24 December 2008 print
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The true measure of a civilisation can be taken by the way that it cares for its most vulnerable members…
No author has been attributed to the above quotation because it has been uttered in varying forms by several distinguished individuals – including Mahatma Ghandi, Winston Churchill, and Pearl S. Buck – all of whom made the same observation in reference to different groups – prisoners, the elderly, the very young, the poor, and, yes, the ill. In 2008, Europe has passed this test of humanity, demonstrating to the world the type of civilisation we are capable of being through the collective actions taken on behalf of some very vulnerable members of the community – the rare disease patients and their families. So many toiled so hard this year to organise the policies falling into place that will protect and benefit us all in the long run. As the year draws its final breath, it is a time of reflection and the moment for gratitude. OrphaNews Europe takes this opportunity to acknowledge the persons and institutions who shaped our newsletter this year either by generating the amazing array of activities on which we reported, by their contributions to our newsletter explaining their work, or simply by taking the time to comment on and improve the contents of the newsletter. These include: Alstrom Syndrome UK, Olga Arguedas, Ségolène Aymé and the Orphanet teams operating in 38 countries, Catherine Berens, the British Paediatric Surveillance Units, Conticanet, Peter Corry, Dorica Dan, Helen Dolk, ECORN-CF, Uta Emmig, EUROCAT, Nick Fahy, Anders Fasth, Alexandra Fourcade, Laura Fregonese, Stephen Groft, Jolanda Huizer, Edmund Jessop, Alastair Kent, Anneli Larsson, Yann Le Cam and the employees and volunteers at Eurordis, Sophie Koutouzov, Virginia Llerra and the Geiser foundation (who are putting rare diseases on the map in Latin America), Jordi Llinares Garcia, Abbey Meyers, Antoni Montserrat, Manuel Posada de la Paz, Ewa Pronicka, Pr. Hilger Ropers, Rumen Stefanov, Ana Stavljenic-Rukavina, Domenica Taruscio, Treat-NMD, Unique, Thomas Wagner, Kersten Westermark and the COMP committee of the EMEA, in addition to the researchers from all four corners of the planet who produced scientific studies that bring us one step closer to understanding, preventing and treating rare diseases, and so many others who have gone beyond the call of duty for a mix of professional and personal reasons and because their private moral compass tells them it is the correct thing to do. To all the men and women striving to make life better for rare disease patients and their families…thank you and may your holiday season be filled with joy.


Spotlight on...
The road less travelled…a geneticist urges developing countries to take their own path and prioritise rare monogenic disorders
The thirteenth Human Genome Meeting, held in Hyderabad, India, in late September presented an opportunity for invited speaker Professor Hans-Hilger Ropers to express his concern with the genomic research priorities some developing countries are adopting. These priorities follow Western epidemiological prerogatives instead of reflecting the unique genetic landscape many developing countries face: specifically, the rare, often severe, monogenic disorders that have a higher prevalence in certain developing countries. Western genomic research programmes prioritise complex multi-gene disorders (such as diabetes and heart disease) that have a high prevalence in rich, largely sedentary countries and which also dangle the carrot of potential lucrative blockbuster treatments. Many developing nations, however, especially those that allow consanguineous marital and parenting arrangements, have a significantly higher frequency of miscarriages, developmental defects and particularly intellectual deficit, which Professor Ropers qualifies as the "biggest unmet challenge in clinical genetics".

His presentation in Hyderabad echoed an article which Professor Ropers was invited to write for the American Journal of Human Genetics and which was published in August 2007. OrphaNews Europe asked Professor Ropers, a human geneticist at the Max Planck Institute for Molecular Genetics in Berlin, Germany, to elaborate on his ideas, and particularly the recommendations he would propose to developing countries defining their genomic research priorities and policies:

OrphaNews Europe: Why do single gene disorders deserve more attention?

Professor Ropers: First, it is likely that monogenic disorders are more common than previously thought, but often they are not recognised as such, because in industrialized societies like ours, single gene disorders are rarely familial. This holds for severe autosomal dominant disorders, where carriers of the gene defect are clinically affected and will rarely reproduce, but also for autosomal recessive defects: in the German population, where on average, each couple has 1.4 children, most affected children are isolated cases; in this situation, the possibility of a genetic causation will often not be considered. Secondly, it is becoming increasingly clear that the complexity of common disorders is often due to genetic heterogeneity, with many different gene defects giving rise to the same phenotype. This is true for mental retardation, where the number of underlying gene defects could run into the thousands, but also for autism and probably for many other disorders which are considered as primarily multifactorial. So far, no more than 10 percent of the human genes have been linked to disease; clearly, this is just the proverbial ‘tip of the iceberg’.

OrphaNews Europe: What could a developing country gain by switching its genomic research priority to rarer monogenic conditions?

Professor Ropers: Developing countries have other health problems than rich, developed ones, such as malnutrition and infectious diseases due to scarcity of food and clean water, or a high perinatal mortality due to low hygienic standards and lack of education. Undoubtedly, these factors can also influence the physical and mental development of a child. But contrary to what most health care policy makers believe, these factors are not the only explanation, and probably not even the most important one, for the higher early childhood mortality, the high rate of developmental defects and the frequent intellectual disability (ID) observed in many developing countries. Given the high rate of parental consanguinity in Arab countries, Turkey, Egypt, Iran, Pakistan and parts of India, it is likely that recessive defects are a major reason for these health problems, and this is supported by numerous observations, e.g. the fact that such conditions are also common in families living abroad, e.g. Pakistanis living in the UK or Turkish families living in Germany.

Contrary to many complex disorders such as type 2 diabetes and obesity, which are lifestyle related, become manifest only later in life or are relatively mild, single-gene disorders are mostly severe, early onset conditions, necessitating life-long care and support. Single gene disorders are also costly: e.g., lifetime costs for the fragile X mental retardation syndrome (FXS) amount to 1 to 2 million euros in developed countries. As an MD and a clinical geneticist, I think that it is our obligation to first focus on the severe genetic disorders before turning to the milder, late-onset conditions. In populations with large consanguineous families, carrier detection and prenatal diagnosis is remarkably efficient in preventing recessive disorders, and thus, their molecular elucidation will significantly reduce health care costs in developing countries. Moreover, identification of the molecular defect is the basis for understanding the relevant pathogenetic mechanisms, which in turn is the key to the development of (patentable) therapeutic drugs.

OrphaNews Europe: Why have governments and industry worldwide to date invested so much in the search for DNA variants in patients with more common complex disorders?

Professor Ropers: In the early 1990s, several important monogenic disorders including Duchenne muscular dystrophy, cystic fibrosis and FXS had already been elucidated, and for the leading laboratories, using positional cloning strategies to identify gene defects underlying Mendelian disorders was becoming routine. This was also the time when the second 5 year plan for the Human Genome Project was written, which requested more money than any previous research project in biology. In this context, presenting common disorders as the future target of genome research was a clever move to ensure continued public support for this endeavour.

