8 May 2013 print
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IRDiRC delivers a successful and inspiring conference: a common goal emphasised

The first IRDiRC conference was held on April 16-17 2013 in the charming city of Dublin, Ireland. Thought leaders from all over the world captured the audience with stimulating, inspirational and highly informative talks on the past, present and future of rare disease research. IRDiRC was unanimously hailed as need of the time to advance the cause of rare disease research. IRDIRC promises to contribute in development of 200 therapies for rare disease and means to diagnose all of them by 2020. Rare disease stakeholders discussed the ways and means to help reach these goals. They provided examples of success stories as well as suggestions of the innovative ways in which stakeholders can come together to fulfill this goal.

This truly international conference was attended by more than 400 participants representing Europe, North America, Australia and Asia. It was recognised by one and all that expertise in rare disease, like the patients, are scattered across the globe. It is thus imperative for the global rare disease community to put their heads together to solve the great big jigsaw of rare disease, of which everyone holds a piece. This meeting boasted of attendance from policy makers, industry leaders, academicians as well as patient organisations from around the world. Representatives from regulatory bodies such as FDA, EMA, the Canadian and Australian regulatory agencies shared their expertise and pushed the need for more regulatory success for orphan drugs. Patient organisations such as Rare Voices Australia, Eurordis and Genetic Alliance US, gave an overview of the current need of patients and how coming together with a common agenda is urgent, but also achievable. Industry partners emphatically expressed the need to work with academicians, patient organisations and regulatory bodies to significantly increase the number and quality of drugs that is accessible to all. The buzz word was collaboration, collaboration, collaboration.

Mirroring the scientific committees of IRDiRC, the conference panels were divided into 3 tracks- therapies, diagnostic and interdisciplinary track-with experts in each area presenting the current outlook and the way forward. The therapies track addressed issues that deal with providing better treatment for patients such as drug repurposing, developing innovative therapies and ensuring an open dialogue with the regulatory bodies so that the treatments developed painstakingly see the light of day. The diagnostic track articulated the current projects that are underway to identify the causes of the rare diseases, the tremendous advancements in Next Generation Sequencing including the use of data generated from it and the crucial understanding of the Human Phenome. The speakers in the Interdisciplinary track highlighted the means by which successful collaborations can lead to successful treatments and diagnostics. They also endeavoured to delineate how future challenges in the extremely complex world of rare disease research can be overcome. Economic and ethical issues such as those that have cropped up due to recent advancements in technology, especially next generation sequencing, were also discussed at length.
Dr Ruxandra Draghia-Akli who is a champion of the rare disease cause and served IRDiRC as its chairperson with impressive results, passed on the baton to Dr. Paul Lasko, a distinguished member in the field of rare disease research. The success of this conference promises a much brighter future for rare disease patients. IRDiRC has 32 members representing research funding bodies. Organisations interested in becoming members of IRDiRC are encouraged to apply.
Go to the IRDiRC website
Photo courtesy: Lensman Photographic Agency

Spotlight on...
Insights from patients and the medical professionals of the rare disease community: results from a survey in US and UK
The Rare Disease Impact Report commissioned by Shire Human Genetic Therapies and developed in collaboration with an external advisory board reveals responses to more than 1,000 survey participants from a multi-stakeholder audience sample, to enlighten us on some extremely important aspects that affect rare disease patients on a daily basis. The report acknowledged that on average it takes more than seven years in the US and five years in the UK for a patient with a rare disease to receive a proper diagnosis which includes visits to up to eight physicians and they are typically misdiagnosed about two to three times. They also found that physicians (both primary care and specialists) often lack the time, resources and information to properly diagnose/manage patients with rare diseases, compared to more common diseases. The report states that around half of the patients and caregivers receive conflicting information from different health care professionals about treatment options in both US and UK, while half of the physicians stated there aren't enough opportunities to network with other physicians who treat rare diseases. Additionally, more than half of patients and caregivers voiced the need to furnish their healthcare professionals with information on their rare disease. The report also estimated the economic impact of diagnosing and managing rare diseases which is significant. Payer respondents reported several factors contribute to the higher costs of care for rare disease patients compared to more common diseases, including the need for more diagnostic tests (100% in the US, 80% in the UK agreed) and more costly diagnostic tests (100% in the US, 90% in the UK agreed). They also found the lack of standards and guidelines for rare disease coverage decisions particularly challenging. In addition, almost all payers delineate the dearth of data/information available to help determine the standards of care for rare diseases (95% in the US, 90% in the UK agreed). Health care coverage is US and UK differ considerably and although most surveyed patients in US had health coverage, 55% incurred direct medical expenses not covered by insurance. In UK, 18% of respondents were not covered by the National Health Service. While 37% of respondents borrowed money from family and/or friends to pay for expenses in the US, only 21% of respondents in the UK did the same. This is an extremely frustrating ordeal for rare disease patients and caregivers and takes a grave emotional toll on them. Patient respondents reported several emotional difficulties managing their disease including depression (75% in the US, 69% in the UK agreed), anxiety and stress (86% in the US, 82% in the UK agreed), isolation from friends/family (65% in the US, 57% in the UK agreed), and worry based or grim outlook of the future(90% in the US, 91% in the UK agreed). For those rare disease patients where treatment options are limited, overall they worry more, feel more depressed, interact less and feel more isolated from family and friends, compared to patients with rare diseases for which there are available treatments.
Read the report


EU Policy News

European Medicines Agency annual report has encouraging results for orphan medicinal products
European Medicines Agency (EMA) has published the annual report of 2012-an eventful year for rare diseases. The report highlights the introduction of the new pharmacovigilance legislation which has led to the Pharmacovigilance Risk Assessment Committee (PRAC) and several changes in the structure of the agency. The agency has also endeavoured for an increased levels of transparency in their proceedings. The report has underscored the progress in bringing orphan medicinal products (OMP) to the market. There was an 18% increase in application for orphan drug designation and a 36% increase in the number of Marketing Authorisation for OMP in 2012 compared to 2011. EMA also reported a 30% increase in the number of applications from micro, small and medium-size enterprises (SMEs), where 68% of the applications submitted by SMEs were for OMP’s. According to the report, “the Agency processed a total of nearly €7.5 million in fee reductions for designated orphan medicinal products” in 2012. The Agency's Committee for Advanced Therapies received 3 applications for Advanced-therapy medicinal products. They also adopted a draft opinion for Glybera, the first gene-therapy medicine approved in the EU, and a “second recommendation on certification on the quality data of a tissue-engineered product”.
Read the EMA annual report for 2012

