29 July 2009 print
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Doing what it ‘TAIEX’ to implement Orphanet in Turkey

In early July, a workshop was held in Ankara, Turkey, for the Technical Assistance and Information Exchange Instrument (TAIEX) of the Institution Building unit of Directorate-General Enlargement of the European Commission. Its aim is to provide to the new Member States, acceding countries, candidate countries, and the administrations of the Western Balkans, short-term technical assistance in line with the overall policy objectives of the European Commission, and in the field of approximation, application and enforcement of EU legislation. Assistance is also provided to those countries included in the EU’s European Neighbourhood Policy, as well as Russia. The workshop had two main objectives. The first sought to gain knowledge on ways to establish an Internet website for Orphanet Turkey in the country’s national language, through which all users - patients and the various professionals - are able to access information on rare diseases. The second objective was to gather a specific scientific advisory board on a regulatory platform, which will collaborate with Orphanet Turkey on issues regarding data provided to Orphanet within the country, and form a consortium of experts within the Turkish Ministry of Health, who shall follow-up with data collection and maintain quality control of current/emerging rare diseases within the country.

The workshop took place at the Refik Saydam Hygiene Center of the Turkish ministry of health and gathered over 60 participants from various departments of the Ministry, academia, patient organisations and the biopharmaceutical industry. The two days were dedicated to investigating the current status of rare diseases and orphan drugs in Europe and discussing how Turkey could benefit from past experience to move forward in policy shaping for rare diseases and orphan drugs. Dr Ségolène Aymé and Dr Laura Fregonese presented relevant public health issues while Pr Maurizio Clementi reported the EMEA experience with the designation of orphan drugs. Dr Krystyna Chrzanowska (Poland) introduced the audience to the network activities of Dyscerne, followed by Dr Rumen Stefanov (Bulgaria), reporting his experience both with a national information centre answering questions from patients and from professionals, and with the establishment of a national plan. Mrs Güliz Karcabaş, director of Actelion Turkey, presented the difficulties faced by Industry to register a new drug in Turkey, in the absence of an orphan drug regulation. The main identified hurdle is the lack of awareness on the part of regulators. Currently seven orphan drugs are available in the country. The final portion of the meeting was chaired by the Orphanet Turkey team, Pr. Ugur Ozbek, Dr Fatma Atalar, and Dr.Tufan Acuner, who presented the challenges they face in collecting information, due to the lack of national support for their activities. The best way to position Orphanet in the country was discussed extensively. Consensus centred on an official endorsement of the activity by the ministry of health and a formal contract between the Orphanet team in Istanbul and the ministry, an approach very similar to the arrangement in France, where Orphanet was first established twelve years ago. The participants expressed a strong wish for an action plan in the field of rare diseases and orphan drugs. A national workshop to continue discussions is being planned for October.

Spotlight on...
Romania could reduce its health burden by diagnosing phenylketonuria early and providing treatment

Phenylketonuria (PKU) is an autosomal-recessive metabolic disease caused by mutations in the PAH gene that lead to a deficiency of phenylalanine hydroxylase, an enzyme necessary for the transformation of phenylalanine into tyrosine. Untreated, PKU can lead to profound irreversible intellectual impairment, as well as hypopigmentation, behavioural and social problems, seizures, tremors, jerking movements in the arms and legs, rocking, hyperactivity, stunted growth, skin rashes (eczema), and microcephaly. Phenylalanine is also toxic to foetal development and severe disorders occur in the children of women whose PKU is untreated during pregnancy. Patients with the disorder have a lifelong inability to metabolise the proteins found in food. However, early diagnosis for PKU is possible via neo-natal screening, practiced systematically in many countries. The immediate and definitive establishment of a reduced-protein diet, including specially formulated nutritional products which assure the specific nutrients necessary for maintaining health, along with the administration of recently developed medication, are allowing PKU patients to live relatively free of symptoms.

Romania is one of the few countries in the European Union in which neo-natal screening is not widely available for PKU or any other genetic illness. Early diagnosis is particularly critical for PKU in order to prevent the installation of irreversible encephalopathy.

The incidence of PKU in Romania is 1 in 7500 newborns. According to the patient association PKU Life Romania there are currently some 900 persons affected by PKU in the country of 22 million inhabitants. However, according to official statistics, the number of PKU patients identified from 1976 until the present time is 180 - all of whom have encephalopathy. These patients, identified in one of the country’s two centres offering diagnostics and treatment for PKU (located in Cluj and Bucharest), were identified via the sporadic testing of newborns that takes place in 10 of the country’s 41 counties. Only 47 children are actually monitored at present - all of whom have severe intellectual deficit due to a chronic lack of special nutritional supplement products and adequate care. There is no specialised medical assistance available for these children. For diagnosed children, the access to protein substitute products – the base of the dietary treatment – is not assured, and other dietetic products cannot be found at all in Romania. In Bucharest, for example, there is only one establishment selling special flour for PKU, but this product does not have the dosage necessary for establishing the correct level of phenylalanine needed per 100 grams. Furthermore, it is a very low quality product; bread made with it becomes hard and inedible after one day.

