17 August 2007 print
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Quality - Controlled!
Finally, a quality assurance database for genetic testing labs

EuroGentest, the FP6 EU-funded network of excellence (contract nr LSHB-CT-2004-512148) devoted to genetic testing, has just released in collaboration with Orphanet the first version of the Quality Assurance database (QAu) for genetic testing laboratories. Accurate genetic diagnosis testing is essential for rare disease patients and their families. To date, there is no standardised mechanism in place to easily evaluate the quality of a given laboratory for every diagnostic test. QAu was developed to meet this need. It is expected that the database will quickly become a necessary resource for geneticists and other professionals around the world in order to provide accurate and reliable test results to patients and their families. To be updated annually, version 1.0 of the database includes profiles for the more than 50% of laboratories surveyed that replied to an in-depth survey. The database is sure to grow quickly as it presents an opportunity for the laboratories themselves to communicate the measures they take to ensure quality. Information was compiled from many sources in order to create the most comprehensive resource possible. The database provides a search engine that is simple to use and has different features depending on the needs of the user. It also has a guide for novice users. The EuroGentest website provides detailed information on the development of the database, including the survey created and the complex and thorough validation process employed to ensure the accuracy of the data received. The web-based survey made an in-depth probe of quality management data while taking confidentiality into account. Accreditation, certification, and licensing status were all considered. A copy of the final validated data was sent to participants for verification and authorisation prior to publication. The QAu database includes all laboratories offering any form of genetic testing (molecular, cytogenetic, biochemical). All the data for the quality assurance of genetic testing laboratories will also be available on the new version of the Orphanet website that is due out in November. To participate in the QAu database (select 'clinical test' and then choose a country).

Spotlight on...
Europe gathers forces to define and meet the challenge of autism...
Autism is a spectrum disorder (ASD) that can severely impact patients and their families. While various studies suggest a disturbance of brain energy metabolism, the cause of autism remains the subject of much debate and is still being researched by geneticists, psychiatrists, paediatric specialists and other professionals. Fragile X syndrome, Landau-Kleffner syndrome, Rett syndrome, and childhood disintegrative disorder are all conditions currently classified as rare that fall within the spectrum of autism. Acknowledging both the health and social implications of ASD, the European Commission (EC) has specifically included it in its public-health work plans since 2005. ASD is currently included in both the "Rare Diseases" and "Major and Chronic Diseases" EC Task Forces.

There is a scarcity of reliable prevalence data for ASD in Europe. The most recent prevalence study was conducted by the CDC in the US in 2002. Although information suggests that "age-specific prevalence rates for classical autism in the EU could vary between 3.3 and 16.0 per 10 000, and could increase to between 30 and 63 per 10 000 once all forms of ASD are included", prevalence has not to date definitively been determined. Whether or not it is useful to use a broad spectrum definition for ASD is also subject to debate. While much of the reported rise in incidence and prevalence appears to be due to changes in diagnostic criteria and awareness in professionals, rather than actual increases in the number of cases of autism, this has by no means been proved conclusively. A dramatic increase in ASD prevalence was observed following the publication of the DSM-IV criteria. Unfortunately, there is no medical test available that can determine absolutely whether or not autism is present. Diagnosis depends upon descriptions of behaviour. Professionals vary in how they apply criteria even when using standardised systems.

Prevalence is essential to burden of disease analysis and accompanying policy-making decisions for defining and creating health, educational and social resources. To date, the social and economic burdens of ASD have not been adequately calculated in terms of epidemiology, except in some specific situations.

Thus, as part of a Directorate of Health and Consumer Protection (DG Sanco) 2005 Call for Proposals, the European Autism Information System (EAIS), officially launched in January 2006 with Dr. Alvaro Ramirez of Ireland's Hope Project as project leader. The goals of the EAIS are summarised in their mission statement:

Improv[ing] the quality of life of children, adults and families affected by Autism Spectrum Disorders through early diagnosis of the condition and the creation of a reliable information system on ASD for Europe which will promote the development of government policies to facilitate appropriate and effective treatments and services.

This central aim of creating an information system in order to store data across the EU will provide a ready source of reliable evidence available "to determine both the prevalence and financial burden of the disease and to monitor ongoing trends". Extending this system into a "full-scale EU surveillance system" at the end of the project is a goal.

EAIS thus has a pilot study in prevalence as one of its major work packages. There is no central recording of ASD cases at the EU level and this work package aims to provide an initial analysis of the European ASD situation using standard methodology across Europe. Selecting tools for determining prevalence is a challenging task when dealing with the heterogenous populations of Europe. Of the many screening devices available, the EAIS is trying to select standardised tools that can be adapted to different cultures and languages. The project is currently in the process of selecting and validating tools and working with the various cultural interpretations of symptoms. A checklist has been developed within this package to determine areas of study for ASD prevalence and to address potential difficulties. A second checklist delineates the data needs for determining the economic implications of ASD.

