14 October 2009 print
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German evaluation moves forward process for implementing strategy for rare diseases...

The German Ministry of Health in August issued the results of a study undertaken in order to review the current medical and social situation for the country’s estimated four million-plus rare disease patients, define priority fields for action, and develop solutions in harmony with the European Council Recommendations, including a strategic plan for rare diseases. The evaluation report was compiled from a variety of sources, including qualitative and quantitative empiric surveys, structured interviews, discussions, and an evaluation of relevant publications. The results highlight the particular issues that rare disease patients and their families encounter in accessing health care services. Several areas in need of action were identified: general care, specialised care, diagnosis and therapy, information, research, the need for a national board of experts (“Aktionsforum”) for rare diseases - as well as a strategic plan of action. The study revealed that patients need improved access to care. Specialised service providers should offer integrated and coordinated therapy. Shared-care models, as well as specialised clinics and reference centres, are needed to meet patient needs. Patients and their families also need timely diagnoses. Current diagnostic methods/procedures are lacking or insufficient and need improvement. For medicinal products, the current outpatient compensation system needs redeveloping in order to implement new reimbursement instruments reflecting the complex, heterogeneous features of many rare diseases. For many rare diseases there is inadequate information available and existing resources are unknown to the majority of persons. For improving information, it is therefore necessary to improve existing services. In terms of research, implementing new or improving existing registries could increase knowledge. Collaboration at the EU level is vital. The study concludes that to improve the health situation in the field of rare diseases, a strategic plan of action corresponding to the priority areas identified at the European level would be helpful. It was suggested that a national plan could be developed by the Aktionsforum group of experts and would ideally include defined objectives and target dates. All relevant stakeholders of the German health system should participate to maximise this plan of action. Part of the challenge of developing a national strategy for rare diseases in Germany, a country of some 82 million inhabitants, is the complexity of the health system. Health care responsibilities are shared and divided between the central government and the country’s 16 federal states (known as “laenders”). At a meeting of the European Project for Rare Diseases National Plans Development (EUROPLAN) that took place in September, it was observed that the federal structure in Germany does not permit a strictly top-down approach, but rather a joint, coordinated and objective-oriented action involving all the actors at both the national- and state-level (e.g. a cooperative network involving all key bodies and organisations) will be necessary. The next step to move forward will be the creation of the Aktionsforum.
Consult the Ministry of Health evaluation (in German language)
Consult the Ministry of Health press release (in German language)
...While France’s second National Plan for Rare Diseases takes shape

On 21 October, 2009, a meeting will take place in order to constitute the working groups and fix concrete objectives for each of the seven elements that will constitute the new four-year French National Rare Disease Plan scheduled to run from 2010-2014. An interministerial representative has been named to shepherd the plan over the next four years, and leaders have been appointed for each of the strategic axes. The final, detailed version of the plan must be delivered to the French government by the end of January 2010. France’s first national plan – which ran from 2005-2008 and was the first of its kind in the world - had ten strategic axes. After an intense period of evaluation of the first plan, the second plan has been streamlined to comprise seven defined priority areas for action. An earlier working version of the second plan consisted of six axes, but it was decided to divide the “research” axe into two parts: one section encompassing fundamental-based research, as well as incorporating human and social science in the context of rare diseases; and the other section focusing on therapeutic investigations. Thus, the axes of the second plan are as follows: “Development Indicators” will work for the development of diverse complex tools providing the necessary knowledge to better monitor the impact of the various actions of the plan. Axe two “Health Care Coverage” will seek to better coordinate medicinal and related services usage and ensure equity. The third axe, “Information and Training” will reinforce support to Orphanet, improve information on disability by coordinating with appropriate national counterparts, and ameliorate rare disease training in France. The fourth axe “Organisation of Care and Diagnostics” will pursue support for diagnostics and will tweak the actions taken vis-a-vis the centres of reference in order to meet any needs not currently covered in this area. Resources will be structured to implicate extra-hospital services as well as the country’s rare disability schema under preparation. The fifth axe, “Targeted Medicines” will address the development of specific products for rare conditions and will also focus on issues concerning price and commercialisation. The sixth axe, “Research” will seek an evolution of the Institute for Rare Diseases, France’s main clearinghouse for calls for proposals in the field of rare disease research. Research will continue on the epidemiology and natural history of rare diseases, genetics, and physiopathological mechanisms. Finally, the seventh axe “European and International Cooperation” will seek enhanced collaboration with industrialised and developing countries in the areas of information, public/private partnerships, research, epidemiology, networks of expertise, et cetera. It is important to remember that these elements identified for priority in the second plan build upon the groundwork of achievements accomplished in these and other areas during the first four years of the French plan. Consult the evaluation report of the first National Plan for Rare Diseases (in French language)