European Medicines Agency publishes report on patient recruitment and geographical location of clinical trials
Due to the public concern around the ethical and scientific execution of clinical trials EMA requires information regarding “the location of conduct and ethical standards applied in respect of clinical trials conducted in third countries” for each marketing authorisation (MAA). This information has been collected since 2005 and reports providing an overview of this information has been previously published in 2009 (containing data from MAA’s from 2005 to 2008) and in 2010 (containing data upto 2009). EMA has published the third report of data of clinical trials for MAAs’ from 2010 and 2011. These reports provides an overview of the distribution of the number of patients, investigator sites and pivotal clinical trials included in MAAs submitted to the EMA, on the number of sites subject to inspection and the geographic location of these inspections.
Read the EMA annual report on Clinical Trials


National & International Policy Developments
US House of representatives approves paediatric disease research bill
The House of Representatives in the US approved a bill that authorises the National Institutes of Health to create up to 20 paediatric research consortia that aims to investigate and develop treatments for paediatric disease, especially for rare diseases like Spinal Muscular Dystrophy. This National Pediatric Research Network Act was written by Democratic representative Lois Capps and encourages research coordination and collaboration in order to accelerate clinical trials in the field of paediatric disease research.
Read the National Pediatric Research Network Act of 2013

Other International News
Fragile X Carrier Screening introduced for the first time in Hong Kong
The Department of Obstetrics and Gynaecology at The Chinese University of Hong Kong (CUHK) introduced the use of Fragile X PCR technology to screen specifically for Fragile X syndrome. They are the first to introduce this technique in this region, which will help identify women who are carriers of this abnormal gene mutation causing Fragile X syndrome. CUHK said that they validated this approach on 14 full-mutation cases, 20 pre-mutation cases, and 75 normal controls and also mention that they can identify the mutation with 100% accuracy using this method.
Guidance Documents and Recommendations
Open for public consultation: Guidelines on the clinical investigation of medicinal products for the treatment of Duchenne and Becker muscular dystrophy
Guidance to evaluate medicinal products to treat Duchenne and Becker muscular dystrophies (DMD and BMD) was recently published by the European Medicines Agency (EMA). This document is now open for public consultation until 31 August 2013. Duchenne and Becker muscular dystrophies are rare diseases and while DMD is life-threatening disease and patients has a short life expectance, patients with BMD live longer. Recent advances in basic and clinical research have opened new perspectives for future therapeutic options in DMD and BMD have led to the increasing number of clinical trials. The guidelines published by EMA have been prepared in lieu of these new developments that provide information and recommendation for clinical strategies. EMA recognises that “due to the heterogeneity in phenotypes of both diseases and the expected treatment goals that also may vary according to disease status” a clear-cut guidance is may not provided by the document and “that the present document should be conceived as general guidance and should be read in conjunction with other relevant EMA and ICH guidelines”.
Read EMA guidelines on DMD/BMD

Open for public consulation: Guidelines on the clinical development of medicinal products intended for the treatment of chronic primary immune thrombocytopenia
Another guidance document open to public consulation is on chronic primary immune thrombocytopenia (ITP). This document describes the information on the clinical development to be documented when an application for a marketing authorisation for a medicinal product is made for the treatment of chronic primary immune thrombocytopenia. The purpose of this guidance is to provide a "harmonised regulatory approach that will lead to a consistent assessment of products by regulators and set clear standards for industry". This documents provides "relevant aspects on the clinical studies to be conducted to assess the efficacy and safety of medicinal products intended for the treatment of chronic ITP".
Read EMA guidelines on immune thrombocytopenia

Suggested guidelines for the diagnosis and management of urea cycle disorders
A recent article in the Orphanet Journal of Rare Diseases have used the Delphi methodology where experts across Europe delineated guidelines that provide practitioners across fields with set a common standard of practice to diagnose and manage Urea cycle disorders (UCDs). Patients with UCD display hyperammonemia which can lead to death or to severe neurological disorders. Symptoms of UCD are frequently undiagnosed or under-diagnosed which may lead to poor treatment outcome even though several lines of effective therapy are currently available. According to the authors the difficulty in diagnosis is possibly “due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. The consensus guidelines provided in this article are based on empirical evidence available so far and according to the authors are “sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues” of UCD.
Read the open access article

Deafness: principles and guidelines for early intervention after confirmation that a child is deaf or hard of hearing (American Academy of Pediatrics)
Access the article via PubMed
Pediatrics ; 131(4):e1324-49 ; April 2013
Bioinformatics, Registries and Data Management
Japanese national registry of muscular dystrophy (Remudy): an international effort
A national registry of Japanese DMD/BMD patients named Remudy (REgistry of MUscular DYstrophy)is described by Nakamura et al., published in Orphanet Journal of Rare Disease. This registry was developed in collaboration with TREAT-NMD and includes male Japanese DMD/BMD patients, most of whom are less than 20 years of age. The registry also covers the type of genetic mutation of the patients, their ambulatory status, steroid and cardiac medicine usage, ventilator and non-invasive support as well as whether the patients are scoliosis surgery recipients. The authors also found that 9.8% of the patients “were eligible to clinical trial focused on ‘skipping’ exon 51”. The authors believe that this registry provides sufficient information to recruit patients for clinical trials as well as to standardise care for DMD/BMD patients. Additionally the authors believe that this DMD/BMD patient registry- the first collaborative effort with an international registry- and will facilitate “the synchronization of clinical drug development in Japan with that in other countries.
Read the open access article