An Early Detection Tools work package is also an important feature of EAIS. While there is presently no cure for autism, research on the efficacy of early, intensive behavioural interventions suggests that developmental trajectories can be positively altered, particularly with respect to language and cognitive development.

The EAIS website includes sections detailing each work package, such as the European Autism Alliance, the Distance Learning Platform, Public Awareness, Early Detection Tools, Pilot Studies and Autism Surveillance. The project spans Europe and includes EFTA and EEA countries. Partner institutions from Ireland, Italy, Denmark, Spain, UK and the Czech Republic lead specific areas of the project and institutions in Scotland, Malta, Romania, Turkey, Italy, Poland and the US contribute efforts. The first quarterly EAIS newsletter has just been published. Contact Dr. Ramirez for further information.

The EC is also supporting other ASD initiatives. One Sixth Framework Programme (FP6) project currently underway is Oxford-based Autism Molgen, (contract nr LSHM-CT-2005-512158), a genetic research effort seeking to identify susceptibility alleles for autism spectrum disorders. Participants include research teams from Denmark, Finland, France, Germany, Greece, Italy, the Netherlands, Sweden and the UK. The project will run through September 2008.

There are also studies available examining possible environmental causes of ASD. The EC in 2004 published the Draft baseline report on neurodevelopmental disorders that considers both voluntary and involuntary exposures to pollutants and their impact on neurodevelopment.

Finally, international non-professional association Autism-Europe , financed in part by the EC, is dedicated to the issue of discrimination and ASD. A European-wide qualitative survey made available in several European languages polling discrimination in health and education was conducted earlier this year. The results will be used notably to draft a political declaration advocating for better health and educational services for ASD patients and to further define their needs.

EU Policy News
European Parliament - practicing what it preaches for disability equal opportunities
The European Parliament promotes equal opportunity and has encouraged various measures designed to help people with disabilities participate in work, social and educational activities. In this spirit, the European Parliament offers a pilot programme of paid traineeships for men and women with a disability. Designed to facilitate integration into the workplace, the traineeships are open to both university graduates and applicants with qualifications below university level. The five-month traineeships aim to provide meaningful, valuable work experience and an opportunity to learn the activities of the European Parliament. The next traineeship will begin on 1 March, 2008. The application period is open from 15 August-15 October, and early submission of applications is encouraged. The European Parliament will provide "appropriate measures, where needed, to enable a person with a disability to have access to, participate in, or advance in employment, or to undergo training, unless such measures would impose a disproportionate burden on the employer".
For more information and application forms

EMEA bestows its 40th positive opinion for orphan drugs
The European Medicines Agency (EMEA) last month bestowed its 40th positive opinion recommending marketing authorisation for an orphan medicinal product since regulation came into effect in 2000. Since that time, over 700 applications for orphan designation have been received by the EMEA, of which 470 received favourable recommendations, 11 were refused and the rest were withdrawn or are still in process. Upon receipt of an orphan designation status, the sponsor is eligible for incentives to develop and market the product, financed though a special EC fund totalling 6 million euros in 2007. Of the over 40 medicines that have to date received a positive opinion for marketing authorisation, some 32% treat rare cancers, 29% treat metabolic diseases, 12% treat blood disorders, 12% treat musculoskeletal and nervous system disorders, and 10% treat cardiovascular diseases. The incentives scheme to develop orphan products has resulted in a steady number of submissions applications: 19 more applications for marketing authorisations for orphan-designated medicines are currently under review, according to a recent EMEA press release.
Orphan medicine application procedures tweaked
The EMEA has a new template available online: The sponsor's report on the maintenance of the designation criteria at the time of marketing authorisation for a designated orphan medicinal product.

Two other EMEA documents concerning orphan medicinal products were revised in July:

Procedures for Orphan Medicinal Product Designation - General Principles
General Information for Sponsors of Orphan Medicinal Products

The revisions concern a change in the number of paper and electronic versions of applications required.

EMEA recruitment is open
The EMEA is recruiting to fill positions in several areas. The EMEA will be accepting applications electronically on-line in order to simplify and accelerate the processing of applications and the selection procedures. Applications must be sent no later than midnight on 30 August 2007. Early application is advised. For more information, including job descriptions and application forms and procedures.

