30 October 2016 print
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France prepares its Third National Plan for Rare Diseases

The second French National Plan for Rare diseases 2011-2014 was extended by two years until the end of 2016 to allow in particular its evaluation by two external bodies: HCSP- Haut Comité de la Santé Publique (HCSP) and the HCERES- Haut Conseil de l’Evaluation de la Recherche et de l’Enseignement Supérieur (HCERES). After the publication of the reports, the announcement was made by the French Minister of Social Affairs and Health, Marisol Touraine, of the decision to launch a third plan (Read in OrphaNews France).

Two personalities were mandated by both the Ministry of Social Affairs and Health and the Ministry of Higher Education and Research to prepare the roadmap for this 3rd Plan: Prof. Sylvie Odent, geneticist and coordinator of a centre of expertise for rare diseases at Rennes University Hospital, and Prof. Yves Lévy, President of the Research Alliance Aviesan and CEO of INSERM in order to comply with health and research attachments of rare diseases.

Prof Sylvie Odent is a pediatrician and geneticist, professor of genetics at the University of Rennes and chief of the Medical Genetics Service of the Rennes University Hospital. She is the coordinator of the rare disease reference centre for developmental anomalies and malformation syndromes, and the president of the Francophone association of clinical geneticists (AFGC). Prof. Yves Lévy is a specialist in immunology, a physician who is also a researcher and academic. He has worked successively in several INSERM research units since 1999. He was the Vice-Dean of the Faculty of Medicine, Paris-Est Créteil University (UPEC). He subsequently became a special advisor to the Minister for Higher Education and Research. He has been the CEO of INSERM since 2014.

Prof. Lévy and Prof. Odent, together with ministries of health and research representatives, presented the preparatory work on 14th October at a multi-stakeholder committee. This committee has also been assigned with the follow up of the preparation process.

Representatives from patient organisations, the healthcare sector, research organisations, national insurance body, industry and information, including Orphanet, as well as the respective ministries representatives discussed on the main themes to be further developed by ad-hoc working groups. A steering committee will be constituted in the coming days to ensure the overall coherence and integration of the recommendations made by working groups.

With this Third Plan, France aims to build on the lessons learned from the previous ones, to consolidate their achievements, but also to go further towards a better integration between health and research, between healthcare and social care, and with European and international policies and initiatives, in order to promote equity to access to diagnosis, global care and innovation for patients.

Save the date for the third IRDiRC conference in Paris, France
The third conference of the International Rare Diseases Research Consortium (IRDiRC) will take place February 8-9, 2017 in Paris, France at the conference center of Université Pierre et Marie Curie (UPMC) Jussieu.

Five years have passed since the initial launch of IRDiRC in 2011 and considerable advances have been made in rare diseases research. This conference presents a unique opportunity to reflect upon this progress, confront barriers, and together, form new collaborations to take on challenges posed by rare diseases. Past conferences were held in Dublin, Ireland and Shenzhen, China.

All stakeholders – investigators, policy makers, opinion leaders, critical thinkers, young researchers, patient advocates and industry alike – active in the area of rare diseases from across the globe are invited to join us to celebrate achievements in the field, identify future milestones and goals, and work toward bringing diagnoses and therapies to all rare disease patients.

Registration for this conference will open shortly. Visit the IRDiRC conference website for more details


EU Policy News
EMA and FDA advance their collaboration by announcing a new cluster on rare diseases
Continuing their successful collaboration, the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) have announced the setting up of a “new ‘cluster’ on rare diseases to share experiences and best practices on each other’s regulatory approach to the development of medicines for these diseases.

While existing EMA/FDA ‘cluster on orphan medicinal products’, while continue to share information and collaborate on orphan designation as well as exclusivity, this cluster include other value-added features “to expand and reinforce international collaboration”.

According to a press release from EMA, “the agencies will exchange information (in a confidential forum) on various aspects of the development and scientific evaluation of medicines for rare diseases. These include topics such as:

• the design of clinical trials in small populations and the use of statistical analysis methods;
• the selection and validation of trial endpoints, i.e. target outcomes of a trial;
• preclinical evidence to support development programmes;
• the design of postmarketing studies, in particular in the context of early access mechanisms such as EMA’s conditional marketing authorisation and FDA’s accelerated approval;
• risk management strategies for longterm safety issues with medicines for rare diseases.”

For further information

EMA appeals interim decision to block release of clinical study report of an orphan medication
The President of the General Court of the European Union (EU), has passed an interim order to suspend the release of documents of a clinical study report for an orphan medication - Translarna, a centrally authorised medicine for the treatment of Duchenne muscular dystrophy. Also blocked is the release of toxicity studies for a veterinary medicine, Bravecto.

The European Medicines Agency (EMA) has appealed these interim orders as the release of documents requested by third parties comes under Regulation (EC) no. 1049/2001, the so called “Transparency Regulation”.

While the companies want to shield, what they believe is commercially sensitive information, EMA believes that they are challenging decisions made in accordance with the transparency regulation.