This plan was based on the ‘common disorder – common variant’ (CDCV) hypothesis – the assumption that for most or all common disorders, there are common genetic risk factors – and it was fuelled by the expectation that within a decade or so, it would be possible to prevent or treat many of these disorders. However, this hypothesis was wrong. Today, 15 years later, after spending billions of dollars for genome wide association studies (GWAS), it is clear that the CDCV hypothesis only holds for a small minority of complex disorders (see also News Feature, Nature 456:18-21, 2008). Strictly speaking, this does not rule out the possibility that specific gene defects play an important role in the pathogenesis of some of the common disorders, as GWAS are only able to ‘see’ changes that are evolutionarily old and shared by many of the patients. Fortunately enough, whole genome sequencing is becoming cheaper every month, and sooner rather than later it will replace GWAS as the strategy of choice for finding sequence variants that predispose to disease.

OrphaNews Europe: What is needed to help a developing country define and implement research policies that would better reflect and serve its particular health needs?

This is an extremely delicate matter. For many years, genome research in industrialized countries was entirely focused on common diseases. For developing countries setting up their own genome programs and trying to catch up, it was therefore natural to think along the same lines, particularly after having been told for half a generation that identifying risk factors for common diseases is a lucrative business that will pave the way for the development of blockbuster drugs. One also has to understand that in most of these countries, genome research has to make money to survive, because compared to the USA, the UK and several European countries, public support is quite limited. For this reason, the Indian Genome Variation initiative is devised as a hub for early stage clinical trials on behalf of foreign pharmaceutical companies.

To some extent, the orientation of this program may also be influenced by its organization. When setting up genome research in a country as large and multi-faceted as India, there is probably no alternative to a top-down approach involving the big institutes for Life Sciences, and this is exactly how this endeavour is presently organized. This is the right setting for GWAS involving large cohorts of patients and controls, but less so for the elucidation of hundreds or thousands of different recessive gene defects underlying early onset disorders, which depends in the first place on the recruitment and thorough clinical characterization of large consanguineous families. Thus, the most important prerequisite for this kind of research is the same as required for genetic health care: a country-wide network of clinical geneticists and genetic centres. Where this infrastructure does not yet exist or is insufficient, all possible efforts should be made to strengthen genetic services and to train clinical geneticists for this task. Moreover, with the Personal Genome around the corner, it is absolutely certain that experienced clinical geneticists will soon be short in supply, not only in developing countries, but worldwide.

OrphaNews Europe: If developing countries were to heed your recommendations, how could developing and developed countries then collaborate in a way that would exploit each entity’s contribution to understanding genetic diseases?

Professor Ropers: After a series of incidents where (mostly) US-based companies successfully tried to obtain patents on Indian plants or plant-derived products, India, China and other countries have adopted legislation banning or severely restricting the exchange of biological material, even in the context of formalized collaborations involving Western countries. Fortunately, other countries where parental consanguinity is common have not followed suit, including Pakistan, India’s nearest neighbour, and Iran, where our own group has found an excellent partner for fruitful collaborative research into recessive forms of cognitive impairment.

As mentioned above, recessive disorders can only be studied efficiently in populations where parental consanguinity and large families are common, e.g. in all countries of the so-called ‘consanguinity belt’ which extends from Morocco to India. Therefore, recessive disorders are a particularly plausible target for genome research in these countries, also because such research will address one of their most important health care problems. (In my personal opinion, they even have a certain moral obligation to focus on recessive disorders, because these diseases cannot be studied elsewhere – as it should be the moral obligation of industrial countries to do what they can to defeat malaria and bilharziosis, because the countries where these disorders are common do not have the know-how or the means to fight against them effectively.)

In the past, there have been various attempts of Western genetic laboratories to recruit families with recessive disorders in the respective countries; in our case, we were fortunate that it was our Iranian colleague who identified us as his potential partner. After more than five years of collaborative research into autosomal recessive cognitive impairment, my conclusion is that these collaborations will only work if (i) there is strong support for these activities within the developing country, (ii) the collaboration is based on the principle of equality, meaning that all results will be the shared property of both partners, and (iii) if they have complementary resources and means – good intentions and trust are necessary, but not sufficient for the success of such trans-national collaborations.

OrphaNews Europe: Could you comment on the advances in technology that are lowering costs and accelerating research and the impact these could have for developing countries (and organisations) inhibited by budget constraints?

Professor Ropers: Systematic research into recessive disorders became possible only a few years ago with the availability of high resolution oligonucleotide arrays, which can be used to type several hundred thousand DNA markers in the genome in one single experiment. This has been a breakthrough for homozygosity mapping in consanguineous families and has paved the way for the chromosomal localization of many recessive gene defects. The next step, however, i.e. the identification of the specific disease-causing mutations, is still a bottleneck for this approach.

Linkage intervals determined by homozygosity mapping tend to be wide and may contain hundreds of genes; screening them for mutations one by one is extremely tedious and costly. A recent alternative entails the enrichment of relevant genomic intervals or the respective coding sequences, followed by high-throughput sequencing using novel (e.g., Illumina, ABI or Roche) ‘next generation’ sequencing platforms. At present, however, this combination of techniques is only available in a few laboratories worldwide. This is one of the reasons why international collaborations are often indispensable for this kind of research, even for laboratories in developing countries where the clinical expertise and the necessary molecular know-how are available.

However, there is hope that this situation will soon change: it is widely believed that in two years from now, (i.e. in the autumn of2010) novel sequencing platforms will be commercially available that will reduce the costs of sequencing the entire (non-repetitive portion of the) human genome to less than 1000 US$, and this development will not stop there. Thus, screening entire genomes for disease-causing mutations will no longer be the privilege of well-equipped and well-financed US-American or European groups, nor will it have to be confined to large genome centres. This will also have far-reaching implications for genetic health care and the organization of genetic services. For developing countries, this development will create a plethora of novel opportunities for making original contributions in the field of genome research – reasons enough to carefully reconsider present ideas and plans, and for avoiding the trodden path of GWAS.


EU Policy News
The report of the final French EU presidency rare disease conference is now available
The report of the fourth and last official event held under the auspices of the French Presidency of the European Union, the National Strategies and Action for Rare Diseases in Europe conference that took place in Paris last 18 November is now available for consultation.
No patents for embryonic stem cells in Europe
An appeal panel at the European Patent Office (EPO) in late November upheld a June decision ruling against patenting for human stem cell cultures prepared from embryos that are destroyed in the process. The Enlarged Board of Appeal of the EPO reached this decision following appeal proceedings on the application of Wisconsin Alumni Research Foundation/Thomson involving a method for obtaining embryonic stem cell cultures from humans and other primates. The EPO provides a uniform application procedure for individual inventors and companies seeking patent protection in up to 38 European countries. According to a press release, the decision issues from provisions of the European Patent Convention, the legal basis for the EPO, and the EU Biotechnology Directive (98/44/EC), implemented in the European Patent Convention in 1999. Specifically, Rule 28 EPC informs the general prohibition under its Article 53(a) EPC by prohibiting patents on uses of human embryos for industrial or commercial purposes. Consult the EPO decision
Policy recommendations specifically for rare cancers
Following the Rare Tumours Conference that took place on 6 November in Brussels, the European Society for Medical Oncology (ESMO) staged a press conference at the European Parliament in December to issue a set of political recommendations designed to better meet the challenges of treating rare cancers. Rare cancers, which encompass all paediatric cancers, represent 20% of all cancers. Survival rates throughout Europe differ significantly and care for many forms is considered insufficient. Thus ESMO has developed recommendations designed to heighten awareness and the priority status for rare cancers. The recommendations suggest actions for stakeholders to take and policies for both the EU and individual Member States. The recommendations are grouped to address regulatory barriers, methodological barriers, the need for centres of expertise and European reference networks, barriers to patient access to care, education of healthcare professionals, and access to information for rare cancers. In a press release, the society specified that the recommendations “tackle issues like the mandatory referral of all suspected cases to centres of expertise, recognition of alternative trial designs for rare cancers … as well as granting access to the best care for all European rare cancers patients” The recommendations emphasise that geographic boundaries should not prevent patients from receiving quality care. Furthermore, the point was made that patients with a fatal form of disease will tolerate more risk in their treatment. Thus, the society would like regulators to raise the bar to allow a higher level of uncertainty in clinical trials for rare cancers. ESMO hopes that their recommendations will enable both the EU and individual Member States to tailor services and treatments to better meet the needs of rare cancer patients and their families. Consult the ESMO Political Recommendations on Rare Cancers