National & International Policy Developments
Switzerland eligible to participate in FP7
Following the signature of a scientific agreement with the European Union, Switzerland has gained eligibility for full participation in the Seventh Framework Programme. Swiss researchers may participate “on an equal footing” with EU scientists in all calls for proposals, including those open since the start of the year. According to CORDIS (the European Community Research and Development Information Service), Switzerland has committed 1.4 billion euros to FP7, some 3% of the overall budget. CORDIS states that Swiss researchers enjoyed a 24% success rate on their FP6 projects – higher than the 20% EU average.
Germany's protection law actually results in higher demise of embryos
German law, in effect since 1991, restricts the number of embryos created per IVF cycle to three, and stipulates that all three must be implanted in the patient regardless of their quality. They can neither be frozen nor discarded. The result of this is a high number of foetal reductions, performed when abnormal foetuses are identified or in multiple pregnancies where reduction is necessary to increase the chance of survival. German experts are protesting this policy, pointing out that it is better to destroy an embryo before it is implanted rather than after implantation has taken place. Germany prohibits the use of embryos for research purposes, although in July, a majority of the German national ethical counsel recommended loosening current regulations on a case-by-case basis rather than imposing across the board the present policy that limits research use to embryonic stem cells obtained outside of Germany prior to 2002 and penalises German scientists who conduct such research abroad. The question will be taken up by the German parliament in the autumn.
Other European news
New UK genetic diseases educational tool uses patient testimony
Telling Stories, Understanding Real Life Genetics is an innovative new electronic resource developed for healthcare professionals employing the real-life stories of patients and their families living with genetic conditions. Amongst the rare genetic diseases described by patients, their parents or caregivers are Charcot-Marie-Tooth disease, Long QT syndrome, Turner syndrome, Severe combined immune deficiency syndrome, Klinefelter syndrome, Niemann-Pick condition, Prader-Willi syndrome, Huntington disease, and a complex congenital condition that has not been identified to date. The user-friendly website is intended to help health professionals, especially nurses, midwives and health visitors, understand and appreciate the relevance of genetics and the impact a genetic illness can have on the daily life of patients. The site is also intended as an educational support, particularly toward the nursing competence in genetics framework that was developed in 2003. A “Catalogue” of stories can be sorted by various themes, such as genetic condition, inheritance, or genetic intervention. With a spectrum of storytellers describing how their condition first emerged, the response of general practitioners and caregivers to symptoms that had often never before been seen, and the often long road to specialised care and treatment, “Telling Stories” provides a powerful testimony of the needs of rare disease patients in the context of the general medical milieu.
UK opens first paediatric clinical research unit
Researchers from Imperial College London and St Mary’s Hospital have opened the UK’s first unit devoted uniquely to paediatric clinical research. Professor John Warner, head of paediatrics at Imperial College, explained the rationale for the new unit. Because children’s metabolism differs from adults and diseases can behave differently in children, downsizing doses of medicines created for adults is not safe. Dr. Warner stated that all research involving children would be carried out ethically and responsibly. Areas under investigation at the new unit include new treatments for Duchenne muscular dystrophy and the prevention of complications from sickle cell anaemia. The unit features inpatient rooms big enough for a child and their parents. The unit is funded by St. Mary’s Paddington Charitable Trust and the George John and Sheilah Livanos Charitable Trust.
Extending non-invasive screening for Down syndrome reduces cases in Denmark
New research reveals that the number of infants born with Down syndrome has been reduced by half in the last three years, following the extension of non-invasive screening to women of all ages. Following the example of many other European countries, Denmark’s National Board of Health introduced guidelines in 2004 that proposed screening to all pregnant women, rather than just those over 35 years old.
A small country making a big effort….
Luxembourg takes stock of RD patients

Being a small country poses special concerns for rare disease patients who already have trouble finding resources adapted to their particular needs. For Luxembourg, the three different languages the Grand Duchy shares complicate matters even further, along with the fact that the tiny country does not have its own university and professionals in Luxembourg must affiliate with outside universities, usually in Belgium, France or Germany. However, Luxembourg is striving hard to identify and fill the gaps its rare disease patients encounter. Orphanet coordinator for Luxembourg Dr. Yolande Wagener, who works with the Luxembourg Ministry of Health, recently visited the Orphanet offices in Paris, along with Bettina Vogel of the Luxembourg Association for Persons with Neuromuscular and other Rare Diseases (ALAN).

As members of the Luxembourg Rare Diseases Working Group, they brought with them the results of their latest endeavour: an appraisal of the current situation for rare disease patients. This document is comprised of over 2000 anonymous surveys containing 316 variables. Amongst the findings the study produced: 16% of respondents identified services that they need but cannot access because they are currently non-reimbursed, including materials (home and vehicle adaptations, for example), special treatments and support (psychological support and therapy, acupuncture, nutritional advice, osteopathy, homeopathy, et cetera), and professional home aid (childcare, meal aid, aid for using catheters, transportation). 26% of respondents identified services needed that are not currently available in Luxembourg, including specialist physicians and centres, oncology services for children, the structure for defining a diagnosis in a shorter time, and support groups. The evaluation will help Luxembourg better plan to meet the needs of its rare disease citizens and their families.