Quantifying muscular dystrophy and neurogenic atrophy diagnosis
A recent article in BMC Medicine describes the development of a method called “Neuromuscular Diseases Computerized Image Analysis (NDICIA), that uses network science analysis to capture the defining signature of muscle biopsy images”. Diagnosis of neuromuscular diseases is highly dependent on histological characterization of muscle biopsies which is often subjective. This method tries to objectively quantify the epithelial organisation in patients suffering from neuromuscular diseases. To this end, the authors compiled images of 102 muscle biopsy images from 70 individuals and each image is represented as a network, with fibers serving as nodes and fiber contacts as links. NDICIA characterizes muscle tissues by representing each image. From this NDCIA can reveal the tissue organisation and to reveal whether the tissue is normal or diseases and this method was validated as it correlated greatly with pathologist evaluation. According to the authors this “approach will serve as a valuable tool for assessing the etiology of muscular dystrophies or neurogenic atrophies, and has the potential to quantify treatment outcomes in preclinical and clinical trials”.
Read the open access article


Orphanet News
Emergency guidelines and documents for general public that are now available online on ORPHANET in English and Italian
Documents in English can be found here
• Malignant hyperthermia

Documents in Italian can be found here
• Sclerosi laterale amiotrofica

• Diabeto insipido nefrogeno congenito

• Poliendocrinopatia autoimmune tipo 1

• Sindrome di Brugada

• Deficit di alfa-1-antitripsina

• Neutropenia costituzionale grave


New Genes

Atypical haemolytic uremic syndrome: recessive mutations in DGKE cause an atypical disease with infantile onset and persistent hypertension, microhaematuria and proteinuria
Consult the PubMed abstract
To read more about "Atypical hemolytic uremic syndrome"

Nature Genetics ; 45(5):531-6 ; May 2013
Hereditary sensory and autonomic neuropathy type 2: a novel homozygous loss-of-function mutation in SCN9A results in HSAN2D, affecting two families
Consult the PubMed abstract
To read more about "Hereditary sensory and autonomic neuropathy type 2"

Neurology ; 80(18):1641-9 ; 30 April 2013
Parkinsonian-pyramidal syndrome: heterozygous G51D mutation in SNCA (alpha-synuclein) responsible for an unusual phenotype in a three-generation pedigree
Consult the PubMed abstract
To read more about "Parkinsonian-pyramidal syndrome"

Ann Neurol. ; doi: 10.1002/ana.23894. [Epub ahead of print] ; 22 March 2013
Colorectal adenomas and carcinomas: highly penetrant germline mutations affecting the proofreading domains of POLE and POLD1 discovered
Consult the PubMed abstract
Nature Genetics ; 45(2):136-44 ; February 2013
Hypomyelination with atrophy of basal ganglia and cerebellum: a de novo mutation in the beta-tubulin gene TUBB4A identified in all eleven patients studied
Consult the PubMed abstract
To read more about "Hypomyelination with atrophy of basal ganglia and cerebellum"

Am J Hum Genet. ; doi: 10.1016/j.ajhg.2013.03.018. [Epub ahead of print] ; 9 April 2013
GAPO syndrome: ANTXR1 mutations found in four ethnically unrelated cases
Consult the PubMed abstract
To read more about "GAPO syndrome"

Am J Hum Genet. ; doi: 10.1016/j.ajhg.2013.03.023. [Epub ahead of print] ; 16 April 2013
Mutations in DYNC1H1, TUBG1, KIF2A and KIF5C cause malformations of cortical development and microcephaly, underlying the importance of centrosomal and microtubule-related proteins
Consult the PubMed abstract
Nature Genetics ; doi: 10.1038/ng.2613. [Epub ahead of print] ; 21 April 2013
Idiopathic pulmonary fibrosis: seven new susceptibility loci identified, including FAM13A, DSP, OBFC1, ATP11A, and DPP9
Consult the PubMed abstract
To read more about "Idiopathic pulmonary fibrosis"

Nature Genetics ; doi: 10.1038/ng.2609. [Epub ahead of print] ; 14 April 2013
Multiple myeloma: constitutive CCND1 c.870G>A polymorphism is a risk factor for the t(11;14)(q13;q32) translocation
Consult the PubMed abstract
To read more about "Multiple myeloma"

Nature Genetics ; 45(5):522-5 ; May 2013
B-cell chronic lymphocytic leukaemia: recurrent somatic POT1 mutations, causing telomere dysfunction, identified in 3.5% of analysed cases
Consult the PubMed abstract
To read more about "B-cell chronic lymphocytic leukemia"

Nature Genetics ; 45(5):526-30 ; May 2013
Idiopathic and/or familial pulmonary arterial hypertension: a significant association at the CBLN2 locus detected
Consult the PubMed abstract
To read more about "Idiopathic and/or familial pulmonary arterial hypertension"

Nature Genetics ; 45(5):518-21 ; May 2013
Microcephaly-capillary malformation syndrome: mutations in STAMBP, encoding a deubiquitinating enzyme, are responsible
Consult the PubMed abstract
To read more about "Microcephaly-capillary malformation syndrome"

Nature Genetics ; 45(5):556-62 ; May 2013
Autosomal-dominant familial focal epilepsies: DEPDC5 mutations are a common cause
Consult the PubMed abstracts
To read more about "Familial focal epilepsy with variable foci"
To read more about "Nocturnal frontal lobe epilepsy"
To read more about "Autosomal dominant epilepsy with auditory features"

Nature Genetics ; 45(5):546-51 ; May 2013
Nature Genetics ; 45(5):552-5 ; May 2013
Juvenile idiopathic arthritis: dense genotyping of immune-related disease regions identifies 14 new susceptibility loci
Consult the PubMed abstract
To read more about "Juvenile idiopathic arthritis"
To read more about "Juvenile rheumatoid factor-negative polyarthritis"
To read more about "Oligoarticular juvenile arthritis"

Nature Genetics ; doi: 10.1038/ng.2614. [Epub ahead of print] ; 21 April 2013
Primary sclerosing cholangitis: nine new risk loci revealed by dense genotyping of immune-related disease regions
Consult the PubMed abstract
To read more about "Primary sclerosing cholangitis"