Developing the transparency regulation, was an extensive and thorough process which involved, stakeholders from academia, patient and healthcare professional organisations and the pharmaceutical industry, as well as the European Ombudsman and the European Data Protection Supervisor. While there were previous challenges to the release of documents, EMA welcomes this opportunity to receive clarity from the court on EMA’s approach.
For further information


National & International Policy Developments
Other European news
Rare, ultra-rare and orphan patients: a new way to stop the diagnostic odyssey at Bambino Gesù Children’s Hospital
Bambino Gesù Children’s Hospital (OPBG) is the largest paediatric hospital in Italy and one of the most prestigious in Europe. It is a referral centre for all paediatric specialties and is recognized at a national and international level. During recent years, OPBG has pioneered new genomic diagnostic tools with excellent results in terms of gene discovery, early diagnosis and patient management. In particular, the Genetics and Rare Disease Unit is daily involved in diagnosis, management and care of rare, ultra-rare and orphan patients on a case-to-case approach based on a multidisciplinary team. This activity and the strong cooperation with patient organizations have driven the need to create a dedicated “undiagnosed clinic”. This outpatient clinic is the first service for undiagnosed children in Italy. The clinic is helping patients and families, both with a web-based (telehealth) and a frontal approach, to solve the unsolved. Based on the individual patient’s clinical presentation and needs, a case manager is designated, in charge of coordinating a multidisciplinary team, with the goal of reaching the diagnosis and improving the management. This “undiagnosed clinic” is benefitting from a well-tried diagnostic and research system and the OPBG partnership in several developing ERNs. This activity is accomplished in collaboration with Hopen Foundation, the national association for genetic disorder without any name.
Read more (in Italian)

Other International News
HHS takes steps to provide more information about clinical trials to the public
The United States Department of Health and Human Services has issued specific requirements for registering clinical trials and submitting summary results information to
ClinicalTrials.gov. They have also provided a list of potential legal consequences in cases of non-compliance. The new rule expands the legal requirements for submitting registration and results information for clinical trials involving U.S. Food and Drug Administration-regulated drug, biological and device products. The National Institutes of Health has also issued a policy for registering and submitting summary results information to ClinicalTrials.gov for all NIH-funded trials.

Important elements of the final rule include:

• "Providing a checklist for evaluating which clinical trials are subject to the regulations and who is responsible for submitting required information;
• Expanding the scope of trials for which summary results information must be submitted to include trials involving FDA-regulated products that have not yet been approved, licensed, or cleared by the FDA;
• Requiring additional registration and summary results information data elements to be submitted to ClinicalTrials.gov, including the race and ethnicity of trial participants, if collected, and the full protocol;
• Requiring additional types of adverse event information"

For further information

Lack of access to orphan drugs in India
To raise prices of orphan drugs or to keep it low – that is the question for rare disease patients in India that are facing an acute lack of access to orphan drugs. Two articles have pointed out to the lack of available drugs for rare disease patients in India due to seemingly analogous reasons - the lack of a plan catering to rare disease patients in India.

The Wire has published an article that describes the desperation of a thallasemia patient in India, due to the sudden irregularity and acute shortage of Desferal – a drug produced by Novartis - in various parts of India. Furthermore the article points out the lack of an orphan drug policy in a country with more than 70 million rare disease patients out of which 100,000 have thalassemia. According the article, there may be a disinterest in getting a rare disease policy as many of these patients may not be able to afford orphan drugs. Desferal is affordable only to around 5% of the thalassemia population. This is an injectable version of the iron chelator used by patients suffering from thalassemia – the price of which has risen 4 times since the 1980s, according to the article. The cheaper version of the drug is an oral chelator which has far more side-effects and even though generic versions of Desferal is available in United States, it is unavailable in India. According to Novartis, the drug is not produced locally and they are trying to make sure no patient goes without the medication.

Another article published in the Hindustan Times has revealed that manufacturers in India have stopped producing Penicillamine – a drug necessary to treat Wilsons Disease. Copper accumulation, observed in patients with Wilson’s disease can cause severe and sometimes fatal neuropsychiatric and hepatic problems. This is controlled by the administration of Penicillamine which reduces copper absorption or removes the excess copper from the body through urine. According to the article, the decision to stop production of the drug comes after the Central Government in India announced a sharp price reduction of its price. The drug is manufactured by local as well as foreign (United States) pharmaceutical companies. The article quotes Professor Shyamol Das, the head of the neurology department of Bangur Institute of Neurology and national president of Movement Disorder Society of India, who says that “Penicillamine has vanished from the market landing patients in deep trouble. Both patients and doctors, mainly neurologists and hepatologists, are looking for the medicine for the past few months. But no one in the drug industry has given us a positive clue about when the medicine will be available in the market.”

Genome services in India: much left to be desires
Nature India has published an article on the lack of genomic screening and testing services in India. In India consanguinity and endogamy are common, leading to a high risk of genetic diseases. According to the article, currently, only 1 state in India - Kerala, has a newborn screening programme, with a couple other states expressing interest. Due to this, most genetic diseases remain undiagnosed at birth in India. The article also points out the lack of geneticists as well as the absence of government controlled diagnostic centres has compounded the problem. Additionally, the growth of private diagnostic centres which are not regulated adequately by the Indian government poses a great risk. These centres provide information that is not trustworthy and unreliable which only increases the diagnostic odyssey faced by many patients and their caregivers. According to the author, “(e)xperts call for universal access to reliable genetic diagnostics in India and emphasise that this will only be achieved if doctors, the government and the private sector chose to step up together.”
Guidance Documents and Recommendations
Neuronal ceroid lipofuscinosis: guidelines for diagnosis
Consult the Pubmed abstract
To read more about "Neuronal ceroid lipofuscinosis"

Mol Genet Metab. ; 119(1-2):160-7 ; September 2016
Screening and Testing
Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics
The Americal College of Medical Genetics and Genomics have updated their position statement on Noninvasive prenatal screening using cell-free DNA (NIPS). This statement has been published in Genetics in Medicine. This statement comes on the heels of new evidence of NIPS being capable of “replace(ing) conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9–10 weeks, and for patients who are not significantly obese.”
Consult the Pubmed abstract


Ethical, Legal & Social Issues
FDA approves Duchenne Muscular Dystrophy drug after pressure from patient groups
After contentious months, the Food and Drug Administration (FDA) recently approved the first drug to treat Duchenne muscular dystrophy (DMD). According to some sources this is an “example of the growing power that patients and their advocates wield over the federal government’s evaluation of drugs.’ Large and impassioned groups of patients, including boys in wheelchairs, and their advocates, weighed in. The muscular dystrophy community is well organised and has lobbied for years to win approval for the drug, getting members of Congress to write letters to the agency. A decision on the drug had been delayed for months.

