17 June 2008 print
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France reviews its rare disease plan and extends patronage to rare disease activities under upcoming EU presidency
The follow-up committee for the French National Rare Disease Plan (2005-2008) has issued a set of conclusions and actions following a series of meetings taking stock of the plan. France was the first European country to implement a rare disease plan, which has since been taken as a model by other countries. The meetings served to review some of the mechanisms the rare disease plan established for rare disease research and care. These include concrete policies assuring the reimbursement of medical care and products for rare diseases. Non-medicinal products for rare disease patients, including special hydrating creams, nutritional supplements and equipment, are now reimbursed, along with certain off-label medicines used in the treatment of rare diseases. In addition, a special rare disease unit has been established within the country’s social security administration. Another group has been created within the health authority to create, advise upon and monitor aspects of medicinal product policy. The funding of a number of research projects was accomplished under the plan. It is now a priority to maintain financing targeting rare disease research within the country’s research funding structure. Developing and supporting common registries, data banks, follow-up cohorts and platforms is also a major objective to continue in order to avoid fragmentation and duplication and to work in a coordinated national effort. Under the plan, 132 centres of reference have been created to date, as well as a number of centres of competence at the regional level. It is necessary to develop a tool to follow the activities of the centres. The protocol for prioritising epidemiological follow up for rare disease needs to be sustained and a designated source needs to be established to collect cohort data for rare diseases.

This stock-taking of the Gaullist plan occurs at the same time France prepares to assume presidency of the European Union on 1 July. Thus the priority France extends to its own rare disease patients now takes on a broader amplification, as the French EU presidency officially extends its patronage to rare disease projects and programmes on the European level. This is wonderful news for rare disease patients throughout Europe. Concretely, a series of events have been planned during the French EU Presidency: The European Symposium on Rare Diseases and Child Disability is being held in Paris, on 10 October, as part of the Sixth World Rett Syndrome Congress. In addition, a conference entitled Europe for Health at the Service of Patients, organised by the French Ministry of Health, is scheduled to take place in Paris on 13-14 October under the patronage of the French EU presidency. Scheduled topics will include health services, safety legislation, and patient mobility, including a session on centres of reference. The Ninth EPPOSI Workshop on Innovative Therapies for Rare Diseases is also being held in Paris on 16-17 October under the patronage of the French EU presidency, featuring the topic, Orphan medicines: partnering along the chain and across borders to share common strategies and tools. Finally, the European Workshop on National Plans for Rare Diseases, will take place in Paris on 18 November. This workshop is organised in collaboration with the French Ministry of Health and also receives the official patronage of the French EU presidency.


Spotlight on...
Treating rare diseases in Costa Rica
Dr. Olga Arguedas is a paediatric immunologist at the National Children’s Hospital in San Jose, Costa Rica. She kindly agreed to give OrphaNews Europe an overview of the rare disease situation in Costa Rica and to comment on her collaboration with European paediatric immunologists:

OrphaNews Europe: What are some of the rare diseases seen in Costa Rica?

Dr. Olga Arguedas: There are so many, but due to the higher incidence compared with the rest of the world the most relevant ones are: Malignant osteopetrosis, Ataxia Telangiectasia, Cystic Fibrosis, Wilson’s Disease, Galactosemia, and Organic Acidaemias.

OrphaNews Europe: How do you account for a higher prevalence of these rare diseases in Costa Rica than is typically seen in other parts of the world?

Dr. Olga Arguedas: This is primarily due to a genetic founder effect secondary to high consanguinity among our Hispanic ancestors.

OrphaNews Europe: Does Costa Rica have any sort of national or regional policy for rare diseases? What resources are available for rare disease research and treatment?

Dr. Olga Arguedas: The country has a free programme of national newborn screening. All treatment and follow-up of children with rare disorders is concentrated in a tertiary hospital: the National Children’s Hospital. This institution has sub-specialists in all paediatric areas. Medical interventions and treatments are fully covered by the country’s Social Security System.

OrphaNews Europe: Are there any special research projects for rare diseases in Costa Rica?

Dr. Olga Arguedas: Yes, we collaborate with researchers from the USA in the isolation of some genes related to ataxia-telangiectasis and cystic fibrosis, also with researchers from Sweden in malignant osteopetrosis, and with Germany in haemoglobinopathies.

OrphaNews Europe: Could you briefly describe Costa Rica’s health system? Are medical interventions and treatments reimbursed for patients? Does the concept of “orphan drug" exist?

Dr. Olga Arguedas: Costa Rica has a highly socialised health system, which covers practically 100% of the population. All medical intervention and treatments, no matter the cost or complexity, are free for patients. Costa Rica has one of the lowest infant mortality rates in Latin America and one of the highest life expectancies in the world. The concept of “orphan drug” exists and is commonly used, particularly in the area of metabolic disorders.

OrphaNews Europe: How did your collaboration with Swedish paediatric immunologist Dr. Anders Fasth come into being? What kind of work do you do?

