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Homage to Victor McKusick…founding father of medical genetics and creator of the OMIM

It is hard to imagine where the field of rare disease research and treatment would be without the immense contribution of Victor McKusick, who died in July at the age of 86 years. Responsible for the development of key theories and practices that take a genetic approach as their basis, the association of specific genes with certain clinical manifestations (the genotype/phenotype relationship), theories of inheritance, the development of prenatal genetic testing, newborn screening, and the burgeoning field of gene therapy can all be traced to the initial efforts of the man who set the ball in motion.

Victor A. McKusick, M.D., University Professor of Medical Genetics at the Johns Hopkins University School of Medicine, and an international pioneer in the field of genetics research, diagnosis and treatment, was born on 21 October, 1921, along with his twin brother Vincent. One of five children, he grew up on a dairy farm in Maine, although his parents were both educators at different points in their lives.

Dr. McKusick decided to pursue medicine following an illness at the age of 15, during which he was administered recently developed antibiotic treatment. He was deeply impressed by the work of the doctors treating him. Following his education, he worked initially in the field of cardiology. Dr. McKusick developed an interest in rare disorders early in his career after encountering a patient with Marfan syndrome, a disorder characterised by heart defects, tall stature, and eye anomalies. Dr. McKusick became fascinated with the condition and its transmission and soon began seeing other Marfan syndrome patients as well as others with inherited illnesses.

"Some of my colleagues thought I was committing professional suicide because I had a reputation in cardiology and was shifting over to focus for the most part on rare, unimportant conditions and so forth," Dr. McKusick once told the Baltimore Sun newspaper. "But it didn't bother me. I felt certain it was going somewhere."

Dr. McKusick began keeping detailed records of the patterns of inheritance and clinical phenotype that he encountered. Utterly captivated by the field, Dr. McKusick in 1957 founded the Division of Medical Genetics at the Johns Hopkins Institute. It was the first such centre in the world. He began working with subjects possessing isolated gene pools, including the Pennsylvania Old Order Amish population. From these groups, he discretely obtained the medical and genetic profiles that permitted identifying specific genes with certain disorders and anomalies, such as dwarfism amongst the Amish population. It has been suggested that his experience living and working on a farm as a child helped him to penetrate the private world of the Amish and gain their trust.

Throughout the 1960s gene mapping slowly increased and Dr. McKusick established the foundation for the identification of genes responsible for thousands of inherited conditions. At a conference in 1969, he proposed mapping every human gene as a method for identifying (and eventually solving) birth defects and genetic conditions. Considered a farfetched suggestion by some at the time, the human genome went on to be completely mapped in 2001. In 1966, Dr. McKusick created the first edition of the Mendelian Inheritance in Man (MIM), probably the most comprehensive human genetic database catalogue. Twelve printed editions have since appeared, along with OMIM, the online version created in 1985, which is continuously updated to include new information. Amongst the plethora of Dr. McKusick’s remarkable achievements, the creation of MIM is considered by many to be his crowning accomplishment. The American Journal of Human Genetics published an article by Dr. McKusick in April 2007 in which he describes the creation of MIM, and the evolutions over the years in organising and categorizing information.

Of Mice and McKusick

In 1960, Dr. McKusick co-founded the Short Course in Medical and Experimental Mammalian Genetics, held in conjunction with the Jackson Laboratory in Bar Harbor, Maine, an internationally recognised centre of excellence in mouse genetics. Dr. McKusick was one of the earliest human geneticists to recognise the value of the mouse as a model for understanding human disease, because of similar developmental and physiological traits between the two species. He thus facilitated collaboration between scientists in both fields and served as a co-director of the Short Course for 49 years. He was planning the 50th such course at the time of death.

In 1988 Dr. McKusick and Giovanni Romeo, professor of Medical Genetics at the University of Bologna, founded the European School of Genetic Medicine (ESGM) in Italy. Taking the Bar Harbor course as a model, the ESGM offers advanced scientific and professional training courses to physicians and scientists across Europe and the Mediterranean countries. The school rapidly established a reputation for excellence and in the last twenty years over 800 faculty members and 5000 students have participated in its ground-breaking courses. In 2007, on the occasion of the 2Oth edition of the Course in Medical Genetics organised by the ESGM, Dr. McKusick, along with Nobel Laureate Mario Capecchi, received an honorary degree from the University of Bologna. A commemorative booklet was created by the European Genetics Foundation to record the occasion.

On his webpage at the Johns Hopkins Medical Center, Dr. McKusick gives a description of his principal activities:

“My interest in the comprehensive collation of information on human genes and genetic disorders is represented by Mendelian Inheritance in Man (and its online counterpart OMIM), to the upkeep of which I devote three-fourths of my full-time schedule. I still see new patients with hereditary disease in consultation, particularly patients with heritable disorders of connective tissue, such as Marfan syndrome, Ehlers-Danlos syndrome, and skeletal dysplasias and follow-up on the course of patients that I have seen in the past. My involvement with the Amish, which was heavy in the past, is limited largely to consultation with others at Hopkins in the design of studies. My ongoing research in the history of Medical Genetics has taken the form of a long chapter in the Emery-Rimoin Principles and Practice of Medical Genetics and several biographical studies. I edit two journals, Medicine (founded in the year that I was born) and a newer journal, Genomics (founded by Frank Ruddle and me in 1987)”.

