30 January 2008 print
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Spain will develop a national strategy for rare diseases
In a meeting held on 23 January, the Spanish Minister of Health announced the creation of a working group to develop a National Strategy for Rare Diseases. The meeting was attended by scientific experts, the Spanish Federation of Rare Disease Patients (FEDER), as well as Ministry of Health representatives, the General Secretary for Health, and the director of rare disease research network CIBERER. Indeed, the experience of both CIBERER and the Rare Diseases Research Institute (from the Instituto de Salud Carlos III) will be incorporated into the discussions. At the same time, the recent recommendations of the Spanish senate that were approved in 2007, as well as the EC Communication on European Action in the Field of Rare Diseases will be taken into account for designing the guidelines of this national strategy. The group will also include representative members from the Autonomous Communities of Spain. It is expected that preparedness activities and tasks for this work will take at least one year. Patient organisations have received this news with optimism and hope, but they are conscious that with general national elections taking place on 9, March, 2008, the measures will have to be implemented by the new government. They are lobbying for this decision to remain unchanged with the new government. The development of a strategy will place Spain on an equal footing with other European countries that are developing specific rare disease plans, including Romania, Portugal, Italy, and Greece. Olé!

Speaking of the Communication, only two weeks remain for responding to this important document on European Action in the Field of Rare Diseases, still open for Public Consultation. Rare Diseases: Europe's Challenges is available in all EU languages and will aid policy makers to define priorities and inform decisions for rare disease strategies in the present and future European Member State health policy programmes. Your feedback to this document is vital in order to demonstrate the level of interest that exists across Europe for developing concrete actions on behalf of rare disease patients and their families.


Spotlight on...
Dr. Peter Corry describes the increasing prevalence of rare diseases amongst Bradford England's Pakistani population
OrphaNews Europe first reported on the increased prevalence of rare genetic diseases in the northern England metropolitan area of Bradford in December 2005, following a news article that appeared in the BMJ describing a local Member of Parliament's controversial call for legislation that would ban consanguineous marriages in the UK. Bradford, located in the county of West Yorkshire, has a significant Pakistani community that practices marriage between first cousins, leading to an increased number of rare autosomal recessive disorders in the local population. Indeed, Bradford medical professionals are contending with over 140 different autosomal recessive diseases, whereas other typical districts of similar size in the United Kingdom usually see between 30 and 40 such disorders. OrphaNews Europe presents an interview with a professional who works with this growing group of patients. Bradford-based paediatrician and neurodisability specialist Dr. Peter Corry has worked extensively with rare disease patients in the area and published several studies on the subject:

OrphaNews Europe: How does the increased number of autosomal recessive illnesses impact your community's medical resources?

Dr. Peter Corry: It has an impact on all services from conception and pregnancy, through paediatrics and other child health services towards either transition to adult services or sometimes death during childhood. I am speaking as a paediatrician working in Bradford, West Yorkshire. We cover a population of about 360,000 of whom about 106,000 are under 18 years of age. There are about 6,000 births each year, and about half are now of Pakistani origin. This population has a preference for cousin marriages and also marriage within the clan.

My own speciality is Neurodisability and I work with colleagues in our Child Development Centre. Our patients have learning or physical disability, with conditions such as Down syndrome, autism, cerebral palsy and spina bifida. However we have had an increasing number of patients with rare, usually autosomal recessive genetic, conditions and this also applies to colleagues in other branches of paediatrics here. In the past decade we have identified at least 148 different autosomal recessive conditions in our children. My answers will concern children with all sorts of conditions although, of course, I know most about the ones with neurodisabilities.

Many of the conditions are complex, many will be unfamiliar to staff, many will require liaison between local staff and more specialist teams. With limited resources, priority has to be given to the children with the most need, so that other children may not receive the routine services they would expect elsewhere.

And many of the rare disorders can be complex, affecting several organs. For instance, our patients with Bardet-Biedl syndrome need attention from an ophthalmologist, nephrologist, plastic surgeon and neurologist as well as our team at the Child Development Centre and others. It isn't really possible to cope with all this in a 20 minute clinic session two or three times a year.

Unfortunately, many of these genetic conditions that we see are life-limiting, so we have to consider the increased number of children who may die in childhood. I have looked at deaths in my own patients over a period of 12 years (1993-2004). During that time there were probably nearly twice as many caucasian as Pakistani children in Bradford. 43 Pakistani children died, of whom 23 had an autosomal recessive genetic condition. 30 white children died, and none of them was thought to have an autosomal recessive condition.