Dr. Olga Arguedas: Dr. Fasth started his collaboration with Costa Rica in the late 1980s, joining Dr. Oscar Porras, an inmunologist who did a PhD in Gothenburg, Sweden on the creation of a paediatric program for stem cell transplantation in Costa Rica. After this, and with the support of the Swedish Agency for Research in Developing Countries (SAREC), he collaborated as a PhD supervisor in a research programme in the epidemiology of rheumatic disorders in children. Up to now, Dr. Fasth continues to collaborate in both areas, advising on difficult cases and actively participating in an exchange programme for medical students between the University of Gothenburg and the University of Costa Rica. Dr. Fasth has visited Costa Rica at least once a year for the last twenty years.

OrphaNews Europe: Can you describe the rare disease services or research facilities in the Hospital de Niños?

Dr. Olga Arguedas: There are special outpatient clinics with multidisciplinary participation, day-hospital programmes, and educational, nutritional, odontological and psychological support.

OrphaNews Europe: What diseases does the country's newborn screening programme cover?

Dr. Olga Arguedas: Yes, there is a National Programme of Newborn Screeening for 24 inherited disorders that includes hypothyrodism, fenilcetonuria, Maple Syrup Disease, Congenital Adrenal Hyperplasia, Galactosemia, Organic Acidemias, B-oxidation defects, and Hemoglobinopathies.

OrphaNews Europe: Are there patient groups for rare disorders in your region? What kind of role they play?

Dr. Olga Arguedas: There are groups for some rare disorders; they play a role in teaching, education, recreation, psychological support and as pressure groups in certain situations.

OrphaNews Europe: Do you collaborate with neighboring countries?

Dr. Olga Arguedas: We collaborate mainly with Nicaragua and Panama - lecturing, advising on specific cases, and as a training centre.
Contact Dr. Olga Arguedas

EU Policy News
EC session highlights value of European-level collaborations for rare disease research
A session dedicated to research on rare diseases (RD), organised by the European Commission, took place in Paris on 6 June during the European Research and Innovation Exhibition, highlighting the added-value of European multidisciplinary approaches.

Dr Catherine Berens (European Commission) explained that the historical support of the European Union to research on RD is based on this value added by pooling the scarce European resources (samples, patients, expertise) and on the complementation by public financial support of insufficient private investments in this area. Dr. Berens presented past and future activities supported through the EU Framework Programmes for Research and Technological Developments. Dr Ségolène Aymé (Orphanet/INSERM) underlined the necessity of multidisciplinary, multinational research projects, as well as networking. She presented an overview of the services provided by Orphanet and its various platforms, supported by the EU through the Research Framework Programmes and the Public Health Programmes to contribuate to networking and collaboration.

The role of patients/patient representatives as initiators and contributors in research was elucidated by Dr Tsveta Schyns-Liharska. Dr Schyns, founder of the European Network for Research on Alternating Hemiplegia, demonstrated that both patients and researchers can benefit from strong collaborations. She presented the example of the FP6 project ENRAH for SMEs (LSSM-CT-2005-516513) that she is coordinating to emphasise how patients can concretely contribute to the research process. Dr Stefanie Possekel (Santhera Pharmaceuticals Ltd) illustrated via the FP6-supported project TREAT-NMD (LSHM-CT-2006-036825) the attractiveness of orphan drug (OD) research for industry and the need to establish effective partnerships with academia, clinicians and patient organisations in order to boost industrial development of OD.

Rare disease reference centre pilot projects chosen for funding
The 2007 work plan for implementing the EU’s 2003-2008 public health action programme prioritises the development of European Reference Networks of Expert Centres for Rare Diseases. A number of projects that meet this description have been selected for funding. Amongst them are three rare disease projects: the European network of paediatric Hodgkin’s lymphoma – European-wide organisation of quality controlled treatment. This initiative seeks to facilitate the establishment of a central reference system including all clinical, CT, MRI and PET data from all patients providing the basis for future guidelines. The European Network of Reference for Rare Paediatric Neurological Diseases (NEUROPED) will focus on a number of conditions, among which Alternating Hemiplegia of Childhood (AHC), Narcolepsy and Rare Surgically Treatable Epileptic Syndromes (RSTES) to include Tuberous Sclerosis, Sturge-Weber, Hypothalamic hamartoma, Landau-Kleffner syndrome and Rasmussen's encephalitis. A reference network for Langerhans cell histiocytosis and associated syndromes in the EU (EURO HISTIO NET 2008) seeks to establish a network for those reference centres organising care and clinical research for Langerhans Cell Histiocytosis (LCH) and associated syndromes in each individual EU country and will share and disseminate the knowledge and experience of different European LCH centres through the realisation of practical objectives, including an international database and diagnosis guidelines.

National & International Policy Developments
French children’s parliament proposes rare disease measure

At the 14th Parlement des Enfants, which took place on 7 June at the French National Assembly, a 449 majority voted in favour of proposing legislation in the form of four specific articles that would guarantee rare disease patients access to medical treatment. The articles call for financing the fabrication and distribution of medicinal products for rare disease patients; full insurance coverage for non-medicinal treatments and equipment such as special skin creams, nutritional supports, and wheelchairs; priority funding for rare disease research; and international cooperation and collaboration in the field of research. The Children’s Parliament, which has been meeting annually since 1994, is composed of 577 children aged 10-11 years, elected by their classmates from across France and the French territories. To date, four decrees proposed by the Parlement des Enfants have been adopted by the republic. This particular measure was proposed by the children of Renan Le Mourillon school in Toulon, who evoked the case of a 12-year-old Toulon girl with Sjogren-Larsson syndrome, (characterised clinically by congenital ichthyosis, mental retardation and spasticity), whose treatment (manufactured abroad) had ceased production, and whose special skin hydrating products were not reimbursed. In fact, France has very recently revised its reimbursement scheme and such products are now reimbursed by the social security administration.