No treatment available for adults with PKU
There are no known PKU adult patients with normal cognitive development in Romania. No adult with PKU has the right to access the proteic substitute products because no adult patient has an official medical diagnosis of PKU. These adult patients are instead classified as having a first grade disability. The irony of this is that the cost of maintaining a person with a first grade disability is superior to the cost of treatment for PKU.

In Romania, newborn screening currently is offered for just two disorders - PKU and hypothyroidism - to 30% of neonates. There are five screening centres in the country, all of which are adequately equipped. However, the extension of screening is hindered by a severe shortage of medical staff. There are only two employees systematically conducting newborn screening. A request made to the screening centre in Cluj from PKU Life Romania to monitor diagnosed PKU children was denied. This means that periodic tests to verify the level of phenylalanine in PKU children are not conducted in the screening centre in Cluj.

In October 2008, the Ministry of Health examined the issue of the extension of screening but did not establish a sound policy on systematic widespread screening. PKU Life Romania has previously taken action vis-a-vis the Ministry of Health over standardised newborn screening and the assurance of treatment for children and adults with PKU. Since its establishment in October 2005, PKU Life Romania has attained for 39 people - adults and children - the possibility of obtaining dietetic products from abroad along with information for parents on dietary habits and the latest news in therapy. The association has also initiated a cooking studio with invited specialists, often from other countries, such as Hungary, and including physicians, dieticians, and chefs. These studios serve to inform patients and their families on dietary matters, and give participants the opportunity to try new recipes. Some 25 families took part in the last studio. PKU Life Romania donates dietary products to these gatherings, though not large quantities, due to limited resources. Other actions of the association include petitioning the Ministry of Health for a standardised widespread newborn screening programme for PKU and other treatable conditions; the assurance of treatment for diagnosed children; the access to treatment and medical assistance for adult PKU patients; access to dietetic products for PKU patients; and counselling and education for patients and their families. The affiliation of PKU Life Romania with the National Alliance of Rare Diseases in Romania (ANBRARO) offers the possibility of direct collaboration with the Ministry of Health. This alliance offers a more effective way to communicate the social dimension of the problems experienced by PKU patients and their families, along with the country’s other rare disease patients, all of whom are awaiting a solution.


EU Policy News
New rare cancer initiative underscores EU recommendations
The campaign European Action Against Rare Cancers launched in late June at the same time the European Commission issued a Communication on cancer. The campaign seeks to underscore the policy initiatives already set out in the cancer Communication and the recently adopted Council Recommendation on Rare Diseases. Some 20% of all cancers are rare – including all the paediatric cancers. The European Action Against Rare Cancers – a joint initiative involving the European Society for Medical Oncology, Eurordis, Orphanet, Novartis Oncology and many others - has established a Call for Action in the form of an international petition that is seeking “targeted actions and policies” for patients, researchers and physicians.
Reflection paper on adeno-associated viral vectors still open for comments

A document issued by the European Medicines Agency addressing quality, non-clinical and clinical issues specific to the development of recombinant adeno-associated viral vectors is open for comments until September. Examples of rare diseases studied using this technology include haemophilia B, cystic fibrosis, Leber congenital amaurosis, and infantile neuronal ceroid lipofuscinosis.
Consult and/or comment on the adeno-associated viral vector reflection paper


National & International Policy Developments
Inherited cardiovascular conditions subject to in-depth needs assessment
Inherited cardiovascular conditions (ICCs) are a group of over 50 identified monogenic disorders primarily affecting the heart, conducting system or vasculature. ICCs include familial hypercholesterolaemia, arrhythmia syndromes (long-QT syndrome, short-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia); cardiomyopathies (caused mainly by mutations in the proteins making up the contractile system of the myofibrils), including hypertrophic and dilated cardiomyopathies; inherited arteriopathies which cause catastrophic rupture of the blood vessels (Marfan, Ehlers-Danlos, and Loeys-Dietz syndromes); and muscular dystrophies (Emery-Dreifuss muscular dystrophy and myotonic dystrophy). Frequently identified upon the event of sudden death, the diagnosis of an ICC disease has implications for the subject’s relatives, who may also be at risk. An expert working group comprised of cardiologists, geneticists, service commissioners, and representatives from key charities, including the British Heart Foundation, Cardiac Risk in the Young, Cardiomyopathy Association, Marfan Association UK, and the Sudden Arrhythmic Death Syndromes, has released a sweeping review, funded and produced by the PHG Foundation, of the status of ICCs and the services available for these conditions across the United Kingdom. Identifying areas in need of improvement, the document, entitled Heart to Heart: Inherited Cardiovascular Conditions Services. A Needs Assessment and Service Review also considers emerging technologies in the field and examines the key changes that would facilitate optimum diagnostic and management services for patients and their families. The survey found inequalities across the UK, with some areas having a much higher concentration of expertise than others. The report proposes that a specialised service for ICCs must be able to “cater for the full range of conditions in both adults and children in a timely fashion; it should include cardiologists, geneticists and expert nurses, along with access to the latest laboratory and pathology services and other key investigations such as imaging, electrophysiology and exercise testing. Integration of these different elements to provide a genuinely multidisciplinary specialist service is critical, as is increased awareness of this service among wider health professionals such as GPs. Bereavement help, counselling and integration of services with voluntary organisations that provide support for families are also essential elements”. The report is divided into ten chapters, focusing on, Science, epidemiology and clinical management; The policy context; The patients’ perspective; Comparative survey of ICC services; What makes a specialist service?; Ethical and legal issues; Horizon scanning: and New technological developments and their potential impact on services. The report concludes with a set of 16 recommendations based on the findings of the survey. These are grouped into the general topics of Establishing a strategy, Commissioning, Education, Enhancing and monitoring the effectiveness and efficiency of services, and Translational research. Referring specifically to services in the UK, the Heart to Heart report and its recommendations nonetheless offers useful and relevant insight to any country developing or refining specialised services for the inherited cardiovascular conditions.
Consult the Heart to Heart report

