25 September 2007 print
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Conference confirms European commitment to rare disease and orphan drug research
The European Commission conference Rare Diseases Research: Building on Success brought together members of government, science, and industry to focus on rare disease needs within the context of the opening year of the Seventh Research Framework Programme (FP7) funding scheme that runs from 2007–2013. Some central themes emerged during the course of the day: avoiding duplication of work in a field with limited resources; increasing multinational collaboration; and the need for long-term funding for many areas of rare disease research. Several speakers emphasised the relevance of rare disease research to common diseases. DG Research Deputy Director-General Zoran Stancic chaired the opening session, calling for increased sensitivity to the issue of rare diseases at the beginning of the FP7. European Commissioner for Science and Research Janez Potocnik kicked the day off with a recorded speech evoking rare diseases as a perfect example of the need for European-level research. Rare diseases, when taken together, are not so rare after all. Raising awareness and identifying the most important areas of research for the 30 million euros available for rare disease research in FP7 are important tasks to accomplish. Conference attendees were graced with the presence of H.R.H Princess Astrid of Belgium, who reminded attendees of the “distress of the entourage” surrounding the rare disease patient. She held up the Belgian neuromuscular centres of reference as a model of progress in the field. Patients are examined routinely each year in these centres.

Parliament member Alojz Peterle spoke of the need for cooperation between the European Commission and the Parliament in order to obtain results in the area of rare disease and orphan drug research.

The morning keynote speaker, French nephrologist Corinne Antignac, described the importance of studying rare diseases. She cited Bardet-Biedl syndrome, an illness that affects just 1 in 120,000 Europeans. Study of this ultra rare disease has led to the opening of new areas in cell biology. Thus, despite the rarity of the illness, some 20 international papers have been published on the disorder since 2000 in major leading medical and science journals. The completion of the human genome was elicited as an important emerging resource, along with new diagnostic tools, such as qPCR technology.

The morning topic of the one-day event was Lessons learnt from research on rare diseases. Sylvia Stockler-Ipsiroglu of University of British Columbia in Canada described the path leading to treatment via creatine replacement therapy in patients with creatine kinase deficiency. As almost always with rare disease research, the call for further progress was sounded, as the therapy developed in this case does not work in all forms of the disease, and only partially in others. Close and long-term follow-up was recommended for learning more about the natural history of the disease.

Massimo Zeviani, from Istituto Nazionale Neurologico Carlo Besta, in Milan, spoke at length of the rare disease study serving as a model for common disorders. Three examples of this were presented: retinoblastoma, which led to the discovery that cancer is a genetic disease; rare, familial Alzheimer disease, which allowed for understanding the general pathology of the disease, and the complex mitochondrial disorders, which have provided knowledge for more common disorders, such as Parkinson disease.

Gert-Jan Van Ommen from Leiden University Medical Centre spoke of rare diseases as drivers for innovation, evoking the example of Duchenne muscular dystrophy, a rare illness affecting 1 in 3500 male children, as an innovative model in which the approach of exon-skipping has proven successful. Van Ommen described the “black box” approach, in which the disease mechanism is not fully revealed until therapy or prevention is administered.

The last speaker of the morning, Carlo Incerti, representing European Biopharmaceutical Enterprises, reminded listeners of the success of the Orphan Drug regulation, in place in Europe since 2000. Although similar legislation has been in effect in the US since 1983, the EU and the US are presently producing rare disease products at a similar pace. He delineated the challenges facing rare disease therapies: few animal models; little natural history data; rare diseases that are often slowly progressing chronic diseases; extremely heterogenic phenotypes; different authorisation requirements between the US, the EU, Japan, and other countries; and limited resources to sustain long-term development with no immediate financial return. Other challenges in developing rare disease treatments include typically small patient numbers; recruitment logistics for patients often located far apart; demonstration of clinical benefits; post-authorisation commitments that can be burdensome for industry; the EU Clinical Trials Directive that adds complexity to the process; and the variance in patient access to approved medicines, depending on the country. The EMEA’s CHMP Guideline on Clinical Trials on Small Populations (February 2007) was cited as an important document for orphan drug trial design. Dr. Incerti also listed the positive aspects of orphan drug research, including the high level of innovation being applied; technologies or treatments that can provide a template for other disorders; and rare disease research and development supporting the personalised medicine concept. The necessity for a partnership between academia and industry was reiterated, with EPPOSI singled out as an example of success in this arena.