Other European news
An international consortium for cord blood and adult stem cell applications launches
On 14 May, Novus Sanguis, a consortium created jointly by the French Foundation Jerome Lejeune and the research group on cord blood at Newcastle University, UK, had its official coming out party. Over 80 diseases, mostly affecting the blood or immune systems, are already treatable with cord blood stem cells, as are certain other disorders affecting the nervous system, heart, metabolism or bone marrow. Founded at the end of 2007, Novus Sanguis’s main objective is to find biotechnological, pharmaceutical and medical applications by researching cord blood stem cells and adult stem cells. The consortium will also orient its research activities toward genetic diseases, including trisomy 21, a disorder to which the Fondation Jerome Lejeune gives considerable support in France.
Other International News
US judge orders insurance plan to pay for rare disease experimental treatment, setting a precedent for other rare diseases
In a case that could potentially impact thousands of other rare disease patients, a judge in the US state of Tennessee has ordered the state’s health insurance to reimburse an experimental treatment for a patient with nephrogenic systemic fibrosis (NSF), a condition that seems to occur only in patients with kidney disease and of which only 200 to 250 cases have been reported worldwide. Patients with NSF present extensive thickening of the skin, and in some cases, distinct papules and subcutaneous nodules. In many cases, the skin thickening inhibits the flexion and extension of joints, resulting in contractures. Severely affected patients may be unable to walk, or fully extend the joints of their arms, hands, legs, and feet. The judge's ruling is considered significant by legal experts on health coverage, because other courts are likely to look to this decision in the future. Rare disease patients in the US often face the predicament of insurance companies refusing to cover a treatment that the FDA has not yet approved. There is no distinct FDA policy on this issue. In the European Union, the EMEA has issued guidelines for compassionate use of medicinal products that have not yet received marketing authorisation, but the decision to coordinate and implement such products resides with each member state.
Learn more about the early access to medical products in Europe


EU Project Follow-up
A new European biobank project seeking to harmonise resources confronts legal bottlenecks
In February of this year, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) was launched in order to create a broadly accessible pan-European network of existing and de novo biobanks and biomolecular resources for global biomedical research. This harmonisation is particularly crucial to rare disease research, which inherently has small sample pools from which to draw. A seminar held last month drew together researchers, academia, industry, and government representatives to address some of the technical, legal, regulatory and financial issues of the project’s preparatory phase. A principal bottleneck has been identified: the diverse and often complex legal frameworks of each member state. Hervé Pero of DG Research asserted the need for a pan-European legal framework compatible with those of member states in order to manage the new European structures. The establishment of rules governing data protection is another priority of this preliminary phase that emerged during the meeting. The BBMRI project is open to participation. A current list of participants is available on the BBMRI website.

Orphanet News
Orphanet attracts interest from afar...
Orphanet was present at the Human Genetics Congress held in Barcelona, Spain from 31 May - 3 June. The Orphanet booth provided an opportunity to meet with the many professional users of the website and to reach new potential registrants among the 2,200 participants. The booth was shared with EuroGentest, an EC funded network of excellence dedicated to promoting quality management of genetic laboratories and genetic services. Orphanet and EuroGentest have collaborated closely since 2005: Orphanet collects information on the quality management of laboratories providing testing for rare diseases and EuroGentest validates the data on accreditation and /EQA/ (External Quality Assessment) of the laboratories. Data on certification are based on laboratory self-reporting. These data are accessible on the Orphanet website which is co-branded with EuroGentest for the section on medical laboratories. In Barcelona, many laboratories completed registration questionnaires requesting to be listed in the Orphanet/Eurogentest database. These laboratories hail from all over the world, leading to a difficult question of where to set boundaries for data collection. Initially, Europe (EU27) was the targeted area for providing information on medical laboratories, but surrounding countries soon applied to join and were accepted. Armenia, Tunisia, Morocco, Algeria, and Lebanon, among others, have since become Orphanet partners. Now, similar requests from Russia, the Ukraine, South Africa, Egypt, Argentina, Chile, and Venezuela, are causing some soul searching - and for valid reasons. The needs of patients and of professionals know no geographic barriers. Yet the Orphanet coordinating team has no mechanism in place to ensure that the process of data collection is managed fairly and that the data are validated before being released. This requires the training and the supervision of the national team in charge of the database, to be done without funding. An impossible challenge.... New avenues for funding the project will have to be identified to meet the needs of the community in less developed countries. We will keep you informed of further developments and in the meantime would welcome any ideas or suggestions.