An example of the pressure on our clinical team is that we have not yet had agreement to hold joint feeding clinics for children with disabilities. These would be so important to enable colleagues to work together on these complex and often life-threatening problems. We have not yet been able to start either the joint clinics with paediatrician, orthopaedic surgeon and physiotherapist to assess children with cerebral palsy who may benefit from surgery or clinics to assess and treat children with injections of botulinum toxin. And this is in a district with an extremely high prevalence of cerebral palsy. In recent weeks, we have been unable to see new patients within the 11 weeks of referral from family doctors, one of the Government health targets.

OrphaNews Europe: What are some of the more rare disorders that you see?

Dr. Peter Corry: There are now more than 20 children with primary ciliary dyskinesia, about thrice the expected prevalence. These children often have their heart on the wrong side and usually develop a gradually worsening lung condition.

I myself have cared for four children with Aicardi-Goutieres syndrome, from three different families. These children can have severe neurological and developmental problems associated with intracranial calcification. There is a child with aspartylglucosaminuria, which is a condition that usually affects Finnish people. There are three or four children with hyperekplexia (startle disease) and one was reported in the literature when autosomal recessive inheritance was identified. A colleague looks after three children with Cockayne syndrome.

My colleague in haematology has had patients with extremely rare conditions such as protein C deficiency, Bernard Soulier syndrome, factor XIII deficiency and Glanzmann thrombasthenia, as well as the rare but more widely known thalassaemia and sickle cell disease. With factor XIII deficiency it is estimated that there are about 15 children in the area around Bradford out of about 50 in the whole of the United Kingdom.

The local ophthalmologists see many children with unusual types of retinitis pigmentosa and have several patients with familial exudative vitreoretinopathy.

Support from colleagues in specialist centres in the UK, as well as in Europe and America, has been invaluable. The Internet and improving communications generally has been useful, and we are making increasing use of the clinical summaries on Orphanet.

OrphaNews Europe: Can you discuss some of the medical interventions that these disorders necessitate?

Dr. Peter Corry: The range of rare conditions that we see is so broad that I can only mention some of the treatments:

Children with metabolic disorders will often require specialised diets. Some of these will be quite complex. Many will need medication, and some will receive new treatments such as substrate deprivation or enzyme replacement. A few may be considered for bone marrow transplants or other "cutting edge" approaches. Especially for those with disorders of intermediary metabolism, frequent admissions may be needed in order to stabilise their condition.

We have many children with neurological conditions. They may need anticonvulsants for seizures or treatments to reduce spasticity such as oral or intra-thecal baclofen or intra-muscular injections of botulinum toxin. Many need orthopaedic surgery because of complications, such as joint contractures or hip dislocation and a few will have surgery to correct spinal curvature.

Some of the weaker children with neuromuscular conditions may need respiratory support with a ventilator or positive airways pressure when asleep, or even at all times of the day and night.

Artificial feeding through a naso-gastric tube or gastrostomy is needed for many with feeding or swallowing difficulties. Our dieticians treat 182 children who are tube-fed, of whom 50% are disabled children attending the Child Development Centre.

Children with anaemias, coagulation or platelet disorders may need regular transfusions of blood or blood products and may also require drug treatments. Children who have frequent intravenous treatments may need indwelling IV catheters.

The list of options seems to be getting longer all the time as new treatments are developed.

Hospital admissions are required, both for acute illnesses and for planned treatments. Many disabled children will be prone to life-threatening chest infections or may need admission to hospital following severe seizures. Some children may need regular admissions for courses of intensive treatment. This will aim to slow down deterioration, such as for children with cystic fibrosis or primary ciliary dyskinesia.

We do not have an intensive-care facility for children in Bradford so our patients are obliged to go to the regional centre in Leeds (or elsewhere, when it is full). More than a third of the beds in the regional ICU are usually occupied by patients from Bradford, although we have only about 6,000 of the 36,000 births in our region each year.

