Editorial
 
Europe shares in the celebration as the US fêtes 25 years of the Orphan Drug Act
 
It was on 4 January 1983 that then-US president Ronald Reagan signed into law the original US Orphan Drug Act. This gesture brought hope for millions of rare disease patients and their families in the US and around the world. Conceived to facilitate the development of new treatments for rare disorders, the Orphan Drug Act offers incentives to industry, notably seven years of market exclusivity as well as tax credits for various stages of research. Over 300 treatments have been brought to market since the Act came into effect; almost two thousand products have received orphan drug designations in the US. The European Union created its own version of this important legislation in 1999 and is quickly catching up in producing medicinal products for rare disorders. Other countries around the world have adopted similar legislation, including Japan, Australia, Korea and Taiwan. Today, the US and the EU enjoy a streamlined procedure for obtaining orphan drug designation that serves to simplify sponsor application in both territories and encourage orphan product development even further. There are several events underway this year to underscore the importance of the 25 year Orphan Drug Act milestone, including an international research conference, an anniversary gala, activities to encourage media coverage, and a campaign to get US President George W. Bush to designate May as "Orphan Drug Month"�. Europe meanwhile has its own publicity project in the works with the designation of 29 February as "European Rare Diseases Day"�. It seems that 2008 is already shaping up as a year of increased awareness for the needs of rare disease patients and their families. Happy New Year!
 


 
EU Policy News
 
Have you responded to the rare disease Communication yet?
 
At the risk of repeating ourselves, we issue a gentle reminder that the Commmunication on European Action in the Field of Rare Diseases is open for Public Consultation. Rare Diseases: Europe's Challenges 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. OrphaNews Europe again emphasises the importance of your response to this document, now available in all EU languages. If you haven't already done so, please take the time to review the Communication and offer feedback in the language of your choice. Your comments are valuable whether you are responding as an individual citizen of an EU country or as a professional representating a particular organisation. While the Communication provides a set of 13 questions designed to facilitate feedback, responding to them is not obligatory and readers are welcome to respond as they wish. For those who agree with the contents of the Communication as they now read, it would still be helpful to the eventual revision process to signal your accord. As was mentioned in our last newsletter, your contributions will be published and made available to Members of Parliament, including those from your country.
 
New ERC funding scheme includes rare disease research amongst recipients
 
CORDIS Express, the news publication of the European Commission's research and development information service, recently reported on the first results of the European Research Council's (ERC) Starting Independent Research Grant distribution scheme intended to boost the careers of researchers at the time they are establishing themselves as independent research leaders. Some 300 candidates were selected as grant recipients from over 9000 applicants from 88 different countries. The grants are available to researchers from all areas of science. Biological and life sciences (including molecular biology, genetics, neurosciences, medical and health science and biotechnology) took about 35% of the total awards. Amongst the recipients is Martin Bergö of the Sahlgrenska Academy at Gothenburg University, Sweden, whose research domain is CAAX protein processing in human disease: from cancer to progeria. He and a US-based research team have identified a new treatment strategy which is currently being tested on children with progeria, a rare genetic disorder that causes premature ageing. This research also provides a new genetic method of studying the underlying mechanisms and treatment of cancer. The ERC, created under the EU's Seventh Framework Programme (FP7), plans to expand considerably its research funding programme in 2008, including the introduction of the Advanced Grant, designed for more experienced researchers. The Advanced Grant call for proposals launched in late November and has a closing date of 22 April for Life Sciences. The next Starting Grant call is scheduled to be posted in the summer of 2008.
 


 
National & International Policy Developments
 
Spain's president reiterates country's commitment to a rare disease national plan
 
Spanish president José Luis Rodriguez Zapatero confirmed his government's commitment to implementing a national plan for rare diseases in order to be in sync with similar efforts being undertaken in other European Union member countries. Presiding over a meeting of the Consejo Nacional de la Discapacidad, the Spanish leader evoked the rights of rare disease patients and their families. The need for rare disease centres of reference was also reiterated. Spain's senate unanimously approved the proposal to create a national plan for rare diseases last February. In the meantime Spain has created a major research initiative for rare disease and orphan drugs (CIBERER), and is funding a rare and paediatric drug clinical trial programme.
 