New Syndromes
Cardiac anomalies and left isomerism: a new autosomal dominant syndrome
The authors report a three-generation family with nine patients affected by a combination of cardiac abnormalities and left isomerism. The cardiac anomalies include non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. The laterality sequence anomalies include left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia and intestinal malrotation, all compatible with left isomerism. This new syndrome is inherited in an autosomal dominant pattern. A genome-wide linkage analysis suggested linkage to chromosome 6p24.3-21.2.
Read the PubMed abstract

Hum Genet ; 595-603 ; January 2008
An immunodeficiency disease with RAG mutations and granulomas
The authors describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein-Barr virus. The authors identified heterozygous mutations in the genes RAG1 or RAG2. The parents and one sibling in the three families were healthy.
Read the PubMed abstract

NEJM ; 2030-2038 ; May 2008
Psychomotor retardation, dystonia, communication skill defects: mitochondrial complex III deficiency associated with a mutation
A consanguineous Israeli Bedouin family presented with an autosomal-recessive nonlethal phenotype of severe psychomotor retardation and extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia, and marked global dementia with defects in verbal and expressive communication skills. A missense mutation was identified in gene UQCRQ, encoding proteins of mitochondrial complex III.
Read the PubMed abstract

Am J Hum Gen ; 1211-1216 ; May 2008
ANE syndrome: Alopecia, Neurological defects, and Endocrinopathy
The authors investigated an autosomal-recessive phenotype characterised by alopecia, progressive neurological defects, and endocrinopathy (ANE syndrome). They identified a loss-of-function mutation in RBM28, encoding a nucleolar protein thought to regulate ribosome biogenesis. The authors propose naming the disorder ANE syndrome.
Read the PubMed abstract

Am J Hum Gen ; 1114-1121 ; May 2008
An oculo-auricular syndrome caused by a mutation in gene NKX5-3
The authors describe a developmental defect affecting the eye and the external ear in three members of a consanguineous family. This syndrome is characterised by ophthalmic anomalies (microcornea, microphthalmia, anterior-segment dysgenesis, cataract, coloboma of various parts of the eye, abnormalities of the retinal pigment epithelium, and rod-cone dystrophy) and a particular cleft ear lobule. The authors identified a deletion in gene NKX5-3 and confirmed the role of this gene in eye development in the zebra fish.
Read the PubMed abstract

Am J Hum Gen ; 1178-1184 ; May 2008

New Genes
Iron-refractory iron deficiency anaemia: mutations in TMPRSS6 at cause
Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, the authors show that iron deficiency anaemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin.
Read the PubMed abstract

Nat Gen ; 569-571 ; May 2008
Paediatric hypothyroidism: a deficit in iodotyrosine deiodinase
DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. The authors screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.
Read the PubMed abstract

NEJM ; 1811-1818 ; April 2008
Ehlers-Danlos syndrome type 6 has deleterious mutations in the Zinc-Finger 469 gene
Ehlers-Danlos syndrome type 6 (also known as brittle cornea syndrome) is an autosomal-recessive disorder characterised by a thin cornea that tends to perforate, causing progressive visual loss and blindness. Additional systemic symptoms such as joint hypermotility, hyperlaxity of the skin, and kyphoscoliosis place this syndrome among the connective-tissue disorders. The disease gene has previously been assigned to a 4.7 Mb interval on chromosome 16q24. Now, the authors have identified two frameshift mutations in the Zinc-Finger 469 gene (ZNF469). The function of ZNF469 is unknown. However, a 30% homology to a number of genes suggests that it could act as a transcription factor involved in the synthesis and/or organisation of collagen fibres.
Read the PubMed abstract

Am J Hum Gen ; 1217-1222 ; May 2008
Autosomal recessive or X-linked nonsyndromic mental retardation due to a defect of glycosylation
Two articles published in The American Journal of Human Genetics describe mutations in gene TUSC3 in patients born into two consanguineous families and presenting an autosomal recessive form of nonsyndromic mental retardation. TUSC3 codes a subunit of the oligosaccharyltransferase (OTase) complex, which catalyses the transfer of an oligosaccharide chain on nascent proteins, the key step of N-glycosylation. In patients with a recessive X-linked form of the disorder, authors identified a mutation in the gene IAP, a paralogue of gene TUSC3. These two studies for the first time link glycosylation errors to nonsyndromic mental retardation.
Read the first PubMed abstract
Read the second PubMed abstract

Am J Hum Gen ; 1158-1164 ; May 2008Am J Hum Gen ; 1150-1157 ; May 2008

Branchio-oculo-facial syndrome: TFAP2A mutations at cause
Branchio-oculo-facial syndrome (BOFS) is a rare autosomal-dominant cleft palate-craniofacial disorder. The major features include cutaneous anomalies, ocular anomalies, characteristic facial appearance, and, less commonly, renal and ectodermal anomalies. The authors of this study identified mutations in the TFAP2A gene in six patients. This gene is already implicated in craniofacial development.
Read the PubMed abstract

Am J Hum Gen ; 1171-1177 ; May 2008
Autism and Tourette syndrome: familial deletion within NLGN4 associated
Neuroligin 4 (NLGN4) is a member of a cell adhesion protein family that appears to play a role in the maturation and function of neuronal synapses. Mutations in the X-linked NLGN4 gene are a potential cause of autistic spectrum disorders, and mutations have been reported in several patients with autism, Asperger syndrome, and mental retardation. The authors describe here a family with a wide variation in neuropsychiatric illness associated with a deletion of exons 4, 5, and 6 of NLGN4. The proband is an autistic boy with a motor tic. His brother has Tourette syndrome and attention deficit hyperactivity disorder. Their mother, a carrier, has a learning disorder, anxiety, and depression. This family demonstrates that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions including mild symptoms.
Read the PubMed abstract