EU Policy News

EMEA to implement the final phase of electronic-only submission procedures
As was reported in the OrphaNews Europe edition of 29 February 2008, the European Medicines Agency (EMEA) began implementing an electronic-only submission procedure for marketing authorisation applications in 2008. The EMEA’s Electronic Common Technical Document (eCTD) format allows for increased standardisation and harmonisation and facilitates the navigation and lifecycle management capabilities. The EMEA is now initiating the final phase of its eCTD format implementation process. Thus beginning 1 January 2010, the EMEA will require that the eCTD format be used for all applications relating to medicinal products for human use. Consult the question and answer document on electronic-only submissions

National & International Policy Developments
Several countries keeping an eye on Guillain-Barré syndrome as H1N1 influenza vaccination campaign gets underway
In 1976, swine flu vaccination administered in the USA was linked to an increased incidence of Guillain-Barré syndrome (GBS), a rare immune-mediated neuropathy that occurs in previously healthy individuals. It is not certain why the vaccine caused an increased incidence; it is thought that stimulation of the immune system is central to the pathogenesis of GBS as well as Fisher syndrome - a related form of the disorder. With the advent of the H1N1 swine flu pandemic, for which vaccination campaigns are getting underway in many countries, the British Paediatric Surveillance Unit is launching a new study designed to monitor reported incidence of GBS and Fisher syndrome. Other country members of the International Network of Paediatric Surveillance Units already monitor GBS as part of their Acute Flaccid Paralysis surveillance, including Australia, Canada and Holland. GBS is considered a significant cause of acute flaccid paralysis worldwide.
Consult the UK study protocol

US Senate introduces act to increase rare disease clinical trial participation
Members of the United States Senate have put forward legislation that would allow patients with rare diseases to participate in clinical drug studies without losing their eligibility for public healthcare coverage, following in the footsteps of the House of Representatives which introduced a similar act last month. Bill S.1675, known as the “Improving Access to Clinical Trials Act" seeks to address the recurring problem experienced by researchers unable to recruit adequate numbers of participants for clinical studies involving rare diseases. Current social security reimbursement legislation in the USA is prohibitive to clinical trial research in that patients receiving supplementary security income cannot simultaneously receive research compensation.

In a news article, Reuters reported that Senator Christopher Dodd, one of the bill’s sponsors, explained “For those living with a rare disease, clinical drug studies can offer a ray of hope: access to cutting-edge medical technologies that may help treat or even cure a serious illness. ... Currently, individuals who receive public assistance often do not participate in compensated clinical trials for fear of losing their Medicaid or Supplemental Security Income. This legislation will remedy this inequity by ensuring that more Americans, including those who receive public assistance, have access to these potentially life-saving clinical drug studies." Consult the proposed legislation

Other International News
First international registry for congenital muscular dystrophy launched

The congenital muscular dystrophies (CMD) are a heterogeneous group of neuromuscular disorders with onset at birth or infancy and characterised by hypotonia, muscle wasting, weakness or delayed motor milestones. This group includes myopathies with abnormalities at different cellular levels: the extracellular matrix, the dystrophin-associated glycoprotein complex, the endoplasmic reticulum, and the nuclear envelope. Cure CMD, a nonprofit advocacy group, launched in mid-August the first international registry for CMDs that will capture data on these diseases. Coordinated by Emory University School of Medicine’s Department of Human Genetics, online help and genetic counsellors will be available to registrants and their families. The CMD International Registry (CMDIR) will soon be available in French, German, Italian and Spanish, although the genetic counselling services will only be offered in English, with the option of a referral to a genetic counsellor or neurologist in the registrant’s home country.