National & International Policy Developments
Declaration of Helsinki revisions protect clinical trial participants around the world
The World Medical Association (WMA), an independent international organisation founded in 1947, provides a forum for its member associations to achieve consensus on high standards of medical ethics and professional competence, and to promote the professional freedom of physicians worldwide. The WMA developed the Declaration of Helsinki, a set of ethical principles adopted to guide medical research involving human subjects. Although not legally binding, the Declaration of Helsinki is considered the reference document for human research ethics. The WMA recently announced that a revised version of the Declaration of Helsinki has now been adopted. A press release issued by the WMA states that “refusing to bow to pressure from industry and government regulatory agencies, the WMA … reaffirmed its controversial stand against practices that open the door to exploitation of research subjects, particularly in developing countries”. The revised document stipulates that for studies comparing new experimental treatments to existing ones, the use of placebos may only be done “in very limited circumstances” under which patients are spared serious or irreversible injury. The revisions also reaffirm that research participants be allowed to benefit from research results by having access to beneficial interventions. The revised declaration also specifies consent procedures for human materials such as blood, tissue and DNA, and requires that trials be registered in a publicly accessible database. The revisions were drafted by a working group from five different countries following “extensive consultation” with medical associations, researchers, government and industry. This is the sixth time the Helsinki Declaration has been revised since its creation in 1964.
Tyrosinemia type 1 returns to Dutch newborn screening programme
More and more rare diseases are treatable if diagnosed before irreversible damage occurs. In January 2007, the newborn screening programme of the Netherlands was extended to include 17 rare disorders. However, one month later the Minister of Health decided to postpone tyrosinemia type 1 screening due to problems with the methodology. The screening laboratories identified an improved method, and in October 2008 tyrosinemia type 1 newborn screening started again. Tyrosinemia type 1 is an inborn error of amino acid metabolism characterised by hepatorenal manifestations. The early-onset acute form of the disorder manifests between 15 days and 3 months after birth with hepatocellular necrosis associated with vomiting, diarrhoea, jaundice, hypoglycaemia, oedema, ascites and gastrointestinal bleeding. Septicaemia is a frequent complication. Renal tubular dysfunction occurs and is associated with phosphate loss and hypophosphataemic rickets. If left untreated, neurologic crises with porphyria, polyneuritis and dystonia may occur in the acute form of the disorder and in rare cases may be the presenting features of the disease. Malignant hepatocellular carcinomas are frequent. Treatment involves administration of nitisinone (NTBC), which obtained European marketing authorisation in 2005 as an orphan drug for the treatment of tyrosinaemia type 1, in combination with a protein-restricted diet to prevent hypertyrosinaemia.
Other European news
Comprehensive perinatal study delivers trove of information
The European Perinatal Health Report, produced by the DG Sanco- and European Commission’s Executive Agency for Health and Consumers-funded EURO-PERISTAT project, provides comprehensive data on topics surrounding the health and care of pregnant women and newborns. The report includes a focus on specific conditions including cerebral palsy and low birthweight. Of particular interest to the rare disease community is chapter 9, Congenital Anomalies: EUROCAT, which presents the surveillance of anomalies involving structural malformations diagnosed prenatally, at birth, or within the first year of life. EUROCAT (the European Surveillance of Congenital Anomalies) is the principal information source for the epidemiology of congenital anomalies in Europe. Using EUROCAT registries and other EURO-PERISTAT sources, data from 26 countries provide a picture of congenital anomalies throughout Europe. Prevalence is broken down into subgroups based on clinical manifestations. Rates of pregnancy termination due to prenatal diagnosis of congenital anomalies are documented, revealing wide differences in prenatal diagnostics between countries, due in part to prenatal screening policies and practices and varying laws and cultural attitudes concerning pregnancy termination. The numbers of foetal deaths and stillbirths with congenital anomaly are also measured. It is emphasised nevertheless that the majority of childen born with a congenital anomaly survive the first year of life. The chapter closes with some considerations concerning future actions and policies around congenital anomalies: “The last few decades have not seen any real progress in primary prevention of congenital anomalies, as evidenced by the lack of decline in prevalence. Implementation of current knowledge with effective policies and research into causes of congenital anomalies have the potential to change this situation, with political will”.
Other International News
First systematic newborn screening tool for fragile X to be put to the test in the USA
Fragile X syndrome is an x-linked genetic disorder characterised by intellectual deficits, learning disabilities, behavioural and psychiatric problems, and physical anomalies that are often not diagnosed right away. It is the most common cause of intellectual deficit in males. Rush University Medical Center (Chicago) and UC Davis (California) have launched a pilot screening programme testing for the FMR1 gene mutation behind fragile X syndrome. It is the first systematic screening tool available for the disorder. Under the pilot study, funded by the National Institutes of Health, newborns at UC Davis, (where the test was developed) and at Rush (where the test was validated) will undergo screening in an aim to screen up to 30,000 infants over the next five years. The study is laying the foundation for eventual screening of all infants born in the USA. Existing diagnostic tools for fragile X are costly and unsuitable for universal screening. In a press release, fragile X expert and paediatric neurologist Dr. Elizabeth Berry-Kravis highlights the added-value of the test: “The significance of universal newborn screening is amplified by the fact that adults related to children with fragile X syndrome often suffer from associated, but frequently misdiagnosed ailments”. Fragile X syndrome is caused by a high number of trinucleotide repeats in the FMR1 gene located on the X chromosome. While a normal FMR1 gene typically has up to 55 repeats, a number above 200 causes fragile X syndrome. However, individuals with between 55 and 200 repeats are considered carriers and are also themselves susceptible to a range of ailments, including premature ovarian failure and fragile X-associated tremor/ataxia syndrome, often misdiagnosed as Parkinson disease. Thus the newborn screening has implications for other family members. The new tool meets all the criteria considered necessary for successful mass newborn screening: it is accurate, quick, inexpensive, and requires a small amount of DNA. Affected infants identified through the screening programme will receive management options.
Major paediatric study in the USA enters next phase
In the USA, a mammoth project designed to follow 100,000 children from birth until age 21 will study the impact of both genetic factors and the environment on health. The study seeks to investigate the factors that influence the development of conditions including birth defects, learning disabilities, autism, and cerebral palsy along with more common conditions (diabetes, asthma, and obesity). The study has entered a new phase with the naming of an additional 27 centres to receive funding, bringing the total to 36 universities, hospitals, health departments, and private companies involved in the project. In a press release, the director of the National Institutes of Health explained that the study would “yield important health information at virtually every phase of the life cycle”. The study will examine genetic, biological, and environmental samples along with statistical information compiled to investigate the relationships between health, genetics, and the environment. Designed to create a composite of the U.S. population, the study will encompass children throughout from rural, urban, and suburban settings, all income and educational levels, and all racial groups. Pregnant women will be included as well as women not yet pregnant, thus providing insight into pregnancy- and birth-related conditions. Although rare diseases are not a specific target of the study, it is hoped that the information reaped may be able to answer questions about rare childhood diseases. Recruitment is due to begin in early 2009 for an initial pilot phase of the study. Visit the National Children’s Study website