Euro J Hum Gen ; 614-618 ; May 2008
Gorlin syndrome: a mutation in PTCH2, a sonic hedgehog signalling pathway gene
Gorlin syndrome, also known as naevoid basal cell carcinoma syndrome, is an autosomal dominant disease, characterised by a range of developmental anomalies and a predisposition to various cancers. Growing evidence suggests that the disorder may result from mutations in genes of the Sonic hedgehog (Shh) signalling pathway. The authors investigated the pathogenic gene in an affected family, finding a novel missense mutation in the PTCH2 gene, thus confirming the role of the sonic hedgehog signalling pathway in this disorder.
Read the PubMed abstract

J Med Gen ; 303-308 ; May 2008
Cardiac hypoplasia: a loss-of-function mutation in the binding domain of HAND1
Hypoplasia of the human heart is the most severe form of congenital heart disease and usually lethal during early infancy. It is a leading cause of neonatal loss. The authors sequenced the HAND1 gene in heart tissues derived from 31 unrelated patients diagnosed with hypoplastic hearts. In 24 patients with cardiac hypoplasia, they detected loss of function mutations in the HAND1 gene.
Read the PubMed abstract

Hum Mol Gen ; 1397-1405 ; May 2008

Research in Action
Fundamental Research
Autosomal recessive spinal muscular atrophy: plastin 3 is a protective modifier
Spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality, is caused by homozygous deletion of the survival motor neuron 1 gene (SMN1). In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. The authors discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3, important for axonogenesis, than their SMA-affected counterparts. Overexpression rescued the axon length and outgrowth defects associated with motor neuron degeneration in SMA mouse embryos and in zebrafish. This study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
Read the PubMed abstract

Science ; 524-527 ; April 2008
Clinical Research
Pyruvate kinase deficiency protects against malaria
Pyruvate kinase deficiency causes various degrees of chronic hemolytic anaemia. This enzyme, encoded by the gene is involved in the transformation of phosphoenol pyruvate into pyruvate and ATP production, a capital stage in the regulation of glycolysis. The authors of this study demonstrate that pyruvate kinase deficiency provides protection against infection and replication of P. falciparum in human erythrocytes, raising the possibility that mutant pyruvate kinase alleles may confer a protective advantage against malaria in human populations in areas where the disease is endemic.
Read the PubMed abstract

NEJM ; 1805-1810 ; April 2008
Cardiac hypertrophy: the genetic causes are the same in children and adults
The childhood onset of idiopathic cardiac hypertrophy that occurs without a family history of cardiomyopathy can portend a poor prognosis. Despite morphologic similarities to genetic cardiomyopathies of adulthood, the contribution of genetics to childhood-onset hypertrophy is unknown. The authors assessed the family and medical histories of 84 children with idiopathic cardiac hypertrophy diagnosed before 15 years of age. In 46 affected children, they identified mutations in genes implicated in adult forms of the disease.
Read the PubMed abstract

NEJM ; 1899-1908 ; May 2008
Acute myeloid leukemia with no cytogenetic anomalies: correlation between genotype and treatment response
Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: NPM1, FLT3, CEPBA, MLL, and NRAS. The authors evaluated the associations of these mutations with clinical outcomes in 872 patients. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3 duplication, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission.
Read the PubMed abstract

NEJM ; 1909-1918 ; May 2008
Hereditary paraganglioma: maternal transmission is possible
Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extraadrenal chromaffin cells (secreting paragangliomas). Inactivating mutations of SDHD, predispose to hereditary paraganglioma (PGL) and/or pheochromocytoma. To date, only paternal transmission has been observed. The authors describe a boy who received the mutation from his mother and developed a glomus tympanicum PGL at 11 years of age. This study shows that maternal transmission of SDHD-linked PGL, even if rare, can occur. Therefore, children who inherited a pathogenic mutation from their mother should be considered as at risk of PGL.
Read the PubMed abstract

J Clin Endocrinol Metab ; 1609-1615 ; May 2008
Prader-Willi syndrome: patients have a high prevalence of central adrenal insufficiency
Prader-Willi syndrome is a rare genetic disorder characterised by hypothalamic-pituitary abnormalities with severe hypotonia during the neonatal period and first two years of life and the onset hyperphagia with a risk of morbid obesity during infancy and adulthood, learning difficulties and behavioural problems or severe psychiatric problems. The authors of this study report central adrenal insufficiency in 15 of 25 patients tested (60%). The high percentage of central adrenal insufficiency in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. They suggest treatment with hydrocortisone during acute illness in PWS patients unless central adrenal insufficiency has recently been ruled out with a metyrapone test.
Read the PubMed abstract

J Clin Endocrinol Metab ; 1649-1654 ; May 2008
Zollinger-Ellison syndrome: identification of risk factors for gastric carcinoids and enterochromaffin-like cell changes
Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES), a sum of manifestations induced by the abnormally high secretion of gastrin by an endocrine tumor in the duodenum or pancreas (gastrinoma). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. Fifty-seven consecutive MEN1/ZES patients participated in this prospective study. The authors conclude that gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and recommend regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions.
Read the PubMed abstract