Other European news
 
French company creates new mutation diagnostic software application
 
France-based Interactive Biosoftware has developed a software application dedicated to mutation diagnostics. Alamut is constructed to rapidly and reliably interpret mutations by synthesizing relevant molecular data and prediction methods within a consistent environment. Alamut was developed in cooperation with the molecular genetic laboratory of the hospital of Rouen and is already being used by several diagnostic laboratories in France, the Netherlands and the Czech Republic.
 
UK hospital reports leukaemia in X-SCID patient following gene therapy treatment
 
The Great Ormond Street Hospital for Children NHS Trust reported last month that a child who underwent a pioneer gene therapy treatment for x-linked severe combined immunodeficiency (X-SCID) has developed leukaemia, a known risk of the intervention. For two years the gene therapy was successful in treating X-SCID, sometimes referred to as the 'boy in the bubble syndrome'�, in which boys are born with no immune system. Ten children with X-SCID and another five with ada-SCID have been treated with the novel gene therapy approach at the London-based hospital. All of the former group and most of the latter have experienced clinical benefits. The family of the child who developed leukaemia received extensive counselling on the risks linked to the treatment prior to beginning the clinical trial. The study has been closed to recruitment while safer formulations of the treatment are being readied. A similar X-SCID trial in Paris, France also led to certain children developing leukaemia (four cases from 11 treated). For more information.
 
Other International News
 
WHO unveils new campaign for paediatric medicines
 
The World Health Organization last month revealed a new campaign designed to intensify efforts to ensure children worldwide have suitable and adapted medicinal products. The Make Medicines Child Size campaign launched alongside a research and development agenda targeting a range of medicines that need to be better tailored to children's needs. The WHO is also developing an internet portal for clinical trials involving children that is scheduled to go online early this year. The need for safe paediatric medicinal products affects children from both wealthy and developing countries and encompasses common diseases along with rare disorders and neglected tropical diseases. In Europe, the EMEA already has measures underway to ensure medicines are safely designed for paediatric patients, including the Paediatric Committee that was formed in 2007 to oversee the approval of medicinal products for children in the EU.
 
Native American children have increased risk of SCID
 
Severe combined immune deficiency (SCID) usually affects 1 in 100 000 of the population. But in the Navajo and Apache nation populations in the US, an estimated one in 2500 is affected with the rare autosomal recessive disorder. For a long time, the increased infant mortality rate in this population was attributed to conditions of poverty and a lack of access to medical treatment. Because the SCID symptoms that manifest in newborns include the same type of maladies that commonly affect young children, such as ear infections, the increased incidence of the disorder was masked. But in recent years doctors were able to uncover the high prevalence of SCID amongst Navajo and Apache tribe members. In SCID patients common infections linger and worsen despite the administration of treatments that normally prove efficacious. About a dozen genes have been linked to SCID. The Native American population is considered to have a particularly severe form of the disease. Diagnosis is usually determined after a series of recurring infections in the months following the patient's birth. SCID is not included in routine newborn screening and prenatal screening is often cost-prohibitive in this population. The only existing treatment to date is bone marrow transplantation, a treatment that has a much higher success rate when undertaken before the patient is three months of age. Affected Native American patients currently have to travel from their home in Arizona to San Francisco, California, to access transplantation.
 


 
EU Project Follow-up
 
AnEUploidy seeks patients for two projects
 
FP6 project AnEUploidy is devoted to furthering the understanding of the molecular basis and pathogenetic mechanisms of aneuploidies by harnessing recent technologies such as human genome sequencing, comparative genome analysis, genome variation, mouse transgenesis, technological platforms for transcriptome and genotypic analysis, bioinformatics tools, and systems biology. AnEUploidy is still seeking patients with any of the following syndromes: Ohdo syndrome, Baraitser-Winter syndrome, Coffin Siris syndrome, Hallermann-Streiff syndrome, Malpuech syndrome, Schinzel Giedion syndrome, Floating Harbor syndrome, IFAP (ichthyosis follicularis, alopecia and photophobia), Aase-Smith syndrome, and Bohring syndrome. These patients will be phenotyped according to a standardised phenotypic list and genotyped with the new Affymetrix Genome-Wide Human 6.0 SNP Array featuring 1.8 million markers. Another AnEUploidy project is collecting a large number of patients with rare chromosome 21 imbalances. These patients will be genotyped with a targeted chromosome 21 array developed by NimbleGen Systems Inc. For further information.
 