New US website for newborn screening boosts visibility and harmonises data reporting
In the United States, the National Library of Medicine (NLM) has announced the launch of a new website. The Newborn Screening Coding and Terminology Guide is defined as “an important step toward efficient electronic exchange of standard newborn screening data”. Developed collaboratively with the Office of the National Coordinator for Health Information Technology, the Health Resources and Services Administration, and the Centers for Disease Control and Prevention – all of the U.S. Department of Health and Human Services - and several expert groups, the new website is designed to offer “a standard framework for reporting the results of newborn screening tests whose contents can be accurately interpreted by recipient electronic systems for use in care, follow-up and analysis. This standard framework will also enable the use and comparison of data from different laboratories”. The guide also allows individual states to adopt a common terminology and coding standards. This move is seen as critical for the electronic exchange of laboratory test information and harmonising screening information for inclusion in electronic health records. The website offers the capacity to capture different resources: conditions, analytes/measurements, or tailored views, for example. Noted on the new website, “Use of these standards can speed the delivery of newborn screening reports, facilitate the care and follow-up of infants with positive test results, enable the use (and comparison) of data from different laboratories, and support the development of strategies for improving the newborn screening process”.
Hurray for Bollywood! The Indian film industry’s depictions of orphan diseases and disabilities help raise awareness
While Hollywood often broaches the theme of autism (Rain Man; Forrest Gump; Little Man Tate; I am Sam) and to a lesser extent other rare diseases (notably Lorenzo’s Oil), the subject also has its place in the booming Mumbai film industry. Over the past forty years, Indian cinema has brought out several films depicting various conditions – intellectual deficit, speech, vision and hearing disabilities, and autism. The latest entry, My Name is Khan, directed by Karan Johar and starring Shah Rukh Khan, portrays a young man living with Asperger syndrome, a neuro-biological disorder belonging to the autism spectrum. While technically not rare – Asperger syndrome is thought to affect as many as one in one thousand predominantly males – it is still an orphan disease for which no cure is available. An essay by University of Rajasthan professor Sudha Rai posted on the Disability in India website reminds Indian film makers of their capacity to “remove biases and stigma against the disabled, correcting superstitious and illiterate attitudes that read disability as a ‘curse’, … by representing the disabled with understanding, sympathy, dignity and conviction”.
Childhood cancer deaths continue to decline in the USA
The most recent study issued by the Centers for Disease Control reports that cancer, though still the leading cause of illness-related mortality in children, continues to decline in the USA. Statistically, over 16 children and/or adolescents per 100,000 are diagnosed with some kind of cancer, of whom nearly three per 100,000 die. However, from 1990 to 2004, childhood leukaemia death rates fell by 3.0% per year, while childhood brain and other nervous system cancers declined by 1.0%, and all other childhood cancers combined by 1.3% per year. In 2005, 4.1 per 100,000 of young people under age 20 years in the U.S. were diagnosed with leukaemia, with 0.8 per 100,000 dying. The number of new cases was highest among children aged one to four years, while the number of deaths was highest among the 10 to 14 age group. Also in 2005 (the most recent year for which statistics are available) some 2.9 of every 100,000 children between 0 and 19 years of age were found to have cancer of the brain or central nervous system, with 0.7 per 100,000 dying. The decrease in mortality is interpreted as a reflection of improved treatment.
Consult the report


Ethical, Legal & Social Issues
Recommendations issued for Sino-European biomedical research will help protect rare disease patients seeking treatment abroad
The 30 January 2008 issue of OrphaNews Europe reported on American and European rare disease patients and their families who were seeking experimental treatment for disorders such as Batten disease, ALS, ataxia, Huntington disease and other conditions in China. BIONET, a consortium of European and Chinese partners, was created and funded under the European Commission Sixth Framework programme and with support from the United Kingdom’s Medical Research Council to examine the challenges facing the ethical governance of research in the life sciences and biomedicine in China and the EU. The final BIONET conference that took place in September has yielded an expert group set of 30 recommendations to be published on best practice in the ethical governance of Sino-European life science research collaborations. Gathered from a series of workshops focusing on issues of ethical governance in various biomedical research areas including assisted reproductive technologies, stem cell research, clinical trials and biobanking, the recommendations are being viewed as a step forward to regulate the growing international stem cell tourist industry. Although the recommendations have not yet been officially released, an article appearing in Nature states that they include “establishing protocols to ensure the clinical trials of unproven therapies, such as stem-cell treatments, are not presented to patients as a cure. Research subjects should not be coerced into taking part in clinical trials and all trial data should be published”.
Biological sample collections from minors for genetic research: the call for a reflection on policy and ethical issues
Genetic research on biological material from minors can yield valuable information on the development and genesis of early-onset genetic disorders and the early interaction of environmental and genetic factors. Stored tissue samples are an important resource for epidemiological genetic research. However, the use of such tissue raises some specific ethical and governance questions, which are not completely covered by the discussion on biological materials from adults. The authors of an article appearing in the European Journal of Human Genetics gathered 29 guidelines and position papers pertaining to the storage and use of biological tissue samples for genetic research, originating from 27 different organisations. Five of these documents have an international scope, three have a European scope and 21 have a national scope. Eleven of the documents did not contain a section on biological materials from minors. The content of the remaining 18 documents was categorised according to four themes: consent, principles of non-therapeutic research on vulnerable populations, ethics committee approval and difference between anonymous and identifiable samples. While these themes are not consistently mentioned in each document, those papers that do discuss the same themes were mostly in agreement with their recommendations. However, the authors conclude that a systematic reflection on the ethical and policy issues arising from the participation of minors in biobank research is lacking.