Nature Genetics ; doi: 10.1038/ng.2616. [Epub ahead of print] ; 21 April 2013
Biliary atresia: GPC1, encoding glypican 1, is a susceptibility gene, supporting a role for Hedgehog signaling in the pathogenesis of this anomaly
Consult the PubMed abstract
To read more about "Biliary atresia"

Gastroenterology ; 144(5):1107-15 ; May 2013
Multiple intestinal atresia: exome sequencing identified homozygous or compound heterozygous mutations in TTC7A in all the French-Canadian families studied
Consult the PubMed abstract
To read more about "Multiple intestinal atresia"

Journal of Medical Genetics ; 50(5):324-9 ; May 2013
Congenital and infantile nephrotic syndrome: a homozygous mutation in ARHGDIA at cause in two sisters
Consult the PubMed abstract
To read more about "Congenital and infantile nephrotic syndrome"

Journal of Medical Genetics ; 50(5):330-8 ; May 2013
Autosomal recessive spinocerebellar ataxia 7: TPP1, already known as involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease, is the causative gene
Consult the PubMed abstract
To read more about "Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia"

Human Mutation ; 34(5):706-13 ; May 2013
Cataract - intellectual deficit – hypogonadism (Martsolf syndrome): a homozygous RAB3GAP1 mutation is responsible in a family
Consult the PubMed abstract
To read more about "Cataract - intellectual deficit - hypogonadism"

Human Mutation ; 34(5):686-96 ; May 2013
Retinoblastoma: MYCN amplifications specifically detected in about 50% of cases with no detectable RB1 mutation
Consult the PubMed abstract
To read more about "Retinoblastoma"

Lancet Oncology ; 14(4):327-34 ; April 2013
Pustulosis palmaris et plantaris and acrodermatitis continua suppurativa of Hallopeau: IL36RN variants at cause
Access to the letter via PubMed
To read more about "Pustulosis palmaris et plantaris"
To read more about "Acrodermatitis continua suppurativa of Hallopeau"

J Invest Dermatol. ; 133(5):1366-9 ; May 2013
Autosomal-recessive intellectual deficit: a truncating mutation in ANK3 identified in three siblings with hypotonia, spasticity and severe behavioural problems
Consult the PubMed abstract
Human Molecular Genetics ; 22(10):1960-70 ; 15 May 2013
Atypical Rett syndrome: 14q12 microdeletions, preserving FOXG1 gene but supposed to cause misregulation of its expression, detected in three patients
Consult the PubMed abstract
To read more about "Atypical Rett syndrome"

European Journal of Human Genetics ; 21(5):522-7 ; May 2013

Research in Action

Clinical Research
Amyotrophic lateral sclerosis: no evidence of benefit of lithium on survival in a phase 3 multicentre, randomised, double-blind, placebo-controlled trial (LiCALS)
Consult the PubMed abstract
To read more about "Amyotrophic lateral sclerosis"

Lancet Neurology ; 12(4):339-45 ; April 2013
SOD1 familial amyotrophic lateral sclerosis: a first-in-human clinical study shows the feasibility of intrathecal delivery of antisense oligonucleotides into the CNS
Consult the PubMed abstract
To read more about "Amyotrophic lateral sclerosis"

Lancet Neurology ; 12(5):435-42 ; May 2013
Precursor B-cell acute lymphoblastic leukaemia: induction of remission of relapsed and refractory disease in two children with chimeric antigen receptor-modified T cells
Consult the PubMed abstract
To read more about "Acute lymphoblastic leukemia"

NEJM ; 368(16):1509-18 ; 18 April 2013
Hepatocellular carcinoma: effectiveness of yttrium-90 radioembolisation in intermediate to advanced cancer, particularly in case of portal vein thrombosis, in a phase 2 study
Consult the PubMed abstract
To read more about "Hepatocellular carcinoma"

Hepatology ; 57(5):1826-37 ; May 2013
Prader-Willi syndrome: growth hormone therapy in childhood and adolescence is associated with improved body composition and metabolic status in adulthood
Consult the PubMed abstract
To read more about "Prader-Willi syndrome"

J Clin Endocrinol Metab. ; 98(2):E328-35 ; February 2013
Growth hormone-deficiency in adulthood: a prospective safety surveillance highlights that patient selection and GH dose titration are important to ensure safety of GH replacement
Consult the PubMed abstract
J Clin Endocrinol Metab. ; 98(3):980-8 ; March 2013
Medium chain acyl-CoA dehydrogenase deficiency: patients have impaired oxidation of fat during exercise and L-carnitine supplementation has no effect
Consult the PubMed abstract
To read more about "Medium chain acyl-CoA dehydrogenase deficiency"

J Clin Endocrinol Metab. ; 98(4):1667-75 ; April 2013
Acute promyelocytic leukaemia: efficacy of arsenic trioxide followed by autologous haematopoietic cell transplantation for relapsed patients in a phase 2 study
Consult the PubMed abstract
To read more about "Acute promyelocytic leukemia"

Blood ; 121(16):3095-102 ; 18 April 2013
Cornelia de Lange syndrome: high rate (around 25%) of somatic mosaicism for an NIPBL mutation in a cohort of 44 reliably diagnosed individuals
Consult the PubMed abstract
To read more about "Cornelia de Lange syndrome"

Journal of Medical Genetics ; 50(5):339-44 ; May 2013
Primary biliary cirrhosis: male patient are at risk of hepatocellular carcinoma at any histological stage of PBC and should be screened for HCC from the early stages of PBC
Consult the PubMed abstract
To read more about "Primary biliary cirrhosis"

Hepatology ; 57(5):1942-9 ; May 2013
Precursor B-cell acute lymphoblastic leukaemia: a potential role for PRDM9 variations in parents on risk of acquiring genetic anomalies associated with leukaemogenesis in children
Consult the PubMed abstract
To read more about "Acute lymphoblastic leukemia"

Genome Res. ; 23(3):419-30 ; March 2013
Idiopathic neonatal cholestasis or later onset unexplained fat-soluble vitamin deficiency: patients should be screened for defects in bile acid conjugation
Consult the PubMed abstract
Gastroenterology ; 144(5):945-55 ; May 2013
Gene Therapy
Beta-thalassaemia: antisense oligonucleotides targeting TMPRSS6, a serine protease that blocks hepcidin expression, improved anaemia in mice
Consult the PubMed abstract
To read more about "Beta-thalassemia"