Thus for decades, Dr. McKusick led the world in searching, mapping and identifying genes responsible for innumerable inherited conditions including Down syndrome, Duchenne muscular dystrophy, achondroplasia, and many other forms of dwarfism. Such discoveries have not only uncovered the mechanisms responsible for the transmission of disease, but have also led to treatments that have profoundly altered the life of patients.

Although a recipient of scores of prizes, distinctions and accolades, it would appear that for Dr. McKusick the ultimate honour came from being able to pursue the field he cherished. We are grateful to that Marfan syndrome patient who altered his path so many years ago and are deeply indebted to Dr. McKusick for the advances in genetics he undertook that have so profoundly impacted rare disease research and treatments.

Dr. Victor McKusick died of cancer on 22 July, 2008, at the age of 86 years.

Spotlight on...
Coordination and collaboration: the keys to translating rare disease genetic test research into clinical practice
A series of articles concerning rare disease genetic testing published in the May 2008 issue of American journal Genetics in Medicine provides valuable insight into the most efficient ways to translate rare disease genetic testing research into clinical practice. Information concerning the genotype of thousands of rare diseases has become available in recent years. Yet the very nature of the rare disease with its low, widely-scattered prevalence hinders research. For the majority of these disorders, the evidence base available consists of case reports and small observational studies, limiting statistical power. The May issue of Genetics in Medicine contains articles that explore ways to encourage rare disease molecular testing:

The Collaboration, Education, and Test Translation Program (CETT), a pilot project that debuted in 2006 specifically to improve translation of rare disease genetic testing from research to clinical practice was developed by the Office of Rare Diseases of the National Institutes of Health in collaboration with the Centers for Disease Control. This model programme is described in an article that reviews the scenario that led to its development and outlines progress made and future endeavours identified to further encourage the translation of research to the clinical setting. At the time the CETT programme was conceptualised, some 20% of rare genetic disease tests never evolved from research to the clinical setting. Initial problems included the lack of funds and resources of most clinical laboratories for developing new tests, data collection and educational material development, as well as the difficulty many researchers experience in identifying clinical laboratories capable of translating test research. The CETT programme developed along the guiding principle that all parties benefit when test quality meets or exceeds defined standards; when stakeholders collaborate; and when quality educational materials explain the nature of tests and how to best utilise results. Within this context, the CETT programme offers a model allowing researchers, clinicians and patient groups to collaborate in order to facilitate quality controlled genetic testing for a particular condition. CETT offers expertise at every step of the process and provides a standardised procedure for test development. Applicants are required to form a “collaborative group” including a clinical lab, a researcher, an expert clinician, and an advocacy group. CETT has a list of laboratories available to participate and can also help to pinpoint appropriate patient groups. Applications are reviewed internally and feedback is provided within two to three months. Any concerns detected via this internal review process must be addressed before the application is forwarded to a review board, consisting of genetic and non-genetic clinicians, researchers, laboratory geneticists and patient advocate communities. The evaluation is based on a number of criteria examining scientific evidence, methodology, health care impact, laboratory qualifications, data collection and storage, education materials and collaboration between applicant members. The Genetics in Medicine article provides a detailed description of how this process was elaborated and how it has been fine-tuned since its conception.
Read more

Molecular Genetic Testing for Ultra Rare Diseases: Models for Translation from the Research Laboratory to the CLIA-Certified Diagnostic Laboratory describes the viability of translating research for rare disease genetic testing in the USA within the context of a centralised approach involving laboratories with Clinical Laboratory Improvement Amendments (CLIA) certification, a mechanism that ensures quality standards. The authors describe their experience with a CLIA-certified molecular diagnostic clinical laboratory to test for a rare developmental brain disorder for which different genes had been identified. Collaboration took place from the outset; quality control measures were incorporated into research studies to allow information generated to be used for diagnostic purposes. Thus, the research laboratory worked under the same quality guidelines defined by CLIA. The work performed by the diagnostic laboratory was budgeted at the beginning. This initial funding was instrumental for development of testing by the diagnostic laboratory and ultimately allowed for the transition into the clinical setting.
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The article Developing a National Collaborative Study System for Rare Genetic Diseases issues from a meeting designed to address this subject and which resulted in a set of principles and recommendations toward the collaboration and coordination of efforts involving both the professional and lay communities in order to enhance translational research for rare diseases. The seven recommendations delineated in the article are geared toward developing a mechanism that facilitates “extensive and comprehensive collaboration” including the newborn screening programmes that currently differ from state to state in the US. The recommendations include creating or enhancing team-based science; an open-source tool kit including well-curated biologics; registries (national or international); standardised ontologies and vocabularies for phenotype assessment; flexible data collection; models that allow dispersed yet integrated research networks; specific training; revised ethical procedures; enhanced communication for clinical trial participants; and new models for intellectual property that would provide incentive for innovation.
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Other related articles in this remarkable series include Issues in genetic testing for ultra-rare diseases: background and introduction; Gene patenting and licensing: the role of academic researchers and advocacy groups; New quality assurance standards for rare disease testing; and Molecular testing: improving patient care through partnering with laboratory genetic counsellors.


