of organisations including, “academic institutions, small and medium sized enterprises and patient groups” that work on overcoming the different challenges faced by rare disease patients. The funded projects range from clinical trials for gene therapy, to advancements in health assessment technology and high throughput research. In the press statement, Máire Geoghegan-Quinn, European Commissioner for Research, Innovation and Science has said: "Most rare diseases affect children and most of them are devastating genetic disorders resulting in greatly reduced quality of life and premature death. We hope that these new research projects will bring patients, their families and health professionals closer to a cure and support them in their daily battle with disease".
Many of the funded projects are part of the International Rare Diseases Research Consortium (IRDiRC), an international initiative that aims to contribute towards finding 200 new therapies for rare diseases as well as diagnostic methods for all of them by the year 2020.
Read the Press Release
Overview of the 26 projects funded by EU


EU Policy News

EMA’s Paediatric Committee: an effort towards better information on the use of medicines in children
To obtain appropriate data for medicinal products for children, the European Medicines Agency (EMA) published the Paediatric Regulation in 2007 and established the Paediatric Committee (PDCO). Under the Paediatric Regulation, pharmaceutical companies have to go through a paediatric investigation plan (PIP) to develop new medicinal products for children as well as for adults. For market authorisation, the PIP must be approved by the PDCO. The regulation also applies, in some cases, to existing medicinal products. The PDCO can also defer clinical studies in children required in a PIP or decide that such study is not needed (e.g. when a medicine is intended for diseases that do not occur in children). The first five-year report to the European Commission on the experience acquired on the Paediatric Regulation, has been published recently. It takes a stalk of what has been achieved in the five years after the regulation came into force and gives a “factual analysis of data collected by the EU Member States and the EMA”. Learn more
In related news, a public consultation is open on the standard PIPs for acute myeloid leukaemia and rhabdomyosarcoma. They aim to highlight the persistent unmet therapeutic needs for these two types of cancer in children.
Consult the press release


National & International Policy Developments
Other European news
Meeting report of the rare disease conference in Macedonia
The meeting report for the first rare disease conference in South-Eastern Europe (SEE) held on November 15-17, 2012 can be accessed from the journal, Prilozi. This meeting was sponsored by the European Academy of Paediatrics with 128 attendees from 21 countries. The meeting touched on several important topics for rare disease including how the policy issues relating to rare disease can be tackled. The conference included discussions on the importance of “registries, teamwork and especially international collaboration as well as the need for comprehensive societal efforts to tackle this issue”. Several experts spoke in detail about specific rare diseases. The conference included a section on the treatment options available for Gaucher’s disease as it is not currently treated in Macedonia. Finally, this meeting stressed the importance on intensive collaboration among SEE countries and also between SEE and EU countries as well as “organizational, educational and scientific integration of SEE and the EU on the rather specific field of RDs”.
Other International News
17 institutions join in to form a rare disease alliance in China
A news release in an online newspaper (www.china.org.cn), reported on the launch of a China Rare Diseases Prevention and Treatment Alliance on Rare Disease Day in Jinan, China. This alliance, founded by Shandong Academy of Medical Sciences, includes 17 medical institutions from 13 provinces in China. According to Han Jinxiang, Communist Party of China Secretary of the Academy, this alliance will be “committed to the establishment of rare disease treatment centres across the country, research on the cure of such conditions, publicity and medical education of rare diseases”.
Guidance Documents and Recommendations
AAP and ACMG recommendations for genetic testing and screening of children.
In addition to the recommendations made by the FIGO report, American Academy of Pediatrics (AAP) and the American college of Medical Genetics and Genomics (ACMG) have collaboratively provided recommendations on several aspects that cover the ethical and political framework of testing and screening in children. Both AAP and ACMG highly recommend that “testing and screening should be driven by the best interest of the child, (and) should be provided in the context of genetic counselling by trained professionals”. They highlight the importance of counselling the caretakers before undergoing testing about its risks and benefits. They also add that caretakers should also be informed about the implications of pharmacogenetic testing which may be “beyond drug selection or testing”. AAP and ACMG are in favour of mandatory newborn screening and encourage predictive genetic testing for adopted children, but does not favour school-based screening or testing or “routine carrier testing in minors when such testing does not provide health benefits”. AAP and ACMG advocate predictive genetic testing for adult onset conditions to be conducted early only if clinical intervention at a young age is imperative for the individual’s well-being. Finally, both AAP and ACMG “strongly discourage the use of direct-to-consumer and home kit genetic testing of children”.
Consult the PubMed abstracts