Other European news
Workshop underscores particular value of narrative medicine for rare disease understanding and management
A workshop was held in June in Rome, Italy, that aimed to promote the knowledge of narrative medicine as a functional tool in the management of patients with rare diseases. Rare diseases are difficult to diagnose and often not treatable. Patients and their families may have a perception of intense isolation, as well as a sense of powerlessness that is shared by the medical and health professionals treating the rare disease patient. Narrative medicine aims to fill the gap between the physician’s bedside clinical knowledge and the patient’s subjective experience. It is a tool that consists of different elements taken from a number of approaches and techniques. The workshop thus presented different perspectives and methodologies in the field of narrative medicine via invited lectures, plenary sessions and a poster session mainly devoted to practical experience. Topics covered narrative medicine in general practice, in paediatrics, in education and in bioethics, and in the framework of rare diseases.
Other International News
First data released on the genetic basis of adverse drug events Stevens-Johnson syndrome and toxic epidermal necrolysis
The US Food and Drug Administration and the International Serious Adverse Event Consortium (SAEC) joined up to investigate the genetic basis of certain adverse drug events. The SAEC is a non-profit international partnership involving leading pharmaceutical companies, academia, and government agencies. The consortium hopes to identify genetic markers that could help predict at-risk patients. The first data from the group were released earlier this year and considered the genetic factors associated with rare cutaneous disorders induced by medicinal products. Stevens-Johnson syndrome and toxic epidermal necrolysis are two such serious rare disorders. These initial results are due to be published later this year. Researchers can obtain free access to study data via a data portal This permits the re-evaluation of initial study results by researchers who can determine their validity as predictive markers.

EU Project Follow-up
European biobank project completes review of over 300 structures
The Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) launched under the EU Seventh Framework Prorgramme in order to create a broadly accessible pan-European network of existing and de novo biobanks and biomolecular resources for global biomedical research. This harmonisation is particularly crucial to rare disease research, which inherently has small sample pools from which to draw. As was reported in the 25 March issue of OrphaNews Europe, the BBMRI issued a set of preliminary recommendations for rare disease biobanking. The BBMRI has now achieved another crucial step by completing a review of more than 300 major biobanks in Europe. According to a news report in Cordis News, the BBMRI seeks to “provide researchers with access to a Europe-wide collection of biomedical quality-assessed samples and data to treat and prevent human diseases” and to “develop a prototype system” that will be functional by the end of next year. This prototype will initially engage the more advanced biobanks and will continuously add others as they are ready. A stakeholder meeting, drawing together patients, clinicians, funding organisations, associated project partners, and industry, is scheduled to take place in September to address the theme of coordinating biobanks.

New Genes

Nance-Horan syndrome and X-linked cataract are allelic disorders
Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterised by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, intellectual deficit. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. In this study, the authors show that NHS and X-linked cataract (CXN) are allelic diseases. Two CXN families, negative for mutations in the NHS gene, were further analysed. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene.
Read the PubMed abstract

To read more about "Nance-Horan syndrome"
To read more about "Non-syndromic congenital cataract"

Hum Mol Genet ; 2643-2655 ; 15 July 2009
Cystic leukoencephalopathy: RNASET2-deficient form resembles congenital cytomegalovirus brain infection
Congenital cytomegalovirus brain infection without symptoms at birth can cause a static encephalopathy with characteristic patterns of brain abnormalities. The authors show that loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to cystic leukoencephalopathy, an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype. Congenital cytomegalovirus infection and RNASET2 deficiency may both interfere with brain development and myelination through angiogenesis or RNA metabolism.
Read the PubMed abstract

To read more about "Cystic leukoencephalopathy without megalencephaly"
To read more about "Fetal cytomegalovirus syndrome"

Nat Genet ; 773-775 ; July 2009
Leigh syndrome: mutation in TACO1 results in cytochrome c oxidase deficiency and late onset of Leigh syndrome
Defects in mitochondrial translation are among the most common causes of mitochondrial disease, but the mechanisms that regulate mitochondrial translation remain largely unknown. The authors identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. They identified a mutation in the TACO1 gene, thought to be one of a family of specific mammalian mitochondrial translational activators.
Read the PubMed abstract