EU Policy News
Cross-border health care: the EC adopts a proposal for a directive aimed at improving healthcare cooperation
Accessing health care is particularly pertinent to European rare disease patients, who often have limited resources of care and expertise in their region. With over 7,000 rare diseases identified to date, it is not possible for each EU country to develop expert care and treatment services for every disorder. Thus, the rare disease patient – perhaps more than any other EU citizen – needs to be able to access medical expertise where it exists. The European Commission in July adopted a proposal for a directive on the rights of patients accessing cross-border healthcare. The proposal tackles the complex issues of reimbursement for care obtained in member states and the coordination of social security schemes; mutual recognition of professional qualifications; discrimination; and the need for a community framework for the protection of personal data. The proposal next has to go through a co-decision process involving the Council of Ministers and the European Parliament. If the readings are not completed before June 2009, the process will have to recommence upon the election of the new parliament rapporteurs. Once a decision is taken, the member states will have one year to implement the directives of the proposal.
EMEA’s paediatric committee blows out its first candle

As part of the Paediatric Regulation (EC No 1901/2006) that came into effect in January 2007 to stimulate research and development of medicines for use in children, ensure that medicines for children are appropriately tested and authorised, and improve information availability, the Paediatric Committee (PDCO) was developed within the European Medicines Agency in July 2007 to provide scientific opinions on medicines intended for use in children. One year later, the PDCO has already delivered over 70 decisions on over 200 applications received for either paediatric investigation plans or waivers and involving twice as many indications. Orphan medicines represent 17% of the total PDCO applications, of which over 70% had paediatric investigation plans submitted and 27% requested waivers. In the course of its first year, the PDCO implemented a number of scientific and operational procedures. An EMEA press release noted that with two-thirds of the applications comprising non-registered products still being conceptualised, a “dramatic impact” is being made on future drug development. Indeed, as of 28 July this year, a medicinal product application for marketing authorisation must include the results of studies in children in accordance with an approved PIP or an EMEA decision on a waiver or a deferral.
Consult the PDCO anniversary report

EMEA survey finds patient groups satisfied
As patient organisations become increasingly involved in core activities of the European Medicines Agency (EMEA), a survey was developed to gauge the level of satisfaction patient groups experience with such involvement. The patient organisation and consumer representatives who responded to the survey, the first of its kind, expressed overwhelming satisfaction with their involvement in EMEA activities and the consequences of participation for their organisations, such as being able to communicate new treatments to their members. The majority of representatives also felt satisfied with the EMEA’s response to their input. Over 20 patient organisations currently participate in EMEA activities, including the International Patient Organisation for Primary Immunodeficiencies, Rett Syndrome Europe, and seven different thalidomide patient groups. Thalidomide, prescribed to pregnant women as a treatment for morning sickness from the late 1950s until the early 1960s, was the first drug to be recognised as a human teratogen.
Consult the survey report

COMP welcomes new members
OrphaNews Europe extends a warm welcome to new Committee for Orphan Medicinal Products (COMP) members: CHMP representative Dr János Borvendég (Hungary), Bruno Sepodes (Portugal) - both nominated by the European Commission on the EMEA's recommendation; and Agnis Zvaigzne as the new COMP member from Latvia.

National & International Policy Developments
Irish report reveals urgent need for rare disease information and support
A report funded by Ireland’s Health Research Board has found an urgent need for information and support resources for both patients and medical professionals encountering rare disease patients in their practice. The report, An investigation into the social support needs of families who experience rare disorders on the island of Ireland, is published by Rehab Care, a unit of independent non-profit organisation Rehab Group. Amongst the findings, 73% of general physicians admit to difficulties in providing patients and families with appropriate information; some 60% of physicians access rare disease information via the internet; and patients need a reliable resource that does not present a worst-case scenario leading to additional stress and worry. The report recommends developing a centre of excellence in Ireland dedicated to rare diseases that could support health professionals and also provide materials suitable for patients and their families. The authors recommend that Orphanet, as a freely-accessible information resource for professionals and patients, receive a high profile in Ireland, along with UK charity Contact a Family.
Consult the report

Independent inquiry examines health service access for UK citizens with intellectual deficit
In response to the 2007 report Death by Indifference, which depicted the demise of six severely learning disabled patients in the UK who were being treated for illnesses other than their disability, an independent inquiry report Healthcare for All provides an assessment of the access to care within the National Health Service for patients with learning disabilities (also referred to as "intellectual deficit"), many of whom have limited speech faculty. The report issues a series of recommendations intended to ameliorate access to health services for these patients, as well as their carers. Hundreds of rare diseases feature intellectual deficit as part of their clinical manifestations.

New Syndromes
Distal inflammatory myopathy: a new entity
The new classification of idiopathic inflammatory myopathy defines three major entities: polymyositis, dermatomyositis, and sporadic inclusion body myositis. The authors report the characteristics of three patients with a rare form of the condition not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. Seven others cases were identified in the literature. The authors suggest that it is important to recognise this atypical presentation as it seems responsive to immunosuppressive agents.
Read the PubMed abstract

Neuromuscul Disord ; 493-500 ; June 2008
Congenital muscular dystrophy: de novo LMNA mutations cause a new form
Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Despite variable severity, there was a consistent clinical pattern. The LMNA mutations identified appear to correlate with a relatively severe phenotype. These results further broaden the spectrum of laminopathies and define a new disease entity that the authors suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD).
Read the PubMed abstract

Ann Neurol ; Epub ahead of print ; 12 June 2008

New Genes
Schwannomatosis: molecular characterisation of SMARCB1 and NF2 in familial and sporadic forms
Schwannomatosis is a rare condition characterised by multiple schwannomas and lack of involvement of the vestibular nerve. A recent report identified bi-allelic mutations in the SMARCB1/INI1 gene in a single family with schwannomatosis. The authors aimed to establish the contribution of the SMARCB1 and the NF2 genes to sporadic and familial forms of the disease. In contrast to the recent report in which no NF2 mutations were identified in a schwannomatosis family with SMARCB1 mutations, in this study a four hit model with mutations in both SMARCB1 and NF2 define a subset of patients with schwannomatosis.
Read the PubMed abstract