The first segment of the afternoon session was led by Leena Peltonen of the University of Helsinki and Finnish National Public Health Institute. Her discourse, Value-added by carrying out research on rare diseases at the European level investigated how population genetics can best be harnessed to aid rare disease research. She lamented the quantity of excellent science that does not translate into product. At a European level, data harmonisation is needed and available resources must be better pooled. Some European bottlenecks needing attention include a lack of expertise, an immature concept of recruitment by academia, a lack of tenure track for young experts, and underdeveloped infrastructures.

Elisabeth Tournier-Lasserve, from CNRS, INSERM and the Institut des Maladies Rares in Paris, discussed models for supporting European rare disease research. In terms of clinical characterisation, large cohorts are needed once a gene is identified for geno/pheno-typing. She cited the some 4000 rare diseases that currently have no existing molecular basis often because patients issue from one-case families. A genome platform is needed to address this. In terms of pathophysiology, for the 1800 or so rare disease genes identified to date, easy access for all European post-genomic platforms is essential. Therapeutic research currently does not have enough partnerships with industry. And as was mentioned by several speakers during the course of the day, clinical trials suffer from high costs and patient sizes that are often very small due to the rarity of an illness. The French national plan for rare diseases might well serve as a model for improving research at the EU level.

Marie Johannesson of Uppsala University Hospital and the Swedish Medical Products Agency spoke of research on rare diseases in a global context. As a member of the EMEA Paediatric Committee, she particularly evoked the need for standardised paediatric medical products that are developed with specific indications for children.

John Burn of the Institute of Human Genetics and Newcastle University in England outlined the future needs of the rare disease and orphan drug research community. As was mentioned by several speakers, long-term funding is necessary for seeing projects through to completion and to translate research into products that will truly serve the rare disease patient and family. Dr. Burn used a metaphor of the tide of medical progress carrying out the more commonplace diseases that are now cured or prevented, leaving on the sand the scattering of rare diseases that are now society’s common problem.

The day finished with a message from Christel Nourissier of EURORDIS, who brought the focus back to the patient and the force that patient groups can contribute to rare disease research and policy. DG-Research Director-General José Manual Silva Rodriguez closed the conference by reiterating the commitment of the European Commission and DG Research to the field of rare diseases and orphan medicinal products.

EU Policy News
COMP adopts 500th orphan designation positive opinion
At the eighty-second meeting of the Committee for Orphan Medicinal Products (COMP), taking place on 11-12 September, the European Medicines Agency group adopted its 500th positive opinion granting orphan designation to a medicinal product. A COMP press release highlights this milestone as evidence of the dedication of the COMP and EMEA, the continuous effort of the various orphan medicine stakeholders, and the overall success of the orphan regulation.

National & International Policy Developments
FDA issues genetic test guidelines for industry and FDA staff
In the US, the FDA has issued two distinct documents concerning genetic testing. The Pharmacogenetic Tests and Genetic Tests for Heritable Markers guidance was issued in June of this year for the pharmaceutical industry and for FDA staff. This guidance seeks to shorten development and review timelines, facilitate rapid transfer of new technology from research to laboratory use, and encourage informed use of pharmacogenomic genetic diagnostic devices. It also provides recommendations for sponsors and reviewers for preparing and reviewing premarket approval applications and premarket notification submissions. Array-based tests are included in the scope of the document, along with single and multiple marker tests. The recommendations set down a basic framework from which manufacturers and scientific reviewers can operate, and include the preparation topics of applications, intended use, device design, analytical studies, instrumentation, and comparison studies. Evaluation, effectiveness and labelling topics are also covered.

A second guidance has been issued as a draft: The In Vitro Diagnostic Multivariate Index Assays (IVDMIA) draft guidance is for industry, clinical laboratories and FDA staff and addresses the definition and regulatory status of the IVDMIAs, as well as premarket pathways and postmarket requirements. The guidance addresses Humanitarian Use Exemption for rare disease diagnoses. A finalised version will be forthcoming.