Many of the children need speech and language therapy, physiotherapy or occupational therapy. Our dieticians are also important for children with nutritional problems. We also have a very good service from children's nurses in the community, or from our hospital outreach team. They may help in the care of children in their homes or schools.
Read the full interview with Dr. Peter Corry
Contact Peter Corry

EU Policy News
DG Research
CORDIS launches service following the progress of joint technology initiatives
CORDIS, the European Commission's Research and Development Information Service, has created a new service that will provide news and information concerning Joint Technology Initiatives (JTIs). JTIs are public-private partnerships between the Commission and industry (and in some cases the Member States). They will be implemented by Joint Undertakings on the basis of Article 171 of the EU Treaty. On 20 December 2007, the European Council adopted 4 JTIs, including the "Innovative Medicine Initiative Joint Undertaking" (IMI JU). The two founding members of the IMI JU will be the European Commission and the EFPIA (European Federation of Pharmaceutical Industries and Associations). The IMI JU will support pre-competitive pharmaceutical research and development. Its goal is to deliver new approaches, methods and technologies for the drug development process, in order to accelerate the development of safe and more effective medicines for patients. More information is available on the IMI website.
EMEA Paediatric Committee issues first waiver decisions
The EMEA Paediatric Committee announced in a press release from its December Meeting the adoption of a decision to grant a waiver for orphan medicine everolimus (Novartis Europharm Ltd). The decision was taken on the grounds that "the disease or condition for which the specific medicinal product is intended occurs only in adult populations". An opinion was also adopted concerning the paediatric investigation plan for orphan drug L-asparaginase, from Medac Gesellschaft fur Klinische Spezialpraeparate mbH, in the therapeutic area of oncology. The EMEA established the Paediatric Committee within the context of new European regulation on paediatric medicines that entered into force on 26 January 2007. The regulation is designed to stimulate research and development of medicines for use in children, ensure that medicines for children are appropriately tested and authorised, and improve information availability. The Paediatric Committee, made up of scientific experts within the EMEA, has as its primary responsibilities the assessment and agreement of paediatric investigation plans, waivers and deferrals. An opinion was also issued recommending a waiver for orphan designated product panobinostate, produced by Novartis in the therapeutic area of cutaneous T-cell lymphoma. In November, the Paediatric Committee adopted an opinion on a list of class waivers for conditions that do not affect children and for which the requirement to submit a paediatric investigation plan could thus be waived. The list includes 17 symptomatic conditions including different types of cancer (lung cancer, basal cell carcinoma, breast and ovarian cancer, multiple myeloma, etc.), neurodegenerative conditions (Alzheimer’s disease, Parkinson’s disease) and other conditions that occur only in the adult population (age-related macular degeneration, menopausal disorders, etc.)
Read the EMEA press release from the December meeting .


National & International Policy Developments
Belgium creates national rare disease steering committee
Belgian stakeholders have formed a national steering committee on rare diseases and orphan drugs, composed of 19 representatives from patient organisations, industry, genetics, therapeutic centers, hospital pharmacies, the HTA agency, insurance groups, the federal health institution and a member of parliament. One of the first activities of this steering committee was to organise a highly successful national symposium on orphan drugs, under the patronage of her Royal Highness Princess Astrid in November 2006. From there, the steering committee has gone on to develop a strategy to increase awareness in Belgium for the problems rare diseases can present and the reimbursement of orphan drugs. Ad hoc working parties have been created to address the issues related to orphan diseases and to develop strategic solutions. On 14 December, 2007 the steering committee was officially installed as the "Fund for Rare Diseases and Orphan Drugs" in the King Baudouin Foundation of Belgium, thus bestowing official recognition of the group's social relevance. A research proposal to study the problems and policies of accessibility to orphan drugs has been approved by the Belgian Health Care Knowledge Center and will be conducted with a professional management team. The financial terms of the project are still being negotiated. The steering committee has also initiated contacts with representatives of different university hospitals to start a common strategy to collect information on the number of patients and treatments. In the meantime, the scientific board of the Belgian Orphanet site has been officially created and will meet on 15 February, 2008 to begin activities concerning information gathering on the existing rare disease services, research, and clinical activities in Belgium.
Wisconsin becomes first US state to screen all newborns for SCID
In the US, the Wisconsin Department of Health and Family Services has approved a plan to extend a pilot newborn screening programme for severe combined immunodeficiency disease (SCID) into the state’s current screening plan of 47 tests administered to newborns. Wisconsin is the first US state to offer SCID testing to all newborns, employing the logic that early detection and treatment of SCID through routine screening in newborns will save lives and prevent repeated and prolonged hospitalizations of afflicted children, ultimately saving millions of dollars in health care costs. The estimated cost for SCID screening in Wisconsin is $70,000 USD annually. Initial funding for the ten-year extension of the SCID screening pilot programme will be provided by the Jeffrey Modell Foundation and the Children's Hospital of Wisconsin, both of which were part of the collaborative effort developing the programme. The US Congress recently passed its first federal legislation concerning funding for SCID screening, under which US states can apply for CDC grants to establish pilot programmes. SCID is the most lethal of the primary immunodeficiency diseases, and is sometimes referred to as the “boy in the bubble disease”, after a television film brought popular awareness to the disease by depicting the true story of a boy who spent his life in a plastic bubble to avoid exposure to infection. He eventually died at age 12.
For more information.