J Med Genet ; 332-339 ; June 2008
Neuroblastoma: chromosome 6p22 locus associated with clinically aggressive form
Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known. The authors performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations. They observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180. Patients who were homozygous for the risk alleles at 6p22 were more likely to have a more aggressive form of neuroblastoma.
Read the PubMed abstract

N Engl J Med ; 2585-2593
Congenital tufting enteropathy: identification of EpCAM as causal gene
Congenital tufting enteropathy is a rare autosomal recessive diarrheal disorder presenting in the neonatal period and characterised by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. Two double second cousins affected with the disorder were genotyped, along with an unaffected sibling. The authors identified decreased expression of the EpCAM gene in affected individuals. Direct sequencing of EpCAM from two additional unrelated patients revealed novel mutations in the gene.
Read the PubMed abstract

Gastroenterology ; 429-437 ; August 2008
Rett syndrome: FOXG1 is responsible for congenital variant
Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. The authors report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization.
Read the PubMed abstract

Am J Hum Genet ; 89-93 ; July 2008
Hirschsprung disease: Mapping of a locus in 3p21
Hirschsprung disease is a congenital disorder in which ganglion cells are absent in variable portions of the lower digestive tract according to which patients are classified. The RET gene is the major gene involved, although reduced penetrance of RET mutations and variable expression of disease phenotype indicates that more than one gene is required. An unidentified RET-dependent modifier on 3p21 appears to be necessary for transmission of one specific phenotype. The authors investigated 6 Mb of the 3p21 region. They found a five-marker haplotype, spanning a 118 kb gene-rich region, overtransmitted to affected offspring. The associated haplotype encompasses three genes involved in neurological phenotypes.
Read the PubMed abstract

Eur J Hum Genet ; 833-840 ; July 2008
Intellectual deficit: detection of known and novel genomic rearrangements by array based comparative genomic hybridisation
Intellectual deficit can be caused by copy number variations (deletions, insertions, duplications), ranging in size from 1 kb to several megabases. The authors evaluated 46 patients with intellectual deficit and congenital abnormalities for cryptic chromosomal imbalances by array-CGH. Four pathogenic rearrangements were detected: two novel, the other two previously reported.
Read the PubMed abstract

J Med Genet ; 432-437 ; July 2008

Research in Action
Fundamental Research
Huntington disease: towards a transgenic model in a non-human primate
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10-15 years of the onset of the symptoms. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here the authors report progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded human huntingtin gene (HTT). Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea.
Read the PubMed abstract

Nature ; 921-924 ; 12 June 2008
Merkel cell carcinoma: p14ARF hypermethylation is common but INK4a-ARF locus or p53 mutations are rare
The exact molecular mechanisms of Merkel cell carcinoma (MCC) tumourigenesis are unknown, but likely involve complex genetic alterations and mutations similar to those seen in many other cancers. In this study, the authors obtained MCCs from 21 elderly patients and analysed their DNA for mutation of exons of interest in several tumour-suppressor genes or oncogenes known to be frequently mutated in skin cancer. Their findings suggest that p14ARF silencing may be an important mechanism in MCC tumourigenesis, and thus a potential target for therapeutic intervention in this highly aggressive tumour type.
Read the PubMed abstract

J Invest Dermatol ; 1788-1796 ; July 2008
Congenital cystic adenomatoid malformation: genetic analysis reveals a novel pulmonary gene
The pathogenesis of congenital cystic adenomatoid malformation (CCAM) is unknown and its natural history is unpredictable. Fatty acid binding protein-7 (FABP-7) has been previously described in brain and breast development, but never before in the lung. In this study, the authors found that FABP-7 was underexpressed in foetal CCAM, suggesting that FABP-7 may have a role in pulmonary development and in the pathogenesis of CCAM.
Read the PubMed abstract

Pediatr Res ; 11-16 ; July 2008
Rapp-Hodgkin syndrome: a translation re-initiation mechanism for the p63 gene is revealed by amino-terminal truncation
Rapp-Hodgkin syndrome (RHS) is characterised by the association of anhidrotic ectodermal dysplasia with cleft lip/palate while Ankyloblepharon Ectodermal defects Cleft lip/palate (AEC) is characterised by congenital ectodermal dysplasia, ankyloblepharon filiform adnatum (apposing eyelid margins connected by abnormal tissue strands); hypodontia (missing teeth); maxillary hypoplasia; and cleft lip/palate. Missense mutations in the p63 gene are associated with either RHS or AEC. The authors report four RHS/AEC-like patients with mutations that introduce premature termination codons in the N-terminal part of the p63 protein and conclude that these mutations are fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes.
Read the PubMed abstract

Hum Mol Genet 2008 ; 1968-1977 ; 1 July 2008
Kallmann syndrome: biallelic mutations in the prokineticin-2 gene in two sporadic cases
Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2 genes have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, the authors report on the identification of PROK2 biallelic mutations in two out of 273 patients presenting as sporadic cases and conclude that homozygous PROK2 mutations account for a few cases of Kallmann syndrome.
Read the PubMed abstract