J Clin Endocrinol Metab ; 1582-1591 ; May 2008
Congenital neutropenia: correlation between HAX1 mutations and phenotype
Homozygous mutations in the gene HAX1 cause an autosomal recessive form of severe congenital neutropenia (CN). By screening 88 patients with CN, the authors demonstrate that the clinical phenotype of HAX1 deficiency appears to depend on the localisation of the mutation and influence on the transcript variants. Their findings suggest that HAX1 isoforms may play a distinctive role in the neuronal system.
Read the PubMed abstract

Blood ; 4954-4957 ; May 2008
Therapeutic Approaches
Tuberous sclerosis complex: rapamycin prevents epilepsy in mouse models
Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSCgene inactivation leads to hyperactivation of the mammalian target of rapamycin signalling pathway. Mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1(GFAP)CKO mice) develop glial proliferation, progressive epilepsy, and premature death. The authors tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1(GFAP)CKO mice. They found that rapamycin has strong efficacy for preventing seizures and prolonging survival in these mouse models.
Read the PubMed abstract

Ann Neurol ; 444-453 ; April 2008
Sickle-cell disease: bosentan reduces morbidity and mortality in mouse models
Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vaso-occlusive crisis (VOC). The authors report that pharmacological inhibition of endothelin receptors by administration of the dual endothelin receptor antagonist bosentan prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that bosentan (an orphan medicine authorised in Europe to treat arterial pulmonary hypertension) could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.
Read the PubMed abstract

J Clin Invest ; 1924-1933 ; May 2008
Diagnostic Approaches
Beckwith-Wiedemann and Silver-Russell syndromes: MS-MLPA as a technique for detecting all chromosome 11p15.5 imprinting defects
Human chromosome 11p15.5 harbours a large cluster of imprinted genes. Different epigenetic defects at this locus have been associated with both Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder characterised by macrosomia, macroglossia, organomegaly and developmental abnormalities and Silver-Russell syndrome (SRS), characterised by growth retardation with antenatal onset, characteristic facies and limb asymmetry. Multiple techniques (Southern blotting, COBRA and microsatellite analysis) have been used so far to detect various DNA methylation abnormalities, uniparental disomies and copy number variations. The authors have evaluated a methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) for the molecular diagnosis of BWS and SRS in 73 patients. The MS-MLPA assay can detect both copy number variations and methylation defects of the 11p15.5 critical region within one single experiment and represents an easy, low cost and reliable system for the molecular diagnostics of BWS and SRS.
Read the PubMed abstract

Euro J Hum Gen ; 565-571 ; May 2008

Patient Management and Therapy
Congenital lactic acidosis: evaluation of long-term treatment with dichloroacetate in children
The authors report results on long-term administration of dichloroacetate in 36 children with congenital lactic acidosis who participated previously in a controlled trial of this drug. They found that oral dichloroacetate is generally well tolerated in young children with congenital lactic acidosis. Although continued dichloroacetate exposure is associated with evidence of peripheral neuropathy, it cannot be determined whether this is attributable mainly to the drug or to progression of underlying disease.
Read the PubMed abstract

Pediatrics ; e1223-e1228 ; May 2008

Orphan Drugs
Five EMEA orphan drug designations for June

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

- treatment of moderate and severe closed traumatic brain injury
- idiopathic pulmonary fibrosis
- prevention of Graft-versus-Host disease
- treatment of traumatic spinal cord injury
- glioma
Consult the European Registry for Orphan designations
Consult the Orphanet list of orphan drugs authorised for marketing in Europe


Courses & Educational Initiatives
A unique online MSc course in haemoglobinopathies
Thalassaemia International Federation (TIF) in collaboration with University College London (UCL) is offering a unique online MSc course in Haemoglobinopathies. The first e-learning course in this field, the course offers health professionals the opportunity to pursue an advanced degree from anywhere in the world. For further information
Advanced Course on Epidemiological, Clinical and Genomic Databases
This workshop, held from 7-12 July, 2008 in Milan, Italy addresses topics including medical records; clinical databases; genomic databanks; epidemiological archives and registers; medical data integration; hospital and health information systems; telecommunication and networking infrastructures; internet in biomedicine; methods of data analysis (classification, clustering, discriminant, regression); and more. For further information
Practical Biobanking Course
Nowgen, A Centre for Genetics in Healthcare, is hosting a 2nd Practical Biobanking Course in partnership with the Centre for Integrated Genomic Medical Research (CIGMR) at The University of Manchester and the UK DNA Banking Network. The first workshop, held at the Nowgen Centre in November 2007, was a great success, attracting 45 delegates from 14 different countries.

This second two day intensive course, taking place 30 June-1 July, is designed for both biobank sponsors and researchers looking to establish and maintain a biological sample resource. The emphasis of the course will be on the practical aspects of establishing and running a successful biobank. For further information

European Advanced Postgraduate Course in Classical and Molecular Cytogenetics - 2009
The course is designed to provide medical graduates, pharmacists, researchers, graduate students and health professionals with advanced training in constitutional, haematological, and oncological cytogenetics. The students will be trained to identify genetic abnormalities using both classical and molecular cytogenetic techniques for diagnosis, prognosis, and fundamental and applied research. The course is co-organised by the European Cytogenetists Association and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training. For further information

What's on Where?
Geneskin: Towards a Better Understanding and Care of Genetic Skin Diseases
Date: 20 June 2008
Venue: Rome, Italy