Other International News
Rare disease patients seeking experimental treatment in China
In recent months, the media have reported on several cases of American and European patients, many children, receiving medical treatment in China for an array of rare diseases. A five-year-old English girl received stem cell treatment for Batten disease in northern China after her mother heard of a Swedish mother who had obtained similar treatment for her child. Other Batten disease patients, including a five-year-old Irish boy and a five-year-old California boy have also been treated in China and have created websites and blogs to document their experiences. The treatment for Batten disease, which involves injecting stem cells into the patient's spinal column, has not been approved in the US or Europe, where stricter controls are in place. Yet in China, the treatment is readily available to those who can pay. Indeed, China Stem Cell News is an English-language website informing prospective patients of numerous treatments available involving stem cell therapy. The site features news updates on the latest research and treatments in China, including rare diseases such as ALS, various forms of ataxia, autism, Huntington disease, Lupus and spinal muscular atrophy. The website also contains testimonials from Western rare disease patients who have received treatment in China. For one Batten disease patient, the cost cited for one course of treatment (including a hospital stay of several weeks) was around 27,000 euros.

Orphanet News
Alexion Europe to fund translation of Orphanet rare disease emergency guidelines into five languages
Rare disease patients in a health emergency situation, whether or not the situation is directly related to their illness, often encounter emergency room professionals unfamiliar with their particular disorder and unsure of how to administer emergency services appropriately and safely. To ameliorate this situation, Orphanet has started creating rare disease emergency care guidelines to be distributed to emergency and intensive care hospital units and also made available on the Orphanet website. Guidelines for six rare diseases are already available in French and three more are being finalised. Now Alexion Europe, a subsidiary of Alexion Pharmaceuticals, is generously providing funding so that this vital information can be translated into the five other languages (English, German, Italian, Portuguese and Spanish) of the Orphanet website.

Providing information on the nature and progression of a particular rare disease, possible emergency scenarios that can occur with the condition, medicine products typically prescribed for the disease and their possible interactions with other products, the guidelines also offer emergency procedure recommendations, including how to evaluate the severity of the emergency condition, possible immediate therapeutic measures to take, and anaesthesia administration considerations, along with website links and references. Translation of these guidelines will go a long way to helping emergency professionals throughout Europe better manage their rare disease patients. The first guidelines to be translated are for the following diseases: osteogenesis imperfecta, Marfan syndrome, tuberous sclerosis, amyotrophic lateral sclerosis, acute hepatic porphyria, porphyria cutanea tarda, Dravet syndrome, paroxysmal nocturnal hemoglobinuria and angioedema. Orphanet identified these diseases from amongst over 5000 listed in their database by conducting an investigation into the needs and experience of emergency room professionals - thereby gathering vital information in order to prioritise. Orphanet plans to create some 30 rare disease emergency care guidelines per year and is excited to be collaborating with Alexion Europe on the translation of the first set.


New Syndromes
A new mitochondrial disease with severe hypotonia, lactic acidaemia and hyperammonaemia
The authors describe three newborns of consanguineous parents presenting antenatal skin oedema, hypotonia, cardiomyopathy and tubulopathy leading to their death within the first week of life. Ultrasound at 36 weeks of gestation revealed generalised oedema. The enzymatic activities of multiple mitochondrial respiratory chain complexes were reduced in muscle. Homozygosity mapping led to the identification of a mutation in the MRPS22 gene, which encodes a mitochondrial ribosomal protein.
Read the PubMed abstract

J Med Genetics ; 784-786 ; December 2007

New Genes
Mutations in smooth muscle alpha-actin cause 14% of inherited thoracic aortic aneurysms and dissections
Inherited forms of thoracic aortic aneurysms and/or dissections can be caused by mutations in the gene encoding the beta-myosin heavy chain. These mutations affect the contraction of vascular smooth muscle cells which have as a major function regulating blood pressure and flow. Through international collaboration, the authors have identified new mutations in the gene encoding alpha-actin. The mutations identified disrupt the formation of actin filaments. Smooth muscle cell contractile force requires cyclic interactions between alpha-actin and the beta-myosin heavy chain. The authors estimate that alpha-actin mutations are responsible for 14% of inherited forms of the disorder.
Read the PubMed abstract