Ethical, Legal & Social Issues
Recent policy changes that expand newborn screening to diseases with no available treatment are questioned by bioethics council
In the USA, the President’s Council on Bioethics has issued The Changing Moral Focus of Newborn Screening, a white paper that discusses which ethical principles should guide newborn screening practices. Over 98% of babies born in the USA undergo screening. Amongst the 4 million screened each year, about 5,000 are identified with a serious heritable disorder. While individual US states vary in the repertoire of diseases included in their screening programmes, this white paper describes how changes in policy have shifted screening to encompass untreatable as well as treatable diseases. As many of these untreatable conditions are not well understood, some stakeholders consider their inclusion as ethically justifiable because screening could lead to knowledge of these conditions and eventually to treatment. This paper is broken down into four chapters. The first describes the practice and policies of screening. It is estimated that many parents do not understand the procedures of newborn screening or their ethical implications. One aim of this report is thus to provide information parents need to better understand the issues and hence make informed choices. The second chapter explores the ethical principles that inform screening practices and considers whether such principles are being neglected in the current climate of expanded screening. The third chapter contemplates the future of newborn screening. The last chapter considers whether screening should be mandatory and issues a recommendation for an ethical framework. The President’s Council concludes that “the potential benefits of mandatory, population-wide newborn screening for diseases for which there is no current treatment are outweighed by the potential harms. These harms will be accentuated once new DNA technologies make it possible to expand screening to target additional diseases and to detect disease susceptibility as well”. The Council does, however, acknowledge that expanded screening programs produce gains in biomedical knowledge that cannot be ignored. To this end, the authors encourage states to implement pilot studies for screening untreatable conditions on a voluntary basis with a mechanism for obtaining informed consent from parents electing to participate. Consult the white paper

Orphanet News
Dutch dentists get the drill on Orphanet
In a recent article, the Dutch editor of the Dutch Dentistry Journal identified Orphanet and the Dutch Steering Group on Orphan Drugs as important resources. The article informs dentists of the Dutch homepage of Orphanet where information on the organisation is provided along with ways to contribute if desired. The international Orphanet site is discussed as a portal to find information on a variety of services for professionals and patients, an encyclopaedia of rare disorders, information on orphan drugs, research activities and patient organisations. The possibility to look for diseases based on symptoms is considered important for dentists, as is the identification of specialised clinics. The reader is advised to clearly define what is being sought in order to avoid getting lost in the wealth of information. Consult the PubMed abstract
New Texts
Prevalence of rare diseases: Bibliographic data - 10th Edition
Prevalence or reported number of published cases listed in alphabetical order of disease
Diseases listed by decreasing prevalence or number of published cases

New Orphanet Journal of Rare Diseases Publications
Malignant mesothelioma
Nephronophthisis (published in the European Journal of Human Genetics, in association with Orphanet)


New Syndromes
Craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis
The authors report two brothers presenting with sagittal craniosynostosis, hydrocephalus, Chiari I malformation, blepharophimosis, small low-set ears, hypoplastic philtrum, radioulnar synostosis, kidney malformation, and hypogenitalism. Their father presented mild brachydactyly. Conventional cytogenetic and array CGH screening did not show any chromosomal gains or losses. Furthermore, molecular genetic screening of genes involved in different craniosynostosis syndromes failed to detect any mutations. The unique range of clinical manifestations in these two patients and the negative findings of the molecular genetic screening suggest the hypothesis of a previously unrecognised syndrome.
Read the PubMed abstract

Eur J Med Genet ; Epub ahead of print ; 6 November 2008
Scoliosis, blindness and arachnodactyly in a large Turkish family
The authors describe a 16-year-old boy from a large Turkish family who appears to have a new distinct dominantly-inherited blindness, scoliosis and arachnodactyly syndrome. He had been suffering from progressive visual loss and strabismus since he was eight years old. His 20-year-old brother had severe kyphoscoliosis, and arachnodactyly of fingers and toes. His 23-year-old sister had only eye findings but no arachnodactyly or scoliosis. His 60-year-old father had mild scoliosis, blindness and arachnodactyly and the mother was normal. Analyses of the genes FBN1, TGFBR1 and TGFBR2 did not reveal any mutations. Further studies are needed to assess the contribution of sex influence to the syndrome because the female relative is less affected.
Read the PubMed abstract

Genet Couns ; 319-330 ; 2008
A new dominantly-inherited pure cerebellar ataxia: SCA 30
The spinocerebellar ataxias (SCAs) are clinically and genetically heterogeneous. Currently, 27 forms are known, with the causative gene identified in 16. Although the majority of dominant pedigrees worldwide have SCAs 1, 2, 3, 6 or 8, new SCAs continue to be delineated. The authors describe a new disorder: SCA 30. An Australian family of Anglo-Celtic ethnicity manifested a relatively pure, slowly-evolving ataxia. Six affected and four unaffected members were examined. MRI and nerve conduction studies were performed in two. The six affected members had a relatively pure, slowly-evolving ataxia developing in mid- to late-life, with only minor pyramidal signs and no evidence of neuropathy. All had hypermetric saccades with normal vestibulo-ocular reflex gain. Only one displayed (slight) gaze-evoked nystagmus. MRI showed cerebellar atrophy with preservation of nodulus/uvula and brainstem. The responsible gene is yet to be determined, but TACSTD1 and ODZ3 are plausible candidates.
Read the PubMed abstract

J Neurol Neurosurg Psychiatry ; Epub ahead of print ; 7 November 2008
A novel Refsum-like disorder that maps to chromosome 20
In a Norwegian consanguineous family, a brother and sister and their third cousin from a small island community present with a slowly progressive disorder starting in childhood with signs of peripheral neuropathy (pes cavus, tendoachilles contracture). Hearing loss and cataract become evident in the third decade. Subsequently, patients develop a disorder of gait due to the combination of ataxia and spasticity, and a pigment retinopathy. While the clinical picture is reminiscent of Refsum disease, affected individuals have normal phytanic and pristanic acid levels in plasma, as well as normal enzymatic activity for alpha-oxidation. The disease was mapped to a 15.96 Mb region on chromosome 20 (20p11.21-q12), containing approximately 200 genes. Sequencing of 23 candidate genes failed to demonstrate detrimental sequence variants.
Read the PubMed abstract