Read the PubMed abstract

Eur J Hum Genet ; 979-990 ; August 2009

EU Project Follow-up
EUNEFRON project for orphan nephropathies featured in specialist publication

The official publication of the European Dialysis and Transplant Association-European Renal Association, Nephrology, Dialysis, Transplantation published a free-access feature article on the European Network for the Study of Orphan Nephrophathies (EUNEFRON). A consortium mobilised in response to the Call HEALTH-2007-2.4.4-1 (Natural course and pathophysiology of rare diseases principally affecting the genitourinary tract) of the Seventh Framework programme (FP7) for health of the European Union, EUNEFRON involves 12 research groups from 10 academic institutions in eight European countries. Launched in May 2008 for an initial duration of four years, the project has a total budget of six million euros. The natural course and pathophysiology of the over 60 rare inherited disorders affecting the kidneys is still limited. Interacting with related FP6 projects, such as the European Renal Genome project EuReGene, EUNEFRON will mobilise a critical mass of expertise to investigate 16 of these disorders affecting the glomerulus, the proximal tubule, the thick ascending limb, the distal convoluted tubule and the collecting duct. As stated in the article, “These diseases are caused by mutations in 20 genes that encode proteins involved in a wide range of functions, including enzymatic activities, transport mechanisms, structure and transcriptional regulation”. EUNEFRON is also initiating a European registry and a network of genetic laboratories to “foster interactions between physicians and researchers, promote clinical and basic research and ensure efficient diagnostic procedures”. The article describes in detail the structure, rationale, aims, and objectives of the EUNEFRON project.


New Syndromes
17q21.31 microduplication: patients are characterised by behavioural problems and poor social interaction
Microdeletions at 17q21.31 have recently been shown to cause a novel syndrome. Here the authors identify the reciprocal 17q21.31 duplication syndrome in four patients. In three cases it was possible to show that duplication arose de novo. Intellectual skills range from normal to mild intellectual deficit. Patients are characterised by poor social interaction, with relationship difficulties reminiscent of autistic spectrum disorders. Other features are rather variable with no striking common phenotypic features. Autistic features observed in these patients suggest that genes in the duplicated interval should be considered as candidates for disorders in the autistic spectrum. This adds 17q21.31 duplications to a growing group of recently identified genomic disorders with variable penetrance and expressivity.
Read the PubMed abstract

J Med Genet ; 524-530 ; August 2009
19q13.11 deletion syndrome: a novel clinically recognisable genetic condition
Deletions of chromosome 19 have rarely been reported, with the exception of some patients with deletion 19q13.2 and Blackfan-Diamond syndrome due to haploinsufficiency of the RPS19 gene. Such a paucity of patients might be due to the difficulty in detecting a small rearrangement on this chromosome that lacks a distinct banding pattern. Using array CGH, this study identified three interstitial overlapping 19q13.11 deletions, defining a minimal critical region of 2.87 Mb, associated with a clinically recognisable syndrome. The three patients share several major features including pre- and postnatal growth retardation with slender habitus, severe postnatal feeding difficulties, microcephaly, hypospadias, signs of ectodermal dysplasia, and cutis aplasia over the posterior occiput.
Read the PubMed abstract

J Med Genet ; 635-640 ; September 2009
PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalised lipodystrophy
The authors describe PTRF mutations in five nonconsanguineous patients who presented with a new syndrome of both generalised lipodystrophy and muscular dystrophy. Muscle hypertrophy, muscle mounding, mild metabolic complications, and elevated serum creatine kinase levels were observed. Skeletal muscle biopsies revealed chronic dystrophic changes, deficiency and mislocalization of all three caveolin family members, and reduction of caveolae structure.
Read the PubMed abstract