Role of CLIA in the age of sequencing for clinical purposes
In a recent article appearing in Applied Translational Genomics the importance of having a regulatory body such as Clinical laboratory Improvement Amendments (CLIA) overseeing the collection and dissemination of genomics data in all laboratories practice is elucidated. The authors highlight the recommendation provided by the Presidential Commission for the Study of Bioethical Issues which proposes “performing all whole genome sequencing in CLIA – approved laboratories”. The authors believe that due to rapid progress in sequencing technology, it is only a matter of time when whole genome/exome sequencing will be available to all. Therefore, the authors believe that the “straightforward practices dictated by CLIA can provide significant protections as the quality of unregulated diagnostics is susceptible to perverse market forces as all of the poor practices above can be tied directly to economic conflicts of interest”. Additionally, findings unearthed from sequencing in labs are “permitted to break the research/clinical barrier if they pose a significant health risk”, which according to the authors is an “enormous waste of potentially life-altering findings”. The authors believe that “primary CLIA sequencing could circumvent this issue and potentially allow clinical analysis and use of all genomic data from many research projects” and assist in delivering this information in a standardized format. The authors emphasise that while “sequencing is relatively standardisable, downstream bioinformatics analyses and interpretive schemes can be extremely variable”. The authors feel that it is imperative to have a regulatory framework such as the CLIA that covers test interpretation and reporting which will assist in standardising the bioinformatics and the interpretative criteria of NGS-based diagnostics. According to the authors “CLIA is the only available avenue to ensure on a constant ongoing basis that these practices, disclosure of validation data, review of personnel, operating procedures and patient protection practices, and requiring a system of constant re-evaluation and improvement”.
Consult the abstract

The path forward for childhood cancers

An entire series in Lancet Oncology explored the current scenario with respect to childhood cancers. The first article in this series outlines the burden of cancer across countries and the projected incidence of childhood cancers. The author recommends a National Plan catering specifically to children and adolescents with cancer that addresses the diverse demographic in high income countries. Another article in the series pointed to the 50 year collaboration between clinical research and front-line care in paediatric oncology as one of the major factors in significantly lower mortality rates among children with childhood cancer. The author in this article believes that it is necessary “to engage the biopharmaceutical industry, regulatory agencies, public health authorities advocacy groups and philanthropic organisations”. In the subsequent article the authors delineate the significant improvements made in terms of cancer care for children in high income countries where the survival rate is 80% but also address the challenges that cancer patients and survivors still have to confront. The author also provided suggestions on what could be the way forward for low-income countries in terms of policy developments that will lead to better care for children suffering from cancer.
Consult the table of contents of the series

Bioinformatics, Registries and Data Management
Analysing the current status of biobanks in U.S.
Data stored in biobanks are instrumental in several translational biomedical research discoveries as they are essential repositories of human specimen and related data. However, research on the “organization and functioning” of biobanks is limited. In an article published in Genome Medicine the authors conducted “the first national survey of biobanks in the U.S” where representatives of 456 (72% response rate) biobanks participated in a “30 minute online survey”. The survey revealed that 17% of these biobanks have existed for over 20 years and 53% were founded to for “research on a particular disease”. The survey also revealed that “majority of biobanks store specimens that can be used for genetic/genomic research”. They also found that while “most biobanks are embedded in one or more other entities” and over a quarter belonged as a part of a larger organisation. According to the authors, this leads to a difficulty and loss of clarity in policy, as decision making bodies may be dispersed across organisations. Widely held concerns among the biobanks included availability of future funding and resources as well as the issue of underutilisation. From the results of the study the authors propose that “the complex organisational landscape of biobanking requires policies as nuanced as the biobanks themselves, whether those policies address subject protection or privacy, or the advancement of research goals".
Consult the PubMed abstract

Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS) - registry Swabia
Nagel et al. published an article describing the successful implementation of “the amyotrophic lateral sclerosis (ALS) registry Swabia, located in the South of Germany”. This paper outlines “the rationale, the study design and the basic characteristics” of the registry. For this registry 420 ALS cases were retrospectively identified from 8.6 million residents of the Swabia region. Additionally, data of “new” ALS patients were also incorporated in the registry after a strict inclusion criteria was satisfied.
Consult the PubMed abstract
Consult Orphanet for Registry details

Pathophenotypic similarity gene network: a novel approach in network medicine
In a novel approach towards network medicine, the authors of the article published in PLOS–One created a pathophenotypic similarity gene network (PSGN) that associates the clinical features(pathophenotypes) with disease causing genes. They then compared this to gene-to-gene network models such as “the human disease network” and “the orphan disease network” and found that this model helped in revealing pairs of genes with significant similarity on several factors that were previously overlooked. To illustrate their model, the authors mapped all the phenotypes and their allied genes that are associated with maple syrup urine disease (MSUD) to prepare a merged pathological module. The authors believe that the “pathophenotypes contribute to identify underlying co-dependencies among disease-causing genes that are useful to describe disease modularity”.
Consult the PubMed abstract

Skeletal dysplasias explained in Bone Dysplasia Ontology
Consult the PubMed abstract
Screening and Testing
Non-invasive Prenatal Testing: The present and the future.