The drug, eteplirsen, applicable to around 13% of the patients, uses exon skipping technology to partially correct the genetic defect, by allowing muscle cells to produce a truncated form of the protein lacking by these patients – dystrophin.

A group of independent experts convened by the FDA voted against the approval of the drug. According to them, there wasn’t sufficient evidence to prove its effectiveness. Although the FDA wanted the manufacturer Sarepta to perform a larger study with a placebo control, the company refused citing that it would be unethical and impractical due to its hints of effectiveness, which would be difficult to enroll children in the placebo group. They had therefore used historical data for comparison, which was considered inadequate by the experts.

The decision on the drug was delayed for months. However, bowing to the pressure from a well-organised DMD patient groups, the FDA had to approve the drug. The patient groups lobbied intensely to get this approval by getting members of congress to write letters to the agency. The final approval is considered a contentious decision by some and encouraging by others.
For further information
Read about this topic in The Lancet


Orphanet News
Orphanet included as a reference in the Italian decree for prescription appropriateness
The Italian Health Ministry included Orphanet as a reference in the new version (July 2016) of the Ministerial Decree of December 09, 2015, on Prescription Appropriateness (Italian title of the Decree: “Condizioni di erogabilità e indicazioni di appropriatezza prescription⠇va delle prestazioni di assistenza ambulatoriale erogabili nell'ambito del Servizio sanitario nazionale”). Consult the full document The Decree sets up specific conditionons for laboratories performing genetic tests in Italy (“Condizioni di erogabilità”, as reported in “Allegato 1” of the Decree). Consult “Allegato 1”

In particular, with regard to genetic tests, the document contains the following reference to Orphanet database con valore diagnostico” (In order to identify single genes, refer to genes reported in the Orphanet database with diagnostic value).: “Per l'individuazione dei singoli geni, si fa riferimento a quelli riportati nella Banca dati Orphanet.

This reference to Orphanet into the Italian legal framework marks an important milestone in its consolidation as a legitimate source of information on rare diseases in Italy.

New Syndromes

Intellectual disability and congenital malformations caused by de novo mutations in SON
In three articles, an intellectual disability syndrome with congenital malformations including brain anomalies was reported. This syndrome is caused by de novo mutations in SON.
Consult the Pubmed abstracts

Am J Hum Genet. ; 99(3):711-9; 720-7 ; September 2016
Am J Med Genet A. ; 170(10):2587-90 ; October 2016
Recessive syndrome of intellectual disability, moderate overgrowth, and renal dysplasia predisposing to Wilms tumour caused by a mutation in FIBP gene
The authors identified the genetic aetiology and the pathogenetic mechanism underlying a rare autosomal recessive overgrowth syndrome in three affected siblings. The overgrowth phenotype in the patients was accompanied by developmental delay, learning disabilities, and variable congenital abnormalities. Findings provided convincing evidence implicating FIBP aberrations in this syndrome and expanded the associated phenotypes to include possible Wilms tumour predisposition.
Consult the Pubmed abstract

Am J Med Genet A. ; 170(8):2111-8 ; August 2016
Autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive delay due to GNB5 mutations
The authors reported mutations in GNB5 that were associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. They observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype.
Consult the Pubmed abstract

Am J Hum Genet. ; 99(3):704-10 ; September 2016
Novel 4q25 proximal deletion syndrome involving PITX2 gene
A de novo 4q25 deletion, proximal to PITX2 gene, has previously been reported once in an adult patient. The patient did not have Axenfeld-Rieger anomaly, but instead had intellectual disability and a complex behavioural phenotype with withdrawn, stereotypic, and ritualistic behaviour. Array comparative genome hybridisation demonstrated a smaller, overlapping 4q25 deletion in a 2-year-old patient and his mother, both having significant phenotypic overlap with the initially reported patient. All 3 patients had distinct facial features (including mild hypotelorism and subtle mandibular asymmetry), developmental delay, and complex behavioural difficulties.
Consult the Pubmed abstract

Mol Syndromol. ; 7(3):138-43 ; July 2016
Neurodevelopmental disorder in six unrelated females associated with variants in HNRNPH2 on the X chromosome
Via whole-exome sequencing, the authors identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo deleterious variants in HNRNPH2, a gene located on the X chromosome. Many of the females also had seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features.
Consult the Pubmed abstract

Am J Hum Genet. ; 99(3):728-34 ; September 2016
Childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy linked to loss-of-function variants in SQSTM1
Using exome sequencing, the authors identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterised by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline.
Consult the Pubmed abstract

Am J Hum Genet. ; 99(3):735-43 ; September 2016
Intrauterine growth restriction and neonatal liver failure associated with mutations in TFAM in two siblings
Through clinical exome sequencing, the authors identified a homozygous missense variant TFAM segregating in a consanguineous kindred of Colombian-Basque descent in which two siblings presented with intrauterine growth restriction, elevated transaminases, conjugated hyperbilirubinemia and hypoglycemia with progression to liver failure and death in early infancy. Results of the liver biopsy in the proband revealed cirrhosis, micro- and macrovesicular steatosis, cholestasis and mitochondrial pleomorphism. Electron microscopy of muscle revealed abnormal mitochondrial morphology and distribution while enzyme histochemistry was underwhelming.
Consult the Pubmed abstract

Mol Genet Metab. ; 119(1-2):91-9 ; September 2016
Hydranencephaly, diaphragmatic hernia and postnatal lethality linked to a homozygous null mutation in PLAT in two children
The authors described a consanguineous family with two children who died shortly after birth due to complications related to severe hydranencephaly and diaphragmatic hernia. A combined exome/autozygome analysis was carried out with informed consent. A homozygous null mutation in PLAT was identified in patient cells.
Consult the Pubmed abstract