To read more about "Leigh syndrome due to cytochrome c oxidase deficiency"

Nat Genet ; 833-837 ; July 2009
Aicardi-Goutières syndrome: SAMHD1 implicated as regulator of the innate immune response
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The authors describe mutations in the SAMHD1 gene and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Read the PubMed abstract

To read more about "Aicardi-Goutieres syndrome"

Nat Genet ; 829-832 ; July 2009
Isolated hypogonadotropic hypogonadism: two studies describe mutations in GNRH1
Two separate studies published in the New England Journal of Medicine and the Proceedings of the National Academy of Sciences of the USA, describe a mutation in the gene GNRH1, encoding gonadotropin-releasing hormone 1, in patients with idiopathic hypogonadotropic hypogonadism. A deficiency in this master reproductive hormone, gonadotropin-releasing hormone, results in the absence of puberty.
Read the first PubMed abstract
Read the second PubMed abstract

To read more about "Normosmic congenital hypogonadotropic hypogonadism"

PNAS USA ; Epub ahead of print ; 30 June 2009
N Engl J Med ; 2742-2748 ; 25 June 2009

Mitochondrial complex I deficiency: mutations in NDUFAF3 at cause
Mitochondrial complex I deficiency is the most prevalent and least understood disorder of the oxidative phosphorylation system. The genetic cause of many cases of isolated complex I deficiency is unknown because of insufficient understanding of the complex I assembly process and the factors involved. The authors have identified mutations in the NDUFAF3 gene, encoding a mitochondrial complex I assembly protein that interacts with complex I subunits.
Read the PubMed abstract

To read more about "NADH-CoQ reductase deficiency"

Am J Hum Genet ; 718-727 ; June 2009
Polymicrogyria: mutations in the beta-tubulin gene TUBB2B at cause
Polymicrogyria is a relatively common but poorly understood defect of cortical development characterised by numerous small gyri and a thick disorganised cortical plate lacking normal lamination. The authors report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week foetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the foetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration.
Read the PubMed abstract

To read more about "Polymicrogyria"

Nat Genet ; Epub ahead of print ; 24 May 2009
3M syndrome: loss of OBSL1 leads to downregulation of CUL7
3M syndrome is an autosomal-recessive primordial growth disorder characterised by significant intrauterine and postnatal growth restriction. Mutations in the CUL7 gene are known to cause the syndrome. In 3M syndrome patients who do not carry CUL7 mutations, the authors discovered seven distinct null mutations from 10 families within the gene OBSL1, a putative cytoskeletal adaptor protein that localises to the nuclear envelope. They also demonstrate that loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels and suggesting that both proteins are involved within the same molecular pathway.
Read the PubMed abstract

To read more about "3M syndrome"

Am J Hum Genet ; 801-806 ; June 2009
Retinitis pigmentosa: mutations in KLHL7 cause an autosomal-dominant form
Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, the authors identify in a six-generation Scandinavian family a disease-causing mutation in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands revealed three different missense mutations in six independent families.
Read the PubMed abstract

To read more about "Retinitis pigmentosa"

Am J Hum Genet ; 792-800 ; June 2009
Alveolar capillary dysplasia: the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 identified
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). The authors identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, they identified four different heterozygous mutations in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA.
Read the PubMed abstract

Am J Hum Genet ; 780-791 ; June 2009
Omodysplasia: mutations in the heparan-sulfate proteoglycan glypican 6 cause the recessive form
The authors report that autosomal-recessive omodysplasia, a genetic condition characterised by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). The biological roles of glypicans, a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans, are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome).
Read the PubMed abstract

To read more about "Omodysplasia"

Am J Hum Genet ; 760-770 ; June 2009
Bowen-Conradi syndrome: mutation of EMG1, a gene essential for ribosome biogenesis at causes
Bowen-Conradi syndrome (BCS) is an autosomal-recessive disorder characterised by severely impaired prenatal and postnatal growth, profound psychomotor retardation, and death in early childhood. Nearly all reported BCS cases have been among Hutterites, with an estimated birth prevalence of 1/355. The authors have identified a mutation in the 18S ribosome assembly protein EMG1 as the probable cause of BCS. This mutation segregated with disease, was not found in 414 non-Hutterite alleles, and altered a highly conserved aspartic acid (D) residue.
Read the PubMed abstract

To read more about "Bowen-Conradi syndrome"

Am J Hum Genet ; 728-739 ; June 2009

Research in Action

Fundamental Research
Steinert myotonic dystrophy: high-fat diet induced adiposity and insulin resistance in mice lacking protein kinase
Steinert myotonic dystrophy 1 (MD1) is caused by a CTG expansion in the myotonic dystrophy protein kinase (DMPK) gene. MD1 patients frequently present insulin resistance and increased visceral adiposity. The authors show that DMPK deficiency is a genetic risk factor for high-fat diet-induced adiposity and insulin resistance using the DMPK knockout mouse model. High-fat fed DMPK knockout mice had significantly increased body weights, hypertrophic adipocytes and whole-body insulin resistance compared with wild-type mice. This nutrient-genome interaction should be considered by physicians given the cardiometabolic risks and sedentary lifestyle associated with MD1 patients.
Read the PubMed abstract