Neurology ; Epub ahead of print ; 26 November 2008
Reciprocal 1q21.1 deletions and duplications linked to micro- or macro-cephaly and developmental and behavioural delays
Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. The authors describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively.
Read the PubMed abstract

Nat Genet ; 1466-1471 ; December 2008
MEDNIK: a new syndrome with mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia
The authors describe four families with a unique syndrome characterized by intellectual deficit, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia. A mutation in the AP1S1 gene, encoding the small subunit sigma1A of the AP-1 complex was found to be at cause. To validate the pathogenic effect of the mutation, the authors knocked down Ap1s1 expression in zebrafish. The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development.
Read the PubMed abstract

PLoS Genet ; e1000296 ; December 2008

New Genes
Leukodystrophy with spastic paraparesis and dystonia: mutations in the fatty acid 2-hydroxylase gene are linked
Homozygosity mapping in nine patients with childhood onset spasticity, dystonia, cognitive dysfunction, and periventricular white matter disease revealed inactivating mutations in the FA2H gene, encoding the enzyme fatty acid 2-hydroxylase that catalyzes the 2-hydroxylation of myelin galactolipids, galactosylceramide, and its sulfated form, sulfatide. In patients with autosomal-recessive unclassified leukodystrophy or complex spastic paraparesis, sequence analysis of the FA2H gene is warranted.
Read the PubMed abstract

Am J Hum Genet ; 643-648 ; November 2008
Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation
Clubfoot is one of the most common severe musculoskeletal birth defects, with a worldwide incidence of 1 in 1000 live births. In the present study, the authors describe a five-generation family with asymmetric right-sided predominant idiopathic clubfoot segregating as an autosomal-dominant condition with incomplete penetrance. Other lower-limb malformations, including patellar hypoplasia, oblique talus, tibial hemimelia, developmental hip dysplasia, and preaxial polydactyly, were also present in some family members. Genome-wide linkage analysis from 13 members of this family revealed a single missense mutation in PITX1, a bicoid-related homeodomain transcription factor critical for hindlimb development, and segregated with disease in this family.
Read the PubMed abstract

Am J Hum Genet ; 616-622 ; November 2008
Geroderma osteodysplastica is caused by mutations in SCYL1BP1
Geroderma osteodysplastica is an autosomal recessive disorder characterised by wrinkly skin and osteoporosis. Here the authors demonstrate that geroderma osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts.
Read the PubMed abstract

To read more about "Geroderma osteodysplastica"

Nat Genet ; 1410-1412 ; December 2008
Joubert syndrome: CC2D2A is mutated
Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, the authors identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.
Read the PubMed abstract

To read more about "Joubert syndrome"

Am J Hum Genet ; 559-571 ; November 2008
Primary ciliary dyskinesia: DNAI2 mutations at cause
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterised by chronic destructive airway disease and randomisation of left/right body asymmetry. Males often have reduced fertility due to impaired sperm tail function. The complex PCD phenotype results from dysfunction of cilia of the airways and the embryonic node and the structurally related motile sperm flagella. This is associated with underlying ultrastructural defects that frequently involve the outer dynein arm (ODA) complexes that generate cilia and flagella movement. The authors identified homozygous loss-of-function DNAI2 mutations in four individuals from a family with PCD and ODA defects. Further mutational screening of 105 unrelated PCD families detected two distinct homozygous mutations.
Read the PubMed abstract

To read more about "Primary ciliary dyskinesia"

Am J Hum Genet ; 547-558 ; November 2008
Progressive myoclonus epilepsy-ataxia syndrome: a homozygous mutation in human PRICKLE1 is at cause
Progressive myoclonus epilepsy (PME) is a syndrome characterised by myoclonic seizures (lightning-like jerks), generalised convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. This report identifies a mutation in PRICKLE1, expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.
Read the PubMed abstract

To read more about "Progressive myoclonus epilepsy"

Am J Hum Genet ; 572-581 ; November 2008
Cousin syndrome: TBX15 insufficiency causes craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature
The authors identified two unrelated individuals with a complex cranial, cervical, auricular, and skeletal malformation syndrome with scapular and pelvic hypoplasia (Cousin syndrome). Both affected individuals were homozygous for genomic TBX15 mutations that resulted in truncation of the protein and addition of a stretch of missense amino acids.
Read the PubMed abstract

To read more about "Pelvis-shoulder dysplasia"

Am J Hum Genet ; 649-655 ; November 2008
Glutaric aciduria type 3: genetic mapping to chromosome 7 and identification of mutations in c7orf10
While screening Old Order Amish children for glutaric aciduria type 1 (GA1) between 1989 and 1993, the authors found three healthy children who excreted abnormal quantities of glutaric acid but low 3-hydroxyglutaric acid, a pattern consistent with glutaric aciduria type 3 (GA3). None of these children had the GCDH mutation that causes GA1 among the Amish. The authors identified a shared homozygous 4.7 Mb region on chromosome 7. Direct sequencing of C7orf10 revealed that the three Amish individuals were homozygous for a nonsynonymous sequence variant. They then sequenced three non-Amish children with GA3 and discovered two nonsense mutations in addition to the Amish mutation. Two pathogenic alleles were identified in each of the six patients. There was no consistent clinical phenotype associated with GA3. In affected individuals, urine molar ratios of glutarate to its derivatives (3-hydroxyglutarate, glutarylcarnitine, and glutarylglycine) were elevated, suggesting impaired formation of glutaryl-CoA.
Read the PubMed abstract

To read more about "Glutaryl-CoA oxidase deficiency"

Am J Hum Genet ; 604-609 ; November 2008
Spondylocostal dysostosis: mutation of hairy-and-enhancer-of-split-7 at cause in humans
Spondylocostal dysostosis (SCD) is an inherited disorder that is characterised by the presence of extensive hemivertebrae, truncal shortening and abnormally aligned ribs. It arises during embryonic development by a disruption of formation of somites. Previously, three genes causing a subset of autosomal recessive forms of this disease have been identified. These genes are all important components of the Notch signalling pathway, which has multiple roles in development and disease. Here the authors have used autozygosity mapping to identify a mutation in a fourth Notch pathway gene, Hairy-and-Enhancer-of-Split-7 (HES7), in an autosomal recessive SCD family. Functional analysis revealed that the mutant HES7 was not able to repress gene expression by DNA binding or protein heterodimerization. This is the first report of mutation in the human HES7 gene, and provides further evidence for the importance of the Notch signalling pathway in the correct patterning of the axial skeleton.
Read the PubMed abstract

To read more about "Spondylocostal dysostosis, autosomal recessive"

Hum Mol Genet ; 3761-3766 ; 1 December 2008
Genital hypoplasia and severe skeletal defects: loss of function of the PLZF gene at cause
Deletions of 11q23 are associated with intellectual deficit, craniofacial dysmorphism, microcephaly and short stature. The authors present a patient with similar clinical findings in addition to absence of the thumbs, hypoplasia of the radii and ulnae, additional vertebrae and ribs, retarded bone age and genital hypoplasia. Genomic DNA from the patient revealed a germline mutation of the PLZF gene, one of five partners fused to the retinoic acid receptor alpha in acute promyelocytic leukaemia.
Read the PubMed abstract