Hum Genet. ; 135(10):1209-11 ; October 2016
A mitochondrial disease characterised by sudden unexpected cardiac arrest in infancy caused by biallelic PPA2 mutations
In a first article, the authors reported seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family.
In a second article, the authors used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in PPA2 that were associated with mitochondrial disease. These individuals showed a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms included seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life.
Consult the Pubmed abstracts

Am J Hum Genet. ; 99(3):666-73; 674-82 ; September 2016
Novel type of Smith-Magenis syndrome with evident peripheral neuropathy due to non-recurrent PMP22-RAI1 contiguous gene deletions
The authors reported molecular and clinical characterisations of six subjects with the reciprocal phenomenon of deletions spanning both genes, PMP22-RAI1. Systematic clinical studies revealed features consistent with Smith-Magenis syndrome, including features of intellectual disability, speech and gross motor delays, behavioural problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy.
Consult the Pubmed abstract

Hum Genet. ; 135(10):1161-74 ; October 2016

New Genes

Noonan syndrome-like disorder with loose anagen hair caused by recurrent de novo missense mutations in PPP1CB in four patients
Consult the Pubmed abstract
To read more about "Noonan syndrome-like disorder with loose anagen hair"

Am J Med Genet A. ; 170(9):2237-47 ; September 2016
Severe infantile-onset encephalopathy associated with biallelic variants in UBA5
Consult the Pubmed abstracts
To read more about "Undetermined early-onset epileptic encephalopathy"

Am J Hum Genet. ; 99(3):683-94; 695-703 ; September 2016
Hypothalamic hamartomas with gelastic seizures due to somatic mutations in PRKACA, GLI3, SHH, IHH, SMO, CREBBP and GLI2
Consult the Pubmed abstract
To read more about "Hypothalamic hamartomas with gelastic seizures"

Am J Hum Genet. ; 99(2):423-9 ; August 2016
Craniosynostosis linked to mutations in CDC45
Consult the Pubmed abstract
To read more about "Craniosynostosis"

Am J Hum Genet. ; 99(1):125-38 ; July 2016
Isolated complex I deficiency caused by mutations in TMEM126B
Consult the Pubmed abstracts
To read more about "Isolated complex I deficiency"

Am J Hum Genet. ; 99(1):208-16; 217-27 ; July 2016
X-linked osteogenesis imperfecta linked to mutations in MBTPS2
Consult the Pubmed abstract
Nat Commun. ; 7:11920 ; July 2016
Primary intraosseous venous malformation caused by loss-of-function mutations in ELMO2 in five families
Consult the Pubmed abstract
To read more about "Primary intraosseous venous malformation"

Am J Hum Genet. ; 99(2):299-317 ; August 2016
Presynaptic congenital myasthenic syndrome with episodic apnea due to compound heterozygous and homozygous mutations in SLC5A7 in six unrelated families
Consult the Pubmed abstract
To read more about "Presynaptic congenital myasthenic syndromes"

Am J Hum Genet. ; 99(3):753-61 ; September 2016
Familial clubfoot with or without associated lower limb anomalies due to missense mutations in FLNB
Consult the Pubmed abstract
To read more about "Familial clubfoot with or without associated lower limb anomalies"

Hum Genet. ; 135(10):1181-9 ; October 2016
Exfoliative ichthyosis linked to loss-of-function mutations in SERPINB8
Consult the Pubmed abstract
To read more about "Exfoliative ichthyosis"

Am J Hum Genet. ; 99(2):430-6 ; August 2016
Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1
Consult the Pubmed abstract
To read more about "Retinitis pigmentosa"

Am J Hum Genet. ; 99(2):470-80 ; August 2016
Congenital diaphragmatic hernia due to de novo frameshift mutation in NR2F2
Consult the Pubmed abstract
To read more about "Congenital diaphragmatic hernia"

Am J Med Genet A. ; 170(9):2457-61 ; September 2016
Familial isolated dilated cardiomyopathy linked to de novo RRAGC mutation
Consult the Pubmed abstract
To read more about "Familial isolated dilated cardiomyopathy"

Hum Genet. ; 135(8):909-17 ; August 2016
Cardiospondylocarpofacial syndrome associated with heterozygous mutations in MAP3K7 in six individuals from four families
Consult the Pubmed abstract
To read more about "Cardiospondylocarpofacial syndrome"

Am J Hum Genet. ; 99(2):407-13 ; August 2016
Frontometaphyseal dysplasia caused by mutations in MAP3K7
Consult the Pubmed abstract
To read more about "Frontometaphyseal dysplasia"

Am J Hum Genet. ; 99(2):392-406 ; August 2016
Acinar dysplasia of the lungs due to mutations in TBX4
Consult the Pubmed abstract
Am J Med Genet A. ; 170(9):2440-4 ; September 2016
Familial adenomatous polyposis linked to compound heterozygous loss-of-function germline mutations in MSH3 in two unrelated individuals
Consult the Pubmed abstract
To read more about "Familial adenomatous polyposis"

Am J Hum Genet. ; 99(2):337-51 ; August 2016
Tufted angioma and kaposiform haemangioendothelioma caused by GNA14 somatic mutations
Consult the Pubmed abstract
To read more about "Kaposiform hemangioendothelioma"
To read more about "Tufted angioma"

Am J Hum Genet. ; 99(2):443-50 ; August 2016
Cystic fibrosis: IL8 gene as a germline modifier
Consult the Pubmed abstract
To read more about "Cystic fibrosis"

Hum Genet. ; 135(8):881-94 ; August 2016
Chronic intestinal pseudoobstruction: RET as a candidate gene
Consult the Pubmed abstract
To read more about "Chronic intestinal pseudoobstruction"

Am J Med Genet A. ; 170(9):2400-3 ; September 2016
Hepatocellular carcinoma: EPB41 as a susceptibility gene
Consult the Pubmed abstract
To read more about "Hepatocellular carcinoma"