 
Orphanet News
 
Orphanet Journal of Rare Diseases has a successful 2007
 
The Orphanet Journal of Rare Diseases (OJRD ) debuted in March 2006 as a free-access online journal dedicated to rare disease research. To date, 100 articles have been published, 30% of which are "highly accessed". The subject matter can be broken down into the following specialties: dysmorphology and chromosomal diseases, about 25%; endocrinology, neurology and immunology 25%; internal medicine (gastroenterology, hepatology, cardiology, pulmonology) 22%; haematology 5%; cancer 5%; ophthalmology 4%; and metabolic diseases 3%. In 2007, OJRD was accepted for tracking by MEDLINE and is thus now indexed by PubMed, PubMed Central, Medline and Scopus. OJRD has about 500 subscribers to date.
 


 
New Genes
 
Spinocerebellar ataxia type 11: mutations in the gene encoding tau tubulin kinase 2 are at cause
 
Spinocerebellar ataxia type 11 is an autosomal dominant disease characterised by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. The authors have identified mutations in TTBK2 gene in two families, of English and of Pakistani origin. TTBK2 encodes tau tubulin kinase 2. Tau protein has been implicated in other neurodegenerative illnesses, such as Alzheimer and Parkinson diseases.
Read the PubMed abstract
 
Nature Genetics ; 1434-1436 ; December 2007
 
Hypertriglyceridemia: a lipase maturation factor causes severe combined deficit
 
Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. The authors have identified the gene responsible for combined lipase deficiency in mice. Through its profound effect on lipase activity, the lipase maturation factor gene emerges as an important candidate gene in human hypertriglyceridemia since a subject homozygous for a deleterious mutation in LMF1 shows lipase deficiency with hypertriglyceridemia.
Read the PubMed abstract
 
Nature Genetics ; 1483-1487 ; December 2007
 
For Brugada syndrome, a GPD1-L mutation affects trafficking of the cardiac sodium channel
 
Brugada syndrome is an autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterised by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac sodium channel gene SCN5A on chromosome 3p21 cause approximately 20% of Brugada syndrome cases. Two research teams have identified mutations in GPD1-L in a family affected by the syndrome and in three patients with sudden infant death syndrome. This gene could be implicated in the transport of the cardiac sodium channel to the cell surface.
Read the first PubMed abstract
Read the second PubMed abstract
 
Circulation ; 2260-2268 ; November 2007
Circulation ; 2253-2259 ; November 2007

 


 
Research in Action
 
Clinical Research
 
Czech dysplasia metatarsal type: type 2 collagen again at cause
 
Czech dysplasia metatarsal type is an autosomal-dominant disorder characterised by an early-onset, progressive spondyloarthropathy with normal stature. Shortness of third and/or fourth toes is a frequently observed clinical feature. The authors have already identified a point mutation in COL2A1, encoding type 2 collagen, in patients presenting symptoms similar to Czech dysplasia metatarsal type. In this study, they present evidence of the same mutation in patients with Czech dysplasia metatarsal type, thus enlarging the phenotype spectrum linked to COL2A1 mutations.
Read the PubMed abstract
 
European J Human Genetics ; 1269-1275 ; December 2007
 
Long QT syndrome: toward a mutation-specific risk stratification
 
Long QT syndrome is characterised by a prolongation of the QT interval on the ECG, more specifically, a prolongation of repolarisation following depolarisation of the cardiac ventricles. It is associated with syncope and sudden death due to ventricular arrhythmias. A mutation in KCNQ1 gene (mutation A341V) has been identified in a South African population presenting a severe form of the syndrome. The authors compared the effect of this mutation in different populations and observed that it is linked to a severe phenotype, independent of the ethnicity of patients. These results can permit a better stratification of risk and better treatment strategy for patients.
Read the PubMed abstract
 
Circulation ; 2366-2375 ; November 2007
 
Intraductal papillary neoplasia of bile duct: a favourable prognosis following surgery
 
This study describes 16 patients presenting a papillary neoplasia of bile duct in the liver. The authors suggest that intraductal papillary neoplasia should be distinguished from other types of peripheral cholangiocarcinoma, as a distinct entity because of its distinct clinical and pathological features and its favourable prognosis that can be expected after complete surgical resection.
Read the PubMed abstract
 