September is National Childhood Cancer Awareness month in the US
In the US, September is Childhood Cancer Awareness Month. All paediatric cancers, such as acute lymphoblastic leukaemia, acute myelogenous leukaemia, and Hodgkin lymphoma, are rare diseases. As part of an ongoing effort to attract more attention and resources for childhood cancers, CureSearch, an organisation uniting the Children's Oncology Group and the National Childhood Cancer Foundation, is lobbying vigorously for passage of the Conquer Childhood Cancer Act of 2007, currently under consideration in both the US House and the Senate. This act, co-sponsored by 136 House members and 35 Senators, would authorise some $150 million over five years for research, the establishment of a national registry, and information services.
Other European news
New database identifies rare genetic conditions by reading faces
An estimated 700 genetic conditions present with a unique facial appearance, some of which have quite subtle features. Many cases are rarely seen and there may be only a few documented cases worldwide. To help practitioners obtain a diagnosis in such cases, researchers from the UCL Institute of Child Care in London have developed a computer software programme that uses 3D photographic images. The software compares a patient’s face to stored images of individuals with specific identified conditions. The clinician can then undertake related molecular testing based on the results of the image search. It is hoped that this new technology will reduce costs, diminish the stress of testing for the child, and help shorten the diagnostic process. Delays in diagnosis can adversely impact the prognosis of an illness when early intervention is needed to halt or reverse the course of the disease. The researchers, including computer scientists, clinical geneticists, molecular biologists and cognitive scientists, plan to test the potential of the images in the training of clinicians to recognise rare genetic conditions and to extend the capabilities to cases where diagnosis is unclear, genetic expertise is limited or the cost of genetic testing is prohibitive.
A new tool for including verbally challenged children in decision making
Researchers from the University of Bristol in the UK have created a resource specifically for school children with little or no speech ability. Rett and Fragile X syndromes are examples of rare autism spectrum disorders that can severely impact verbal communication. I want to choose too was developed as part of the University of Bristol’s Participation in Education (PIE) programme, and presents ideas and strategies for involving speech-disabled children in peer interactions, as well as classroom, school, and community activities. Developed for teachers and others to enhance the inclusion of speech-disabled children in decision making and other interactions, needs were identified via a survey designed to determine the exclusion of disabled children with little or no verbal communication from decision-making processes in school and then by closely following a dozen children with little or no speech as they interacted with their entourage on a daily basis. Choice-making receives particular emphasis as a process that can enrich a child’s experience at school. Many suggestions and ideas are presented for enabling children to communicate choices and participate in decision making and many mechanisms are employed, including signing, visual aids and electronic support. I want to choose too is a richly illustrated, user-friendly tool that includes booklets, a CD-Rom, and lists of resources.
Other International News
International specialists call for improving paediatric palliative care
There are a number of rare diseases involving children that lead to early mortality characterised by painful and distressing episodes. The 17 August online edition of the Lancet contains a report by a group of international paediatric palliative care specialists calling for an increase in research for children’s specific clinical, physical and psycho-social needs. The article outlines the ongoing challenge of creating a definition of paediatric palliative care that is relevant to all cultures and nations with their varying resources available. Specific examples in the report include two infants with trisomy 18, who both suffer from ventricular septal defects, yet present with varying phenotype expression and different environmental circumstances that call for different elements in terms of palliative care. Other case studies include a 12 year old with cystic fibrosis, and a four-month-old with rare disease diencephalic syndrome. The report calls specifically for more research for managing pain and fatigue, determining whether treatments inadvertently increase suffering and prolong dying, and providing care that reduces suffering in the patient’s entourage.
South Korean rare disease conference reveals sustained efforts for rare disease patients
The South Korean NIH held its second conference on rare diseases in Seoul on 31 August with Ségolène Aymé, director of Orphanet and leader of the EC Rare Diseases Task Force, as international guest speaker, following in the footsteps of Stephen Groft, from the US NIH Office of Rare Diseases, who was guest speaker at the first conference, held in 2006. South Korea opened an Orphan Drug Center within the FDA in 1999, which is in charge of supplying medications to patients. Since 2001, subsidies on rare disease patients’ medical expenses have been provided for more than 100 disease groups. The total annual budget is over 78 200 million Korean won (60.2 million euros). The South Korean NIH established an information service to respond to both telephone and e-mail inquiries in 2004. This service also maintains a Korean-language website that provides textual information translated from NORD for 400 diseases, as well as a list of relevant clinics and support groups in the country. Information on rare disease prevalence statistics in the country is also available. The conference covered all aspects of rare diseases and orphan drugs, testifying to both the dynamism of Korean research and the goodwill of governmental agencies to collaborate effectively in order to improve the life of affected patients.

The sessions were chaired by the president of KORD, the Korean umbrella group for patient organisations. Discussions have begun to establish a formal collaboration between the Korean Office of Rare Diseases and Orphanet - a welcome development.