Nat Genetics ; 1488-1493 ; December 2007

Research in Action
Fundamental Research
Severe congenital neutropenia: folding errors of the neutrophile elastase are at cause
Severe congenital neutropenia is characterised by a low level of polynuclears without any other clinical or biological abnormality. About half of all cases present a mutation in the gene encoding the neutrophile elastase. The authors of this study show that the mutations alter the folding of the protein, bringing about the programmed death of polynuclear cell precursors. The cellular mechanism in question, called UPR (unfolded protein response) has already been implicated in the pathogenesis of certain rare diseases, such as Wolcott-Rallison syndrome.
Read the PubMed abstract

Blood ; 4179-4187 ; December 2007
Autosomal dominant polycystic kidney disease: the effect of Pkd1 mutations depend upon the stage of kidney development
Autosomal dominant polycystic kidney disease, characterised by the progressive replacement of the renal tube by cysts, is an important cause of end-stage renal disease, for which there is no proven therapy. The presence of mutations in PKD1 is the major cause of this disease. The authors show that the precocious inactivation (within the first 13 days of life) of this gene in mice results in the formation of numerous cysts in the first three weeks of life. If, however, the gene is inactivated after the 14th day of life, the cysts begin to develop only after five months. Thus the effects of the inactivation Pkdl seems to depend upon the stage of kidney development, with the 14th day playing a critical role.
Read the PubMed abstract

Nat Medicine ; 1490-1495 ; December 2007
Cystic fibrosis: Cleavage of CXCR1 on neutrophils disables bacterial killing
Although cystic fibrosis patients often suffer from bacterial infections of the upper respiratory tract, these patients present an accumulation of neutrophils associated with a high concentration of interleukin-8, two characteristics of an inflammatory reaction. The authors of this study identify the molecular mechanisms that explain this contradiction: the CXCR1 receptor specific to interleukin-8 is permanently cleaved to the surface of neutrophils, compromising their anti-bacterial activity. The study also shows that the inhalation of alpha1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis.
Read the PubMed abstract

Nat Medicine ; 1423-1430 ; December 2007
Clinical Research
Rett syndrome can be caused by MeCP2 homozygous mutations
Rett syndrome is a severe neurodevelopmental disorder affecting the central nervous system. It primarily affects females, making it one of the most common genetic causes of severe intellectual disability in females. The disorder is most commonly caused by the presence of a de novo heterozygous mutation in MeCP2 gene, located on the X chromosome. The authors describe for the first time the case of a 21-year-old woman with a classic form of Rett syndrome carrying a homozygous MeCP2 mutation. Chromosome analysis showed a normal karyotype, and haplotype analysis ruled out the possibility of parental disomy or microdeletion in MECP2 gene.
Read the PubMed abstract

Eur J Med Genet ; 465-468 ; November/December 2007
Cardio-facio-cutaneous, Costello and Noonan syndromes share genotype-phenotype correlations due to mutations in the RAS pathway
Cardio-facio-cutaneous syndrome, Noonan syndrome, and Costello syndrome are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of four genes in 130 patients. Analysis of the major phenotypic features suggests significant clinical overlap between Costello syndrome and Cardio-facio-cutaneous syndrome. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to easily distinguish Noonan syndrome from Cardio-facio-cutaneous syndrome.
Read the PubMed abstract

J Med Genetics ; 763-771 ; December 2007
Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletions
Patients carrying a deletion in the 11p13 region develop a syndrome named WRAG (Wilms turmour, aniridia, genitourinary anomalies, and mental retardation). Aniridia and Wilms tumours can equally develop in an isolated manner and are thus associated with mutations in two genes in the 11p13 region: WT1 and PAX6. The authors investigated deletions in this region in 193 aniridia patients via high-resolution chromosomal deletion analysis. They found that 77% with a submicroscopic deletion in WT1 gene developed Wilms tumour versus only 42.5% of those with a visible deletion. Thus, high-resolution deletion analysis is a useful tool for assessing the risk of Wilms tumour in neonates with aniridia. Moreover, patients presenting a submicroscopic WT1 deletion have an increased risk of tumour development.
Read the PubMed abstract