In a recent article published in the Ultrasound in Obstetrics & Gynecology, the authors discuss some emerging techniques for Non-Invasive Prenatal Testing (NIPT) and the ethical implications and possible impact of incorporating NIPT into the current prenatal programmes. The recent advancements in NIPT technology allows the usage of diverse methods to detect chromosomal abnormality. The author highlights deep sequencing technology called massively parallel sequencing allows millions of DNA molecules to be counted as a highly sensitive technique. Alternative methods of detecting aneuploidy discussed by the author include examining “DNA methylation between fetal and maternal genomic loci”, foetal or placental gene and, paternally inherited sequences for Y chromosome abnormalities. In addition, counting strategies for monogenic diseases have also been applied.
The author asserts that prenatal detection of chromosomal anomalies fulfill all the criteria laid out by The World Health Organisation to qualify as screening tests and NIPT appears to be the best available prenatal test for Trisomy 21 due to the high specificity and low risk associated to it. The authors emphasise the importance incorporating NIPT has into existing screening programs but adds that as a consequence this may require changes in the “timing and weight of other screening tests” during pregnancy. Due to the accelerated progress in NIPT technology and the myriad ethical and professional dilemma it may bring about, the author urges the International Society of Ultrasound in Obstetrics and Gynecology(ISUOG) to make a formal statement regarding NIPT.
Consult the Journal
In a related article, the advancement and benefits of NIPT technology are exemplified. In this study, the authors isolated cell-free DNA (cf-DNA) from maternal plasma of 11 women “carrying fetuses with subchromosomal duplications and deletions, translocations, mosaicism, and trisomy 20 diagnosed by metaphase karyotype”. They then utilised massively parallel sequencing (MPS) for counting the DNA and found that not only can fetal molecular karyotype be obtained by MPS of maternal plasma cfDNA but this method of karyotyping is “equivalent to a chromosome microarray and in some cases is better than a metaphase karyotype”. Thus the authors believe that MPS provides “enhanced fetal genomic resolution with the improved safety of a noninvasive maternal blood test”.
Consult the PubMed abstract

Congenital adrenal hyperplasia in Sweden:100 years on
In a recent study published in The Lancet, the authors identified 606 patients diagnosed with congenital adrenal hyperplasia (CAH) in Sweden between 1915 and 2011, to evaluate the effects of neonatal screening in detection and care of these patients. CAH is an endocrine disorder with effects on brain and behaviour leading to sex differences wherein affected girls behave more like boys than non-affected girls. The authors found that there was “an apparent increase in the incidence of CAH during the past century, with increases in line with improvements in diagnosis and treatment over time”. Previous studies assumed that female preponderance in the salt-wasting form of this disorder is caused by missed diagnosis in girls and increased mortality among boys. However, this study showed that neonatal screening of the disease helped identify both boys and girls with salt-wasting congenital adrenal hyperplasia as they were equally missed.
Consult the abstract


Ethical, Legal & Social Issues

Roles of genetic counsellors in the Direct-to-Consumer Genetic Testing industry
In an article published in the Journal of Genetic Counseling, the authors discuss how the profession of genetic counselling is represented on Direct-to-Consumer Genetic Testing (DTC GT) websites, blogs and other online materials. In recent years, the DTC GT industry has expanded considerably and with this expansion has emerged the concern on how the general public, who now has easy access to various genetic testing products available online, would interpret the genetic information provided from these tests “not ordered through a healthcare professional”. In light of this concern, critics have demanded for pre- and post-test genetic counselling to be provided to customers. This article “examines the provision of genetic testing counselling in the emerging DTC GT market, analysing how these calls for genetic counsellors"
Consult the PubMed abstract

Emotional reactions of parents of infants with congenital heart disease
A pilot study recently published in The Journal of Maternal-Fetal & Neonatal Medicine addresses a number of issues concerning the reactions of parents of infants suffering from severe congenital heart disease (CHD). The study focuses on evaluating “emotional distress, depression and quality of life” in parents of newborns with CHD hospitalised for the first time, with emphasis on the time of diagnosis (prenatal and postnatal) and the difference of reaction of mothers from that of fathers.
Consult the PubMed abstract

Austrialia upholds decision on patenting on human genes
The federal court of Australia has ruled in favour of Myriad Genetics and Genetic technologies and dismissed the 2010 lawsuit to prevent the patenting of BRCA1 and BRCA2. This has been a blow for researchers and patients alike, who believe that this patenting law will impede research and genetic testing in addition to escalating costs of both. Genetics technologies had also previously demanded health services to stop testing individuals against their patented genes. The plaintiffs argued that their patent is not on the human gene itself, but on the extracted genetic material that mimics the one observed in patients susceptible to breast and ovarian cancer. They believe that the skill and expertise required to isolate it warrants a patent. An appeal for this decision has been filed in the federal court of appeals in Australia. Learn more

New Syndromes

Developmental cerebellar ataxia and cognitive impairment associated with a homozygous SPTBN2 mutation
The authors report on three members of a consanguineous family suffering from a childhood-onset developmental cerebellar ataxia and marked cognitive impairment. All three cases exhibit dysmetria and dysdiadochokinesia of the limbs, unsteady gait with delayed acquisition of walking alone, abnormal eye movements, convergent squint, motor, language and global developmental delay, and global cognitive impairment with full scale IQ scores falling in the learning disabled range. MRI brain reveals progressive cerebellar atrophy except for one case, maybe because of its young age. Aa all the affected individuals carry a homozygous mutation in the SPTBN2 gene encoding β-III spectrin, the authors named this novel ataxic syndrome SPARCA1 (Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1). According to them, it belongs to a new group of disorders, the neuronal spectrinopathies, which also includes SCA5 (spinocerebellar ataxia type 5) and a form of West syndrome
Consult the PubMed abstract