NIH funds interdisciplinary consortia embodying a new research approach
The US National Institutes for Health has announced funding for nine interdisciplinary research consortia designed to create a new approach to health issues that have not been resolved by more traditional means. Funding of these consortia “represents a fundamental change in both the culture within which biomedical and behavioural research is conducted and the culture within the NIH where research projects are normally managed by an individual Institute or Center”. Interdisciplinary research will integrate a wide range of disciplines, including basic, clinical, behavioural and social research and will involve different team members learning to approach a problem using methods typically employed by different disciplines. It is expected that the consortia will result in new ways of approaching difficult health challenges. Amongst the nine consortia, Neurotherapeutics will implement an interdisciplinary approach toward developing molecular therapeutics for neurogenetic illnesses, using the rare late-onset disease fragile X associated tremor/ataxia syndrome as its principal paradigm. Four separate but interacting research projects will involve scientists from such diverse fields as chemistry, developmental paediatrics, mouse behaviour, and cellular neurophysiology. Another consortium will work with genome engineering, focussing on gene repair for monogenic disorders of the bone marrow and lymphoid systems. Genome-based drug discovery and organ design and engineering are other consortia receiving NIH funding. For more general information and details of each consortium.
Xeroderma pigmentosum short film wins award
Shade, a short film produced by Kimberly Williams-Paisley, is winning awards at various film festivals across the US. The film depicts a young woman living with xeroderma pigmentosum, a rare genetic photodermatosis characterised by cutaneous hyperpigmentation arising in sun-exposed regions of the body during the first months of life. Copies of Shade are available from the Xeroderma Pigmentosum Society.

Orphanet News
New Texts
New Orphanet Journal of Rare Diseases publications
Acute graft versus host disease
Sotos syndrome
Hypereosinophilic syndromes

New Research Projects open for Recruitment
A multicenter trial of Abagovomab maintenance therapy in patients with epithelial ovarian cancer after complete response to first line chemotherapy (Germany)
Efficacy Multicentre Trial of ImmunoTherapy Vaccination With Abagovomab to Treat Ovarian Cancer Patients (MIMOSA) (Spain)
A multicenter trial of Abagovomab maintenance therapy in patients with epithelial ovarian cancer after complete response to first line chemotherapy (Italy)
Safety and Efficacy of Orally Administered Fx-1006A in Patients With Familial Amyloid Polyneuropathy (FAP): A Randomized, Double-Blind, Placebo-Controlled Study (Portugal)


New Syndromes
Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy
Four children presented with ataxia, delayed dentition, hypomyelination and cerebellar atrophy, clinically identical to four cases already described in the literature. The authors propose labelling this new leukoencephalopathy ADDH (ataxia, delayed dentition, and hypomyelination).
Read the PubMed abstract

Neuropediatrics ; 64-70 ; April 2007
A third variant of lethal contractural syndrome is discovered
Lethal congenital contractural syndrome is a severe form of arthrogryposis. Two variants of the disorder have been described, of which type 2, observed in an Israeli Bedouin family, is characterised by multiple joint contractures, micrognathia, atrophy of the anterior horn of the spinal cord and distended bladder. The authors now describe in a consanguineous family a novel form of the syndrome, type 3. It is similar to type 2 but presenting with no bladder anomaly. A homozygous mutation in gene PIP5K1C, encoding enzyme PIPKIgamma involved in the phosphatidylinositol pathway has been identified.
Read the PubMed abstract

Am J Hum Genet ; 530-539 ; September 2007
A new sex development disorder with congenital adrenal hypoplasia, aniridia, craniofacial and skeletal abnormalities
Two siblings present with an unusual constellation of congenital abnormalities comprising 46,XY sex development disorder, congenital adrenal hypoplasia, aniridia, dysmorphic facial features, intrauterine growth retardation, and minor skeletal abnormalities. The authors propose that this combination of anomalies represents either a new syndrome or a variant of a known condition such as IMAGe syndrome.
Read the PubMed abstract

Am J Med Genet A ; 2085-2088 ; 15 Sep 2007

New Genes
Lethal congenital contractural syndrome type 2 is caused by a mutation in ERBB3
Lethal congenital contractural syndrome type 2 is an autosomal recessive neurogenic form of arthrogryposis associated with atrophy of the anterior horn of the spinal cord. The authors have discovered a mutation modifying the splicing of gene ERBB3 leading to a truncated protein. ERBB3 encoding an activator of the phosphatidylinositol pathway, is necessary for generating Schwann cell precursors that normally accompany peripheral axons of motor neurons. (See the related article in the New Syndromes section above).
Read the PubMed abstract

Am J Hum Genet ; 589-595 ; September 2007
Arts syndrome is caused by mutations leading to impaired purine biosynthesis
Arts syndrome is characterised by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment and optic atrophy. The researchers have identified missense mutations in PRPS1 in a Dutch and an Australian family. In vitro the enzyme encoded by mutated PRPS1 is completely inactive, blocking purine biosynthesis. A clinical trial aiming at increasing purine biosynthesis with S-adenosylmethionine treatment is currently underway in two Australian brothers.
Read the PubMed abstract