J Med Genetics ; 787-790 ; December 2007
Benign familial neonatal epilepsy: submicroscopic rearrangement testing needs to be integrated into current diagnostics
The familial forms of benign neonatal epilepsy are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. The authors of this study identified three deletions and a submicroscopic duplication of KCNQ2 in four of nine cases previously testing negative for coding or splice site mutation by sequencing KCNQ2 and KCNQ3. Thus the authors suggest integrating high resolution techniques (multiplex ligation-dependent probe amplification was used in this study) into standard mutation analysis.
Read the PubMed abstract

J Med Genetics ; 791-796 ; December 2007
Stevens-Johnson syndrome: two recent medications are linked to disease onset
Stevens-Johnson syndrome and toxic epidermal necrolysis are rare but severe cutaneous adverse reactions (SCAR) related to a variety of medications. They have a significant public health impact because of high mortality and morbidity. A multinational case-control study conducted in Europe between 1997 and 2001 evaluated the risk of medications to induce SCAR. Cases were actively detected through a hospital network covering more than 100 million inhabitants. Amongst other findings, this study revealed a strong association between the disease and the administration of two medicines commercially licensed in recent years: nevirapine (an anti-retroviral) and lamotrigine (an anti-epileptic). The study also detected a weak association with sertraline (an anti-depressant), pantoprazole (a proton pump inhibitor), and tramadol (an analgesic). Strong associations were also confirmed for anti-infective sulfonamides, allopurinol, carbamazapine, phenobarbital, phenytoin, and oxicam-NSAIDs, with some changes in relative numbers of exposed cases. Thus, many cases were still related to a few "old" drugs with a known high risk.
Read the PubMed abstract

J Invest Dermatol ; 35-44 ; January 2008
Congenital adrenal hyperplasia: testicular tumours are also found in boys under ten
Adult males with congenital adrenal hyperplasia often have infertility due to testicular adrenal rest tumours. This study reveals the presence of such tumours in a population of boys aged between two and ten years who are diagnosed with congenital adrenal hyperplasia.
Read the PubMed abstract

J Clin Endocrinol Metab ; 4583-4589 ; December 2007
Laminopathies: a new phenotype characterised by severe metabolic alterations and frequent muscle signs
Mutations in LMNA are responsible for a group of diseases named laminopathies, including the lipodystrophies, with complex genotype/phenotype relationships. The authors performed LMNA sequence analysis in 277 patients presenting a lipodystrophy and/or a resistance to insulin. They also observed a new phenotype with non-codon 482 associated mutations, characterised by a clinical absence of lipoatrophy, numerous severe metabolic irregularities, and frequent muscular signs.
Read the PubMed abstract

J Clin Endocrinol Metab ; 4835-4844 ; December 2007
Congenital adrenal hyperplasia: glucocorticoid therapy diminishes bone mineral density
Patients with classical congenital adrenal hyperplasia (CAH) receive lifelong, often supraphysiological, glucocorticoid therapy. Pharmacological doses of glucocorticoids are an established risk factor for osteoporosis. The authors demonstrate that women with hyperplasia due to a 21-hydroxylase deficiency present low bone mineral density and an increased risk of fractures. The authors recommend an increased surveillance for these risks and an optimisation of glucocorticoid dosage from puberty onward.
Read the PubMed abstract

J Clin Endocrinol Metab ; 4643-4649 ; December 2007
Therapeutic Approaches
Myotonic dystrophy type 1: a new therapeutic target in disease mouse models
Myotonic dystrophy type 1 is caused by the expansion of tri-nucleotides in an untranslated region of DMPK. This expansion seems to cause abnormal splicing regulation in a group of genes. A ClC-1 gene exon is thus erroneously included, disturbing the activity of the chloride channel that it encodes. The authors tested the effect of a morpholino antisense oligonucleotide that successfully excluded this exon in disease mouse models, thus re-establishing normal expression of the chloride channel and reducing myotonia. This study confirms the association between ClC-1 function and myotonia as well as presenting a possible therapeutic target for myotonic distrophy type 1.
Read the PubMed abstract

Journal of Clinical Investigation ; 3952-3957 ; December 2007
Diagnostic Approaches
Pheochromocytoma: urinary free metanephrine testing is the best diagnostic marker
Pheochromocytomas are catecholamine-secreting tumours developing in the adrenal medulla. Diagnosis is based on an elevated level of catecholamines in the urine. The authors compared the efficacy of different diagnostic markers (24-h urinary free metanephrines, 24-h urinary vanillyl mandelic acid, urinary catecholamines, and plasma catecholamines) in 159 patients. They demonstrate that measuring the level of urinary free metanephrines provides 100% sensitivity.
Read the PubMed abstract