J Med Genet ; 731-737 ; November 2008

Research in Action
Fundamental Research
Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium
Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment protein NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol.
Read the PubMed abstract

To read more about "Niemann-Pick disease, type C"

Nat Med ; 1247-1255 ; November 2008
Clinical Research
Myotonic dystrophy type 2 found in two of sixty-three persons diagnosed as having fibromyalgia
Because of its high prevalence, fibromyalgia (FM) is a major general health issue. Myotonic dystrophy type 2 (DM2) is a recently described autosomal-dominant multisystem disorder. Besides variable proximal muscle weakness, myotonia, and precocious cataracts, muscle pain and stiffness are prominent presenting features of DM2. After noting that several mutation-positive DM2 patients had a previous diagnosis of FM, suggesting that DM2 may be misdiagnosed as FM, the authors invited 90 randomly selected patients diagnosed as having FM to undergo genetic testing for DM2. Of the 63 patients who agreed to participate, 2 (3.2%) tested positive for the DM2 mutation.
Read the PubMed abstract

To read more about "Proximal myotonic myopathy"

Arthritis Rheum ; 3627-3631 ; November 2008
The Human Phenotype Ontology: a tool for annotating and analysing human hereditary disease
Computational analysis of phenotypic data has been hampered by lack of adequate computational data structures. Therefore, the authors have developed a Human Phenotype Ontology (HPO) with over 8000 terms representing individual phenotypic anomalies and have annotated all clinical entries in Online Mendelian Inheritance in Man with the terms of the HPO. The authors show that the HPO is able to capture phenotypic similarities between diseases in a useful and highly significant fashion. Consult the HPO tool
Read the PubMed abstract

Am J Hum Genet 2008 ; 610-615 ; November 2008
The 17q21.31 microdeletion syndrome: a clinical and molecular delineation
The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained intellectual deficit. The authors report the molecular and/or clinical characterisation of 22 individuals with this syndrome. They estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays they narrow the 17q21.31 critical region to a 424 kb genomic segment encompassing at least six genes.
Read the PubMed abstract

To read more about "Monosomy 17q21.31"

J Med Genet ; 710-720 ; November 2008
Genetic testing for paediatric neurological disorders
Paediatric neurological disorders encompass a large group of clinically heterogeneous diseases, of which some are known to have a genetic cause. Over the past few years, advances in nosological classifications and in strategies for molecular testing have substantially improved the diagnosis, genetic counselling, and clinical management of many patients, and have facilitated the possibility of prenatal diagnoses for future pregnancies. However, the increasing availability of genetic tests for paediatric neurological disorders is raising important questions with regard to the appropriateness, choice of protocols, interpretation of results, and ethical and social concerns of these services. The authors discuss how these concerns affect genetic counselling.
Read the PubMed abstract

Lancet Neurol ; 1113-1126 ; December 2008
Primary progressive aphasia: Abeta amyloid and glucose metabolism in three variants
Alzheimer disease (AD) is found at autopsy in up to one third of patients with primary progressive aphasia (PPA), but clinical features that predict AD pathology in PPA are not well defined. The authors studied the relationships between language presentation, Abeta amyloidosis, and glucose metabolism in three PPA variants. They found that language phenotype in PPA is closely related to metabolic changes that are focal and anatomically distinct between subtypes, but not to amyloid deposition patterns that are diffuse and similar to AD.
Read the PubMed abstract

To read more about "Aphasia, primary progressive"

Ann Neurol ; 388-401 ; October 2008
Chromosome 6q16 deletion: detailed phenotype-genotype study narrows the critical region for Prader-Willi-like phenotype
Most patients with an interstitial deletion of 6q16 have Prader-Willi-like phenotype, featuring obesity, hypotonia, small hands and feet, and developmental delay. Here the authors describe a detailed clinical presentation of five patients with overlapping interstitial 6q16 deletions and Prader-Willi-like phenotype. These patients share the following main features with previously reported cases: global developmental delay, hypotonia, obesity, hyperphagia, and eye/vision anomalies. The authors were able to narrow the shortest region of deletion overlap for the presumed gene(s) involved in the Prader-Willi-like syndrome to 4.1 Mb located at 6q16.1q16.2. These results support the evidence that haploinsufficiency of the SIM1 gene is responsible for obesity in these patients. A possible involvement of the GRIK2 gene in autistic-like behaviour, of POPDC3 in heart development, and of MCHR2 in the control of feeding behaviour and energy metabolism is also hypothesised.
Read the PubMed abstract

To read more about "Non-distal monosomy 6q"

Eur J Hum Genet ; 1443-1449 ; December 2008
Infantile spinocerebellar ataxia and mitochondrial recessive ataxia syndrome associated with neuronal complex I defect and mtDN
Infantile-onset spinocerebellar ataxia (IOSCA) is a severe neurodegenerative disorder caused by the recessive mutation in PEO1. The results of mtDNA analyses were compared to findings in a similar juvenile or adult-onset ataxia syndrome, mitochondrial recessive ataxia syndrome (MIRAS), caused by the W748S mutation in the mitochondrial DNA polymerase (POLG). The authors show here that IOSCA brain does not harbour mtDNA deletions or increased amount of mtDNA point mutations, whereas MIRAS brain shows multiple deletions of mtDNA. However, IOSCA, and to a lesser extent also MIRAS, show mtDNA depletion in the brain and the liver. The results of this study indicate that IOSCA is a new member of the mitochondrial DNA depletion syndromes.
Read the PubMed abstract

To read more about "Spinocerebellar ataxia, infantile onset"

Hum Mol Genet ; 3822-3835 ; 1 December 2008
Retroperitoneal fibrosis: asbestos-related pleural and lung fibrosis in patients
Retroperitoneal fibrosis (RPF) is a rare fibroinflammatory disease that leads to hydronephrosis and renal failure. In a case-control study, the authors have recently shown that asbestos exposure was the most important risk factor for RPF in the Finnish population. The aim of this study was to evaluate the relation of asbestos exposure to radiologically confirmed lung and pleural fibrosis among patients with RPF. An asbestos-related pleural finding was common in the asbestos-exposed RPF patients, but only a few of these patients had parenchymal lung fibrosis. RPF without asbestos exposure was not associated with pleural or lung fibrosis. The findings suggest a shared aetiology for RPF and pleural fibrosis and furthermore possibly a similar pathogenetic mechanism.
Read the PubMed abstract

To read more about "Retroperitoneal fibrosis"

Orphanet J Rare Dis ; 3:29 ; November 2008
Gene Therapy
Xeroderma pigmentosum: homing meganucleases constitute a possible strategy for repairing DNA lesions
Xeroderma pigmentosum is a monogenic disease characterised by hypersensitivity to ultraviolet light. The cells of xeroderma pigmentosum patients are defective in nucleotide excision repair, limiting their capacity to eliminate ultraviolet-induced DNA damage, and resulting in a strong predisposition to develop skin cancers. The use of rare cutting DNA endonucleases-such as homing endonucleases, also known as meganucleases, constitutes one possible strategy for repairing DNA lesions. The authors describe two engineered heterodimeric derivatives of the homing endonuclease I-CreI that cleave DNA from the human XPC gene (xeroderma pigmentosum group C), in vitro and in vivo. These derivatives induced high levels of specific gene targeting in mammalian cells while displaying no obvious genotoxicity.
Read the PubMed abstract