J Clin Invest ; 2623-2633 ; September 2009
Autosomal recessive arthrogryposis: mutations in SYNE-1 responsible
Arthrogryposis multiplex congenita (AMC) is a group of disorders characterised by congenital joint contractures caused by reduced foetal movements. The authors describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterised by bilateral clubfoot, decreased foetal movements, delay in motor milestones, then progressive motor decline after the first decade. A mutation in the SYNE-1 gene was found in the family.
Read the PubMed abstract

Hum Mol Genet ; 3462-3469 ; 15 September 2009
16p subtelomeric duplication: a clinically recognisable syndrome
The authors report on two patients with duplication of the subterminal region of chromosome 16p and presenting with closely overlapping facial features and neurological impairment. Distinct facial anomalies include high forehead, sparse eyebrows, blepharophimosis, short nose, everted upper lip, high-arched palate, wide-spaced teeth, and cupped anteverted ears. Susceptibility to vascular anomalies, in particular pulmonary hypertension and portal cavernoma, was found in one patient.
Read the PubMed abstract

Eur J Hum Genet ; 1135-1140 ; September 2009
Acute infantile liver failure due to mutations in the TRMU gene
The authors report on 13 unrelated infants who presented with acute liver failure and lactic acidemia with normal mtDNA content. Four died during the acute episodes, and the survivors never had a recurrence. The longest follow-up period was 14 years. The authors identified mutations in the TRMU gene, which encodes a mitochondria-specific tRNA-modifying enzyme, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase.
Read the PubMed abstract

Am J Hum Genet ; 401-407 ; September 2009
Xp11.22-p11.23 duplication associated with intellectual deficit, speech delay, and EEG anomalies in males and females
Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. The authors identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with intellectual deficit, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggest that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
Read the PubMed abstract

Am J Hum Genet ; 394-400 ; September 2009
Cerebral folate transport deficiency: a treatable neurodegenerative disorder with disturbed myelin metabolism
The authors identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRalpha or FRbeta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements.
Read the PubMed abstract

Am J Hum Genet ; 354-363 ; September 2009

New Genes

NARP/MILS-like syndrome caused by a novel mutation in the (mt) tRNA(Pro) gene
The authors present a patient with a disorder clinically similar to NARP/MILS syndrome, consisting of ataxia, retinitis pigmentosa, dysarthria, neurosensorial deafness, nystagmus and leukoencephalopathy. A novel heteroplasmic G to A transition at nucleotide 15 975 was found, affecting the T arm of the mitochondrial (mt) tRNA(Pro) gene. This is the fourth pathogenic tRNA(Pro) point mutation to be associated with an mt disorder.
Read the PubMed abstract

To read more about "NARP/MILS syndrome"

182 Eur J Hum Genet ; 1092-1096 ; August 2009
Cohen syndrome, cutis verticis gyrate, and sensorineural deafness: a novel VPS13B mutation in two brothers
The authors earlier described a syndrome characterised by microcephaly, cutis verticis gyrata, retinitis pigmentosa, cataracts, hearing loss and intellectual deficit in two brothers from a non-consanguineous Lebanese family. The single locus on the long arm of chromosome 8 that showed homozygosity by descent comprised the gene responsible for Cohen syndrome (CS), VPS13B. After sequencing VPS13B in the patients, the authors found a homozygous splice site mutation. Several possible explanations for the overlap between CS and the clinical features observed in these patients are discussed.
Read the PubMed abstract

Eur J Hum Genet ; 1076-1079 ; August 2009
Congenital dyserythropoietic anemia type II: Mutations affecting the secretory COPII coat component SEC23B at cause
Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases. CDA type II (CDAII) is the most frequent. It is characterised by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance. Here the authors show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII.
Read the PubMed abstract

To read more about "Dyserythropoietic anemia, congenital, type II"

Nat Genet ; 936-940 ; August 2009
BNAR syndrome: FREM1 mutations at cause
An autosomal-recessive syndrome of Bifid Nose and Anorectal and Renal anomalies (BNAR) was previously reported in a consanguineous Egyptian sibship. Here, the authors report the results of linkage analysis, on this family and on two other families with a similar phenotype, which identified mutations in FREM1, which encodes an extracellular matrix component of basement membranes.
Read the PubMed abstract

Am J Hum Genet ; 414-418 ; September 2009
Progressive familial heart block type I: impaired endocytosis of the ion channel TRPM4 is associated
Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In three branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, the authors identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. These data reveal a gain-of-function mechanism underlying this type of familial heart block.
Read the PubMed abstract

To read more about "Cardiac conduction defect, familial"