Am J Hum Genet. ; 99(2):275-86 ; August 2016

Research in Action

Clinical Research
Lesch-Nyhan syndrome: the dopamine D1 receptor antagonist ecopipam could be a useful treatment
Consult the Pubmed abstract
To read more about "Lesch-Nyhan syndrome"

Mol Genet Metab. ; 118(3):160-6 ; July 2016
Mucopolysaccharidosis type 4A: evaluation of long-term efficacy and safety of elosulfase alfa enzyme replacement therapy
Consult the Pubmed abstract
Consult this study on Orphanet

To read more about "Mucopolysaccharidosis type 4A"

Mol Genet Metab. ; 119(1-2):131-43 ; September 2016
Retinitis pigmentosa: long-term safety and benefit of Argus II retinal implant
Consult the Pubmed abstract
To read more about "Retinitis pigmentosa"

Ophthalmology ; 123(10):2248-54 ; October 2016
Duchenne muscular dystrophy: idebenone reduces respiratory complications
Consult the Pubmed abstract
Consult this French study on Orphanet
Consult this Spanish study on Orphanet

To read more about "Duchenne muscular dystrophy"

Neuromuscul Disord. ; 26(8):473-80 ; August 2016
Duchenne muscular dystrophy: givinostat treatment counteracts histological disease progression in boys without improvements in functional tests
Consult the Pubmed abstract
To read more about "Duchenne muscular dystrophy"

Neuromuscul Disord. ; 26(10):643-649 ; October 2016
Primary mitochondrial disease: the majority of patients tolerate solid organ transplantation
Consult the Pubmed abstract
Mol Genet Metab. ; 118(3):178-84 ; July 2016
Combined immunodeficiency due to DOCK8 deficiency: allogeneic haematopoietic stem cell transplantation ameliorates the symptoms
Consult the Pubmed abstract
To read more about "Combined immunodeficiency due to DOCK8 deficiency"

J Allergy Clin Immunol. ; 138(3):852-859 ; September 2016
Myasthenia gravis: azathioprine is well tolerated and 30% of the patients go into complete stable remission
Consult the Pubmed abstract
To read more about "Myasthenia gravis"

Muscle Nerve ; 54(3):405-12 ; September 2016
Myasthenia gravis and pregnancy: high rate of clinical worsening of the disease in the mother
Consult the Pubmed abstract
To read more about "Myasthenia gravis"

Muscle Nerve ; 54(4):715-20 ; October 2016
Metachromatic leukodystrophy, juvenile form: better gross motor and language outcome with allogeneic haematopoietic stem cell transplantation
Consult the Pubmed abstract
To read more about "Metachromatic leukodystrophy, juvenile form"

JAMA Neurol. ; 73(9):1133-40 ; September 2016
Glioblastoma: superior overall survival in elderly patients with combined-modality therapy with radiation and chemotherapy
Consult the Pubmed abstract
To read more about "Glioblastoma"

JAMA Neurol. ; 73(7):821-8 ; July 2016
Medium chain acyl-CoA dehydrogenase deficiency: findings from 221 newborn-screened neonates
Consult the Pubmed abstract
To read more about "Medium chain acyl-CoA dehydrogenase deficiency"

Mol Genet Metab. ; 119(1-2):75-82 ; September 2016
FGFR2-related bent bone dysplasia: clinical and radiographic delineation
Consult the Pubmed abstract
To read more about "FGFR2-related bent bone dysplasia"

Am J Med Genet A. ; 170(10):2652-61 ; October 2016
Therapeutic Approaches

Crigler-Najjar syndrome: a translationally optimised AAV-UGT1A1 vector drives safe and long-lasting correction of the disease in rats and mice
Consult the Pubmed abstract
To read more about "Crigler-Najjar syndrome"

Mol Ther Methods Clin Dev. ; 3:16049 ; July 2016
Spinal muscular atrophy: suboptimal survival motor neuron antisense oligonucleotide treatment and plastin 3 overexpression rescues survival and motor abilities in a mouse model
Consult the Pubmed abstract
To read more about "Proximal spinal muscular atrophy type 1"
To read more about "Proximal spinal muscular atrophy type 2"
To read more about "Proximal spinal muscular atrophy type 3"
To read more about "Proximal spinal muscular atrophy type 4"

Am J Hum Genet. ; 99(3):647-65 ; September 2016
Amyotrophic lateral sclerosis: statins accelerate disease progression and shorten survival in mice
Consult the Pubmed abstract
To read more about "Amyotrophic lateral sclerosis"

Muscle Nerve ; 54(2):284-91 ; August 2016
Fabry disease: development of a cellular model system for neuronal dysfunction
Consult the Pubmed abstract
To read more about "Fabry disease"

Mol Genet Metab. ; 119(1-2):144-50 ; September 2016
Diagnostic Approaches

Primary mitochondrial disease and secondary mitochondrial dysfunction: review on diagnosis
Consult the Pubmed abstract
Mol Syndromol. ; 7(3):122-37 ; July 2016
Fabry disease: fever contributes to the diagnostic delay
Consult the Pubmed abstract
To read more about "Fabry disease"

Eur J Intern Med. ; 32:26-30 ; July 2016
Niemann-Pick disease type C: review of diagnostic tests
Consult the Pubmed abstract
To read more about "Niemann-Pick disease type C"

Mol Genet Metab. ; 118(4):244-54 ; August 2016
Early-onset Niemann-Pick disease type C: a suspicion index to aid screening of patients aged less than or equal to four years
Consult the Pubmed abstract
To read more about "Niemann-Pick disease type C"

BMC Pediatr. ; 16:107 ; July 2016
Simpson-Golabi-Behmel syndrome: whole exome sequencing and array-based molecular karyotyping as aids to prenatal diagnosis in foetuses
Consult the Pubmed abstract
To read more about "Simpson-Golabi-Behmel syndrome"
To read more about "Simpson-Golabi-Behmel syndrome type 2"