Journal of Clinical Investigation ; 123(4):1531-41 ; April 2013
Therapeutic Approaches
Glioblastoma: efficacy of p53 restoration therapy is improved markedly by an episodic dosing regimen
Consult the PubMed abstract
To read more about "Glioblastoma"

PNAS ; 110(16):E1480-9 ; 16 April 2013
Transmissible spongiform encephalopathies: tacrolimus and astemizole identified as antiprion agents, the latter prolonging the survival time of prion-infected mice
Consult the PubMed abstract
To read more about "Transmissible spongiform encephalopathies"

PNAS ; 110(17):7044-9 ; 23 April 2013
Acute graft versus host disease: transient blockade of Notch ligands Delta-like1/4 in the peritransplant period provided durable protection in a mouse model
Consult the PubMed abstract
To read more about "Graft versus host disease"

Journal of Clinical Investigation ; 123(4):1590-604 ; April 2013
Acquired epidermolysis bullosa: topically applied flightless I neutralizing antibodies improved healing of blistered skin in a murine model
Consult the PubMed abstract
To read more about "Acquired epidermolysis bullosa"

Journal of Clinical Investigation ; 133(4):1008-16 ; April 2013
Liver failure: silencing of the dual-specific kinase MKK4 robustly increased the regenerative capacity of hepatocytes in mouse models of acute and chronic liver failure
Consult the PubMed abstract
Cell ; 153(2):389-401 ; 11 April 2013
Acute myeloid leukaemia: administration of a candidate haematopoietic cell kinase inhibitor to model mice significantly reduced leukaemia stem cells burden
Consult the PubMed abstract
To read more about "Acute myeloid leukemia"

Sci Transl Med. ; 5(181):181ra52 ; 17 April 2013
Mucopolysaccharidosis type 2: improvement of CNS defects via continuous intrathecal enzyme replacement by osmotic pump in MPS 2 mice
Consult the PubMed abstract
To read more about "Mucopolysaccharidosis type 2"

Am J Med Genet A. ; 161(5):1036-43 ; May 2013
Pancreatic carcinoma: vaccination with ENO1 (alpha-enolase) DNA prolonged survival of genetically engineered mice with pancreatic cancer
Consult the PubMed abstract
To read more about "Pancreatic carcinoma"

Gastroenterology ; 144(5):1098-106 ; May 2013

Patient Management and Therapy

Midbrain and hindbrain malformations: advances in clinical diagnosis, imaging, and genetics
Consult the PubMed abstract
Lancet Neurology ; 12(4):381-93 ; April 2013
Amyotrophic lateral sclerosis: a review on changes in cognition and behaviour, and implications for assessment
Consult the PubMed abstract
To read more about "Amyotrophic lateral sclerosis"

Lancet Neurology ; 12(4):368-80 ; April 2013
Pheochromocytoma: pheochromocytoma crisis is not a surgical emergency according to a large retrospective cohort study and a literature review
Consult the PubMed abstract
To read more about "Hereditary pheochromocytoma-paraganglioma"

J Clin Endocrinol Metab. ; 98(2):581-91 ; February 2013
Sarcoidosis: advances in genetics may be useful to improve patient management
Consult the PubMed abstract
To read more about "Sarcoidosis"

Journal of Medical Genetics ; 50(5):290-7 ; May 2013
Epilepsy: latest developments in clinical genetic testing and new molecular genetics platforms
Consult the PubMed abstract
Journal of Medical Genetics ; 50(5):271-9 ; May 2013
Arrhythmogenic right ventricular dysplasia: a review of recent advances in genetics
Consult the PubMed abstract
To read more about "Arrhythmogenic right ventricular dysplasia"

Journal of Medical Genetics ; 50(5):280-9 ; May 2013
Rabies: neuropathogenesis, diagnosis, and management
Consult the PubMed abstract
To read more about "Rabies"

Lancet Neurology ; 12(5):498-513 ; May 2013
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical evaluation for connective tissue dysplasia should be routinely performed
Consult the PubMed abstract
To read more about "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency"

J Clin Endocrinol Metab. ; 98(2):E379-87 ; February 2013
Multiple endocrine neoplasia type 1: patients with mutations affecting the JunD interacting domain should be considered for surgical indications, genetic counselling and follow-up
Consult the PubMed abstract
To read more about "Multiple endocrine neoplasia type 1"

Human Molecular Genetics ; 22(10):1940-8 ; 15 May 2013

Orphan Drugs
Regulatory News
11 positive opinions recommending orphan designation at the April 2013 COMP meeting
The European Medicines Agency Committee for Orphan Medicinal Products (COMP) adopted eleven positive opinions issued at the April 2013 COMP meeting for the treatment of:

- Graft-versus-host disease
- B-cell acute lymphoblastic leukaemia
- Non-dystrophic myotonia
- Adrenocortical carcinoma
- 5q spinal muscular atrophy
- Adenosine deaminase-deficient severe combined immunodeficiency
- Cytomegalovirus disease in patients with impaired cell mediated immunity
- Malignant mesothelioma
- Cystic fibrosis
- Retinitis pigmentosa
- Transglutaminase-1-deficient autosomal recessive congenital ichthyosis

Political and Scientific News
Challenges and opportunities of drug repositioning
An article in Trends in Pharmacological Sciences addresses the issue of Drug repositioning which is an especially important topic to discuss for orphan drug developers. According to the author “This is is an innovation stream of pharmaceutical development that offers advantages for drug developers along with safer medicines for patients. In this article the author has provided examples of success stories of drugs that have been successfully repositioned to a new indication but also discusses the challenges that come with repositioning drugs. The author believes that a repositioned drug with proven known safety has both economic, social and ethical benefits. Along with discussing the challenges the author has provided with a revised model for effective drug repositioning.
Consult the PubMed abstract