PLoS Genet ; 8(12):e1003074 ; December 2012
MGME1 mutations in patients with a mitochondrial disorder inducing external ophthalmoplegia, emaciation and respiratory failure
A new mitochondrial disorder has been identified by the authors in two families with individuals presenting with external ophthalmoplegia, emaciation and respiratory failure. These features are also observed in a sporadic case. First symptoms manifest during childhood as ptosis. Then mild progressive external ophthalmoplegia, diffuse skeletal muscle wasting and weakness, profound emaciation and respiratory distress set in. Depending on the case, intellectual deficiency, gastrointestinal troubles, nephritic colics, spinal deformities, cardiac anomalies, and mild ataxia are also noted in the affected members of the two families while the secondary manifestations exhibited by the sporadic case are chronic renal failure, cardiac arrhythmia, depressive episodes, and memory deficits. Brain imaging shows cerebellar atrophy in the first ones and mild cerebral atrophy in the last one. Skeletal muscle biopsy reveals scattered COX-negative fibers and ragged red fibers. The same homozygous MGME1 mutation is found in the familial cases. MGME1 is also mutated in the sporadic case, but the mutation is different.
Consult the PubMed abstract

Nat Genet ; 45(2):214-9 ; February 2013
A progressive mitochondrial myopathy linked with DNA2 mutations
Examination of two siblings, brother and sister, and two other probands allowed the authors to characterise a new progressive mitochondrial myopathy. As regards the first two patients, onset occurred during childhood and their main neurological symptoms are limb-girdle weakness, the sister having also mild ptosis. Data about the two other cases mention a young adult onset and neurological anomalies in the form of slight limb-girdle and ptosis or lower limb weakness. Additional clinical features vary depending on the case and are hypotonia, hypostenia, dyspnea (exertional or episodic), depression, hyperthyroidism, ophthalmoplegia, myalgia, dysphoria, and diplopia. Muscle biopsy of all patient shows COX-negative fibers and all carry a heterozygous DNA2 mutation.
Am J Hum Genet ; 92(2):293-300 ; February 2013
Limb-girdle muscular dystrophy with cerebellar involvement in two patients with an ISPD mutation
Looking for new genetic causes of dystroglycanopathies, the authors found recessive ISPD mutations in nine patients of seven families presenting with various phenotypes. Seven cases have already known pathologies (limb-girdle muscular dystrophy (LGMD) with or without intellectual deficiency and congenital muscular dystrophy (CMD) without intellectual deficiency and with or without LGMD). A new phenotype characterised by features of LGMD with cerebellar involvement has been identified in the two others cases. Their first symptoms appeared during infancy in the form of hypotonia, ocular anomalies (among which oculomotor apraxia, coloboma, severe myopia and strabismus) and feeding problems. Both suffer from proximal muscle weakness and, when the articlewas written, the younger, aged 8.5, was fully ambulant with a waddling-type gait while the oldest, aged 23, could walk with great difficulties and had respiratory failure and mild swallowing difficulties. Brain MRI of the first one shows cerebellar cysts and that of the second one reveals brainstem hypoplasia, cerebellar hypoplasia and fourth ventricle dilatation. Dystrophic features are detected by muscular tissue studies.
Consult the PubMed abstract

To read more about "Autosomal recessive limb-girdle muscular dystrophy"
To read more about "Congenital muscular dystrophy"

Brain ; 136(Pt 1):269-81 ; January 2013
Digital and facial abnormalities, mild-to-moderate intellectual disability and short stature mapping to X chromosome
The authors have detected a new phenotype in eight males belonging to the same family. With a variable severity, it is characterised by: digital abnormalities including postaxial polydactyly, cutaneous syndactyly, brachydactyly, and camptodactyly, mild-to-moderate intellectual disability, short stature, microbrachycephaly, scoliosis, cerebellar and renal hypoplasia. The specific facial features also mentioned are low-set ears, low posterior hairlines, narrow forehead, midface hypoplasia, arched eyebrows, right ptosis, epicanthic folds, convergent strabismus, nystagmus, broad nose, flat philtrum, thick lips, high palate, gingival hyperplasia, and microdontia. Genetic studies detected a candidate region on the Xp11.4-p11.21 locus suggesting that this novel syndrome is an X-linked recessive disorder.
Consult the PubMed abstract

Am J Med Genet A ; 161(2):237-43 ; February 2013
A syndromic form of intellectual disability with very variable severity identified in AUTS2 anomaly carriers
The selection of 21 individuals from 17 families carrying an AUTS2 aberration led the authors to determine a novel variable syndromic phenotype notably including intellectual disability and/or developmental delay, autism, sound sensitivity, short stature, microcephaly, feeding difficulties, hypotonia, cerebral palsy and/or spasticity, and facial dysmorphisms (hypertelorism, highly arched eyebrows, proptosis, ptosis, short and/or upslanting palpebral fissures, epicanthal folds, prominent nasal tip, anteverted nares, deep and/or broad nasal bridge, short and/or upturned philtrum, micrognathia and retrognathia, low-set ears, and narrow mouth). Although less frequent, skeletal anormalies including signs of arthrogryposis, umbilical or inguinal hernia, and heart defects are also observed. The severity of this syndrome is very variable, the most serious cases being these with 3’ AUTS2 deletions.
Consult the PubMed abstract