J Clin Endocrinol Metab ; 4602-4608 ; December 2007

Patient Management and Therapy
Japanese encephalitis virus: a second generation vaccine improves immune response
Japanese encephalitis virus is caused by a flavivirus spread by wild birds, amplified by domestic pigs, and transmitted to humans mainly by a mosquito of the genus Culex. The virus mainly occurs in rural areas of China, Korea and Japan, in sub-tropical regions of Asia, and in some regions of Oceania. While no treatment exists, there is a vaccine available to prevent the disease. The authors of this study describe a phase III randomised clinical trial comparing the commercialised vaccine to a second-generation one. The new vaccine has a better immunogenicity and a similar safety profile.
Read the PubMed abstract

The Lancet ; 1847-1853 ; December 2007
Idiopathic thrombocytopenic purpura: eltrombopag increases platelets
The pathogenesis of chronic idiopathic thrombocytopenic purpura involves antibody-mediated platelet destruction and reduced platelet production. In a randomised placebo clinical trial including 118 relapse or refractory patients, the authors tested the effect of oral thrombopoietin receptor agonist eltrombopag. After 43 days of treatment, they observed increased platelet counts in a dose-dependent manner in patients with relapsed or refractory idiopathic thrombocytopenic purpura.
Read the PubMed abstract

NEJM ; 2237-2247 ; 29 November 2007
Friedreich ataxia: encouraging results with recombinant human erythropoietin
Friedreich ataxia is characterised by difficulties coordinating movements associated with neurological signs (dysarthria, loss of reflexes, decrease of deep sensation, pes cavus and scoliosis), cardiomyopathy and sometimes diabetes mellitus. The disease is caused by a frataxin deficiency, which impacts mitochondrial function and the energetic metabolism of the cell. In an open-label clinical pilot study, the authors administered recombinant human erythropoietin to patients three times weekly. Erythropoietin, initially identified as a cytokine acting on the differentiation and survival of erythrocytes, has also shown to have neuro and cardioprotective capacities. After eight weeks of treatment, the authors of this study observed an increase in frataxin and a decrease in oxidative stress markers.
Read the PubMed abstract

Ann Neurol ; 521-524 ; November 2007

Orphan Drugs
CHMP issues negative marketing authorisation opinion for amyloidosis treatment
The Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion for Kiacta (eprodisate disodium), recommending the refusal of marketing authorisation for the amyloid A amyloidosis medicinal product produced by Neurochem Luxco II. Kiacta received an orphan designation in August 2001. Read more about the CHMP opinion.

What's on Where?
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.
More details

Third Eastern European Conference on Rare Diseases and Orphan Drugs
Date: 1-2 March 2008
Venue: Plovdiv, Bulgaria

Participants from Bulgaria and Eastern Europe will present their achievements in the field of prevention, diagnosis and treatment of rare diseases. A specialized workshop with speakers from leading US, European and Bulgarian organisations and institutions will take place in order to discuss best practices in the field of rare diseases and orphan drug access.
More details and to register

Rare Diseases: Channels and Transporters
Date: 8-12 March 2008
Venue: Sant Feliu de Guixols, Spain

The conference is devoted to channels and transporters involved in rare inherited diseases. Specifically TRP and CLC channels, connexins, mitochondrial transporters, heteromeric amino acid transporters, neurotransmitter transporters, ABC transporters and related diseases will be covered.
For further details

Second European Symposium on Rare Anaemias
Date: 13-14 March 2008
Venue: Nicosia, Cyprus

Sessions include current progress in prenatal and neonatal diagnosis of haemoglobinopathies, iron overload and chelation therapy, very rare anaemias, treatment of haemoglobinopathies, and red blood cell hereditary disorders.
For further details

Genomic Disorders 2008
Date: 17-20 March 2008
Venue: Cambridgeshire, UK

Topics to be discussed will include copy number variation and assays, structural variation predisposing to genomic rearrangement, mechanisms underlying genomic disorders, genomic rearrangements in common diseases and genetic syndromes, model organisms in the study of genomic disorders and potential therapeutic approaches.
For further details

Fifth International Congress on FMF and Systemic Autoinflammatory Diseases
Date: 4-8 April 2008
Venue: Rome, Italy

This conference will review current knowledge of the mechanisms of innate immunity and their relevance to the pathogenesis of autoinflammatory and other chronic diseases.
For further details

ICORD 4th International Conference on Rare Diseases and Orphan Drugs
Date: 20-22 May 2008
Venue: Washington, DC US
For further details