Prenat Diagn. ; 36(10):961-965 ; October 2016
Chudley-McCullough syndrome: prenatal imaging features
Consult the Pubmed abstract
To read more about "Chudley-McCullough syndrome"

Am J Med Genet A. ; 170(9):2426-30 ; September 2016
Noonan, cardiofaciocutaneous and Costello syndromes: objective studies of the face
Consult the Pubmed abstract
To read more about "Noonan syndrome"
To read more about "Cardiofaciocutaneous syndrome"
To read more about "Costello syndrome"

Am J Med Genet A. ; 170(10):2570-7 ; October 2016
Van den Ende-Gupta syndrome: clinical algorithm for diagnosis
Consult the Pubmed abstract
To read more about "Van den Ende-Gupta syndrome"

Am J Med Genet A. ; 170(9):2310-21 ; September 2016
Alternating hemiplegia of childhood: recognisable facial features
Consult the Pubmed abstract
To read more about "Alternating hemiplegia of childhood"

Am J Med Genet A. ; 170(10):2698-705 ; October 2016
Dementia pugilistica: review on diagnosis
Consult the Pubmed abstract
To read more about "Dementia pugilistica"

JAMA Neurol. ; 73(6):743-9 ; June 2016
Amyotrophic lateral sclerosis: greater contribution of thoracic electromyography as diagnostic criteria than cranial electromyography
Consult the Pubmed abstract
To read more about "Amyotrophic lateral sclerosis"

Muscle Nerve ; 54(3):378-85 ; September 2016
Lichen myxedematosus: diagnostic criteria
Consult the Pubmed abstract
To read more about "Lichen myxedematosus"

Int J Dermatol. ; [Epub ahead of print] ; September 2016

Patient Management and Therapy
Infantile hypophosphatasia: review on physical therapy management of infants and children
Consult the Pubmed abstract
To read more about "Infantile hypophosphatasia"

Mol Genet Metab. ; 119(1-2):14-9 ; September 2016
Mucopolysaccharidoses: review on pathogenesis and treatment of spine disease
Consult the Pubmed abstract
Mol Genet Metab. ; 118(4):232-43 ; August 2016
Skeletal dysplasia: review on emerging targeted drug therapies
Consult the Pubmed abstract
Am J Med Genet A. ; 170(10):2596-604 ; October 2016
Familial adenomatous polyposis and Lynch syndrome: review on controversies in surgery
Consult the Pubmed abstract
To read more about "Familial adenomatous polyposis"
To read more about "Lynch syndrome"

Fam Cancer. ; 15(3):447-51 ; July 2016
Familial adenomatous polyposis in paediatrics: review on natural history and management
Consult the Pubmed abstract
To read more about "Familial adenomatous polyposis"

Fam Cancer. ; 15(3):477-85 ; July 2016
Arthrogryposis syndrome: review on gene ontology
Consult the Pubmed abstract
To read more about "Arthrogryposis syndrome"

Mol Syndromol. ; 7(3):101-9 ; July 2016
Uterine malformations: review on aetiology
Consult the Pubmed abstract
Am J Med Genet A. ; 170(8):2141-72 ; August 2016
Brain malformations: review on genetics
Consult the abstract
Molecular Syndromology ; 7(4):220-223 ; September 2016
Lynch syndrome: two reviews on genetics
Consult the Pubmed abstracts
To read more about "Lynch syndrome"

Fam Cancer. ; 15(3):385-93; 395-403 ; July 2016
Silver-Russell and Beckwith-Wiedemann syndromes: a review
Consult the Pubmed abstract
To read more about "Silver-Russell syndrome"
To read more about "Beckwith-Wiedemann syndrome"

Mol Syndromol. ; 7(3):110-21 ; July 2016
Alport syndrome in women and girls: a review
Consult the Pubmed abstract
To read more about "Alport syndrome"

Clin J Am Soc Nephrol. ; 11(9):1713-20 ; September 2016
Toriello-Carey syndrome: a review
Consult the Pubmed abstract
To read more about "Toriello-Carey syndrome"

Am J Med Genet A. ; 170(10):2551-8 ; October 2016
Syndromes with supernumerary teeth: a review
Consult the Pubmed abstract
Am J Med Genet A. ; 170(10):2611-6 ; October 2016
Autoinflammatory diseases: review on classification, diagnosis and management
Consult the Pubmed abstract
J Clin Pathol. ; [Epub ahead of print] ; September 2016
ATTRV30M amyloidosis: review on management of asymptomatic carriers
Consult the Pubmed abstract
To read more about "ATTRV30M amyloidosis"

Muscle Nerve ; 54(3):353-60 ; September 2016
Benign multifocal stenosing ulceration: a review
Consult the abstract
Journal of Rare Diseases Research & Treatment ; 1(1):6-8 ; 2016
Addison disease: review on epidemiology, quality of life and complications of the disease
Consult the Pubmed abstract
To read more about "Addison disease"

Eur J Endocrinol. ; 175(3):R107-16 ; September 2016
Spinal muscular atrophy: review on nutrition
Consult the Pubmed abstract
To read more about "Proximal spinal muscular atrophy type 1"
To read more about "Proximal spinal muscular atrophy type 2"
To read more about "Proximal spinal muscular atrophy type 3"
To read more about "Proximal spinal muscular atrophy type 4"

Neuromuscul Disord ; 26(7):395-404 ; July 2016
Zika virus disease: a review
Consult the Pubmed abstract
To read more about "Zika virus disease"
To read more about "Zika virus disease"

JAMA Neurol. ; 73(7):875-9 ; July 2016
Familial atypical multiple mole melanoma syndrome: a review
Consult the Pubmed abstract
To read more about "Familial atypical multiple mole melanoma syndrome"