Am J Hum Genet. ; 507-518 ; Sept 2007
Mutations in PRPS1 found in X-linked Charcot-Marie-Tooth syndrome type 5
In two families afflicted by X-linked Charcot-Marie-Tooth syndrome type 5, the researchers have discovered missense mutations in PRPS1, also implicated in Arts syndrome (see above abstract). The patients present with hearing impairment, gating disturbance, and visual loss. The mutations identified lead to partial activity loss of the enzyme encoded by PRPS1, implicated in purine synthesis.
Read the PubMed abstract

Am J Hum Genet ; 552-558 ; September 2007
NOBOX homeobox gene mutation causes premature ovarian failure
The researchers sequenced the NOBOX gene in 96 women with premature ovarian failure. NOBOX is critical to early folliculogenesis. The heterozygous missense mutations were discovered in the homeobox domain, disrupting binding to the DNA in a dominant-negative way.
Read the PubMed abstract

Am J Hum Genet ; 576-581 ; September 2007
CHMP4B mutations in autosomal dominant cataracts
Two missense mutations have been discovered in gene CHMP4B in two families of which certain members present autosomal dominant cataracts. CHMP4B encodes a protein essential to intracellular endosome transport.
Read the PubMed abstract

Am J Hum Genet. ; 596-606 ; September 2007
Isolated renal hypomagnesemia caused by an impairment in epidermal growth factor (EGF) secretion
In two sisters from a consanguineous family, suffering from isolated renal hypomagnesemia, the authors discovered a homozygous mutation in the gene encoding epidermal growth factor, preventing the secretion of the growth factor and consequently the activation of its receptor. Without such activation the channel transporting magnesium out of the epithelium is only partially activated, leading to the retention of this ion in the cells.
Read the PubMed abstract

J Clin Invest ; 2260-2267 ; August 2007
Dominant negative STAT3 mutations in hyper-immunoglobulin E syndrome
Hyper-immunoglobulin E is an immunodeficiency disorder characterised by a highly elevated serum IgE level, recurrent staphylococcal skin abscesses and cyst-forming pneumonia and skeletal abnormalities. Inheritance is autosomal dominant; sporadic cases are also found. Two studies, published respectively in the New England Journal of Medicine and Nature, identify mutations in STAT3, the gene encoding human signal transducer and activator of transcription 3. De novo mutations were observed in sporadic cases, while mutations explaining the autosomal dominant transmission were observed in familial forms. The mutant protein inhibits function of the wild-type protein, strongly diminishing STAT3 activity in peripheral blood cells.
Read the first PubMed abstract
Read the second PubMed abstract

N Engl J Med ; E-pub ahead of print ; 19 September 2007
Nature ; 1058-1062 ; August 2007

Research in Action
Clinical Research
An atypical form of nemaline myopathy is caused by missense mutations in the nebulin gene
Nemaline myopathy is a recessive neuromuscular disease characterised by muscular weakness of varying severity, non-progressive in most cases. Patients are usually carriers of at least one gene mutation interrupting the translation of the gene encoding nebulin. In seven Finnish families, the authors identified homozygous missense mutations in the nebulin gene, linked to an atypical form of the disorder. The patients presented muscle weakness affecting the ankle dorsiflexors, finger extensors and neck flexors.
Read the PubMed abstract

Brain ; 465-476 ; June 2007
Endocrine abnormalities in patients with Fanconi anaemia
An autosomal recessive disease linked to chromosomal instability, Fanconi anaemia is distinguished by a heterogenous phenotype including medular insufficiency, variable malformative syndrome and cancer predisposition. A retrospective study of 45 patients shows that 73% present endocrine anomalies, including growth hormone deficits, hypothyroidism or glucose metabolism anomalies. The authors recommend comprehensive endocrine and metabolic evaluation in Fanconi anaemic patients.
Read the PubMed abstract

J Clin Endocrinol Metab ; 2624-2631 ; July 2007
Mutations in SBDS gene in acquired aplastic anaemia
The authors identified in four patients with acquired aplastic anaemia, a heterozygous mutation in gene SBDS encoding a protein of unknown function. Homozygous mutations of this gene are responsible for the development of the autosomic recessive Shwachman-Diamond syndrome, which is characterised by aplastic anaemia, amongst other symptoms. The authors propose that the mutation in question accelerates the telomere shortening of leukocytes.
Read the PubMed abstract