J Clin Invest ; 2737-2744 ; September 2009

Research in Action

Fundamental Research
Progeroid syndromes: insights into skin cancer and aging
Despite their rarity, diseases of premature aging, or "progeroid" syndromes, have provided important insights into basic mechanisms that may underlie cancer and normal aging. In this review, the authors highlight these recent developments in Hutchinson-Gilford progeria syndrome (HGPS), Werner syndrome, Bloom syndrome, Cockayne syndrome, trichothiodystrophy, ataxia-telangiectasia, Rothmund-Thomson syndrome, and xeroderma pigmentosum. Though they are caused by different mutations in various genes and often result in quite disparate phenotypes, deciphering the molecular bases of these conditions has served to highlight their underlying basic similarities. Studies of progeroid syndromes, particularly HGPS, the most dramatic form of premature aging, have contributed to the knowledge of fundamental processes of importance to skin biology, including DNA transcription, replication, and repair, genome instability, cellular senescence, and stem-cell differentiation.
Read the PubMed abstract

J Invest Dermatol ; 2340-2350 ; October 2009
Fragile X syndrome: from molecular genetics to therapy
The core aim of this review is to summarise two decades of molecular research leading to the characterisation of cellular and molecular pathways involved in the pathology of Fragile X syndrome and as a consequence to the identification of two new promising targets for rational therapy, namely the group 1 metabotrope glutamate receptors and the gamma-amino butyric acid A receptors. As no current clinical treatments are directed specifically at the underlying neuronal defect due to absence of the FMRP protein, this might open new powerful therapeutic strategies.
Read the PubMed abstract

To read more about "Fragile X syndrome"

J Med Genet ; 577-584 ; September 2009
Clinical Research
Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis
In their studies on the molecular basis of osteopoikilosis, Menten et al have identified three individuals with microdeletions on chromosome 12q14.4, which removed several genes including LEMD3, the osteopoikilosis gene. In addition to osteopoikilosis, affected individuals had growth retardation and developmental delay. The authors now report a smaller 12q14.4 microdeletion in a boy with severe pre and postnatal growth failure, and mild developmental delay. The authors conclude that the 12q14.4 microdeletion syndrome can occur with or without deletion of LEMD3 gene; in LEMD3-intact cases, the phenotype includes primordial short stature and failure to thrive with moderate developmental delay, but osteopoikilosis is absent. Such cases will likely be diagnosed as Silver-Russell-like or as primordial dwarfism.
Read the PubMed abstract

To read more about "Osteopoikilosis - short stature - intellectual deficit"

Eur J Hum Genet ; 1141-1147 ; September 2009
Budd-Chiari syndrome: etiology, management, and outcome
Budd-Chiari syndrome (BCS) is a hepatic venous outflow obstruction. What is known about the syndrome is based on small studies of prevalent cases. To characterise the causes and treatment of incident BCS, 163 incident cases of BCS were identified and followed. The authors found that most patients with BCS have at least 1 thrombotic risk factor, and many have more than 1; myeloproliferative disorders are most common. One- and 2-year survival rates are good with contemporary management, which includes noninvasive therapies (anticoagulation and diuretics) and invasive techniques. Transjugular intrahepatic portosystemic shunting seems to have replaced surgical shunting as the most common invasive therapeutic procedure.
Read the PubMed abstract

To read more about "Budd-Chiari syndrome"

Ann Intern Med ; 167-175 ; 4 August 2009
Hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation
Hereditary thrombocythemia is a rare autosomal dominant disorder caused by mutations in either the thrombopoietin gene (TPO) or its receptor c-MPL. TPO mutations described so far lead to thrombopoietin overproduction through increased translation of m-RNA. Unilateral transverse reduction limb defects are usually sporadic and generally thought to be caused by vascular disruptions. Reports of inherited unilateral limb defects are extremely rare. In the present study, the authors describe a family with segregation of G185T TPO mutation in the 5’ UTR region in 4 subjects with thrombocythemia. Three of these patients also present congenital transverse limb defects. Association of these events gives a strong hint of the in vivo involvement of thrombopoietin in vasculogenesis, confirming the role of TPO in human development of the hemangioblast, the embryonic progenitor of the hematopoietic and endothelial lineages. This is the first report showing that vascular disruptions could be secondary to specific gene derangements.
Read the PubMed abstract

To read more about "Thrombocytosis, familial"

Blood ; 1655-1657 ; 20 August 2009
Myeloid neoplasms and acute leukemia: Revision of the WHO classification
Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues incorporating new information, and including new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterised. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarising hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.
Read the PubMed abstract