Fam Cancer. ; 15(3):487-91 ; July 2016
Special issue of ‘American Journal of Medical Genetics Part C’ on care and advances in the management of children with trisomy 13 and 18
Consult the special issue
To read more about "Trisomy 13"
To read more about "Trisomy 18"

American Journal of Medical Genetics Part C ; 172(3) ; September 2016
Special issue of ‘Human Genetics’ on gene editing
Consult the special issue
Human Genetics ; 135(9) ; September 2016
One new and five updated GeneReviews published
GeneReviews are expert-authored, peer-reviewed disease descriptions ("chapters") presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions. One new GeneReviews has been published for:
3q29 recurrent deletion
Five updated GeneReviews have been published for:
Fanconi anaemia
WAS-related disorders
Polycystic kidney disease, autosomal recessive
Familial porphyria cutanea tarda
IMAGe syndrome


Orphan Drugs
Regulatory News
FDA approves Ilaris for three new rare disease indications
The United States Food and Drug Administration approved Ilaris (canakinumab) for rare and serious autoinflammatory diseases in adult and pediatric patients: Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS); Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD); and Familial Mediterranean Fever (FMF).

These three hereditary diseases, characterised by periodic attacks of fever and inflammation and severe muscle pain had no previously approved therapies.

Fee for Using a Rare Paediatric Disease Priority Review Voucher in Fiscal Year 2017
The Food and Drug Administration (FDA) is announcing the fee rate for using a rare paediatric disease priority review voucher for fiscal year 2017. FDASIA authorises FDA to determine and collect rare paediatric disease priority review user fees for certain applications for review of human drug or biological products when those applications use a rare paediatric disease priority review voucher.


Medical Research Grant Application Guidelines : Progeria Research Foundation
The foundation is proving several grants such as Innovator Awards, Established Innovator Award, and Specialty Award. Details are provided on their website
AFM Telethon: Call for proposals
Several call for proposals are being made available by AFM Telethon. They have published a call for proposals for Spinal Muscular Atrophy and Collagen VI Call for Projects.
For further information

Myotubular trust - seventh call for projects (open to international applications)
The Myotubular Trust are holding a seventh call for research projects. They are looking to fund further projects that will help find a cure and / or a treatment for any of the three types of myotubular myopathy (congenital X-linked recessive; congenital autosomal recessive; autosomal dominant), focusing on research that would not generally be funded by public or industrial funding sources. This call will be open to research bodies internationally.

We will be looking for the following types of application:
1. A project grant applied for by a Principal Investigator to fund a project for 2-3 years duration to be carried out by a Post-Doctoral researcher, or PHD student
2. A Myotubular Trust fellowship – basic science (3-4 years duration), where the scientist has identified a group that he or she wants to work with. Award is made to a named individual.
The deadline for receipt of applications is the Wednesday 30th November 2016
For further information

9th Call for SMA Research Proposals
This new Call for SMA Projects will be open to any research project (those of a collaborative nature are encouraged) aimed at finding a therapy for Spinal Muscular Atrophy (SMA) or at elucidating the basic pathophysiological processes of the disease. Priority will, however, be given to projects concentrating on the following areas:

a. Understanding and Function of the SMN Complex and possibly other factors, independent of SMN, as it relates to the pathophysiology of SMA
b. Innovative Approaches for Therapy of SMA, including targeting non-SMN pathways
c. Projects addressing bottlenecks impairing rapid translation from basic research to clinical trials, including;
•Innovative outcome measures & endpoints
•Appropriate methodology to follow disease progression and treatment effect.
The deadline for receipt of applications is the 8 December 2016.
For more information


Courses & Educational Initiatives

Metabolic Myopathies Course
Date: 3-5 November, 2016
Venue: Paris, France

Target audience and participant profile: Neurologists, neuromuscular specialists, internists, cardiologists, geneticists, pediatricians, biochemists, willing to improve their knowledge in the diagnosis and treatment of metabolic myopathies + differential diagnosis with other inherited or genetic myopathies. For further information, please contact Cecilia Kellquist, Coordinator and member of the board, ckellquist@rrd-foundation.org or visit www.rrd-foundation.org.

Orphan Drug and Rare Disease Seminar
Date: 18 November, 2016

Venue: Marseille, France

This Eudipharm training seminar aims at raising awareness among clinical research actors on drug development specificities for rare diseases. This edition will offer a first day on regulatory issues and the second day will focus on drug re-positioning and personalised medicine, thanks to the participation of clinical research experts and authorities.
For further information

European Advanced Postgraduate Course in Classical and Molecular Cytogenetics
Date: March, 2017

Venue: Nimes, France

For further information

An Online Educational Resource for Limb Girdle Muscle Weakness
Limb girdle muscle weakness (LGMW) can result from multiple causes. Early and accurate diagnosis is critical to optimal disease management. The diagnosis can involve clinical, electromyogram, and genetic findings. Patient specific multidisciplinary management plans, including genetic counseling, should be developed. Currently, there are drugs available for some conditions. Many providers lack the skills to provide optimal care due to the heterogeneous presentation, complex diagnosis, and rarity of LGMW disorders.
For further information


What's on Where?