Am J Hum Genet ; 92(2):210-20 ; February 2013

New Genes

Parkinsonism: DNAJC6 mutations induce different types of familial juvenile forms that expand the spectrum of parkinsonian phenotypes
Consult the PubMed abstracts
Parkinsonism Relat Disord ; 19(3):320-4 ; March 2013
PLoS One ; 7(5):e36458 ; 2012
Mutations in CYP26C1 are responsible Focal facial dermal dysplasia type IV
Consult the PubMed abstract
To read more about "Focal facial dermal dysplasia"

Hum Mol Genet ; 22(4):696-703 ; February 2013
Macrodactyly of fingers, unilateral: somatic gain-of-function PIK3CA mutations establish a link with other overgrowth syndromes
Consult the PubMed abstract
To read more about "Macrodactyly of fingers, unilateral"

Hum Mol Genet ; 22(3):444-51 ; February 2013
Congenital short bowel: FLNA mutations identified in patients with other congenital anomalies
Consult the PubMed abstract
To read more about "Congenital short bowel syndrome"

Genet Med ; t 4 ; October 2012
Early infantile epileptic encephalopathy is a calcium channelopathy when caused by CACNA2D2 mutations
Consult the PubMed abstract
To read more about "Early infantile epileptic encephalopathy"

J Med Genet ; 50(2):118-23 ; February 2013
Progressive myopathy with hypotrophy of type I fibres, myofibrillar disarray and cardiomyopathy: a hereditary myosinopathy due to recessive MYL2 mutations
Consult the PubMed abstract
Brain ; 136(Pt 1):282-93 ; January 2013
Isolated cytochrome C oxidase deficiency: a FAM36A mutation in a patient with less severe phenotype compared with other complex 4 deficiencies
Consult the PubMed abstract
To read more about "Isolated cytochrome C oxidase deficiency"

Hum Mol Genet ; 22(4):656-67 ; February 2013
Maple syrup urine disease: a PPM1K mutation inducing a PP2Cm deficiency identified in a mild form
Consult the PubMed abstract
To read more about "Maple syrup urine disease"

Hum Mutat ; 34(2):355-62 ; February 2013
Solitary fibrous tumour/hemangiopericytoma: present in numerous cases, NAB2-STAT6 fusion could be a molecular signature
Consult the PubMed abstracts
To read more about "Solitary fibrous tumor"

Nat Genet ; 45(2):131-2, 180-5 ; February 2013
Exstrophy-epispadias complex: mutations in one of the two TP63 promoters are a risk factor
Consult the PubMed abstract
To read more about "Exstrophy-epispadias complex"

PLoS Gene ; 8(12):e1003070 ; December 2012
Arrhythmogenic right ventricular dysplasia: a causal relationship with CTNNA3 mutations suspected
Consult the PubMed abstract
To read more about "Arrhythmogenic right ventricular dysplasia"

Eur Heart J ; 34(3):201-10 ; January 2013
Acromegaloid facial appearance syndrome, hypertrichosis with acromegaloid facial appearance, Cantu syndrome: a phenotypic spectrum linked with ABCC9 mutations
Consult the PubMed abstract

Research in Action
Clinical Research
Blastic NK-cell lymphoma: high-dose therapy followed by stem cell allograft can provide durable disease control; is it due to graft-versus-leukaemia effect?
Consult the PubMed abstract
To read more about "CD4+/CD56+ hematodermic neoplasm"

Blood ; 121(3):440-6 ; January 2013
Immune thrombocytopenic purpura: treatment with eltrombopag for up to 3 years is safe and effective in increasing and maintaining platelet counts
Consult the PubMed abstract
To read more about "Immune thrombocytopenic purpura"

Blood ; 121(3):537-45 ; January 2013
Gastrointestinal stromal tumour: regorafenib significantly improves progression-free survival in patients who have failed previous therapies
Consult the PubMed abstract
Consult this study on Orphanet

To read more about "Gastrointestinal stromal tumor"

Lancet ; 381(9863):295-302 ; January 2013
Congenitally corrected or uncorrected transposition of the great arteries: 3-year valsartan therapy does not provide major improvements
Consult the PubMed abstract
To read more about "Congenitally corrected transposition of the great arteries"
To read more about "Congenitally uncorrected transposition of the great arteries"

Circulation ; 127(3):322-30 ; January 2013
Severe haemophilia A: a comparison of the risks of developing inhibitor with plasma-derived factor VIII and three generations of recombinant products
Consult the PubMed abstract
To read more about "Severe hemophilia A"

N Engl J Med ; 368(3):231-9 ; January 2013
Stem Cells

Acute liver failure: human liver stem cells reduce apoptosis and necrosis and enhance regeneration in liver of a mouse model
Consult the PubMed abstract
To read more about "Acute liver failure"