Other International News
March of Dimes issues report card for newborn screening in the US
The 2007 March of Dimes annual report on newborn testing states that while almost 90% of US babies are now screened for 21 disorders – double the number in 2005 - the American College of Medical Genetics insists that being tested for 29 mostly rare treatable disorders would permit intervention that could prevent death and lessen disability. The 29 conditions are broken down into five categories: amino acid metabolism disorders, organic acid metabolism disorders, fatty acid oxidation disorders, hemoglobinopathies, and others. PKU, which can result in severe mental retardation if not detected and treated early, is amongst the conditions that newborn screening could prevent, ameliorate or cure. Homocystinuria, citrullinemia, maple syrup urine disease, multiple carboxylase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency are other examples. Newborn screening in the US is governed on a state-by-state basis, with only 14 states currently requiring testing in all 29 of the treatable conditions. Currently, 6.2% of US infants will be screened for less than 10 of the disorders.
US fertility patients favour embryo donation for research purposes
A new survey in the US finds that over half of US fertility patients are willing to donate unused embryos for stem cell research purposes. The findings increase by tenfold the estimated number of embryos available – should legislation permit their wider use. The study was published in the review Science. It is estimated that some 400,000 frozen embryos are currently being stored in the US.
A rare disease on the silver screen
Director Michael Moore immortalises the plight of a rare disease sufferer – who dies after his insurance company refuses to pay for a needed bone marrow transplant considered “experimental” – in his new documentary Sicko, a scathing indictment of the current US health care system.

Orphanet News
Orphanet Journal of Rare Diseases included in MEDLINE
After only one year of publication, the Orphanet Journal of Rare Diseases (OJRD) has been selected for indexing in MEDLINE based on the recommendation of the Literature Selection Technical Review Committee (LSTRC), an NIH-chartered advisory committee of external experts. MEDLINE is the U.S. National Library of Medicine's premier bibliographic database that contains over 15 million references to journal articles in life sciences with a concentration on biomedicine. The inclusion of OJRD by MEDLINE reflects its growing importance in the field, and is a strong endorsement of its achievements to date.
New Texts
New Orphanet Journal of Rare Diseases publications
Anorectal malformations
Ehlers-Danlos syndrome type IV
Multi-minicore Disease
Loss-of-function genetic diseases and the concept of pharmaceutical targets
Sweet's syndrome - a comprehensive review of an acute febrile neutrophilic dermatosis

New Research Projects open for Recruitment
Trial of beta-blocker therapy vs Angiotensin II receptor blocker therapy in individuals with Marfan syndrome
GRASPALL Study: administration of L-Asparaginase entrapped into red blood cell for the treatment of recurrent Acute Lymphoblastic Leukemia
A randomized, phase III trial of Patupilone vs Pegylated Liposomal Doxorubicin in Taxane in patients with recurrent epithelial ovarian, primary fallopian or primary peritoneal cancer


New Syndromes
Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus characterise SOLAMEN syndrome
Two patients from Cowden disease families present a phenotype distinct from what is typically found in the syndrome. In addition to the classical manifestations of Cowden disease, these patients present congenital dysmorphisms, including segmental overgrowth, arteriovenous and lymphatic vascular malformations, lipomatosis and linear epidermal nevus. The two patients are carriers of a PTEN gene mutation. In one patient, another mutation in the second allele of the gene was identified. This bi-allelic inactivation may explain the extension of the phenotype. The authors propose calling this syndrome SOLAMEN: Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus. Read the PubMed abstract
Eur J Hum Genet ; 767-773 ; July 2007

New Genes
Ciliary gene RPGRIP1L is mutated in Joubert and Meckel syndromes
A fourth gene has been linked to both Meckel and Joubert syndromes. RPGRIP1L codes a protein localised in the basal body and centrosomes of the cilia cells. The mutations impact the interaction with the proteins necessary for cilia functioning. The identification of this fourth gene confirms a common cilia cell dysfunction for Meckel and Joubert syndromes.
Read the first PubMed abstract
Read the second PubMed abstract

Nat Genet. 2007 ; 875-881 ; July 2007
Nat Genet ; 882-888 ; July 2007

Mutated PORCN gene in Goltz syndrome
Goltz syndrome (focal dermal hypoplasia), an X-linked dominant multisystem birth defect, is characterised by diverse cutaneous symptoms and a wide variety of anomalies affecting the eyes, teeth, CNS, and urinary, gastro-intestinal and cardiovascular systems. Two different teams have identified mutations in PORCN gene, coding a putative O-acyltransferase, of which the homologue in the Drosophila Melanogaster fly is involved in the Wnt signalling pathway.
Read the first PubMed abstract
Read the second PubMed abstract