To read more about "Steinert myotonic dystrophy"

FEBS Lett ; 2121-2125 ; 18 June 2009
Wiskott-Aldrich syndrome: recent advances in understanding the pathophysiology
Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signalling and cytoskeletal reorganisation in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the relatively mild X-linked thrombocytopenia to the classic full-blown WAS phenotype characterised by thrombocytopenia, immunodeficiency, eczema, and high susceptibility to developing tumours and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene-corrected autologous hematopoietic stem cells could represent an alternative therapeutic approach. The authors focus on recent progress in understanding the molecular and cellular mechanisms contributing to the pathophysiology of WAS.
Read the PubMed abstract

To read more about "Wiskott-Aldrich syndrome"

Blood ; 6288-6295 ; 18 June 2009
Clinical Research
Familial Mediterranean fever: one MEFV mutation sufficient for diagnostic purposes
Familial Mediterranean Fever (FMF) manifests as short febrile episodes occurring at variable intervals, with intermittent abdominal, thoracic, joint and/or cutaneous pain, and the possible development of renal amyloidosis. Autosomal recessive transmission is caused by mutations affecting both alleles of the gene MEFV. Two separate studies describe patients carrying mutations on one allele and presenting a characteristic phenotype of the disease. The authors suggest that the detection of a single mutation in the presence of characteristic symptoms is sufficient to confirm diagnosis and initiate treatment.
Read the first PubMed abstract
Read the second PubMed abstract

To read more about "Familial mediterranean fever"

Arthritis and Rheumatism ; 1851-1861 ; June 2009
Arthritis and Rheumatism ; 1862-1866 ; June 2009

Congenital lymphoedema: recessive primary form caused by a VEGFR3 mutation
Heterozygous mutations in VEGFR3 have been identified in some familial cases with dominantly inherited primary congenital lymphoedema, also known as Nonne-Milroy disease. Recessive cases of primary lymphoedema with a genetic cause are not known, except for two families with syndromic hypotrichosis-lymphoedema-telangiectasia, with a SOX18 mutation. In this study, the authors present the first case of isolated primary congenital lymphoedema with recessive inheritance, caused by a homozygous mutation in VEGFR3. Thus, in addition to congenital lymphoedema disease with dominant inheritance, VEGFR3 alterations can cause isolated recessive primary congenital lymphoedema.
Read the PubMed abstract

J Med Genet ; 399-404 ; June 2009
Dyskeratosis congenita: the spectrum of cancer susceptibility
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. The spectrum of cancer susceptibility in this disorder has not been described. There were more than 500 cases of DC reported in the literature from 1910 to 2008; the National Cancer Institute (NCI) prospective DC cohort enrolled 50 cases from 2002 to 2007. Sixty cancers were reported in 52 literature cases, while 7 occurred among patients in the NCI DC cohort. The 2 cohorts were comparable in their median overall survival (42 years) and cumulative incidence of cancer (40%-50% by age 50 years). The most frequent solid tumours were head and neck squamous cell carcinomas (40% of patients in either cohort), followed by skin and anorectal cancer. The frequency and types of cancer in DC are surpassed only by those in Fanconi anemia (FA), indicating that FA and DC have similarly high risks of adverse haematologic and neoplastic events, and patients with these diseases should be counselled and monitored similarly.
Read the PubMed abstract

To read more about "Dyskeratosis congenita"

Blood ; 6549-6557 ; 25 June 2009
Immune thrombocytopenia: pathogenic and clinical diversity
The authors review the pathophysiology of several common secondary forms of immune thrombocytopenia and suggest that the primary form is also best thought of as an autoimmune syndrome. Better understanding of pathogenesis and tolerance checkpoint defects leading to autoantibody formation may facilitate patient-specific approaches to diagnosis and management.
Read the PubMed abstract

Blood ; 6511-6521 ; 25 June 2009
Cadasil: a review of the current understanding of the disease
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. In this review, the authors summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.
Read the PubMed abstract

To read more about "CADASIL syndrome"

Lancet Neurol ; 643-653 ; July 2009
Prader-Willi syndrome: a clinical research database aids the investigation of a rare genetical neurodevelopmental disorder
Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research database has been established to structure data collection and to enable multinational investigations into the development of children and adults with PWS. The development of the database has proved to be complex with various administrative and ethical issues to be addressed, concerned with data ownership and establishing the rules for data entry, retrieval and sharing compatible with data protection laws, and which are likely to be acceptable to participants, their families, and to individual research groups.
Read the PubMed abstract

To read more about "Prader-Willi syndrome"

J Intellect Disabil Res ; 538-547 ; June 2009
Diagnostic Approaches
Lissencephaly and subcortical band heterotopia: intragenic deletions and duplications of the LIS1 and DCX genes
Classical lissencephaly, or isolated lissencephaly sequence (ILS), and subcortical band heterotopia (SBH) are neuronal migration disorders associated with severe intellectual deficit and epilepsy. Abnormalities of the LIS1 and DCX genes are implicated in the majority of patients with these disorders. The molecular basis of disease in patients with ILS and SBH, in whom no abnormalities have been identified, has been questioned. The authors studied a series of 83 patients with ILS, SBH or pachygyria, in whom no abnormalities of the LIS1 or DCX genes had been identified, for intragenic deletions and duplications by multiplex ligation-dependent probe amplification. Their results show that intragenic deletions and duplications of the LIS1 or DCX genes account for a significant number of patients with ILS and SBH, where no molecular defect had previously been identified.
Read the PubMed abstract