Hepatology ; 57(1):311-9 ; January 2013
Gene Therapy
Leber congenital amaurosis: gene augmentation therapy durably improves vision but does not stop retinal degeneration in humans and dogs with RPE65 mutations
Consult the PubMed abstract
To read more about "Leber congenital amaurosis"

Proc Natl Acad Sci U S A ; 110(6):E517-25 ; February 2013
Therapeutic Approaches
Retinitis pigmentosa: functional rescue in mice by transplantation of rod precursors or reprogramming of adult rods into cells with cone-like properties
Consult the PubMed abstracts
To read more about "Retinitis pigmentosa"

Proc Natl Acad Sci U S A ; 110(3):1101-6, 110(5):1732-7 ; January 2013
EEC syndrome: a small compound rescues impaired corneal or epidermal differentiation in two cellular models
Read the Pubmed abstracts
To read more about "EEC syndrome"

Proc Natl Acad Sci U S A ; 110(6):2152-6, 2157-62 ; February 2013
Neurofibromatosis type 1: MEK inhibition reduces aberrantly proliferating cells in human and mouse tumours
Consult the PubMed abstract
To read more about "Neurofibromatosis type 1"

J Clin Invest ; 123(1):340-7 ; January 2013
Down syndrome: lithium rescues synaptic plasticity, learning and memory performance in a mouse model
Consult the PubMed abstract
To read more about "Down syndrome"

J Clin Invest ; 123(1):348-61 ; January 2013
Marfan syndrome: an antibody directed against GxxPG motifs ameliorates aortic and pulmonary manifestations in Marfan mice
Consult the PubMed abstract
To read more about "Marfan syndrome"

Hum Mol Genet ; 22(3):433-43 ; February 2013
Chronic autoimmune hepatitis: adoptive transfer of Treg cells from xenoimmunised mice induces remission in a type 2 mouse model
Consult the PubMed abstract
To read more about "Chronic autoimmune hepatitis"

Hepatology ; 57(1):217-27 ; January 2013
Idiopathic and/or familial pulmonary arterial hypertension: beneficial effect of restored expression of two microRNAs in model rat
Consult the PubMed abstract
To read more about "Idiopathic and/or familial pulmonary arterial hypertension"

Nat Med ; 19(1):74-82 ; January 2013
Diagnostic Approaches

Kawasaki disease: levels of some proteins present in urine, notably meprin A and filamin C, can be useful for diagnosis
Consult the PubMed abstract
To read more about "Kawasaki disease"

EMBO Mol Med ; 5(2):210-20 ; February 2013
Hereditary nonpolyposis colon cancer: comparison of diagnostic performances between three methods
Consult the PubMed abstract
To read more about "Hereditary nonpolyposis colon cancer"

Gut ; 62(2):272-9 ; February 2013
Mitochondrial DNA disorders: challenge and success of preimplantation genetic diagnosis
Consult the PubMed abstract
J Med Genet ; 50(2):125-32 ; February 2013

Patient Management and Therapy

Pemphigoid diseases: an overview
Consult the PubMed abstract
Lancet ; 381(9863):320-32 ; January 2013
Noonan syndrome: from clinical signs through diagnosis down to management
Consult the PubMed abstract
To read more about "Noonan syndrome"

Lancet ; 381(9863):333-42 ; January 2013
Esophageal carcinoma: last advances in treatment, prevention, surveillance and screening
Consult the PubMed abstract
To read more about "Esophageal carcinoma"

Lancet ; 381(9864):400-12 ; February 2013
Autosomal dominant cerebellar ataxia type 3: a review of the phenotypic and genotypic characteristics
Consult the PubMed abstract
To read more about "Autosomal dominant cerebellar ataxia type 3"

Orphanet J Rare Dis ; 8:14 ; January 2013
LEOPARD syndrome: clinical aspects, molecular mechanisms and major genotype-phenotype correlations
Consult the PubMed abstract
To read more about "LEOPARD syndrome"

Mol Syndromol ; 3(4):145-57 ; October 2012
Myelofibrosis with myeloid metaplasia: for which patients and when resort to haematopoietic stem cell transplantation?
Consult the PubMed abstract
To read more about "Myelofibrosis with myeloid metaplasia"

Curr Opin Hematol ; 20(2):130-6 ; March 2013
Amyotrophic lateral sclerosis: an overview of emerging and tractable drug targets
For further details
To read more about "Amyotrophic lateral sclerosis"

Expert Opinion on Orphan Drugs ; 1(1):5-20 ; January 2013
Paediatric Behcet disease: a focus on the neuro-ophthalmological features
Consult the PubMed abstract
To read more about "Behcet disease"

Orphanet J Rare Dis ; 8:18 ; January 2013

Orphan Drugs

Regulatory News
February CHMP meeting highlight
The CHMP adopted a positive opinion to extend the indication of Privigen to treat chronic inflammatory demyelinating polyneuropathy. Privigen was previously indicated to treat other rare conditions such as Guillain-Barre syndrome and Kawasaki disease.
EMA's Summary of opinion for Privigen