Funding announced to develop treatment for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
The Ataxia of Charlevoix-Saguenay Foundation is offering an annual research grants for work aimed at developing treatments for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Such funding is offered regardless of where the research is being conducted and the deadline to apply is May 23, 2013. Further information and the application form can be obtained on the Foundation’s website
Funding available to investigate treatment for plexiform neurofibroma
The Neurofibromatosis Therapeutic Acceleration Program (NTAP) invite proposals for projects that help the acceleration of the development of effective treatment of plexiform neurofibromas at any time. Application deadline is June 14 2013 .
NTAP is a privately funded research program housed within Johns Hopkins University in Baltimore, Maryland who have funded several research projects that advance the knowledge of Neurofibromatosis.
For further details

NORD announces seed grants for rare disease research
NORD has announced funding opportunities in 6 areas of rare disease research. NORD has invited applicants from within the US and overseas to apply with a letter of intent by 15 May 2013. Full proposals are due by 11 September 2013. Researchers with projects in the following areas are encouraged to apply

RFPs for Pseudomyxoma Peritonei (PMP), Spring 2013
Two grants are available through NORD ($50,000/grant) for research related to Pseudomyxoma Peritonei (PMP).

RFP for Growth Failure in Children with Cardiofaciocutanous (CFC) Syndrome
Funding is available ($30,000) for research on growth failure in children with cardiofaciocutaneous (CFC) syndrome.

RFP for Glycine Encephalopathy, aka Nonketotic Hyperglycinemia, Spring 2013
Funding for research related to Glycine Encephalopathy, aka Nonketotic Hyperglyinemia, is available through NORD's Research Seed Grant Program ($34,000).

RFP for Adult Primary Lateral Sclerosis (PLS)
Funding is available ($30,000) for research on Primary Lateral Sclerosis (PLS).

RFP Available for Research Related to Dubowitz Syndrome
Funding is available ($30,000) for research on Dubowitz Syndrome
For further details

Jerome Lejeune Foundation announces Prix International Sisley-Jérôme Lejeune
Prix International Sisley-Jérôme Lejeune awards € 30,000 to researchers who work towards finding therapies for genetic diseases that lead to intellectual disability. The deadline for submissions is 12 May 2013.
For further in formation on Prix International Sisley-Jérôme Lejeune

Call for Abstracts from researchers studying Rare Diseases for publication in the Journal of General Internal Medicine
The Effective Health Care Program within the US Department of Health and Human Services’ Agency for Healthcare Research and Quality is accepting abstract submissions for a journal supplement on research methods for evaluating patient health outcomes in rare diseases. The proposed supplement will focus on innovative patient-centered health outcomes research methodology and its application to rare diseases or drugs/devices used to treat such patients. Abstract submissions are due by May 31, 2013.
For Further Information


Partnersearch, Job Opportunities
Position for Bioinformatics Group at The Institute of Genetic Diseases Imagine
The Institute of Genetic diseases at Necker Enfants-Malades Hospital, in Paris invites applications from the area of bioinformatics, computational biology, and/or statistical genetics. Imagine, is an multidisciplinary research center, supported by a rare disease Foundation. Application deadline is 15 May.
Learn more about the Institute
Learn more about the position


Courses & Educational Initiatives
International Summer School “Clinical practice guidelines on rare diseases”
Date: 8-12 July, 2013
Venue: Rome, Italy

Istituto Superiore di Sanità is inviting applications from participants who would like to learn more about development process of clinical practice guidelines.
The following topics will be covered:
o Identifying key clinical issues to be included (scope)
o Developing review questions using PICO and planning the systematic review
o Identifying evidence: formulating, executing and documenting a search strategy
o Assessing the quality of relevant studies, summarizing and interpreting the body of evidence to make recommendations
o Obtaining formal consensus in the absence of evidence (Delphi-like method)
o Appraising synthesis documents: guidelines and systematic reviews
The course format consists of brief presentations followed by individual or small group exercises.
This course is free of charge and application/registration is currently open. Please, feel free to circulate this information to those who may have an interest in attending.
For further details

The 1st radiz Rare Diseases Summer School
This course has been announced for 4-6th July 2013 in Zurich, Switzerland and will focus on a wide variety of subjects in the area of rare diseases, from disease mechanisms and animal models, to improving diagnoses, to novel therapeutics. These will be presented in the form of lectures by international experts on rare diseases. Please apply by sending a short CV, a letter of motivation including a brief description of your project or research interest, and one letter of recommendation to saskia.karg@kispi.uzh.ch. For further details

What's on Where?

7th Alstrom Syndrome International Family Conference and Scientific Symposium
Date: 9-13 May 2013
Venue: Massachusetts, USA

Medical professionals and scientists will hold Symposia on Thursday, 9 May and Saturday 11 May.
For further details

18th Update in the management of gaucher disease and other Lysosomal disorders
Date: 13-16 May 2013
Venue: Zaragoza, Spain

The goal of this programme is to provide participants with an update on diagnosis, treatment and management of Gaucher disease, Niemann-Pick C and other lysosomal disorders. This course is directed to physicians involved in diagnosis and treatment of lysosomal diseases.
Further Details

Autoinflammation 2013: 7th International Congress of the International Society of Systemic Auto-Inflammatory Diseases
Date: 22- 26 May 2013
Venue: Lausanne, Switzerland

The meeting will offer a unique opportunity to gather experts from all over the world to discuss the latest scientific and clinical issues on different topics, including the challenges of the new treatments for autoinflammatory diseases such as familial Mediterranean fever; new monogenic autoinflammatory diseases; systemic-onset JIA; Behçet; granulomatous diseases; amyloidosis; and other conditions.
For further details

4th International DSD (Disorders of Sex Development) Symposium
Date: 7-9 June 2013
Venue: Glasgow, UK

This symposium should be of interest to health care staff, clinical and basic scientists and parent & patient support groups. Plenary Sessions planned include: Priorities for the Future, Drug-based Therapeutic Interventions, Care & Communication, Navigating the Information Highway, Management of the Retained Gonad.
For further details

European Human Genetics Conference 2013
Date: 8-11 June 2013
Venue: Paris, France

This international conference organized by the European Society of Human Genetics focuses on the current and future advancements in human and medical genetics.
For further details