To read more about "Lissencephaly"
To read more about "Subcortical band heterotopia"

Eur J Hum Genet ; 911-918 ; July 2009
Hereditary recurrent fevers: international quality assessment for molecular diagnosis finds need for improvement
Hereditary recurrent fevers (HRF) are rare diseases caused by molecular defects in genes involved in the regulation of innate immunity. Sixty-seven international laboratories participated in an external quality assessment (EQA) scheme, which was developed to appraise the accuracy of genetic testing. Reports were evaluated for the 12 items recommended by the OECD (Organisation for Economic Co-Operation and Development) guidelines for molecular diagnostics. The best documented items were the name of the gene, the biologist, or the patient, whereas information on the test and screening limits, and clinical interpretation of the disease inheritance were scarcely provided. The mutation nomenclature was incomplete in about 70% of the cases. The authors identified almost 30% genotyping error rate, which decreased markedly in the last year. The combined performance on the basis of the correct identification of all genotypes by a given laboratory was only 40%, showing a critical need for improvement.
Read the PubMed abstract

To read more about "Familial mediterranean fever"
To read more about "TRAPS syndrome"
To read more about "Partial mevalonate kinase deficiency with recurrent fever +/- hyperIgD"
To read more about "Marshall's syndrome with periodic fever"

Eur J Hum Genet ; 890-896 ; July 2009

Patient Management and Therapy

Dementia with Lewy bodies: memantine looks encouraging in early trials
Dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. The authors tested the safety and efficacy of the N-methyl D-aspartate receptor antagonist memantine in patients with PDD or DLB via a parallel-group, 24-week, randomised controlled study versus placebo. They found that patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm these preliminary findings.
Read the PubMed abstract

To read more about "Lewy body dementia"

Lancet Neurol. 2009 ; 613-618 ; July 2009
Acute lymphoblastic leukaemia: treating paediatric patients without cranial irradiation is possible
Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. The authors conducted a clinical trial involving 498 patients to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. They found that with effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL.
Read the PubMed abstract

To read more about "Leukemia, lymphoblastic, acute"

N Engl J Med ; 2730-2741 ; 25 June 2009
Charcot-Marie-Tooth disease: from diagnosis to treatment
Charcot-Marie-Tooth disease is the most common inherited neuromuscular disorder. There have been substantial advances in elucidating the molecular bases of this genetically heterogeneous neuropathy and, in most cases, molecular diagnosis is now possible. At present, there is no drug therapy for Charcot-Marie-Tooth disease, and rehabilitation therapy and surgical procedures for skeletal deformities are the only available treatments, although best practice has not been defined. Progesterone antagonists, neurotrophic factors, ascorbic acid, and curcumin have shown promising results in experimental models, and ascorbic acid is being studied in large randomised controlled trials.
Read the PubMed abstract

To read more about "Charcot-Marie-Tooth disease"

Lancet Neurol ; 654-667 ; July 2009
Hereditary breast and ovarian cancer: factors influencing intrafamilial communication of genetic information
This literature review summarises factors at the individual, familial, and community levels, as well as cross cutting elements relating to the complexity of hereditary breast and ovarian cancer genetic information and responsibilities that this information can give rise to. These factors are complex and may result in conflicting senses of responsibility. This review sheds light on the factors that contribute to resolve this dilemma.
Read the PubMed abstract

To read more about "Breast cancer, familial"

Eur J Hum Genet ; 872-880 ; July 2009

Orphan Drugs

Eighteen positive opinions for orphan designation at the July COMP meeting
At the July 2009 meeting of the Committee for Orphan Medicinal Products (COMP), eighteen positive opinions were issued for the treatment of:
- myelodysplastic syndrome
- chronic myeloid leukaemia
- prevention of graft rejection during pancreatic islet transplantation
- acute lung injury
- angioedema caused by C1 inhibitor deficiency
- soft tissue sarcoma
- carcinoid tumours
- acute myeloid leukaemia
- Duchenne muscular dystrophy
- familial adenomatous polyposis
- anal fistula
- Cushing disease
- acromegaly
- multiple myeloma
- Hodgkin lymphoma
- haemophilia B
- haemophilia A
- prevention of scarring post glaucoma filtration surgery

Consult the European Register of Designated Orphan Medicinal Products
Consult the Orphanet list of orphan drugs authorised for marketing in Europe