Histol Histopathol ; 41-50 ; January 2008
 
Ichthyosis: filaggrin mutations are genetic modifying factors
 
X-linked ichthyosis is a rare form of ichthyosis visible from the first days of life with prolonged exfoliation of the newborn. Two brothers with the disease are carriers of the same mutation in STS gene, although they present varied phenotypes. In the child most severely affected, the authors have identified an additional mutation in the gene encoding filaggrin. Mutations in this gene have already been identified in patients with ichthyosis vulgaris. Moreover, the frequency of mutations in this gene is elevated in the general population, making filaggrin a potential modifier of other genodermatoses.
Read the PubMed abstract
 
J Invest Dermatol ; 2795-2798 ; December 2007
 
Therapeutic Approaches
 
Epidermolysis bullosa simplex: doxycycline prolongs survival in disease mouse models
 
Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin K5 or K14 genes. It is widely regarded as a mechanobullous disease, resulting from a weakened cytoskeleton, causing extensive cytolysis. In this study, the authors analysed the transcriptome of K5-/- mice. They observed an increase in proinflammatory cytokines IL-6 and IL-1beta, which lead them to test the effect of doxycycline, a molecule known for its anti-inflammatory effect in mice. This molecule produced a downregulation of matrix metalloproteinase 13 and IL-1beta, indicating an effect on transcription. These data offer a novel small molecule-based therapy approach for EBS.
Read the PubMed abstract
 
J Invest Dermatol ; 2781-2789 ; December 2007
 
Diagnostic Approaches
 
Erythropoietic protoporphyria: FECH deletions comprise 10% of familial cases
 
Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria characterised by partial deficiency of ferrochelatase (FECH). The consequence of this deficiency is the accumulation of protoporphyrin IX in the red blood cells, plasma, skin and liver, leading to a hypersensitivity to light and hepatobiliar symptoms in some patients. Using quantitative analysis, the authors identified deletions in FECH gene in 19 of 33 patients studied. Extending the procedure to a 189 patient cohort, the authors demonstrate that quantitative analysis raises the rate of detection of mutations by 10% to 93%. Thus, it is proposed that quantitative analysis be integrated into existing protocols for detecting FECH mutations.
Read the PubMed abstract
 
J Invest Dermatol ; 2790-2794 ; December 2007
 


 
Patient Management and Therapy
 
Multiple myeloma: lenalidomide improves patient response and survival
 
Multiple myeloma is a malignant neoplasm of plasma cells manifested by skeletal destruction, bone pain, and presence of abnormous immunoglobulins. Standard treatment consists of administering large doses of dexamethasone. Two studies published in the New England Journal of Medicine present two phase 3 clinical trials analysing the effect of lenalidomide in conjunction with the standard treatment on patients with relapsed or refractory multiple myeloma. The authors observed a better response in the patients receiving lenalidomide versus those receiving a placebo. Moreover, patient survival was increased in this group. Lenalidomide, commercialised as Revlimid (Celgene Europe) in Europe, received European marketing authorisation for this indication in June 2007.
Read the first PubMed abstract
Read the second PubMed abstract
 
New Eng J Med ; 2123-2132 ; 22 November 2007
New Eng J Med ; 2133-2142 ; 22 November 2007

 
Cystic fibrosis: lung transplantation seen as more deleterious than beneficial
 
The authors studied via a retrospective study the effect of pulmonary transplantation in American children with cystic fibrosis. Of 514 patients on a waiting list for transplantation between 1992-2002, (248 of whom actually received lung transplantation) the authors estimate that this treatment would be beneficial in only five cases and would appear to be deleterious in 315 cases. A prospective, randomised trial is needed to clarify whether and when patients derive a survival and quality-of-life benefit from lung transplantation.
Read the PubMed abstract
 
New Eng J Med ; 2143-2152 ; 22 November 2007
 
Amyotrophic lateral sclerosis: minocycline does not improve patient functioning or survival
 
Amyotrophic lateral sclerosis is a degenerative disease of the nervous system caused by a progressive loss of motor neurons. The authors present the results of a randomised clinical trial testing the efficacy of minocycline against a placebo. Minocycline is an anti-apoptotic and anti-inflammatory molecule with proven efficacy in neurological disease mouse models. Administration of minocycline has rather deleterious effects on patient motor functioning.
Read the PubMed abstract
 