Blood ; 937-951 ; 30 July 2009
Esophageal atresia and associated malformations
Esophageal atresia is a common type of congenital malformation. The etiology of esophageal atresia is unclear and its pathogenesis is controversial. The authors conducted this study in a geographically well-defined population, evaluating the birth prevalence of esophageal atresia and associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 99 patients with esophageal atresia, 46 had associated malformations. These included patients with chromosomal abnormalities (8 patients); non-chromosomal recognised syndromes (4 patients), including one each CHARGE syndrome, Fanconi anemia, Fryns syndrome, and Opitz G/BBB syndrome; associations including VACTERL (10 patients), and one schisis; one oculo-auriculo-vertebral spectrum; one malformation complex, a sirenomelia, and non-syndromic multiple congenital anomalies (MCA) (21 patients). Malformations of the cardiovascular system (24%), urogenital system (21%), digestive system (21%), musculoskeletal system (14%), and central nervous system (7%) were the most common other congenital malformations occurring in patients with esophageal atresia and non-syndromic MCA. The malformations associated with esophageal atresia could be classified into a recognisable malformation syndrome or pattern in 25 out of 46 patients.
Read the PubMed abstract

To read more about "Esophageal atresia"

Eur J Med Genet ; 287-290 ; September-October 2009
Fabry disease: changing pattern of causes of death – the Fabry Outcome Survey
Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past seven years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.
Read the PubMed abstract

To read more about "Fabry disease"

J Med Genet ; 548-552 ; August 2009
Diagnostic Approaches
Marfan syndrome: minimal combination of clinical features for efficient FBN1 mutation detection
Mutations identified in the fibrillin-1 (FBN1) gene have been associated with Marfan syndrome (MFS). However, FBN1 gene mutations are found in an ill-defined group of diseases termed "type I fibrillinopathies", which are associated with an increased risk of aortic dilatation and dissection. The authors compiled the molecular data obtained from the screening of the FBN1 gene in 586 probands. They found that the best predictor of the identification of a mutation in the FBN1 gene was the presence of features in at least three organ systems, combining one major, and various minor criteria. They also show that their original recommendation of two systems involved with at least one with major criterion represents the minimal criteria because in probands not meeting these criteria, the yield of mutation identification drastically falls. This recommendation should help clinicians and biologists in identifying probands with a high probability of carrying a FBN1 gene mutation, and thus optimise biological resources.
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To read more about "Marfan syndrome"

Eur J Hum Genet ; 1121-1128 ; September 2009
Familial ovarian cancer: annual screening ineffective
A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan-Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement. Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.
Read the PubMed abstract

To read more about "Ovarian tumor"

J Med Genet ; 593-597 ; September 2009

Patient Management and Therapy

Medulloblastoma: treatment with a hedgehog pathway inhibitor
Medulloblastoma is the most common malignant brain tumour in children. Aberrant activation of the hedgehog signalling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumour and reduction of symptoms. Molecular analyses of tumour specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1, a key negative regulator of hedgehog signalling.
Read the PubMed abstract

To read more about "Medulloblastoma"

N Engl J Med ; 1173-1178 ; 17 September 2009
Antiphospholipid syndrome; mantle cell lymphoma; von Willebrand disease; Waldenström macroglobulinemia…how they are treated
In the How I treat section of the journal Blood, four articles examine four different rare diseases: antiphospholipid syndrome, mantle cell lymphoma, von Willebrand disease, and Waldenström macroglobulinemia. The authors present treatment approaches and discuss different clinical and diagnostic aspects for each disease.
Read the PubMed abstract
Read the PubMed abstract
Read the PubMed abstract
Read the PubMed abstract

To read more about "Antiphospholipid syndrome"
To read more about "Mantle cell lymphoma"
To read more about "Von Willebrand disease"
To read more about "Waldenström macroglobulinemia"

Blood ; 1158-1165 ; August 2009
Blood ; 1469-1476 ; August 2009
Blood ; 2020-2030 ; September 2009
Blood ; 2375-2385 ; September 2009


Orphan Drugs

Thirteen positive opinions for orphan designation at the September COMP meeting
At the September 2009 meeting of the Committee for Orphan Medicinal Products (COMP), thirteen positive opinions were issued for the treatment of:
- primary peritoneal cancer
- fallopian tube cancer
- progressive supranuclear palsy
- pancreatic cancer
- Huntington disease
- ovarian cancer
- inborn errors in primary bile acid synthesis responsive to treatment with cholic acid
- inhalation anthrax disease
- post-exposure prophylaxis of inhalation anthrax disease
- pancreatic cancer (two products)
- hepatocellular carcinoma
- myasthenia gravis