The final meeting of the EU funded Coordination Action project “Rare genetic skin diseases: advancing diagnosis, management and awareness through a European network” includes talks by both members of the GENESKIN consortium and invited speakers on the most recent advances in research, diagnosis, therapy and management of inherited skin diseases. Registration is free.
For further details

5th International Cystinosis Conference
Date: 27-28 June 2008
Venue: Dublin, Ireland

World experts in the field of Cystinosis will attend and the latest research in this very rare disease will be presented. The event is unique as it combines a high-level scientific and medical conference as well as being a family and patient friendly conference.
For further details

15th International Paediatric Colorectal Club Meeting
Date: 29 June- 1 July 2008
Venue: Salamanca, Spain

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. View the programme.
For further details

15th Retina International World Congress
Date: 4-5 July 2008
Venue: Helsinki, Finland

Clinical diagnostics of retinal dystrophies, genetic diagnostics and research, Usher syndrome, ongoing clinical trials.
For further details

Supporting Policy Development in Genomics Symposium
Date: 6 July 2008
Venue: Montreal, Canada

Policy-makers and researchers from a variety of fields are convened to this international symposium in view of outlining a roadmap towards a more concerted research approach to inform policy.
For further details

New and Developing Technologies for Genetics Diagnostics
Date: 7-8 July 2008
Venue: Salisbury, UK

This meeting will cover a wide range of techniques and issues relevant to genetic diagnostics in the 21st century. The meeting will focus on new sequencing technologies, non-invasive prenatal diagnosis, molecular cytogenetics copy number determination.
For further details

3rd workshop on Molecular Targets for Cancer - turning knowledge on therapeutics, prevention and biomarkers into applications
Date: 11-12 July 2008
Venue: Bergen, Norway

This workshop will address childhood and adult rare cancers, the tumor microenvironment, poor prognosis cancers, and resistance to therapy.
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

Barth Syndrome: On Track Toward a Cure - 4th International Conference
Date: 21-26 July 2008
Venue: Florida, USA

This conference will be dedicated to increasing knowledge and accelerating advances in research for this rare metabolic genetic disorder. It will bring together basic scientists, clinical researchers, treating physicians, other professionals, and affected individuals and families to focus on the syndrome through a series of carefully organised sessions.
For further details

International Society for Genetic Eye Diseases and Retinoblastoma Meeting 2008
Date: 28-30 August 2008
Venue: Strasbourg, France

This meeting will include novel therapies for inherited eye diseases and retinoblastoma; molecular diagnosis of inherited eye diseases and retinoblastoma; phenotype/genotype analysis; update on management issues; and interactive sessions on rare cases, with short clinical presentations.
For further details

Inaugural Birt Hogg Dube Syndrome Symposium
Date: 3 September 2008
Venue: Roskilde, Denmark

Laboratory research session in the morning and a clinical session in the afternoon. Keynote presentation and opportunity for a number of short talks in each session. There will be poster presentations. This is an opportunity for researchers and clinicians to present their work, share ideas and set up collaborations to promote BHD research and to establish screening guidelines for BHD patients.
For further details

6th International Conference on Frontotemporal Dementia
Date: 3-5 September 2008
Venue: Rotterdam, The Netherlands

Symposium highlights include: Caregivers burden; Early onset dementia AD; Genetic Counseling; Aphasic syndromes; Tau; Progranulin; TDP-43 protein; Genetics of the FTD; ALS spectrum; Animal and Cell Models; Neuropathology and biochemistry of FTD; Clinical spectrum FTD; Pharmacological treatments; and more.
For further details

19th European Meeting on Dysmorphology
Date: 4-5 September 2008
Venue: Strasbourg region, France

Sessions will focus on MCA/MR syndromes; foetal pathology; new microdeletion/duplication syndromes; dysmorphology and esophageal atresia/tracheoesophageal fistula.
For more information

First AnEUploidy Workshop
Date: 12-14 September 2008
Venue: Geneva, Switzerland

The AnEUploidy integrated project aims to contribute to the understanding of the molecular basis and pathogenic mechanisms of aneuploidies. With the aim of furthering the primary objectives of this project, this international workshop will share and discuss the newest results in this field. A limited number of junior travel fellowship will be granted.
For further details

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

The programme will cover four main topics through keynote lectures, abstract presentations and educational workshops: juvenile arthritis, juvenile dermatomyositis, vasculitis and pain. There will be novel symposia such as sport and exercise in young people.
For further details

2nd Congress of Ring14 International Association for Rare Neurogenetic Diseases Research
Date: 25-27 September 2008
Venue: Reggio Emilia, Italy

An interesting and varied programme for professionals, patients and their families.
For further details

13th International Meeting of the World Muscle Society
Date: 29 September-2 October 2008
Venue: Newcastle upon Tyne, UK

New Insights into the pathogenesis of facioscapulohumeral muscular dystrophy, myotonic dystrophy and other dominant muscular dystrophies, Advances in the understanding and treatment of myasthenic disorders, Therapeutic advances in neuromuscular disorders, Advances across the neuromuscular field, including treatment and management.
For further details

International Conference on Thalassaemia and Haemoglobinopathies
Date: 8-11 October 2008
Venue: Singapore