Blood ; 1141-1146 ; 15 August 2007
Two markers for the diagnosis of arthropathy in haemochromatosis
Haemochromatosis is a genetic disease marked by a surcharge of iron due to an abnormally high level of digestive absorption. To discern haemochromatosis-associated arthropathy from rheumatoid arthritis, the Austrian-based research team analysed anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor levels in 87 patients. Contrary to what is observed in rheumatoid arthritis, haemochromatosis patients were constantly anti-CCP negative. The authors propose integrating these criteria into differential diagnosis of CCP-negative arthritis. Testing for anti-CCP antibodies discriminates haemochromatosis arthropathy from rheumatoid arthritis.
Read the PubMed abstract

Ann Rheum Dis ; 1249-1251 ; September 2007
An international study linking phenotypes and mutations in Marfan syndrome
Mutations in FBN1, encloding fibrillin-1, cause Marfan syndrome and have been associated with a wide range of overlapping phenotypes. The Universal Mutation Database, providing international FBN1 mutation data from 1013 patients, has permitted the establishment of a correlation between phenotypes and gene mutations. The authors thus demonstrated that patients with a mutation producing a cysteine have a strong likelihood to present ectopia lentis. A mutation causing premature termination codon had more severe skeletal and skin phenotype. Mutations in exons 24 and 32 are linked to more severe and complete phenotype, with cardiac anomalies and poor prognosis.
Read the PubMed abstract

Am J Hum Genet ; 454-466 ; September 2007
Specific RMRP mutations predict skeletal dysplasia phenotype
Autosomal recessive skeletal dysplasias present a wide spectrum of phenotypes, including differing growth deficits, hair and cartilage dysplasia, defective erythrogenesis, and immunodeficiency. Mutations in RMRP encoding a mitochondrial ribonuclease RNA component, are responsible for the clinical spectrum. Analysing patient phenotypes of 13 different mutations, the authors show that mutations leading to a reduction of ribosomal RNA cleavage are more often linked to bone dysplasia while mutations provoking reduced cleavage in RNA messengers are more often linked to hair hypoplasia, immune deficiencies, and haematological abnormalities.
Read the PubMed abstract

Am J Hum Genet ; 519-529 ; September 2007

Patient Management and Therapy
Nogo-A is a prognostic marker in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis may be preceded by muscle weakness and atrophy as well as inferior member fasciculation. However, these clinical signs can also evolve into other muscle pathologies. A French research team analysed muscle expression of Nogo-A, a protein associated with myelin and inhibiting neurite growth in muscular biopsies of patients presenting these signs. Nogo-A presence has a 91% positive predictive value, 94% sensitivity, and 88% specificity. The authors thus propose introducing dosage of this marker as a diagnostic test in order to reduce the length of time before neuroprotector treatment is introduced.
Read the PubMed abstract

Ann Neurol ; 15-20 ; July 2007
Duchenne muscular dystrophy mortality and perindopril preventive treatment: a ten-year follow-up
Duchenne muscular dystrophy is associated with muscle weakness and often fatal myocardial dysfunction. The researchers tested the efficacy of perindopril, an angiotensin-converting enzyme inhibitor, on 57 children aged 9-13 presenting normal left ventricular ejection fraction. The three-year double-blind protocol, followed by open-label perindopril treatment for up to ten years, demonstrated early administration increased survival.
Read the PubMed abstract

Am Heart J ; 596-602 ; September 2007
Allogeneic bone marrow transplantation in mevalonic aciduria
Mevalonic aciduria is a rare autosomal recessive illness characterised by severe periodic attacks of fever, inflammation, developmental delay, ataxia, and dysmorphic features. A three-year-old boy underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. Sustained remission of febrile attacks and inflammation were observed during a 15-month follow-up period.
Read the PubMed abstract

N Engl J Med ; 2700-2703 ; 28 June 2007
Miglustat improves the clinical spectrum in patients with Niemann-Pick disease type C
Niemann-Pick disease type C is a neurodegenerative disorder caused by an intracellular lipid trafficking error that leads to an accumulation of glycosphingolipids in the lysosomes. Miglustat, an inhibitor of glycosphingolipid synthase that is able to cross the blood-brain barrier, was used in a randomised trial including 29 children over age 12. At 12 months, Miglustat has improved or stabilised several markers, including auditory acuity and swallowing capacity.
Read the PubMed abstract