Nat Genet. ; 833-835 ; July 2007
Nat Genet ; 836-838 ; July 2007

Mutations in LCA5 cause Leber congenital amaurosis
Leber congenital amaurosis causes blindness or severe visual impairment at birth or within the first few months of life. To date, eight gene mutations and five loci have been linked to the recessive autosomic transmission of the disease. The authors have identified mutations in LCA5 contained in one of the loci. LCA5 codes lebercilin, a protein expressed widely during development and localised in the connecting cilia of photoreceptors. The authors also identified 24 proteins linking lebercilin to centrosomal and ciliary functions. These proteins represent candidate genes for Leber congenital amaurosis and other ciliopathies.
Read the PubMed abstract

Nat Genet. 2007 ; 889-895 ; July 2007
GJA8 is mutated in a severe congenital autosomal recessive form of cataracts
Cataract is defined as partial or complete cristalline opacity. Hereditary forms are genetically and clinically heterogeneous. In the majority of cases, transmission is autosomal dominant and six genes have been implicated to date. The Indian research team has identified a mutation in GJA8 in a family with a severe congenital form of the disease.
Read the PubMed abstract

J Med Genet. ; e85 ; July 2007
Deletion at ITPR1 underlies spinocerebellar ataxia 15 in humans
The authors of this study observed a severe autosomal recessive movement disorder that spontaneously appeared in their laboratory mice. Through linkage and sequence analysis, they identified a microdeletion in gene itpr1. In human pathologies, the autosomal dominant transmission of spinocerebellar ataxia 15 has been linked to a locus containing this gene. The authors show that deletions in ITPR1 are responsible for the disease in at least three families.
Read the PubMed abstract

PLoS Genet. ; e108 ; 22 June 2007
Familial T-cell non-Hodgkin lymphoma in children caused by biallelic MSH2 mutations
Familial T-cell non-Hodgkin lymphomas are rare lymphoid system tumours for which the cause is identifiable in most cases. The British research team identified biallelic deletions in MSH2 in three children from the same family presenting with T-cell lymphoma and hyper-and hypo-pigmented skin lesions. MSH2, already implicated in other childhood tumours, codes a protein involved in DNA reparation.
Read the PubMed abstract

J Med Genet. ; e83 ; July 2007
Autosomal recessive dyskeratosis congenital: genetic heterogeneity and mutations in NOP10
Dyskeratosis congenital is defined by multiple characteristics including mucocutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. It exhibits marked clinical and genetic heterogeneity. X-linked recessive and autosomal dominant forms are caused by mutations in DKC1 and TERT genes, respectively, suggesting that the disease is primarily one of defective telomere maintenance. Through analysis of homozygous regions in 16 consanguineous families with 25 affected individuals, the authors linked several loci to the autosomal recessive form of the illness. They identified a mutation in NOP10 in a large consanguineous family. As with DKC1 and TERT, NOP10 codes a telomerase complex protein.
Read the PubMed abstract

Hum Mol Genet. ; 1619-1629 ; 1 July 2007
A breakpoint in MBOAT1 causes novel brachydactyly-syndactyly syndrome
The authors describe a patient of short stature with facial dysmorphia, syndactyly and severe brachydactyly, who cannot be classified following current terminology (Bell classification). The scientists identified a de novo translocation t(4;6) (q12;p23) that disrupts gene MBOAT1, one of a family of genes that codes a transmembrane protein linked to O-acyltransferase.
Read the PubMed abstract

Eur J Hum Genet. ; 743-751 ; July 2007

Research in Action
Fundamental Research
Mutations in PRPF3 form detrimental aggregates and cause photoreceptor cell degeneration in retinitis pigmentosa
PRPF3 is a splicing machinery element expressed ubiquitously. Mutations in this gene cause autosomal dominant retinitis pigmentosa, a disease that affects the retina only. The Italian and British researchers studied the intracellular localisation of normal and pathological proteins, notably in the retina photoreceptors, the cells affected in retinitis pigmentosa. The mutated protein forms aggregates in the cell nucleus, but causes death only in photoreceptor cells. These observations explain the tissue specificity and the dominant transmission of the disease.
Read the PubMed abstract

Hum Mol Genet. ; 1699-1707 ; 15 July 2007
Clinical Research
A new phenotype is linked to HRas pathway signalisation
Rare cases of newborns and young children presenting myopathy characterised by excess muscle spindles, hypertrophic cardiomyopathy and variable features resembling Noonan syndrome have been described, but the genetic basis remains unknown. The researchers analysed PTPN11 and RAS genes, already implicated in Noonan syndrome. HRAS mutations, two of which have been observed in Costello syndrome, were observed in four of five patients analysed.
Read the PubMed abstract