The 11th International Conference on Thalassaemia and Haemoglobinopathies and the 13th International Thalassaemia TIF Conference for Thalassaemia Patients and Parents. "Equal Access to Quality Medical Care for Every Patient with Thalassaemia" is the theme of this year's conferences.
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

EPPOSI 9th Workshop on Partnering for Rare Diseases Therapy Development
Date: 16-17 October 2008
Venue: Paris, France

Mark your calendars for the 2008 EPPOSI workshop, taking place at the National Assembly in Paris. The theme of the workshop is Orphan drugs: partnering along the chain and across the borders - Sharing strategies and tools for access to diagnosis and treatment.
For further details

Rare Tumors in Europe: Challenges and Solutions
Date: 6 November 2008
Venue: Brussels, Belgium

Details to follow shortly.
For further information


Press & Publications
The Lancet puts the focus on rare diseases and orphan drugs
The 14 June issue of the Lancet contains a series of articles exploring rare disease and orphan drug policies and practices. Written by authors on both sides of the Atlantic, these articles address the pertinent themes that need exploring in order for rare disease and orphan drug policies to go forward efficiently:

Why Rare Diseases Are an Important Medical and Social Issue reiterates that, taken all together, rare diseases impact a significant portion of the population. The majority of rare diseases is genetic in origin, phenotypically heterogeneous, and is often severely disabling, diminishing the sufferer’s quality of life and posing a considerable burden on affected families. Thus the authors recommend increasing public research in the field and boosting drug development initiatives.

Empowerment of Patients: Lessons from the Rare Diseases Community reviews the increasingly active role patient groups are having in influencing policy, disseminating information, and forwarding research. This is particularly true in the field of rare diseases, where patients have been obliged to fight a hard battle for recognition and improved care. The legitimacy of this participatory role is evidenced by the appointment of patient representatives to the European Commission’s Committee for Orphan Medicinal Products.

Gene Therapy of Inherited Diseases presents a balanced, realistic historical appraisal of the complex but potentially promising approach of gene therapy, which could be especially relevant to the large number of rare genetic diseases. However, the authors point out that this treatment approach is still in its early stages and is just one strategy amongst others that must be developed further for rare diseases. The first positive outcome from gene therapy took place more than 20 years after research began. Advances in vector design and stem cell biology, coupled with growing knowledge of immunogenicity prevention, conspire to encourage further clinical study in this field.

Does Orphan Drug Legislation Really Answer the Needs of Patients? concludes that, despite some limitations (and the ever-present cloud of economic considerations), the incentives laid out in the orphan drug legislation in the US and Europe are working to encourage development of orphan products - including treatments for very rare disorders. It must be acknowledged that advancements in biotechnology also contribute to a growing interest in orphan drugs. An interesting consequence of the orphan legislation pointed out in the article concerns the development of treatments for diseases that are considered rare in developed countries but which have high prevalence elsewhere in the world (including tuberculosis and malaria) and which are benefiting from current US orphan drug legislation.

This issue of the Lancet also has articles focusing on specific rare diseases, including Rett syndrome. OrphaNews Europe encourages readers to explore this trove of information at their earliest convenience.

A consideration of screening policies: the Dutch perspective
As the genetic basis of many diseases – especially rare disorders – becomes unravelled, the possibility of diagnosing these disorders, and the potential for inheritance, becomes more available. Coupled with an explosion in diagnostic technology, genetic screening possibilities are expanding on a daily basis. However, as is well known, the discovery of treatments for many rare diseases is advancing at a slower pace, leaving policy makers and health professionals with the quandary of how to manage diseases that could be diagnosed, but which have no treatment options available. Against this backdrop, two critical studies have been issued by the Dutch Health Council that attempt to define policies that will best protect citizens and result in beneficial health management of patients.

The first report focuses specifically on neonatal screening. Reviewing the over thirty (all rare) disorders recommended by current international reference literature, the report evokes the purpose of neonatal screening - avoiding irreparable health damage. The Dutch Health Council’s Committee on Neonatal Screening thus divides potential disease screening candidates into three categories. Those for which: 1) considerable, irreparable damage can be prevented; 2) less substantial or insufficient evidence of prevention of damage to health; 3) no prevention of damage to health. (For certain disorders, such as Duchenne muscular dystrophy or fragile-X syndrome, current screening cannot contribute to damage prevention). Using this system of catagorising diseases, the committee recommends expanding its current policy to add 15 disorders to its neonatal screening programme. It is estimated that the expanded programme will detect an additional 90 or so patients per year, coming primarily from sickle-cell disease (40 patients estimated) and MCAD-deficiency (14-18 patients). The advisory report also considers issues of information and consent.

The second report issued focuses on the increase in novel screening techniques, the phenomena of private sector screening services and self-screening kit products, and seeks to determine responsible screening criteria, equitable screening availability, and increasing government protection for consumers. The Netherlands has legislation (the Population Screening Act) designed to protect consumers from harmful risks associated with screening such as false-positives and over-diagnosis. However, self-screening kits produced outside the EU and sold via internet fall through the cracks. This report makes recommendations that would permit the government to offer protective legislation for the entire dynamic arena of publicly and privately available screening and self-testing kits: Organise continually proactive intervention spanning all areas of screening; Develop a quality mark for responsible screening; link the quality mark to standards of professional conduct; Transform the Population Screening Act into a flexible safety net; Ensure central control.
Consult the first report
Consult the second report


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