To read more about "Xeroderma pigmentosum"

Nature ; 107-111 ; 6 November 2008
Diagnostic Approaches
Autoimmune polyendocrinopathy syndrome type I: autoantibodies against type I interferons as an additional diagnostic criterion
In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The authors recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. In this study, the authors sought to detect autoantibodies against interferon-alpha2 and interferon-omega in antiviral neutralization assays in 39 APS-I patients. They found antibodies against interferon-alpha2 and/or interferon-omega in all 39 APS-I patients. Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.
Read the PubMed abstract

To read more about "Autoimmune polyendocrinopathy, type 1"

J Clin Endocrinol Metab ; 4389-4397 ; November 2008
Inherited epidermolysis bullosa with pyloric atresia: prenatal diagnosis by immunofluorescence analysis of villous trophoblasts
Genetic mutations invalidating the genes for integrin alpha6beta4 and, in some cases, plectin are associated with junctional and simplex epidermolysis bullosa with pyloric atresia. These recessive inherited conditions are characterised by pregnancies with fetal bullae, pyloric atresia, polyhydramnios, and neonatal mucocutaneous blistering, which often results in early postnatal demise. To date, first-trimester DNA-based prenatal diagnosis is not applicable to affected kindred carrying as yet unidentified genetic mutations. Here, the authors show that first-trimester chorionic villi strongly express both integrin alpha6beta4 and plectin, which persist throughout the pregnancy. Based on this observation, they implemented 25 prenatal diagnoses in kindred at risk for by immunomapping, which identified three PA-JEB-affected foetuses and 22 healthy ones. In 19 cases, including the three PA-JEB pregnancies, the results were confirmed by chorionic villous DNA-based tests, which also led to the identification of seven previously unreported mutations in the alpha6beta4 integrin genes. The prediction was further sustained by the birth of 22 healthy babies. These results validate chorionic villi immunofluorescence examination as a tool for prenatal diagnosis of junctional and simplex epidermolysis bullosa with pyloric atresia and indicate that this procedure could be devised for EB with muscular dystrophy, which is also associated with genetic mutations in plectin.
Read the PubMed abstract

To read more about "Epidermolysis bullosa"

J Invest Dermatol ; 2815-2819 ; December 2008

Patient Management and Therapy
What process attributes of clinical genetics services could maximise patient benefits?
There is limited evidence about what process attributes of clinical genetics services may be highly valued by patients and service providers. The aim in this qualitative grounded theory study was to explore what process attributes may be highly valued by those stakeholders. Seven focus groups and nineteen one-to-one interviews were conducted. Five process attributes were identified as highly valued by patients and health professionals: (1) local and accessible services (2) open access and follow-up, (3) coordinated, tailored family care, (4) quality of the patient-clinician relationship and (5) time to talk. These findings will be useful in designing models of service delivery that could be tested in intervention studies.
Read the PubMed abstract

Eur J Hum Genet ; 1467-1476 ; December 2008
Prader-Willi syndrome: recommendations for diagnosis and management
An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs and 85 additional registered participants. Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international Prader-Willi syndrome (PWS) conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioural disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioural problems from psychiatric illness.
Read the PubMed abstract

To read more about "Prader-Willi syndrome"

J Clin Endocrinol Metab ; 4183-4197 ; November 2008
Behcet disease: EULAR management recommendations
Nine recommendations were developed for the management of different aspects of Behcet disease by a multidisciplinary committee including experts from six European countries plus Tunisia and Korea. Recommendations related to the eye, skin-mucosa disease and arthritis are mainly evidence based, but recommendations on vascular disease, neurological and gastrointestinal involvement are based largely on expert opinion and uncontrolled evidence from open trials and observational studies. The need for further properly designed controlled clinical trials is apparent.
Read the PubMed abstract

To read more about "Behcet disease"

Ann Rheum Dis ; 1656-1662 ; December 2008
Refractory inflammatory myopathies: a high incidence of disease flares in an open pilot study of infliximab
To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies, a total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to the International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.
Read the PubMed abstract

Ann Rheum Dis ; 1670-1677 ; December 2008
Neuroblastoma: virus-specific T cells engineered to coexpress tumour-specific receptors
Cytotoxic T lymphocytes (CTLs) directed to nonviral tumour-associated antigens do not survive long term and have limited antitumour activity in vivo, in part because such tumour cells typically lack the appropriate costimulatory molecules. The authors engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumour-associated antigen expressed by human neuroblastoma cells. They reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumour activity mediated through their chimeric receptors. They show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity.
Read the PubMed abstract

To read more about "Neuroblastoma"

Nat Med ; 1264-1270 ; November 2008

Orphan Drugs
Six EMEA orphan drug designations for December

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

- acute liver failure
- systemic sclerosis
- Stagardt disease
- medullary thyroid carcinoma
- retinitis pigmentosa
- pancreatic cancer
Consult the European Registry for Orphan designations
Consult the Orphanet list of orphan drugs authorised for marketing in Europe


Partnersearch, Job Opportunities
Network of Excellence CliniGene seeks pharmacist or MD specialising in gene transfer & therapy regulation oriented research
A position is available for a pharmacist to work in collaboration with the six Technology-Task Forces and the Biosafety and Immunotoxicology platforms (PF) of the , a project funded by European Commission DG-research. The work programme involves the compilation of safety and quality issues, biodistribution and pharmacotoxicology, building up "generic vector safety and efficacy profiles" which will help the submission of clinical trial dossiers to regulatory agencies. The Pharmacist/MD candidate must have a strong scientific background in gene and cell biology with potential therapeutic applications. Writing scientific and regulation related documents in English is mandatory. Interaction with the private sector is understood as full part of the job. Please forward CV + hand written letter of motivation with three references (either letters or email addresses) to:
the Clinigene-NoE coordinator,
Laboratoire de Biotechnologie & Pharmacologie Génétique Appliquées (L.B.P.A.)
Ecole Normale Supérieure de Cachan (ENSC),
61, avenue du President Wilson
F-94235 Paris-Cachan Cedex FRANCE
Email address


What's on Where?
The Multiple Faces of Lamins in Aging and Disease
Date: 6-9 January 2009
Venue: Vienna, Austria

This workshop will bring together scientists from diverse research areas, working on lamins and laminopathies – with a particular focus on newly emerging aspects in lamin function (e.g. stem cell, signaling). It is also intended to foster interdisciplinary interactions between basic scientists and clinical researchers as well as patient organizations.
For further details

EuroGentest Workshop: Validation of Diagnostic Tests in Clinical Molecular Genetics
Date: 8-9 January 2009
Venue: Prague, Czech Republic

Genetic tests must be validated before diagnostic use to ensure that they perform according to the laboratory requirements, and test validation is a formal requirement of many accreditation standards including ISO 15189. This workshop will examine the validation requirements of ISO 15189 and address practical ways of meeting them in the laboratory.
For further details

IBC Conference: Ushering in the New Era of Orphan Disease R&D, Clinical & Business Strategies
Date: 5-6 February 2009
Venue: Bethesda MD, USA

Conference organiser IBC’s Inaugural Orphan Diseases conference will aim to deliver valuable information in a strategically organized and refined format for both industry and non-profit organizations. Regulatory Perspectives from the FDA & EMEA will provide global advice for successful commercialization; Scientists from Siena Biotech, NIH & Novartis will help understand common orphan disease mechanisms; and the National Organization for Rare Disorders (NORD) will describe effective mentoring strategies for new orphan disease companies to ensure success.
For further details

International Conference on Rare Diseases and Orphan Drugs (ICORD 2009)
Date: 23-25 February 2009
Venue: Rome, Italy

More detailed information will follow soon.
For further details

Second International Rare Disease Day
Date: 28 February 2009
Venue: Everywhere!