J Med Genet. ; 459-462 ; July 2007
Autism enlarges the spectrum of disorders linked to Williams-Beuren region duplications
The Williams-Beuren chromosomic region, located at 7q11.23, is deleted in the syndrome bearing the same name. Only four cases of duplication in this region have been observed to date: one presents severe language delay, the three others have variable psychomotor development and language delays. The French research team describes a fifth patient with a duplication of this locus, with autism, severe language delay and intellectual deficit. Thus this region may be implicated in various clinical phenotypes and probably contains one or more genes sensitive to gene dosage.
Read the PubMed abstract

Journal of Medical Genetics ; 452-458 ; July 2007
91% of neonatal diabetes diagnosed before 6 months avoid permanent diabetes
Transitory neonatal diabetes during the first months of life presents hyperglycemia, staturo-ponderal delay and in some cases severe dehydration and acidocetosis. The majority of cases is due to anomalies of the imprinted region on chromosome 6q24, although 14 patients with k(ATP) channel gene mutations have been reported. In 97 patients, the authors found that 71% had anomalies in the 6q24 region and 26% carried potassium channel gene mutations (13% in KCNJ11 and 13% in ABCC8). KCNJ11 and ABCC8 mutation carrier phenotypes were identical and distinct from patients with anomalies in the imprinted region, who have lower birth weight and were diagnosed and remitted earlier. In 42 other patients studied, the authors observed that 91% of infants diagnosed before 6 months of age remitted, while those diagnosed after 6 months developed permanent diabetes.
Read the PubMed abstract

Diabetes ; 1930-1937 ; July 2007
Gene Therapy
Targeted delivery of protein across the blood-brain barrier in Gaucher disease mouse models
Gaucher disease is a lysosomal surcharge disease. Enzyme substitution is possible but no improvement in neurological symptoms has been observed. The authors fused the low-density lipoprotein receptor-binding domain of the apolipoprotein B to glucocerebrosidase. Fourteen days after injecting via lentivirus vector system in Gaucher disease mouse models, strong enzymatic activity was detected in the brain and linked to the presence of glucocerebrosidase in the neurons, astrocytes and endothelial cells. This approach thus allows the enzyme to cross the blood-brain barrier.
Read the PubMed abstract

PNAS ; 7594-7599 ; May 2007
Gene therapy proves effective in Parkinson disease
Parkinson disease is characterised by dopaminergic neuronal loss leading to changes in the cerebral mechanisms that control movement, such as the decreased inhibitory GABAergic input to the subthalamic nucleus. In this Phase 1 clinical trial on 12 Parkinson disease patients were treated with unilateral viral vector injection of glutamic acid decarboxylase gene into the subthalamic nucleus. This treatment resulted in an improvement in motor functions with no complications. The results offer hope for other, including rare, neurodegenerative diseases.
Read the PubMed abstract

The Lancet ; 2097-2105 ; June 2007
Diagnostic Approaches
Clinical outcome of preimplantation genetic diagnosis for cystic fibrosis
Cystic fibrosis is an autosomal recessive disease caused by mutations in the gene coding CFTR, and for which preimplantation genetic diagnosis is possible. The Belgian study analysed the data for PGD over an 11-year period, finding that 68% of requests led to at least one complete PGD cycle. In 80% of cycles, embryo transfer was performed and ongoing pregnancy was obtained in 22.2% of cycles. After embryo transfer, a couple had a 27.8% change of giving birth to a liveborn child. No misdiagnosis was recorded.
Read the PubMed abstract

Eur J Hum Genet ; 752-758 ; July 2007
Three protein markers identified for molecular diagnosis of Hirschsprung disease
Hirschsprung disease is one of the most frequent digestive tube malformations, resulting in an anomaly of enteric nervous system development. A Chinese team of researchers has developed a new molecular diagnostic test. By analysing serum proteins by mass spectrometry technology, they detected three specific protein markers, with 100% sensitivity and specificity.
Read the PubMed abstract

Pediatrics ; e56-60 ; July 2007

Patient Management and Therapy
Yttrium-90 ibritumomab tiuxetan tested for safety and efficacy in patients with diffuse large B-cell lymphoma
Yttrium-90 ibritumomab tiuxetan is a radioactive product with EMEA orphan status designation for treating diffuse large B-cell lymphoma. The authors conducted a Phase 2 nonrandomised clinical trial in elderly patients with first relapsed or primary refractory diffuse large B-cell lymphoma ineligible for stem-cell transplantation. The average survival rate was between 4.6-22.4 months depending on the first intention treatment, with an absence of disease progression from 1.6-5.9 months. Phase 3 studies are underway.
Read the PubMed abstract

Blood ; 54-58 ; July 2007

Orphan Drugs
Twelve EMEA orphan drug designations for July

The COMP (Committee for Orphan Medicinal Products) adopted the following 12 positive opinions on orphan medicinal product designation at its July meeting for the treatment of:

- hepatocellular carcinoma (two products)
- acute myeloid leukaemia
- cutaneous forms of lupus erythematosus
- chronic non-infectious uveitis
- cystic fibrosis (two products)
- hereditary factor X deficiency
- ornithine-transcarbamylase deficiency
- Hodgkin's lymphoma
- tuberculosis
- renal cell carcinoma

Consult the European Registry for Orphan designations
Consult the Orphanet list of orphan drugs authorised for marketing in Europe

Marketing authorisation recommended for Yondelis for advanced soft tissue sarcoma
The CHMP has recommended marketing authorisation for Yondelis (trabectedin), from PharmaMar S.A., for the treatment of advanced soft tissue sarcoma. Yondelis is the 42nd orphan medicinal product to receive a positive opinion. EMEA review began on 16 August 2006 with an active review time of 210 days.
Switzerland authorises therapeutic vaccine for glioblastoma
DCVax-Brain, made by Northwest Biotherapeutics, has received authorisation from the Swiss Institute of Public Health (Bundesamt fur Gesundheit) to make the product commercially available for the treatment of glioblastoma in Switzerland. Glioblastoma are malignant astrocytic brain tumours. DCVax-Brain is the first commercially available therapeutic vaccine for such cancers and has received orphan drug status in both the US and the EU.
Carbaglu receives US fast-track designation for NAGS deficiency
The US Food and Drug Administration (FDA) has given fast track status to Carbaglu (carglumic acid) developed by Orphan Europe for the treatment of N-acetylglutamate synthase (NAGS) deficiency. NAGS deficiency, the most severe urea cycle disorder is a very rare genetic disease with extremely high plasma levels of ammonia, leading to permanent and irreversible CNS damage. Carbaglu was granted orphan drug status in the US in 1998 and in Europe in 2000. It received EU marketing authorisation in 2003. The FDA granted Carbaglu a fast tract designation in May 2007 as it is intended to treat a serious or life-threatening condition and potentially address an unmet medical need.
Rare disease clinical trial design: the role of evidence-based medicine
While randomised controlled trials are considered the gold standard, they are unfortunately not often feasible for rare diseases, which by their very nature have small sample sizes. Thus the authors consider the utility and validity of evidence-based medicine and particularly historical analysis. They conclude that evidence-based methodology can "minimize bias" and help "maximize the truth" of observed new data.
Read the Pubmed abstract

Cancer Control ; 160-166 ; April 2007

FDA grants for rare disease medicine clinical trials available
The Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) is pleased to announce the availability of funds for fiscal year (FY) 2009 and FY 2010 in the form of grant awards to support clinical trials on the safety and effectiveness of products for rare diseases and conditions. Contingent on availability of FY 2009 and FY 2010 funds, it is anticipated that $14.2 million will be available for new applications, competing awards, and non competing continuation awards. For FY 2009, the application receipt date is 6 February, 2008, and for FY 2010, the application receipt date is 4 February, 2009.

These studies are intended to provide acceptable data to the FDA that will substantially contribute to the approval of new products, or new indications for already marketed products. In the FDA OOPD grants program, products for rare diseases and conditions (orphan products) are defined as drugs, biologics, medical devices, and medical foods indicated to treat or diagnose a rare disease or condition with a prevalence of fewer than 200,000 people in the United States.

The complete text of the FDA request for applications is available.

Grants for Global Health rare disease programs available
Support for the creation of new multidisciplinary global health educational and research programs is available from the Fogarty International Center of the National Institutes of Health in the US. Many international and multinational collaborative research efforts have been developed with a focus on rare diseases, including cancers and neurological disorders. The grant aims to increase interactions among global health researchers in diverse fields, and to encourage new investigators to consider working in global health. A major component of the grant is the development of new multidisciplinary curricula and associated activities. Opportunity is restricted to certain low and middle income countries as described by the World Bank. If you have an interest in this program, please contact Dr. Flora Katz of the Fogarty International Center to discuss specific details or questions. For more information

News from the Patients' Associations
RAPSODY workshop studies centres of reference and RD patient needs
Eurordis embarked on the DG Sanco supported Rare Disease Patient Solidarity project (RAPSODY) in May 2006 with the aim of improving quality and access to essential services for rare disease patients at the European level.

A synthesis of the preliminary outcomes of 11 national workshops on European Networks of Centres of Reference (ENCR) was presented at a workshop in Prague on 12-13 July. National reports indicate that the added value of European Reference Networks is expected to be real and impressive.

Anticipated benefits include a global and multidisciplinary approach to patients' problems, more accurate diagnoses, the possibility to collect sufficient data for conducting clinical research, good value for money, and the external evaluation of certified centres. Networks are likely to be committed to cooperation in order to elaborate best practice guidelines and to share data and biological resources. All participants recommended taking a bureacratic approach and giving preference to the development of standards.

Further progress of the RAPSODY project will be presented at the European Conference on Rare Diseases in Lisbon on 27-28 November 2007.