Two new reports elucidate orphan drug policy and practice in Belgium
Two informative documents recently published offer a snapshot of orphan drug availability in Belgium. Policies for Orphan Diseases and Orphan Drugs, compiled by the Belgian Health Care Knowledge Centre, is a comprehensive English-language report that compares the Belgian orphan drug reimbursement policy with other countries, estimates the current budget impact of orphan drugs, forecasts the expected future budget impact, and offers recommendations for policy makers concerning orphan drugs. In Belgium, (as of the end of 2008) 31 orphan drugs are reimbursed, two of which do not have orphan drug status, but are nonetheless reimbursed for an orphan indication. A French-language article appearing in the Journal de Pharmacie de Belgique also presents an overview of the orphan drugs with marketing authorisation in Europe, and discusses the products available and eligible for reimbursement in Belgium, illustrated with tables and graphs presenting statistics, including the prevalence of the indications with existing orphan drug treatments.
Consult the English-language report
Consult details of the French-language article


Courses & Educational Initiatives
e-MSc course in Haemoglobinopathies launched at UCL
An online postgraduate course was recently launched at University College London to address the urgent need for specialist education in the field of haemoglobin disorders. This pioneering e-degree course was developed in collaboration with the Thalassaemia International Federation with the aim of improving patient care through training of medical profesionals.

The course uses a virtual classroom, videoconferencing and other internet-based technologies to provide specialist postgraduate qualifications to students from anywhere in the world. It is taught by a faculty of internationally recognised experts and covers all aspects of the prevention and holistic care of thalassaemia and sickle cell disease. Students have the choice between a full MSc degree, a postgraduate diploma or a certificate, which can be completed on a full-time or part-time basis. Interested candidates can apply now to start in September 2009. For further details and to apply, please contact the UCL Course Administrator or the Thalassaemia International Federation.

Vector Development and Gene Therapy summer school course
Organised by the German Society for Gene Therapy in cooperation with the Center for Molecular Medicine Cologne, the Vector Development and Gene Therapy summer school course will take place from 2-4 September 2009 in Cologne. The course will provideg a broad overview on current topics in Vector Development and Gene Therapy. A limited number of traineeships will be offered. Students will have the possibility to visit the respective laboratories to learn more about specific methods or techniques complementing the theoretical course. For more information

What's on Where?

Treatment Options in Phenylketonuria and Related Pediatric Neurotransmitter Disorders
Date: 29 August 2009
Venue: San Diego, California USA

Key Topics include challenges in the pharmaceutical treatment of PKU and treatment of paediatric neurotransmitter disorders.
For further details

14th International World Muscle Congress
Date: 9-12 September 2009
Venue: Geneva, Switzerland

New methods for assessing disease progression in neuromuscular disorders; the extracellular matrix in normal and diseased muscle (including collagen and glycosylation disorders, fibrosis, patterning and cell grafting); advances in treatment of neuromuscular disorders. A satellite teaching course will also be held from 8-9 September 2009.
For further details

Rare neurometabolic and neurogenetic disease in adults: a joint French-Italian workshop
Date: 10-11 September 2009
Venue: Siena, Italy

A satellite meeting of the 13th European Federation of Neurological Societies congress, featuring an overview of rare diseases, and updates on mitochondrial encephaloneuromyophaties, spinocerebellar ataxias, small vessel diseases, late onset leukodystrophies, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, dysimmune chronic neuropathies, treatable neurometabolic genetic diseases.
For further details

ESH Eleventh International Conference – Chronic Myeloid Leukaemia
Date: 11-13 September 2009
Venue: Bordeaux, France

Held in association with the International CML Foundation, this conference will consider the biological basis of therapy.
For further details

Genetics and Genomics of Vascular Disease Workshop
Date: 13-16 September 2009
Venue: Hyannis, MA

The programme will present cutting edge research in areas like genome wide association studies in human populations, mouse QTL mapping of vascular phenotypes, and pathogenesis of vascular and developmental diseases using human patients and mouse models.
For further details

European Working Group on Rett Syndrome – 2009 Meeting
Date: 17-18 September 2009
Venue: Stresa, Italy

An opportunity to discuss Rett syndrome-related science, to find collaborators for grant applications, and to exchange reagents and ideas. Moreover, the close contact with the parents associations should also help to focus better on the scientific problems that need to be resolved to find a cure for patients.
For further details

Adaptive Immunity and the Pathogenesis of Rheumatic Diseases – A Translational Research in Paediatric Rheumatology Conference
Date: 24–27 September 2009
Venue: Genoa, Italy

This third Translational Research in Paediatric Rheumatology conference will showcase the growing body of evidence that the regulation of central and peripheral B and T cell development plays a pivotal role in the pathogenesis of autoimmune diseases, highlighting the molecular and cellular mechanisms involved in the activation of the effector functions of adaptive immunity, their involvement in the pathogenesis of chronic rheumatic diseases, and the potential identification of targets to modulate the activity of the adaptive immune system.
For further details

British Paediatric Neurology Association: Rare Disorders Symposium
Date: 29 September 2009
Venue: Harrogate, England

A stand-alone satellite symposium on rare disorders will take place as part of the 8th Paediatric Neurology Conference, exploring a number of themes relating to rare disorders.
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".
For further details

XXth Congress of International Society of Haematology - European and African Division
Date: 10-13 October 2009
Venue: Cairo, Egypt