Eur J Hum Genet ; 865-868 ; July 2008
Roberts syndrome: new ESCO2 mutations identified cause loss of acetyltransferase activity
Roberts syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion. The authors have identified 10 new mutations expanding the number to 26 known ESCO2 mutations. They observed that the majority of these mutations result in complete or partial loss of the acetyltransferase domain. The cellular phenotype resulting from loss of autoacetyltransferase activity causes cohesion defects, proliferation capacity reduction and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. Decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, could be a factor in the development of phocomelia and cleft palate in RBS.
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Hum Mol Genet ; 2172-2180 ; 15 July 2008
Machado-Joseph disease: striatal and nigral pathology in a lentiviral rat model
Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, the authors overexpressed ataxin-3 in the rat brain using lentiviral vectors (LV) to generate an in vivo MJD genetic model and to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.
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Hum Mol Genet ; 2071-2083 ; 15 July 2008
Waardenburg syndrome: a sensitised mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy
Waardenburg syndrome is characterised by a wide bridge of the nose; pigmentary disturbances such as two different colored eyes, white forelock and eyelashes and premature graying of the hair; and some degree of cochlear deafness. Haploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10(LacZ/+)). Here, the authors established an N-ethyl-N-nitrosourea mutagenesis screen to identify modifiers that increase the phenotypic severity of Sox10(LacZ/+) mice. Analysis of 230 pedigrees identified three modifiers. Linkage analysis confirmed their locations on mouse chromosomes 13, 4 and 3, respectively, within regions distinct from previously identified WS loci. Positional candidate analysis identified a truncation mutation in a hedgehog(HH)-signaling mediator, GLI-Kruppel family member 3 (Gli3). This study demonstrates the feasibility of sensitized screens to identify disease modifier loci and implicates GLI3 and other HH signaling components as modifiers of human neurocristopathies.
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Hum Mol Genet ; 2118-2131 ; 1 July 2008
Long QT syndrome: fever-induced QTc prolongation and ventricular arrhythmias in the type 2 congenital form
Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterised by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognised triggers of these cardiac events include emotional and acoustic stimuli. Here the authors investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in two LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. The authors postulate that a weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.
Read the PubMed abstract

J Clin Invest ; 2552-2561 ; July 2008
Phenylketonuria: loss of function is caused by impaired molecular motions and conformational instability
Phenylketonuria is a hereditary metabolic disease, characterized by deficiency of phenylalanine hydroxylase, an enzyme necessary for the transformation of phenylalanine into tyrosine. Untreated, phenylketonuria leads to intellectual deficit, sometimes profound, as well as hypopigmentation. A significant share of patients benefits from pharmacological doses of tetrahydrobiopterin (BH(4)), the natural PAH cofactor. Phenylketonuria is hypothesised to be a conformational disease, with loss of function due to protein destabilisation, and the restoration of enzyme function that is observed in BH(4) treatment might be transmitted by correction of protein misfolding. To elucidate the molecular basis of functional impairment in PAH deficiency, the authors investigated the impact of ten PAH gene mutations identified in patients with BH(4)-responsiveness on enzyme kinetics, stability, and conformation of the protein. Residual enzyme activity was generally high, but allostery was disturbed in almost all cases and pointed to altered protein conformation. Their results substantiate the view that PAH deficiency is a protein-misfolding disease in which global conformational changes hinder molecular motions essential for physiological enzyme function.
Read the PubMed abstract