13th International Conference for Behçet's Disease and 5th Patients' Convention
Date: 24-27 May, 2008
Venue: Klagenfurt, Austria

With presentations and discussions on oral, eye, genital and skin involvement, as well as paediatric patients, drug trials and future perspectives.
For further details

First Conference on Translational Research in Paediatric Rheumatology
Date: 29 May - 1 June 2008
Venue: Genoa, Italy

Using the field of rare paediatric rheumatic disorders as a paradigm, Anticipating Changes in Drug Development for Children: Building on Paediatric Rheumatology will examine the medicine research and development process, from pre-clinical and early-phase clinical development, to biomarker validation, study design and management, data analysis, ethical review, regulatory submission and research governance. The conference is meant to further stimulate interaction among the three major stakeholders in the drug development process, namely, academia, industry and regulatory authorities.
For further details

14th International Conference on Prenatal Diagnosis and Therapy
Date: 1-4 June 2008
Venue: Vancouver, Canada

Conference sessions will include foetal imaging, cytogenetics, foetal DNA/RNA, PGD, screening, teratology, and legal aspects of prenatal diagnostics and therapy. The deadline to submit an abstract for this conference is 4 February 2008.
For further details

Fourth International Neuroacanthocytosis Symposium: Bridging Clinical and Basic Aspects
Date: 1-2 July 2008
Venue: Oxford and London, England

Including clinical aspects of chorea acanthocytosis and McLeod syndrome, muscle and nerve neuropathology and syndromes related to NA.
For further details

Genetic Alliance Annual Conference 2008
Date: 11-13 July 2008
Venue: Bethesda, MD, US

Brings advocates, health professionals, policy makers, industry representatives, researchers, and community leaders together for workshops and discussions.
For further details

Fourth International Conference on Metals and Genetics
Date: 21-24 July 2008
Venue: Paris, France

The main topics will include metal-associated diseases: molecular and systemic biology approaches; characterisation and speciation of metal in proteins and biological tissues; and metals and environmental health implications.
For further details

15th Paediatric Rheumatology European Society Congress
Date: 14-17 September 2008
Venue: University College London, UK

Details forthcoming.
For further details

6th World Rett Syndrome Congress
Date: 10-13 October 2008
Venue: Paris, France

Various aspects of Rett syndrome and MECP2 functioning, including fundamental, clinical and management topics.
For further details

Tenth International Meeting on Osteogenesis Imperfecta
Date: 15-18 October 2008
Venue: Ghent, Belgium

Topics include: Bone homeostasis, murine models/collagen biology/biophysics, classification, genetics: genotype-phenotype, prenatal diagnosis/preimplantation diagnosis, biphosphonates, orthopedic management, hearing loss: physiopathology, surgery and imaging, other medical management issues, stomatology/dentistry, psychosocial aspects, new (therapeutic) perspectives.
For further details


Press & Publications
Prader-Willi Syndrome: Coping With the Disease - Living With Those Involved
This textbook, written by a researcher who has spent many years working with Prader-Willi syndrome patients and their families, discusses the disease and its treatment options. Suitable for non-professionals, this book presents the clinical picture of the syndrome, its genetic cause, current research results and treatment options. Recently translated into French, Spanish and Italian languages also.

Author: Urs Eiholzer
Publisher: S. Karger Publishers, 2005

Treating Tourette Syndrome and Tic Disorders: A Guide for Practitioners
A multidisciplinary framework for assessment and treatment. Current knowledge on the neurobehavioral underpinnings, clinical presentation, and strategies for managing symptoms and providing effective support for this group of disorders, with an emphasis on integrating medication and psychosocial therapies. Includes three reproducible assessment tools.

Author: Peter Hollenbeck , Douglas W. Woods , John C. Piacentini, John T. Walkup -Eds.
Publisher: Guilford Press, 2007


Orphanews Europe, the newsletter of the Rare Diseases Task Force
Orphanews Europe is supported by the European Commission's DG SANCO
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Louise Taylor
Contact Us
Editorial Board: Ségolène Aymé, Catherine Berens, Helen Dolk, Anders Fasth, Laura Fregonese, Edmund Jessop, Matthieu Levi-Strauss, Jordi Llinares-Garcia, Antoni Montserrat, Annie Olry, Manuel Posada de la Paz, Ewa Pronicka, Claire Scharf-Kroener, Janos Sandor, Domenica Taruscio, Paloma Tejada, T.O.F. Wagner
For more information on the Rare Diseases Task Force
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