12th European Symposium on Congenital Anomalies
Date: 12-14 June 2013
Venue: Zagreb, Croatia

Topics include 50 years after thalidomide therapy, Childhood morbidity and mortality due to congenital anomalies, Medication in pregnancy, Prevention of congenital anomalies, Prenatal diagnosis, Preconceptional and prenatal care, Environmental risks, Outcomes of children with a congenital anomaly, Public health policies, Genetics of congenital anomalies, Health care for children with congenital anomalies
For further details

10th HHT Scientific Conference
Date: 12-15 June 2013
Venue: Cork, Ireland

HHT is a genetic disorder that causes abnormalities of blood vessels. The conference will include presentations on basic research on HHT to clinical research, drug development as well as policy issues.
Learn more

World Orphan Drug Congress Asia
Date: 18 June 2013
Venue: Singapore

This commercial one-day event will bring together orphan drug manufacturers and developers to expedite orphan drugs for patients.
For further details

6th International Conference on Children's Bone Health
Date: 22-25 June 2013
Venue: Rotterdam, Netherlands

The conference is to try to get a better understanding in healthy and disease states of bone development by discussing molecular pathways as well clinical characteristics.
For further details

Cardio-Facio-Cutaneous (CFC) meeting: strategies to study RASopathies and other rare diseases
Date: 24 June 2013
Venue: Haifa, Israel

This meeting will review the RAS pathway related developmental anomalies (RASopathies) with a focus on the CFC molecular and cellular mechanism of action as well as different therapeutic strategies for rare diseases.
For further details

Fifth BHD Symposium and Second HLRCC Symposium
Date: 28-29 June 2013
Venue: Paris, France

This conference will be an excellent opportunity for stakeholders of Birt-Hogg-Dubé Syndrome to participate and network. The conference will comprise of invited lectures by worldwide experts, followed by panel discussion, and will also include a poster exhibition
For further details

9th European Cytogenetics Conference
Date: 29 June - 02 July 2013
Venue: Dublin, Ireland

An opportunity for cytogeneticists to come together to discuss developments ranging from applications in prenatal or cancer diagnosis to chromosome biology in epigenetics and evolution.
For further details

LeukoTreat Final Public Conference
Date: 3-6 July 2013
Venue: Berlin, Germany

The LeukoTreat project funded by the European Commission under the 7th Framework Programme for Research and Development aimed at developing therapeutic strategies for leukodystrophy (LD) as well as more common white matter disorders and neurodegenerative diseases. In this final conference the results of the project will be presented and discussed.
For further details

8th International Prader-Willi Syndrome Conference
Date: 17-21 July 2013
Venue: Cambridge, UK

An opportunity for all involved worldwide in research, working or living with people with PWS to present current research and explore best practice in clinical and day to day management of PWS.
For further details

International Symposium on Urea Cycle Disorders (UCD)
Date: 1-2 September 2013
Venue: Barcelona, Spain

The symposium will focus on recent advances in UCD clinical and translational research which provide insights into the pathophysiology of these disorders. These advances will form the basis for the development of novel therapeutic approaches for UCDs that aim at decreasing mortality and preventing the effects of hyperammonemia on brain function. The satellite symposium will provide a forum for international researchers, clinicians, trainees and patients’ families to share and discuss research in UCD. This meeting will be the first formal joint meeting between the Urea Cycle Disorders Consortium (UCDC) and the European-Registry and Network for Intoxication Type Metabolic Disease (E-IMD).
For further details

Orphan Drugs Summit 2013
Date: 11-13 September 2013
Venue: Copenhagen, Denmark

This commercial event will highlight several burning topics revolving market authorisation of Orphan Medicinal Products such as market access, regulatory framework, clinical trial development as well as financing
For further details

2nd Conference of 'EB-CLINET - Clinical Network of EB Centres and Experts'
Date: 17-18 September 2013
Venue: Salzburg, Austria

The conference will present and discuss the work packages initiated during the 2012 EB clinet meeting.
For further details

Mitochondrial Disease: Translating biology into new treatments
Date: 2-4 October 2013
Venue: Cambridge, UK

This is a brand new conference that will discuss mitochondrial medicine. During this interactive conference several experts will speak about translational mitochondrial medicine. Abstracts are due by 16 July 2013 and the registration deadline is on 20 August 2013
Learn more

The 10th Balkan Congress of Human Genetics and 2nd Alps Adria Meeting on Human Genetics (AABC2013)
Date: 10-12 October 2013
Venue: Bled, Slovenia

This congress will deal with several issues pertaining rare genetic disorders, with sessions focusing exclusively on rare human disease.
For further details

Orphan Drugs and Rare Diseases
Date: 14-15 October 2013
Venue: London, UK

This commercial orphan drugs conference focuses on the current rare diseases drug development landscape where world leading expert speaking faculty will highlight cutting edge research via case studies taking place in previously untreatable patients with highly rare diseases, current regulatory policies involving the FDA & EMA, new drug discoveries and partnerships in clinical trials and drug development with patient groups.
For further details

Orphan Drug & Rare Disease Seminar “Accelerating access to therapeutic innovation”
Date: 17-18 October 2013
Venue: Marseille; France

This event, jointly organised by Eudipharm, F-Crin and OrphanDev, will aim to address issues that to help fill the current discrepancies in translational research for rare diseases and creating awareness of clinical research sectors.
For further details

3rd European Rett Syndrome Conference Maastricht, “Research Update & Preventive Management”
Date: 17-19 October 2013
Venue: Maastricht, The Netherlands

This conference aims to gather renowned researchers and clinicians working in the area of Rett Syndrome, to encourage interdisciplinary international cooperation. The conference also aims to provide stakeholders with the latest information on treatment of symptoms as well as preventative manangement.
For further details

Thalassemia International Federation World Congress
Date: 19-23 October 2013
Venue: Abu Dhabi, United Arab Emirates

Topics for this conference includes “all aspects of prevention, management and care of thalassemia and sickle cell disease and a one-day patient programme”.
For further details