Am J Hum Genet ; 5-17 ; July 2008
Clinical Research
Sarcoglycanopathies: a revised spectrum of mutations
To define the spectrum of mutations in alpha-, beta-, gamma-, and delta-sarcoglycan (SG) genes, the authors analysed these genes in 69 probands with clinical and biological criteria compatible with the diagnosis of autosomal recessive limb-girdle muscular dystrophy. For 48 patients, muscle biopsies were available and multiplex western blot analysis of muscle proteins showed significant abnormalities of alpha- and gamma-SG. Mutations were detected in 57 patients and homozygous or compound heterozygous mutations were identified in 75% (36/48) of the patients with abnormal western blot, and in 52% (11/21) of the patients without muscle biopsy. This study highlights the high frequency of exonic deletions of alpha- and gamma-SG genes, as well as the presence of a hotspot of duplications affecting exon 1 of the beta-SG gene. In addition, protein analysis by multiplex western blot in combination with mutation screening and genotyping results allowed to propose a comprehensive and efficient diagnostic strategy and strongly suggested the implication of additional genes, yet to be identified, in sarcoglycanopathy-like disorders.
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Eur J Hum Genet ; 793-803 ; July 2008
Chronic granulomatous disease: hepatic involvement and portal hypertension predict mortality
Chronic granulomatous disease (CGD) is a rare genetic disorder, predisposing affected individuals to recurrent infectious complications and shortened survival. Liver involvement in CGD includes vascular abnormalities, which may lead to noncirrhotic portal hypertension. The authors evaluated the impact of noncirrhotic portal hypertension on survival in CGD using records from 194 patients of whom 24 died, all from infectious complications. The data from this study suggest mortality in patients with CGD is associated with the development of noncirrhotic portal hypertension, likely owing to injury to the microvasculature of the liver from repeated systemic and hepatic infections. The slope of decline in platelet count may be a useful measure of progression of portal hypertension over time as it showed to be an independent factor associated with mortality.
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Gastroenterology ; 1917-1926 ; June 2008
Turner syndrome: reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls
Individuals with Turner syndrome (TS) are at increased risk for impaired glucose tolerance and diabetes mellitus. It is unknown whether pharmacological GH treatment commonly used to treat short stature in TS alters this risk. The authors compared adiposity and glucose tolerance in GH-treated vs. untreated girls with TS. They found abdominal adiposity significantly lower and glucose tolerance significantly better in GH-treated vs. untreated girls with TS, suggesting that beneficial effects upon body composition and regional fat deposition outweigh transient insulin antagonism associated with GH administration.
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J Clin Endocrinol Metab ; 2109-2114 ; June 2008
McCune-Albright syndrome: thyroid dysfunction associated with elevated 5'-deiodinase activity
McCune-Albright syndrome (MAS) is caused by mutations in the GNAS gene leading to constitutive cAMP signaling and multiple endocrine dysfunctions, including thyroid involvement. This study of 100 MAS patients involved functional and morphological evaluation of the thyroid. The patients with abnormal thyroid ultrasound findings had higher T(3) to T(4) ratio, indicating an elevated 5'-deiodinase activity.
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J Clin Endocrinol Metab ; 2383-2389 ; June 2008
Acromegaly: changing patterns in diagnosis and therapy
Acromegaly is an acquired disorder related to excessive production of growth hormone (GH) and characterised by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. It is most often diagnosed in middle-aged adults (average age 40 years, men and women equally affected). Due to insidious onset and slow progression, acromegaly is often diagnosed four to more than ten years after its onset. However, the increased morbidity and mortality of acromegaly makes early diagnosis and therapy critical. The authors sought via a retrospective study involving 100 patients over two decades whether the type of medical professional who first diagnoses acromegaly, the major complaint prompting medical attention, or the management paradigms used in the setting of novel medical therapies have changed over time. Acral changes (24%) and headaches (20%) were most prevalent presenting symptoms prompting diagnosis. The primary care physician most often initiated the evaluation (44%). The interval between symptom onset and diagnosis decreased compared with previous reports. Radiation therapy was used less frequently in the decade after 1994. The increased use of brain magnetic resonance imaging may contribute to the many incidentally discovered cases and to the shortened time interval to diagnosis.
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J Clin Endocrinol Metab ; 2035-2041 ; June 2008
Sjogren syndrome and localised nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?
The authors report 8 patients with Sjogren syndrome (SS) and localised nodular cutaneous amyloidosis and recommend that SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity.
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Arthritis Rheum ; 1992-1999 ; July 2008
Hypochondroplasia and acanthosis nigricans: a new syndrome caused by the p.Lys650Thr mutation in the FGFR3 gene?
Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast growth factor receptor 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papilomatous pigmented hyperkeratosis of the skin which has been recognised in some genetic disorders more severe than HCH involving the FGFR3 gene. A clinical, biochemical and radiological study was performed on the patient and 12 members of the patient’s family. In addition, exon 11 and 13 of FGFR3 were analyzed. Results: The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, demonstrating the coexistence of both conditions due to the same mutation. It might represent a true complex which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.
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Eur J Endocrinol ; Epub ahead of print ; 26 June 2008
Rett syndrome: evaluation of CSF neurotransmitters and folate in 25 patients
Rett syndrome is a progressive neurodevelopmental entity caused by mutations in the MECP2 gene. It has been postulated that there are alterations in the levels of certain neurotransmitters and folate in the pathogenesis of this disease. Here the authors evaluated CSF folate, biogenic amines and pterines in 25 Rett syndrome patients. Treatment with oral folinic acid was started in those cases with low folate. Their results support that folinic acid supplementation has no significant effects on the course of the disease. They report discrete and novel neurotransmitter abnormalities that may contribute to the pathogenesis of RD highlighting the need for further studies on CSF neurotransmitters in clinically and genetically well characterised patients.
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Brain Dev ; Epub ahead of print ; 20 June 2008
Budd-Chiari syndrome: long-term results and prognostic factors of transjugular intrahepatic portosystemic shunt