What's on Where?
8th International Congress of Autism: A World of Possibilities
Date: 31 August - 2 September 2007
Venue: Oslo, Norway

The congress will be hosted by members of the Autism Association of Norway scientific committee.
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1-day Conference: Clinical Research for Rare Diseases: Opportunities, Challenges and Solutions
Date: 5 September 2007
Venue: Washington, DC
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Rare Diseases Research: Building on Success - a European Conference
Date: 13 September 2007
Venue: Charlemagne Building- Brussels, Belgium

This EC conference will focus on increasing the visibility of rare diseases research and raising awareness within the 27 EU Member States and the European Parliament on the research needs in this area, providing the rare diseases community with the opportunity to express their needs in terms of research, and the EC with input for future FP7 calls for research proposals.
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International Conference on Rare Diseases and Orphan Drugs (ICORD)
Date: 14-15 September, 2007
Venue: Brussels, Belgium
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4th Stem Cell Gene Therapy Conference
Date: 13-17 September 2007
Venue: Halkidiki, Thessaloniki, Greece
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EuroGentest Workshop on internal auditing for genetic testing laboratories
Date: 20-21 September 2007
Venue: Leuven, Belgium

Registration is open for this EuroGentest workshop on internal audit for genetic testing laboratories that will feature presentations, role play, video fragments and group discussions on how to prepare, execute and report internal audits. Registration deadline: 15 July 2007

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The Third World Congress of Alpha1-Antitrypsin deficiency patients
Date: 28-30 September 2007
Venue: Rome

Each participating country/group will be expected to give a short presentation to the congress on patients, possibilities and problems in their area to provide a perspective on the Alpha-1 situation world-wide.
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EFGCP Children's Medicines Working Party 3rd Annual Conference on EU Paediatric Regulation
Date: 9 October 2007
Venue: Brussels, Belgium

First European Experiences & Strategic Outlook
With a pre-conference workshop on 8 October on the background of off-label drug use in children, US and EU paedriatric legislations, and the basics of child physiology and paediatric clinical trials.
More details on the conference and workshop.

8th EPPOSI Partnering Workshop on Orphan Drugs
Date: 18-19 October 2007
Venue: Copenhagen

This year's workshop is dedicated to exploring the topic The Reality of Orphan Medicines and will provide a platform for consensus building and the cultivation of partnerships between patients, academia, and industry as well as European and member state authorities in order to convert policy issues and scientific developments into therapies for rare diseases.

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3rd International Meeting on Congenital Disorders of Glycosylation
Date: 18-19 October 2007
Venue: Paris

This international meeting on CDG is preceeded by the 3rd Orphan Focus Course on "Protein Glycosylation in Health and Disease" on Oct 16-17.

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Biology and clinical applications of cord blood cells
Date: 19-21 October 2007
Venue: Paris, France
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4th European Conference on Rare Diseases (ECRD 2007)
Date: 27-28 November 2007
Venue: Lisbon, Portugal

This important rare disease conference will be held in English and simultaneously translated into French, German, Portuguese and Spanish.
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15th Annual Meeting, Int'l ALS/MND Associations Alliance & 18th ALS/MND Int'l Symposium
Date: 1-3 December 2007
Venue: Toronto, Canada
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Press & Publications
Pediatric Lymphomas
Addressing the pathogenesis, diagnosis, therapy, and delayed complications of paediatric lymphomas, this text includes historical perspectives and practical advice based on a critical and balanced selection of data.

Authors: Howard J. Weinstein, Melissa M. Hudson, and Michael P. Link -Eds
Publisher: Springer, 2007.

Unstrange Minds: Remapping the World of Autism
The history and epidemiology of autism is presented for professionals and for parents of autistic children. Valuable information concerning interventions and educational settings is provided. Written by a father and scientist trying to better understand his daughter and describe her disorder.

Author: Roy Richard Grinker
Publisher: Basic Books, 2007.

Diseases of the Thyroid in Childhood and Adolescence
This book provides interesting insights into thyroid diseases, including rare conditions, in children and adolescents.

Authors: Gerasimos E. Krassas, Scott A. Rivkees, and Wieland Kiess -Eds.
Publisher: Karger, 2007


Orphanews Europe, the newsletter of the Rare Diseases Task Force
Orphanews Europe is supported by the European Commission's DG SANCO
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Louise Taylor
Contact Us
Editorial Board: Ségolène Aymé, Catherine Berens, Kathy Beuzard-Edwards, Helen Dolk, Anders Fasth, Edmund Jessop, Matthieu Levi-Strauss, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Claire Scharf-Kroener, Janos Sandor, Arrigo Schieppati, Rumen Stefanov, Domenica Taruscio, Joan Luis Vives Corrons
For more information on the Rare Diseases Task Force
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