Lancet Neurol ; 1045-1053 ; December 2007
 
Immune thrombocytopenic purpura: a combination of four products proves effective
 
Patients with severe immune thrombocytopenic purpura may require an acute increase in the platelet count for surgery or ongoing hemorrhage as well as long-term maintenance treatment. Certain of these patients may be refractory to steroids, intravenous anti-D, intravenous immunoglobulin and splenectomy. The authors studied acute platelet increases in 35 patients completely unresponsive to intravenous immunoglobulin or high-dose steroid treatment. Patients were administered a 3- or 4-drug combination including intravenous immunoglobulin, intravenous methylprednisolone, Vinca alkaloids, and/or intravenous anti-D. Subsequent maintenance therapy with the oral combination of danazol and azathioprine was given to 18 of the 35 patients. Seventy-one percent of the patients responded to the intravenous combination treatment with acute platelet increases of at least 20 x 10(9)/L to a level greater than 30 x 10(9)/L. Two thirds of the patients given maintenance therapy achieved stable platelet counts greater than 50 x 10(9)/L without other treatments.
Read the PubMed abstract
 
Blood ; 3526-3531 ; November 2007
 
Primary amyloidosis: high-dose melphalan and stem cell transplantation have long-term benefits
 
Primary amyloidosis is characterised by the accumulation of amyloid fibres throughout the organism, formed by immunoglobulin light chains. The authors followed 80 patients treated more than ten years ago via large doses of melphalan and stem cell transplantation. Results show that this treatment approach leads to durable remissions and prolonged survival.
Read the PubMed abstract
 
Blood ; 3561-3563 ; November 2007
 
Paroxysmal nocturnal hemoglobinuria: eculizumab reduces the risk of thromboembolism
 
Paroxysmal nocturnal hemoglobinuria is characterised by intravascular hemolytic anemia, venous thrombosis (particularly within the abdomen), and cytopenia due to deficient bone marrow production of blood cells. The authors administered the complement inhibitor eculizumab to 195 patients between 2002 and 2005. The risk of thromboembolism was greatly reduced by the treatment, demonstrating a clinical efficacy. Eculizumab is commercialised by Alexion under the name Soliris. It received marketing authorisation in Europe in June 2007.
Read the PubMed abstract
 
Blood ; 4123-4128 ; December 2007
 
Crigler-Najjar disease: orlistat treatment decreases plasma bilirubin concentrations
 
Crigler-Najjar syndrome is associated with a complete hepatic deficit of bilirubin glucuronosyltransferase activity and becomes apparent during the neonatal period by early, intense jaundice due to unconjugated bilirubin. The authors conducted a randomized, placebo-controlled, double-blind, cross-over trial of orlistat in 16 patients, simultaneous with their regular treatment. They observed increased faecal fat excretion and fecal unconjugated bilirubin excretion in the treated group. Orlistat treatment also significantly decreased plasma unconjugated bilirubin concentration.
Read the PubMed abstract
 
Pediatr Res ; 725-730 ; December 2007
 
Turner syndrome: mode of estrogen administration does not alter efficacy
 
In patients with Turner syndrome, transdermal administration of estrogen is often preferred to oral delivery for treating growth delay. The authors compared the effects of both methods on the metabolism of 11 Turner syndrome adolescents. No difference was observed.
Read the PubMed abstract
 
J Clin Endocrinol Metab ; 4154-4160 ; November 2007
 
Inherited arrhythmias: recommendations for classification, treatment and diagnosis
 
In September 2006, the US Office of Rare Diseases and the National Heart, Lung and Blood Institute co-organised a workshop to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. A major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and, in many respects, contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides a framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. The present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.
Read the PubMed abstract
 
Circulation ; 2325-2345 ; November 2007
 
A survey of attitudes regarding carrier testing in incompetent children
 
The aim of this study is to gather information from European clinical geneticists about their practices and attitudes with regard to carrier testing in incompetent children. One hundred and seventy-seven respondents completed the questionnaire. For all autosomal recessive and X-linked disorders studied, the majority of respondents were very unwilling or unwilling to provide a carrier test to a 6-year-old asymptomatic child on parental request (range 73-91%). For almost all disorders, respondents from Eastern and Southern European countries are more willing to provide a carrier test to a 6-year-old asymptomatic child than respondents from Western and Northern European countries. Overall, the survey showed an adherence to existing recommendations and guidelines regarding carrier testing in incompetent minors, although for every condition studied, a group of clinical geneticists was willing or very willing to provide a carrier test to a 6-year-old child on parental request.
Read the PubMed abstract
 
European J Human Genetics ; 1211-1217 ; December 2007
 


 
Orphan Drugs
 
Four EMEA orphan drug designations for January
 

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