Pomalyst receives accelerated approval from FDA

Another orphan drug Pomalyst indicated to treat multiple myeloma has been approved by the FDA in February. Multiple myeloma also known as plasma cell myeloma is a rare form of cancer affecting older adults, where abnormal plasma cells accumulate in the bone marrow and hamper normal blood cell production. Pomalidomide, the active ingredient in Pomalyst is a thalidomide analog that works by directly inhibiting angiogenesis and growth of multiple myelomas. Pomalyst is indicated for multiple myeloma patients who do not respond to treatment with other cancer drugs, including lenalidomide and bortezomib therapies, and whose disease has “progressed within 60 days of the last treatment (relapsed and refractory)”. According to the National Cancer Institute, approximately 21,700 Americans are diagnosed with multiple myeloma and 10,710 die yearly from the disease. Although pomalidomide has been given an orphan designation by European Medicines Agency, it is does not have market authorisation for Europe yet.
Read the Press Release
Go to the Pomalyst website
EMA on Pomalidomide


Grant for rare disease research in adults
The Foundation for the Development of Internal Medicine in Europe (FDIME) has announced a "research grant for physicians (<38 years)". This is a 3 year grant that furnishes the researcher with 20,000 euros per year. Application deadline: 30 March 2013 For further details
Funding announced to develop treatment for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
The Ataxia of Charlevoix-Saguenay Foundation is offering an annual research grants for work aimed at developing treatments for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Such funding is offered regardless of where the research is being conducted and the deadline to apply is May 23, 2013. Further information and the application form can be obtained on the Foundation’s website

Partnersearch, Job Opportunities
Position for Bioinformatics Group at The Institute of Genetic Diseases Imagine
The Institute of Genetic diseases at Necker Enfants-Malades Hospital, in Paris invites applications from the area of bioinformatics, computational biology, and/or statistical genetics. Imagine, is an multidisciplinary research center, supported by a rare disease Foundation. Application deadline is 15 May.
Learn more about the Institute
Learn more about the position

Research Associate/ Postdoctoral Scientist: to lead on impact activities for EU network
Position open for dynamic scientist to work on the EU funded RD-Connect project. Candidates with PhD in relevant area (e.g. Genetics), high level of knowledge in Omics/translational research field, interest is healthcare and demonstrated experience in the industry are encouraged to apply. You will join an international, multidisciplinary team at the Newcastle Muscle Centre led by Professors Kate Bushby, Volker Straub and Hanns Lochmüller and situated within the Institute of Genetic Medicine at the International Centre for Life in Newcastle upon Tyne. Learn more

What's on Where?

3rd Annual World Orphan Drug Congress
Date: 9-11 April 2013
Venue: Washington DC, USA

This commercial event brings together industry, patient groups, payers and government seeking to expedite orphan drugs to patients.
For further details

4th International Patient Congress and the International Research Conference
Date:11-13 April 2013
Venue: Barcelona, Spain

To commemorate the 50th anniversary of the discovery of Alpha-1 Antitrypsin Deficiency by Carl-Bertil Laurell and Sten Eriksson in 1963, Alpha-1 communities from around the world will take part in two major events in Barcelona, Spain.
For further details

First GENCODYS International Conference: Integrative Networks in Intellectual Disabilities
Date: 14-17 April 2013
Venue: Paphos, Cyprus

Proposed topics include: Cognitive disorders (CD): Phenotype-Genotype networks; gene identification, gene networks-complex inheritance; Linking CD genes and behavioural traits to neural networks; Disease mechanisms in CD – the synapse, gene regulation, epigenetic conditions, common pathways; therapeutic intervention.
For further details

International Rare Diseases Research Consortium Conference 2013
Date: 16-17 April 2013
Venue: Dublin, Ireland

IRDiRC will team up researchers and organisations investing in rare diseases research in order to deliver 200 new therapies for rare diseases and means to diagnose most rare diseases by the year 2020.
For further details

World Federation of Hemophilia 13th International
Musculoskeletal Congress 2013 Date: 18-21 April 2013
Venue: Chicago, USA

This Congress brings together world-leading orthopaedic surgeons, haematologists, and physiotherapists specialized in the treatment and care of patients with bleeding disorders. Participants will spend three days not only analyzing and discussing new medical developments but also looking at problems and issues in different parts of the world.
For further details

7th Alstrom Syndrome International Family Conference and Scientific Symposium
Date: 9-13 May 2013
Venue: Massachusetts, USA

Medical professionals and scientists will hold Symposia on Thursday, 9 May and Saturday 11 May.
For further details

Autoinflammation 2013: 7th International Congress of the International Society of Systemic Auto-Inflammatory Diseases
Date: 22- 26 May 2013
Venue: Lausanne, Switzerland

The meeting will offer a unique opportunity to gather experts from all over the world to discuss the latest scientific and clinical issues on different topics, including the challenges of the new treatments for autoinflammatory diseases such as familial Mediterranean fever; new monogenic autoinflammatory diseases; systemic-onset JIA; Behçet; granulomatous diseases; amyloidosis; and other conditions.
For further details

4th International DSD (Disorders of Sex Development) Symposium
Date: 7-9 June 2013
Venue: Glasgow, UK