Check with the official website in coming weeks to locate activities in your region.
For further details

BPSU 2009 Conference
Date: 3 March 2009
Venue: London, England

The British Paediatric Surveillance Unit (BPSU) has put together a programme that reviews the contribution the BPSU has made to the understanding and control of uncommon childhood conditions, it’s impact on public health policy and it’s development of partnerships.
For further details

3rd International Congress on Rare Pulmonary Diseases and Orphan Drugs
Date: 20-21 March 2009
Venue: Milan, Italy

This conference will consider new issues in rare pulmonary diseases and examine aspects of individual disorders.
For further details

Drug Information Agency 21st Annual EuroMeeting
Date: 23-25 March 2009
Venue: Berlin, Germany

Alongside the traditional areas of drug development, regulation and patient safety, topics featured include information technology, the importance of appreciating the patient perspective, and the connection between drugs and medical devices (combination products).
For further details

Molecular Mechanisms of Neurodegeneration
Date: 8-10 May 2009
Venue: Milan, Italy

Addressing the most important issues involved in protein toxicity in neurons, providing participants with updated information that could be useful to researchers in the field of neurodegenerative disorders.
For further details

7th World Congress on Melanoma
Date: 12-16 May 2009
Venue: Vienna, Austria

A joint meeting with the 5th Congress of the European Association of Dermato-Oncology. Clinicians and researchers will focus on the state of the art in prevention, recognition, and treatment of cutaneous neoplasms covering melanoma and non melanoma skin cancer as well as lymphomas and rare skin tumours. Deadline for submission of abstracts: 31 January, 2009.
For further details

8th Balkan Meeting on Human Genetics
Date: 14-17 May 2009
Venue: Cavtat, Croatia

"Rare diseases – public policy, research, diagnosis and management" is one of the topics featured in this conference. Deadline to submit an abstract is 20 January 2009.
For further details

12th International Congress on Neuronal Ceroid Lipofuscinoses
Date: 3-6 June 2009
Venue: Hamburg, Germany

The aim of this meeting is to facilitate and speed up exchange between expert scientists and physicians, but also to confront young researchers with the challenges of the largest group of degenerative brain diseases in young people. Deadline for submission of abstracts: 28 February, 2009.
For further details

Fourth International Conference on Birth Defects and Disabilities in the Developing World
Date: 4-7 October 2009
Venue: New Delhi, India

The theme of the Fourth International Conference is "Translating Research into Cost-effective Services for the Care and Prevention of Birth Defects, Preterm Birth and Consequent Disabilities". Deadline for submission of abstracts: 15 April, 2009.
For further details


Press & Publications
Everything you need to know about rare diseases in Spain
An impressive compilation of articles on rare diseases has been rounded up for a supplementary issue of Spanish regional review Anales del sistema sanitario de Navarra. The Spanish-language (abstracts for all articles are also available in English) series kicks off with Rare Diseases: Medicine’s Challenge in the XXI Century, which asserts that rare diseases are receiving an increasing amount of attention both in the scientific world and in society as a whole, presenting a coordination challenge to both entities. Rare Diseases: Concept, Epidemiology and State of the Question in Spain describes how the Spanish Network of Research Epidemiology for Rare Diseases (REpIER) developed the first atlas showing the geographical distribution of rare diseases in Spain, assessed the Spanish rare disease registries, contributed to the further development of regional plans on rare diseases, as well as to social and health actions, and established an accurate list of the group of needs to be solved. This information was contributed to the European Commission for the Communication on Rare Diseases. Rare Diseases in Paediatrics reminds readers that “few areas of paediatric care are as susceptible to the revision of lines of action, and require such professional training, as the care of the child with a rare disease (RD) and his/her family, especially if there are malformations. The lifelong impact, which many RDs entail, make continuous monitoring of the child compulsory, centred both on the evolutionary aspects of the RD and on the family’s adaptation to the problem. … In spite of the unquestionable complexity involved in exploring this field, the paediatrician must acquire knowledge of these diseases in order to ground his involvement in the diagnosis and monitoring of these patients”. Other articles address the topics of Low Height and Rare Diseases; Inborn Errors of Metabolism as Rare Diseases with a Specific Global Situation; Adult-Onset Metabolic Diseases; Laboratory Diagnosis of Rare Diseases; Genetically Based Diseases; The Pharmacist, Rare Diseases and Orphan Medicines; On-Line Resources in Dealing with Rare Diseases; Infrastructure and Resources of Social, Educational and Health Support in Rare Diseases; Needs in Rare Diseases During Paediatric Age. These articles will be of great interest to all readers of the Spanish language. Feliz navidad!
Behind the genes: Schuyler’s Monster offers the reader a poignant reminder of why we keep trudging forward
This final article for OrphaNews Europe 2008 looks beyond the genes (and proteins and chromosomes) that won’t behave the way they are supposed to; beyond the struggle for policies, treatment access, equity; beyond the ethical and legal debates, the efforts to coordinate and harmonise, and the constant fight for money and resources, coming full circle, back to the patients – so often children - and their families living day to day with a rare disease. Schuyler’s Monster is just one story amongst millions unfolding daily around the world. Written by the father of a child with bilateral perisylvian polymicrogyria, a genetic disease of cerebral cortical malformation characterised by developmental delays, epilepsy, pseudobulbar palsy, and which causes major difficulties with speech acquisition and feeding, this simply-told tale walks us through the first sickening realisation that something is awfully wrong, through the drawn out hunt for a diagnosis, to the final bitter confrontation with the truth that no one has yet figured out how to make this disease go away. Struggling to obtain access to a pricey computerised medical device that would allow their daughter to communicate electronically, this book describes the typical battles the rare disease family must be prepared to wage. Written with humour, sadness, hope and eloquence, Schuyler’s Monster describes the courage and spirit of a little girl and her parents as they fight the rare disease “monster” which they refuse to let defeat their happiness.
Schuyler’s Monster
Author: Robert Rummel-Hudson
Publisher: St. Martin’s Press
ISBN-13: 978-0-312-37242-2


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, Olaf Bodamer, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Manuel Posada de la Paz, Ewa Pronicka, Claire Scharf-Kroener, Armelle Regnault, Janos Sandor, Domenica Taruscio, Paloma Tejada, T.O.F. Wagner
For more information on the Rare Diseases Task Force
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