Budd-Chiari syndrome (BCS) is a rare, life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. One hundred twenty-four BCS patients treated with TIPS in 6 European centres were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation. Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival.
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Gastroenterology ; Epub ahead of print ; 21 May 2008
Langerhans cell histiocytosis: incidence in children
Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology. To determine incidence, the authors identified all children <15-years old treated for LCH between 1992-2001 at the Karolinska University Hospital in Stockholm. They also contacted the Departments of dermatology, orthopedics, and neurosurgery for possible additional patients. Twenty-nine children (16 males) with LCH were identified, with a median age at diagnosis of 3.8 years. All children but one had a definitive diagnosis of LCH. The minimum incidence of LCH is estimated to 8.9/10(6) children per year. At diagnosis, 20 children (69%) had single system and 9 (31%) multisystem manifestations. Interestingly, 22 children (76%) were diagnosed during the fall and winter
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Pediatr Blood ; 76-81 ; July 2008
Stem Cells
Rett syndrome: transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo
Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) transcription factors act as effectors of neurogenesis in the brain, with MEF2C the predominant isoform in developing cerebrocortex. Here, the authors show that conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size. NSC proliferation and survival were not affected. Conditional null mice surviving to adulthood manifested more immature electrophysiological network properties and severe behavioural deficits reminiscent of Rett syndrome, an autism-related disorder. These data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex.
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PNAS ; 9397-9402 ; 8 July 2008
Gene Therapy
Wiskott-Aldrich syndrome: improved lentiviral vectors mimic endogenous expression profiles throughout haematopoiesis
Wiskott-Aldrich syndrome (WAS) is a rare hereditary immune deficiency with recessive inheritance linked to the X chromosome and characterised by the association of thrombocytopenia with small-sized platelets, eczema and repeated infections. Gene therapy requires highly efficient and well-controlled vectors. The authors designed a novel lentiviral vector that sustained high transgene levels along the whole lymphoid lineage in vivo and clearly improved transgene levels in in vitro and in vivo hCD34+-derived macrophages, erythroid cells, megakaryocytes and B cells while supporting a high expression in human T cells.
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Gene Ther ; 930-941 ; June 2008
Therapeutic Approaches
Cystic fibrosis: mortality trends among infants and young children in Spain
This paper analyses mortality trends among infants and young children who died with a diagnosis of cystic fibrosis (CF) in Spain between 1981-2004. During this period, overall CF mortality in Spain decreased by an annual average of 4% in both sexes. Mortality rates declined for patients under 15 years while it rose for those over 15 years. Mean and median age at death from CF increased with time, from a median of 4.4 years (males) and 3.8 years (females) in 1981 to 20.1 years (males) and 17.7 years (females) in 2004. The results of this study show that, as in other Western countries, CF is no longer a major cause of death in childhood, and that the challenge now lies in caring for adults who suffer from this disease. Other authors have shown that the decrease in mortality is associated with improved treatment for pulmonary complications, better nutritional control and lung transplants.
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Eur J Epidemiol ; 523-529 ; 2008
Leukaemia: PML targeting eradicates quiescent initiating cells
The existence of a small population of cancer-initiating cells responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse. Chronic myeloid leukaemia is a paradigmatic haematopoietic stem cell disease in which the leukaemia-initiating-cell pool is not eradicated by current therapy, leading to disease relapse on drug discontinuation. Here the authors define the critical role of the promyelocytic leukaemia protein (PML) tumour suppressor in haematopoietic stem cell maintenance, and present a new therapeutic approach for targeting quiescent leukaemia-initiating cells and possibly cancer-initiating cells by pharmacological inhibition of PML.
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Nature ; 1072-1078 ; 19 June 2008
Marfan syndrome: angiotensin II blockade and aortic-root dilation
Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan syndrome, a heritable condition that affects the connective tissue. Recent data from mouse models of the disease suggest that aortic-root enlargement is caused by excessive signalling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). The authors of this study evaluated the clinical response to ARBs in 18 paediatric Marfan syndrome patients who had severe aortic-root enlargement. They found that the use of ARB therapy in patients with Marfan syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.
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N Engl J Med ; 2787-2795 ; 26 June 2008
Diagnostic Approaches
Autoimmune hepatitis: a simplified set of criteria for diagnosis
Autoimmune hepatitis is a chronic inflammatory liver disease of unknown cause that is nearly always associated with the presence of autoantibodies. Diagnosis of the disorder may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The study finds that a reliable diagnosis of AIH can be made using a very simple diagnostic score.
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Hepatology ; 169-176 ; July 2008
Epidermolysis bullosa with pyloric atresia: immunofluorescence analysis of villous trophoblasts - a tool for prenatal diagnosis
Genetic mutations invalidating the genes for integrin alpha6beta4 and, in some cases, plectin, are associated with junctional and simplex epidermolysis bullosa with pyloric atresia (PA-JEB and PA-EBS), respectively. These recessive inherited conditions are characterised by pregnancies with fetal bullae, pyloric atresia, polyhydramnios, and neonatal mucocutaneous blistering, which often results in early postnatal demise. To date, first-trimester DNA-based prenatal diagnosis is not applicable to affected kindred carrying as yet unidentified genetic mutations. Here, the authors show that first-trimester chorionic villi strongly express both integrin alpha6beta4 and plectin, which persist throughout the pregnancy. They implemented 25 prenatal diagnoses in kindred at risk for the disorder by immunomapping, which identified three PA-JEB-affected foetuses and 22 healthy ones. In 19 cases, including the three PA-JEB pregnancies that were prematurely terminated, the results were confirmed by chorionic villous DNA-based tests, which also led to the identification of seven previously unreported mutations in the alpha6beta4 integrin genes. The authors’ prediction was further sustained by the birth of 22 healthy babies. These results validate chorionic villi immunofluorescence examination as a tool for prenatal diagnosis of PA-JEB and PA-EBS.
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J Invest Dermatol ; Epub ahead of print ; 19 June 2008