First International Primary Immunodeficiencies Congress (IPIC)
Date: 7-8 November 2013
Venue: Estoril, Portugal
The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the First International Primary Immunodeficiencies Congress (IPIC), a congress for all stakeholders with an interest in primary immunodeficiencies (PIDs). IPIC will provide a two-day programme focusing on clinical developments including PIDs pathogenesis, treatment, management of complications and more. Access to diagnosis and care, SCID newborn screening and other key world developments will also be addressed.
For further details

World Orphan Drug Congress 2013
Date: 14 November 2013
Venue: Geneva, Switzerland

This commercial conference and exhibition bringing together buyers, sellers and key influencers from across the orphan and rare disease industry. Having welcomed over 1000 orphan and rare disease stakeholders in only its 3 year history, the event in Europe’s logical choice for Biotech and Pharma orphan drug players who want to meet Rare Disease Networks, Patient Groups, COMP Members, HTA Experts, Regulators and Payers.
For Further Information

XIIIth International Congress on Neuromuscular Diseases (ICNMD)
Date: 5-10 July 2014
Venue: Nice, France

ICNMD is regular meeting of the Research Group on Neuromuscular Diseases-World Federation of Neurology that takes place every 4 years for the past 50 years. This conference will present a unique opportunity for sharing scientific advances by those involved in the fields of improving care, understanding disease pathogenesis, and developing innovative treatments in muscle, neuromuscular junction, peripheral neuropathies and motor neuron diseases.
For further details

14th International Congress on Neuronal Ceroid Lipofuscinoses (Batten Disease)
Date: 22-25 October 2014
Venue: Córdoba, Argentina

Batten disease is a common name for a group of rare, neurodegenerative genetic disorder affecting approximately 1 in 30,000 individuals. There is presently no known cure for Batten disease.


Media, Press & Publications
The Orphanet Journal of Rare Diseases thanks its reviewers

The Orphanet Journal of Rare Diseases would like to thank all the reviewers (List of contributing reviewers) who have contributed to the journal in volume 7 (2012). Reviewers' role is vital to ensure quality to reported scientific facts. Usually they are the best experts in their field and it is why they are requested to give their opinion. It means that they are all over busy and do their reviews on their spare time, often at night and on week-ends. The rare disease community should know who they are. It is why we enlight their contribution.
Link to Orphanet Journal of Rare Diseases

Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence
Consult the PubMed abstract
Lancet Neurology 2013 Apr;12(4):406-14

16th International Vasculitis & ANCA Workshop
The 16th International Vasculitis & ANCA Workshop took place on 14-17 April 2013 in Paris. The lectures texts, abstracts, and posters presented in this congress are published in a special issue of La Presse Médicale appearing in April 2013.
Consult the table of contents
La Presse Médicale 2013 Apr;42(4Pt2):491-790


Orphanews International, the newsletter of the European Union Committee of Experts on Rare Diseases
Orphanews International is supported by the European Commission's DG SANCO (EUCERD Joint Action N° 2011-22-01)
and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Ségolène Aymé
Editor: Divya Unni
Contact Us
Editorial Board: Ségolène Aymé, Kate Bushby, Catherine Berens, Barbara Cagniard, Virginie Hivert, Helena Kaariainen, Odile Kremp, Yann Le Cam, Jordi Llinares-Garcia, Antoni Montserrat, Catherine Pouzat, Charlotte Rodwell, Jaroslaw Waligora

EUCERD Country Representatives: Helmut Hintner (Austria), Pol Gerits (Belgium), Rumen Stefanov (Bulgaria), Ivo Baric (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek Jr. (Czech Republic), Marianne Jespersen (Denmark), Inna Vabamae (Estonia), Helena Kaariainen (Finland), Alain Garcia (France), Birgit Schnieders (Germany), Christos Katamis (Greece), Zsuzsanna Lengyel (Hungary), Thor Thorarinsson (Iceland) , John Devlin (Ireland), Annick Raas-Rotshild (Israel), Bruno Dallapiccola (Italy), Antra Valdmane (Latvia), Romalda Baranauskiene (Lithuania) , Yolande Wagener (Luxembourg), Miriam Dalmas (Malta), Jolande Huizer (Netherlands), Stein Are Aksnes (Norway), Jacek Gralinski (Poland), Alexandre Diniz (Portugal), Emilia Severin (Romania), Borut Peterlin (Slovenia), Frantisek Cisareik (Slovak Republic), Isabel Pena-Rey (Spain), To be nominated (Sweden) , Sabina Gallati (Switzerland), Edmund Jessop (UK)
EUCERD ECDC Representative: Andrew Amato
EUCERD Patient Organisation Representatives: Dorica Dan, Yann Le Cam, Christel Nourissier, Bianca Pizzera
EUCERD Pharmaceutical Industry Representatives: Wills Hughes-Wilson, Kevin William Loth, Samantha Parker, Barbara Valenta
EUCERD Rare Disease Projects under Health Programmes Representatives: Ségolène Aymé, Jean Donadieu, Dian Donnai, Laura Fregonese, Ester Garne, Domenica Taruscio, Joan Luis Vives Corrons, Thomas Wagner, Susan Webb
EUCERD Rare Diseases Research Projects under Framework Programmes for Research and Technological Development Representatives: Jean-Yves Blay, Kate Bushby, Marc de Baets, Olaf Hiort, Sophie Koutouzov, Gerard Wagemaker
EUCERD European Commission Participants: Catherine Berens, Iiro Eerola, Jordi Llinares-Garcia (EMA), Georgios Margetidis, Jaroslaw Waligora, Antoni Montserrat Moliner, Michael Huebel, Bruno Sepodes (EMA-COMP)

Orphanet Partner Country Representatives: Tamara F. Sarkisian (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Ana Stavljenic-Rukavina (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Riitta Salonen (Finland), Joerg Schmidtke (Germany), Helen Michelakakis (Greece), András Becskeházi (Hungary), Andrew Green (Ireland), Lina Basel (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Viadutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Jorge Sequeiros (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Borut Peterlin (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Ugur Ozbek (Turkey), Dian Donnai (UK)
For more information on the European Union Committee of Experts on Rare Diseases
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