Including up-to-date knowledge and the most recent scientific achievements in the field.
For further details

ESH Conference on Myelodysplastic Syndromes
Date: 22-25 October 2009
Venue: Mandelieu, France

Covering diagnostics, overlapping syndromes, treatment approaches and more. Deadline for scholarships and abstracts: 15 September 2009
For further details

EPPOSI: 10th Workshop on Partnering for Rare Disease Therapy Development
Date: 26-27 October 2009
Venue: Brussels, Belgium

The topic of this year’s workshop of the European Platform for Patients’ Organisations, Science and Industry is “10 years after the adoption of the EU Orphan Medicines Regulation: Where do we go? Three key themes will be addressed: “What is the impact of the economic crisis on the field of rare diseases – and what is the vision on further progress in R&D, diagnosis and patient care? Building on the public policy base of the last 10 years: how to advance policies in the next five years? Rare cancers: specific challenges within rare diseases.
For further details

European Society for Phenylketonuria Annual Conference 2009
Date: 30 October – 1 November 2009
Venue: Antalya, Turkey

The conference offers the opportunity to exchange the latest experiences via workshops and presentations. Delegates of member associations will discuss the situation regarding European health politics and European networks. An industrial exhibition will inform on the latest product developments.
For further details

TREAT-NMD/NIH International Conference
Date: 17-19 November 2009
Venue: Brussels, Belgium

The aim of the meeting is to share progress in the area of translational medicine in inherited neuromuscular diseases and set the future collaborative agenda. This conference will build on achievements of the NIH and TREAT-NMD. It will be a highly interactive meeting with a strong focus on the key issues surrounding "trial readiness" in the neuromuscular field.
For further details

OI in motion: Rehabilitation and Physiotherapy in Osteogenesis Imperfecta
Date: 20-22 November 2009
Venue: Rheinsberg, Germany

Topics include: Rehabilitation of children; rehabilitation of adults; assessments of motor functions; orthoses/mobility aids; and international experiences.
For further details

ESF-UB Conference in Biomedicine: Rare Diseases II: Hearing and Sight Loss
Date: 22-27 November 2009
Venue: Sant Feliu de Guixols, Spain

A conference of the European Science Foundation. The meeting will bring together experts in sensory neuroscience, developmental biology, genetics, cell biology, modelling, translational research and therapy. It aims at promoting exchanges between the scientists of the two fields and beyond, at stimulating the emergence of new research projects at the interface between disciplines and at training young researchers in this interdisciplinary field.
For further details

International Conference on Myasthenia
Date: 1-2 December 2009
Venue: Paris, France

The conference will bring together research scientists and clinicians from around the world who specialise in myasthenia, to review the latest developments, exchange experiences and ideas, and broaden knowledge and understanding of this rare disease. A session dedicated to the interaction between clinicians, scientists, and patient associations is also scheduled.
For further details

2nd Pan-European Conference on Haemoglobinopathies
Date: 13-14 March 2010
Venue: Berlin, Germany

This conference aims to further strengthen the national and regional support networks for thalassaemia patients in Europe, and increase awareness among European medical professionals and national health authorities of the disorder, its proper management and prevention.
For further details

18th International Workshop on Vascular Anomalies
Date: 21-24 April 2010
Venue: Brussels, Belgium

The programme for this workshop will be available soon.

5th European Conference on Rare Diseases 2010
Date: 13-15 May 2010
Venue: Crakow, Poland

Details will be available soon.


Press & Publications

Texts on haemoglobinopathies now available in Italian and French...and coming soon in Spanish
The Thalassaemia International Federation (TIF) publishes an extensive range of educational publications on thalassaemia and other haemoglobinopathies, aimed at patients, their families, health professionals and the general readership. Some of their books are now available in two major European languages: French and Italian. The books can be downloaded free of charge from the TIF website. Furthermore, the Guidelines for the Clinical Management of Thalassaemia will soon be available in Spanish.

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, Charlotte Rodwell, Claire Scharf-Kroener, Paloma Tejada, Aurélie Vandeputte
National Contact Point: Jean Jacques Cassiman (Belgium), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), Andres Metspalu (Estonia), Riitta Salonen (Finland), Manfred Stuhrmann (Germany), Michael Petersen (Greece), János Sándor (Hungary), Andrew Green (Ireland), Judith Melki (Israel), Bruno Dallapiccola and Domenica Taruscio (Italy), Andre Megarbane (Lebanon), Vaidutis Kucinskas (Lithuania), Alfred Cuschieri (Malta), Abdelaziz Sefiani (Morocco), Martina Cornel (Netherlands), Stein Are Aksnes (Norway), Jolanta Sykut-Cegielska (Poland), Jorge Sequeiros (Portugal), Dragica Radojkovic (Serbia), Ludovit Kadasi (Slovakia), Borut Peterlin (Slovenia), Miguel del Campo and Manuel Posada de la Paz (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Habiba Chaabouni-Bouhamed (Tunisia), Fatmahan Atalar and Ugur Ozbek (Turkey), Edmund Jessop and Idoia Gomez-Paramio (United Kingdom)
For more information on the Rare Diseases Task Force
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