Genome Editing for Gene and Cell Therapy, a Herrenhausen Symposium
Date: 3-4 November 2016
Venue: Hanover, Germany

Through talks, a poster session and a panel discussion, the meeting will help identify the scientific, clinical and regulatory hurdles that remain to be overcome. The exchange of ideas and expertise will also help guide the path forward.
For further information

Kennedy's Disease 2016 Conference
Date: 9-11 November 2016
Venue: San Diego, United States

KDA family and researchers join in for indepth presentations on what is working and what isn't quite getting it done. This is a no holds barred discussion that is much appreciated by all the patients and families. Researchers from different labarotories across the globe sit down and compare notes and make presentations to one another on what they are doing.
For further information

Global Summit on Rare Diseases and Orphan Drugs
Date: 15-17 November 2016
Venue: Dubai, United Arab Emirates

The aim of this conference is to bring together bright minds to give talks that are idea‐focused, and on a wide range of subjects, to foster learning, inspiration and wonder – and provoke conversations that matter.
For further information

The Prader Willi Syndrome Association UK national conference 2016
Date: 19-20 November 2016
Venue: Derbyshire, United Kingdom

The conference programme is split into two different age ranges in PWS:
• Birth to 16 years on Saturday
• 16 years and over on Sunday
The programmes for children and adults with PWS will be appropriate to the age group on each day.
For further information

International Primary Immunodefiencies Congress
Date: 8-10 November 2017
Venue: Dubai, United Arab Emirates

For further information

First International SYNGAP1 Conference
Date: 30 November – 1 December 2016
Venue: Texas, United States of America

This conference will utilize a novel multi‐disciplinary approach to bring together patient families, clinicians and researchers as equal stakeholders in order to accelerate research discovery and close the gap to clinical impact.
For further information

3rd IRDiRC conference
Date: 8-9 February 2017
Venue: Paris, France

All stakeholders – active investigators, policy makers, opinion leaders, critical thinkers, young researchers and patient advocates alike – active in the area of rare diseases from across the globe are invited to join us to celebrate achievements in the field, identify future milestones and goals, and work toward bringing diagnoses and therapies to all rare disease patients.
For further information

2017 Rare Disease Day Symposium Alagille Syndrome — New Research, New Hope
Date: 24 February 2017
Venue: La Jolla, United States

The 2017 SBP Rare Disease Day Symposium will focus on Alagille Syndrome, with emphasis on the areas of biliary paucity, genetic mechanism, Notch signaling, and biliary development/regeneration. Scientists, clinicians, advocates, patients and their families are invited to join experts in the ALGS field to foster new perspectives, ideas, and collaborations and accelerate efforts toward a cure for this syndrome.
For further information

7th International Meeting on Pulmonary Rare Diseases and Orphan Drugs
Date: 24-25 February 2017
Venue: Milan, Italy

This meeting will highlight that rare diseases represent an important field of medicine not only for pulmonologists who are skilled in diagnosing and treating particular groups of these illnesses but for all respiratory physicians
For further information

Rare and Undiagnosed Diseases: Discovery and Models of Precision Therapy (C2)
Date: 5-8 March, 2017
Venue: Massachusetts, United States of America

Through this meeting, participants should become familiar with rare and undiagnosed disease programs, acquire insights into new disease mechanisms, learn about potential therapeutic targets, and establish collaborations that enhance rare disorder expertise and new disease discovery. The meeting will bring together physicians who are expert in rare disorders with scientists who know metabolic pathways and mechanisms, advancing understanding and therapy.
For further information

11th European Cytogenetics Conference 2017
Date: 1-4 July 2017
Venue: Florence, Italy

For further information


Commercial events

Orphan Drugs and Rare Diseases
Date: 19-20 October, 2016
Venue: London, United Kingdom

The conference will discuss the latest regulatory developments, explore how to reduce costs and learn from the latest innovations in the orphan drug landscape.
For further information

Drug Developmental Forum
Date: 19-21 September, 2016
Venue: Boston, United States of America

This event will cover the entire drug development process from basic research through clinical trials.
For further information


OrphaNews, The Newsletter of the Rare Diseases Community.
OrphaNews is supported by the European Commission's DG SANTE ( RD-ACTION Joint Action N° 677024) and the French Muscular Dystrophy Association (AFM)
Editor-in-chief: Kate Bushby, Ana Rath
Editor: Divya Unni
Editors for Scientific Content: Sophie Höhn
Contact Us
Editorial Board: Valentina Bottarelli, Victoria Hedley, Yann Le Cam, Stephen Lynn, Charlotte Rodwell, Domenica Taruscio, Ariane Weinmann

Advisory Editorial Board: Ségolène Aymé, Anna Bucsics, Paul Boom, Bruno Dallapiccola, Jordi Llinares-Garcia, Adam Heathfield, Alastair Kent, Dominique Péton-Klein, Milan Macek, Till Voigtländer

Orphanet Partner Country Representatives: Romi Armando (Argentina), Kristine Hovhannesyan (Armenia), Hugh Dawkins (Australia), Till Voigtlander (Austria), Rumen Stefanov (Bulgaria), Micheil Innes (Canada), Ingeborg Barisic (Croatia), Violetta Anastasiadou (Cyprus), Milan Macek (Czech Republic), John Rosendahl Ostergaard (Denmark), Vallo Tillmann (Estonia), Sirpa Ala-Mello (Finland), Joerg Schmidtke (Germany), Eileen Treacy (Ireland), Annick Raas-Rothschild (Israel), Bruno Dallapiccola (Italy), Tomoko Kodama (Japan), Jana Lepiksone (Latvia), André Mégarbané (Lebanon), Vaidutis Kucinskas (Lithuania), Yolande Wagener (Luxembourg), Abdelaziz Sefiani (Morocco), Gert-Jan van Ommen (Netherlands), Stein Are Aksnes (Norway), Malgorzata Krajewska-Walasek (Poland), Paul Nogueira (Portugal), Cristina Rusu (Romania), Dragica Radojkovic (Serbia), Laszlo Kovacs (Slovakia), Luca Lovrecic (Slovenia), Francesc Palau (Spain), Désirée Gavhed (Sweden), Loredana D'Amato Sizonenko (Switzerland), Dorra H'mida (Tunisia), Ugur Ozbek (Turkey), Sarah Stevens (UK)
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Disclaimer : This newsletter is part of the project / joint action .677024 / RD-ACTION. which has received funding from the European Union.s Health Programme (2014-2020).
The content of newsletter represents the views of the Editorial Board only and is his/her sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.

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