Lancet Neurol ; 765-772 ; September 2007
Proposals for revising WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis
An international group of experts has reviewed the World Health Organisation diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis, proposing that JAK2 mutation testing be a major diagnostic criterion for polycythemia vera, complementary to the histologic diagnosis performed in the other two conditions. They also recommend lowering the platelet threshold from 600 to 450x10(9)/L for diagnosing essential thrombocythemia.
Read the PubMed abstract

Blood ; 1092-1097 ; 15 August 2007
The Gene Dossier process evaluates genetic tests and recommends those to be provided by the NHS
The United Kingdom Genetic Testing Network (UKGTN) was established in 2002 as a collaborative network of National Health Services (NHS) molecular genetic laboratories offering tests for human single gene germ-line disorders. The network has developed a Gene Dossier process to evaluate tests and recommend which tests will be provided by the NHS.
Read the PubMed abstract

Eur J Hum Genet ; 917-921 ; September 2007

Orphan Drugs
Seventeen EMEA orphan drug designations for September

The COMP (Committee for Orphan Medicinal Products) adopted the following 17 positive opinions on orphan medicinal product designation at its September meeting for the treatment of:

- hepatocellular cancer
- chronic lymphocytic leukaemia (3 products)
- retinitis pigmentosa
- Leber's congenital amaurosis
- acute myeloid leukaemia
- Herpes simplex virus stromal keratitis
- corneal graft rejection
- gastro-entero-pancreatic neuroendocrine tumours
- non-traumatic osteonecrosis
- idiopathic pulmonary fibrosis
- glioma
- Gaucher disease
- Acanthamoeba keratitis
- acute lymphoblastic leukaemia (2 products)
Consult the European Registry for Orphan designations
Consult the Orphanet list of orphan drugs authorised for marketing in Europe

Genzyme receives US technology honour for rare disease treatment efforts
Genzyme Corporation was honoured at the US White House in July for improving the health of rare disease patients. Company officials received the US National Medal of Technology from US President George W. Bush. Since its creation in 1981, Genzyme has developed four first-ever treatments for rare diseases: Cerezyme (imiglucerase for injection) for Gaucher disease; Fabrazyme (agalsidase beta) for Fabry disease; Aldurazyme (laronidase), developed with partner BioMarin Pharmaceutical for MPS I; and Myozyme (alglucosidase alfa) for Pompe disease.

UK funding opportunity for research databases
The Economic and Social Research Council, in partnership with Wellcome Trust, the Engineering and Physical Sciences Research Council and the Medical Research Council, wishes to stimulate and support the use of electronic databases for health research, taking advantage of the new electronic technologies which are under development. In this pursuit, funding opportunities are currently available across three main areas: 1) Health research using electronic patient records and major longitudinal cohort databases, 2) Training programmes and workshops, and 3) Public engagement activities. For further information

News from the Patients' Associations
Going to great lengths for ataxia telangiectasia patients: the AT CureTour
A California athlete is committed to running 63 marathons in 63 days to raise awareness, as well as money, for children suffering from ataxia telangiectasia (AT), an incurable autosomal recessive disorder that combines severe humoral and cellular immune deficiencies and progressive cerebellous ataxia. AT affects one in 40,000 children. Athlete Tim Borland will push a stroller, sometimes carrying a patient, as he runs, to draw attention to the fact that children with the disease are usually wheelchair-bound by age ten. The Herculean effort, called the AT CureTour, got underway on 3 September and is due to conclude at the finish line of the New York City Marathon on 4 November. Efforts will benefit the A-T Children's Project, which is following progress of the event on their website.

What's on Where?
Annual Workshop of the Italian Network for the Promotion of Folic Acid and Prevention of Congenital Defects
Date: 5 October 2007
Venue: Istituto Superiore di Sanita, Rome, Italy

Main topics will be the presentation and discussion of activities performed within the Network; up to date results concerning basic biomedical, clinical and social-healthcare research, nutritional status of the population, registration of congenital malformations, transfer of results from research to clinical practice, social-health care regulation, training, informing and updating practitioners and citizens, and risk-benefit assessment of prevention interventions.
More details including abstracts of the lectures will be available soon

EFGCP Children's Medicines Working Party 3rd Annual Conference on EU
Date: 9 October 2007
Venue: Brussels, Belgium

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

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

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

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

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

Biology and Clinical Applications of Cord Blood Cells
Date: 19-21 October 2007
Venue: Paris, France
More details

Euro-Ataxia AGM 2007
Date: 9-10 November 2007
Venue: Paris, France

Topics include advances in fundamental and clinical research, and promoting awareness in medicine, science and society.
More details