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


News from the Patients' Associations
New interactive website designed for school children promotes awareness for genetic diseases in a fun and friendly way

Jeans for Genes is a UK-based charity dedicated to raising funds in order to aid ongoing research and provide care for children and families affected by genetic disorders. As part of its mission to raise awareness and promote understanding, Jeans for Genes has launched an exiting new tool developed by genetics and education experts, in consultation with primary and secondary teachers. Genes Are Us, an educational web-based resource for schools, gives pupils the opportunity to explore how genes make each person unique, through a series of short films in which children affected by genetic disorders tell their stories. The materials, including films, activities, animations, and discussion formats, are presented in a colourful, user-friendly format, and aim to engage school children in dynamic discussions about the hopes and realities of living with a genetic disorder, encouraging them to show respect for each other’s differences and appreciate that everyone is unique.

Alström Syndrome UK develops handbook for professionals and patients

Alström syndrome is an extremely rare multisystemic disorder caused by mutations in the ALMS1 gene and characterised by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. The Alström Syndrome UK group offers support for patients with Alström syndrome, as well as their carers and the professionals working with them. Alström Syndrome UK has developed another tool to furnish assistance. The Alström Syndrome Booklet is a handbook developed for consultants, general practitioners and other health professionals, along with parents and family members. Funded by the National Health Service National Specialised Commissioning Group, the booklet furthers understanding and knowledge for diagnosing the disorder and provides information on advancements made in treatments. A detailed checklist of possible signs and symptoms is provided, along with an outline of what an annual check-up should include. A discussion of the genetics of the disease is also included. The handbook is free and can be obtained online or by emailing the Alström Syndrome UK Support Group.


What's on Where?

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

Covering diagnostics, overlapping syndromes, treatment approaches and more.
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

International Patient Organisation for Primary Immunodeficiencies – First Global Leaders Meeting
Date: 30 October – 1 November 2009
Venue: London, UK

Provide a platform for a Global Collaboration of all stakeholders involved with primary immunodeficiency.
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

6th International Conference on Rare Diseases and Orphan Drugs
Date: 18-20 March 2010
Venue: Buenos Aires, Argentina

The 6th International Conference on Rare Diseases and Orphan Drugs (ICORD 2010) for the first time will be convened in the southern hemisphere in agreement with its aim of globalisation of rare disease research and orphan products development activities.
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.

14th International Conference on Behçet Disease
Date: 8-10 July 2010
Venue: London, England

Presenting new developments in basic and clinical science to bear on the specific issues of Behçet Disease (BD). Topics to be covered will include immunology of BD, vasculitis in BD, genetic basis of BD, regional inflammation and paediatric BD. The programme will also include debates on topics of current interest or controversy.
For further details

Men 2010: 12th International Workshop on Multiple Endocrine Neoplasia
Date: 16-18 September 2010
Venue: Viareggio, Italy

This two-day meeting will provide a forum for educating basic and clinical investigators on the most recent advances in the area of hereditary endocrine tumours.
For further details


Press & Publications

Calcium and Bone Disorders in Children and Adolescents
Authors: Jeremy Allgrove, Nick Shaw –Eds.
Publisher: S Karger, June 2009
ISBN-13: 978-3805591614

The main part of this publication describes in detail the disorders associated with hypocalcemia, hypercalcemia, rickets, phosphate metabolism, primary and secondary osteoporosis. The genetic nature of many of these conditions is highlighted. The final chapter comprises case reports illustrating some of the problems that are examined in previous chapters.

The Sorting Society: The Ethics of Genetic Screening and Therapy
Authors: Loane Skene, Janna Thompson –Eds.
Publisher: Cambridge University Press, September 2008
ISBN-13: 978-0521689847

This book focuses on the ethical, legal and social issues raised by genetic testing and therapy. Contributing to the debate on a major issue affecting all of society over the next generation, this work offers an interdisciplinary perspective and considers both the pros and cons of genetic testing, presenting a well rounded argument.


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: Ségolčne Aymé
Editor: Louise Taylor
Contact Us
Editorial Board: Ségolčne Aymé, Catherine Berens, Olaf Bodamer, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Charlotte Rodwell, Paloma Tejada, Aurélie Vandeputte
National Contact Point: Till Voigtländer (Austria), 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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