This symposium should be of interest to health care staff, clinical and basic scientists and parent & patient support groups. Plenary Sessions planned include: Priorities for the Future, Drug-based Therapeutic Interventions, Care & Communication, Navigating the Information Highway, Management of the Retained Gonad.
For further details

12 th European Symposium on Congenital Anomalies
Date: 12-14 June 2013
Venue: Zagreb, Croatia

Topics include 50 years after thalidomide therapy, Childhood morbidity and mortality due to congenital anomalies, Medication in pregnancy, Prevention of congenital anomalies, Prenatal diagnosis, Preconceptional and prenatal care, Environmental risks, Outcomes of children with a congenital anomaly, Public health policies, Genetics of congenital anomalies, Health care for children with congenital anomalies
For further details

10th HHT Scientific Conference
Date: 12-15 June 2013
Venue: Cork, Ireland

HHT is a genetic disorder that causes abnormalities of blood vessels. The conference will include presentations on basic research on HHT to clinical research, drug development as well as policy issues.
For further details

World Orphan Drug Congress Asia
Date: 18 June 2013
Venue: Singapore

This commercial one-day event will bring together orphan drug manufacturers and developers to expedite orphan drugs for patients.
For further details

6th International Conference on Children's Bone Health
Date: 22-25 June 2013
Venue: Rotterdam, Netherlands

The conference is to try to get a better understanding in healthy and disease states of bone development by discussing molecular pathways as well clinical characteristics.
For further details

Fifht BHD Symposium and Second HLRCC Symposium
Date: 28-29 June 2013
Venue: Paris, France

This conference will be an excellent opportunity for stakeholders of Birt-Hogg-Dubé Syndrome and and Hereditary Leiomyomatosis with Renal Cell cancer, to participate and network. The conference will comprise of invited lectures by worldwide experts, followed by panel discussion, and will also include a poster exhibition. Abstract deadline is 29 March 2013
For further details

9th European Cytogenetics Conference
Date: 29 June - 02 July 2013
Venue: Dublin, Ireland

An opportunity for cytogeneticists to come together to discuss developments ranging from applications in prenatal or cancer diagnosis to chromosome biology in epigenetics and evolution.
For further details

8th International Prader-Willi Syndrome Conference
Date: 17-21 July 2013
Venue: Cambridge, UK

An opportunity for all involved worldwide in research, working or living with people with PWS to present current research and explore best practice in clinical and day to day management of PWS.
For further details

2nd Conference of 'EB-CLINET - Clinical Network of EB Centres and Experts'
Date: 17-18 September 2013
Venue: Salzburg, Austria

The conference will present and discuss the work packages initiated during the 2012 EB clinet meeting.
For further details

Mitochondrial Disease: Translating biology into new treatments
Date: 2-4 October 2013
Venue: Cambridge, UK

This is a brand new conference that will discuss mitochondrial medicine. During this interactive conference several experts will speak about translational mitochondrial medicine. Abstracts are due by 16 July 2013 and the registration deadline is on 20 August 2013
For further details

3rd European Rett Syndrome Conference Maastricht, “Research Update & Preventive Management”
Date: 17-19 October 2013
Venue: Maastricht, The Netherlands

This conference aims to gather renowned researchers and clinicians working in the area of Rett Syndrome, to encourage interdisciplinary international cooperation. The conference also aims to provide stakeholders with the latest information on treatment of symptoms as well as preventative manangement.
For further details

Thalassemia International Federation World Congress
Date: 19-23 October 2013
Venue: Abu Dhabi, United Arab Emirates

Topics for this conference includes “all aspects of prevention, management and care of thalassemia and sickle cell disease and a one-day patient programme”.
For further details

First International Primary Immunodeficiencies Congress (IPIC)
Date: 7-8 November 2013
Venue: Estoril, Portugal
The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the First International Primary Immunodeficiencies Congress (IPIC), a congress for all stakeholders with an interest in primary immunodeficiencies (PIDs). IPIC will provide a two-day programme focusing on clinical developments including PIDs pathogenesis, treatment, management of complications and more. Access to diagnosis and care, SCID newborn screening and other key world developments will also be addressed.
For further details

14th International Congress on Neuronal Ceroid Lipofuscinoses (Batten Disease)
Date: 22 to 25th October 2014
Venue: Córdoba- Argentina
Batten disease is a common name for a group of rare, neuro-degenerative genetic disorder affecting approximately 1 in 30,000 individuals. There is presently no known cure for Batten disease


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
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, Catherine Pouzat, Charlotte Rodwell, Jaroslaw Waligora

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), Zsuzsanna Lengyel (Hungary), Thor Thorarinsson (Iceland) , John Devlin (Ireland), Annick Raas-Rotshild (Israel), Bruno Dallapiccola (Italy), Antra Valdmane (Latvia), Romalda Baranauskiene (Lithuania) , Yolande Wagener (Luxembourg), Miriam Dalmas (Malta), Jolande Huizer (Netherlands), Stein Are Aksnes (Norway), Jacek Gralinski (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, Dian Donnai, Laura Fregonese, 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, Sophie Koutouzov, 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: Tamara F. Sarkisian (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), András Becskeházi (Hungary), Andrew Green (Ireland), Lina Basel (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Viadutis 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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