Second World Congress on Hypospadias and Disorders of Sex Development
Date: 16-18 November 2007
Venue: Rome, Italy

Topics include new insights in sex determination and differentiation; genes and sexual differentiation; gender assignment; medical management of DSD in the infant, child and adolescent; surgical approaches; and psychosocial management.
More details

2nd Pan Arab Human Genetics Conference
Date: 20-22 November 2007
Venue: Dubai, United Arab Emirates

Topics include ethical perspectives as well as a scientific programme including newborn screening, genetic disorders in Arab populations, complex and recessive disorders, premarital genetic screening, mutation detection, and establishing databases.
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First Egyptian-German Workshop on Disorders of Sex Development
Date: 24-25 November 2007
Venue: Cairo, Egypt

Topics include epidemiology, cytogenetic and biochemical analyses, molecular basis, diagnostic and therapeutic surgery, cultural and religious perspectives, and clinical managements.
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4th European Conference on Rare Diseases (ECRD 2007)
Date: 27-28 November 2007
Venue: Lisbon, Portugal

This important rare disease conference will be held in English and simultaneously translated into French, German, Portuguese and Spanish.
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15th Annual Meeting, Int'l ALS/MND Associations Alliance & 18th ALS/MND Int'l Symposium
Date: 1-3 December 2007
Venue: Toronto, Canada
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EuroGentest Workshop: Towards Accreditation-Managing the Human Side of Change
Date: 7-8 February 2008
Venue: Nice, France

Within the context of introducing quality management leading toward accreditation, this workshop addresses overall insights into the ‘human, behavioural’ side of change with techniques to manage this part of the change process, using case studies and role play to help apply these insights and techniques to real life situations.
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Press & Publications
A rare disease feast for French readers
The August 2007 issue of French-language medical journal Reanimation is highly recommended reading. Focussing on rare diseases and orphan medicinal products in relation to intensive care, articles address specific diseases and groups of diseases including Brugada syndrome, Marfan syndrome, and metabolic disorders. Other topics include a review of rare disease care in the emergency room setting, and resources currently available in France, including centres of reference, information services, and coordinated information tools for emergency rooms.
Can rare disease research help more general conditions?
Prompted by the emerging health crisis of late-onset neurodegenerative diseases (Alzheimer, Parkinson, et cetera) in the developed world, the August editorial in Practical Neurology queries whether data from rare disease research can be extrapolated to provide information for more common conditions. While conceding that rare diseases deserve attention, the author nevertheless mentions the amount of rare disease research funds distributed in terms of the number of patients impacted and poses the question as to whether such research might not serve a dual purpose. Citing the example of rare conditions CADASIL and Fabry disease that can lead to stroke, the author reviews research that has attempted to find a common genetic link between these rare conditions and typical sporadic stroke victims. While it is the author's opinion that to date rare disease genetic research has not often proven fruitful for more common conditions, the editorial acknowledges that rare disease models could possibly still be useful in certain cases for determining therapies applicable to rare and more common conditions. In summation, whether rare disease research will help cure or prevent major neurological illnesses remains, “an open question”.
What’s in a name?
Should eponyms be abandoned?

The 1 September issue of the BMJ asks a question pertinent to rare disease research with its frequent unearthing of new syndromes: Should eponyms be abandoned? An eponym names a disease after the person who discovered it. With an average of one new rare syndrome being reported each week, the question of what to name a new discovery is a decision researchers must take. Authors in the BMJ present persuasive arguments both favouring and opposing the use of eponyms.
NEJM examines ALS
The editorial of the 23 August 2007 issue of the New England Journal of Medicine explores the research efforts devoted to understanding the causes of amyotrophic lateral sclerosis (ALS). An accompanying article in the same issue describes a genomewide association study of ALS patients. ALS is a quickly progressive motor neuron degenerative disease, with death typically occurring within three to five years after onset. The editorial concludes that to date genomic studies raise more questions than they answer and that clinical phenotyping research must also continue.
Consultations in Dermatology: Studies of Orphan and Unique Patients
A handbook on dermatologic differential diagnosis and clinical management presenting sixty-two unusual clinical cases.

Authors: Walter B. Shelley, E. Dorinda Shelley
Publisher: Cambridge University Press


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
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Editorial Board: Ségolène Aymé, Catherine Berens, Helen Dolk, Anders Fasth, Edmund Jessop, Matthieu Levi-Strauss, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Claire Scharf-Kroener, Janos Sandor, Arrigo Schieppati, Rumen Stefanov, Domenica Taruscio, Joan Luis Vives Corrons
For more information on the Rare Diseases Task Force
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