Orphan Drugs
An assessment of orphan drug development across Europe: policies encouraging innovation prove crucial at the national level
An article published in the journal Drug Discovery Today assesses the orphan drug playing field in Europe, taking stock of accomplishments as well as areas where growth is needed. With the milestone of 500 medicinal products receiving orphan designation in Europe in 2007, it is clear that the mechanisms put in place less than ten years ago to encourage innovation in the field of rare disease treatments are working. In this article, the authors consider orphan drug development from a national perspective, breaking down the number of designations per country and examining whether the level of pharmaceutical innovation within a country matched its orphan drug development performance. The study found that of the 521 orphan designations delivered by the end of 2007, 300 (58%) were originally developed by European companies or institutions, and the remainder originated from outside Europe (predominantly from the USA). Of the 300 European designations, distributed amongst companies from 12 of the 27 EU member state countries, plus Norway and Switzerland, the authors found a positive correlation between orphan drug development and general innovation, measured via the annual European Innovation Scoreboard which assesses the innovation performance of EU member states.

Switzerland, Denmark and Sweden, leaders in orphan drug development, were also the top ranking countries in innovation performance from 2002–2006. Biopharmaceutical innovation is an even clearer indicator of orphan drug development performance. Using three key measures, each of which represents a consecutive stage in drug development: biomedical scientific output, innovation in pharmaceutical development (measured in terms of R&D expenditure, pharmaceutical patent applications and the number of SMEs active within the pharmaceutical sector), and pharmaceutical output (in terms of orphan designations), the study found a strong positive correlation between pharmaceutical innovation and orphan drug designations. Of the three stages of innovation, the second (pharmaceutical development) proved particularly pertinent to the production of orphan drug designation. As the article notes, not all countries can easily translate biotechnological discovery into concrete innovation, particularly smaller countries which often do not have the industrial resources needed. This is a factor to keep in mind when developing innovation-based policies at the national and European levels to encourage the development of orphan drugs in Europe. Countries with more pharmaceutical SMEs, and countries that invest more in pharmaceutical R&D, do develop more orphan drugs. Thus innovation policies need to encourage development at these levels.
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FDA approves first drug for chorea in Huntington disease
The U.S. Food and Drug Administration has announced approval for Xenazine (tetrabenazine) manufactured by Prestwick Pharmaceuticals, Inc., Washington, D.C., for the treatment of chorea in patients with Huntington disease. Xenazine is the first treatment of any kind approved in the U.S. for any symptom of Huntington disease.

Partnersearch, Job Opportunities
First Myotubular Trust Call for Proposals
The Myotubular Trust was founded as a charity in 2006 to raise money for research toward a cure and/or treatment for myotubular myopathy. There are three genetically distinct forms of Myotubular Myopathy. The most common is x-linked, and also the most severe. It usually presents in the newborn period and is characterised by breathing and swallowing difficulties in addition to the general muscle weakness. The other forms, either dominant or recessive in inheritance, are usually milder and vary widely.

The Myotubular Trust has established a scientific board, which will make a recommendation to the trustees on which projects to fund. A first call for research projects will be held in mid- to late-September 2008. Completed applications will be due by mid December 2008. Awards will be made in April 2009. The trust seeks to fund projects that will help find a cure or a treatment for any of the three types of myotubular myopathy, focusing on research that would not generally be funded by public or industrial sources. This call will be open to European research bodies only and seeks 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 with whom he or she wants to work.
For further information
For email enquiries


News from the Patients' Associations
International cutis laxa meeting benefits both patients and professionals

The only patient association for rare disease cutis laxa held its first truly international meeting in May, a triple-pronged event that allowed for the exchange between patients from all over the world, as well as an interchange between experts of this extremely rare disorder, and, finally, the meeting of patients and professionals, which included medical consultation sessions.

The third Paris Information Day for Cutis Laxa, held 9-10 May, for the first time included patients from some far-flung corners of the world, including Argentina, Lebanon, and Australia. Three volunteer interpreters were on hand to help smooth communication, allowing for a true exchange of experiences between patients of this rare disease, which is characterised by degenerative changes in elastic fibres resulting in loose, pendulous skin, and possible anomalies in the vocal cords, bones, cartilage, blood vessels, bladder, kidney, digestive system, heart and lungs. Organised by patient group Cutis Laxa Internationale in collaboration with the French Reference Centre for Rare Diseases with Skin Symptoms (MAGEC), located at Necker Children’s Hospital in Paris, the reference centre team of experts conducted individual consultations for every sufferer, whether from France or abroad. Medical files were evaluated and the professional staff was able to assess whether patient care was appropriate and relevant. Consultations with other specialists, such as cardiologists or geneticists were organised the same afternoon. The accompanying conference, open to both professionals and patients, included the sessions, The Centre of Reference for Genetic Disorders with Cutaneous Expression; Tribology, an experimental device: A new approach for Cutis Laxa; and Rights and ethics in the specific context of rare disorders. The sessions included time for questions from the audience. A parallel event was hosted in Saint Louis, Missouri, for patients in the USA who were unable to attend the Paris-based conference. It was the very first information meeting for cutis laxa patients held in the USA and included genetic testing for the eight patients present.

Cutis Laxa Internationale currently counts 142 members. It is estimated that there are 500-1000 patients worldwide. No official registry exists, but the website serves as a base for recording the profile and statistics of patients.


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

What's on Where?
Inaugural Birt Hogg Dube Syndrome Symposium
Date: 3 September 2008
Venue: Roskilde, Denmark

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

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

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

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

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

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

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

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

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

International Society for Cellular Therapy Europe First Regional Meeting
Date: 14-16 September 2008
Venue: Antwerp, Belgium

The International Society for Cellular Therapy (ISCT) Europe Regional Meeting programme is attractive for translational researchers, laboratory practitioners and clinicians. General/educational presentations will be followed by interactive workshops on topical items and oral abstract sessions to present recent progress. Technical issues will be presented. Also featured is a meeting with EU representatives to discuss future EU-funding of cell therapy projects.
For further details

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

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

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

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

European Research Conference in Paediatric Neurology
Date: 3-4 October 2008
Venue: Tubingen, Germany

The meeting enables researchers to meet colleagues in the same field in order to facilitate collaboration, and to foster the building of research networks. Most of the meeting is therefore reserved for discussion and interaction in the following working groups: Neurometabolic diseases, Autoimmune diseases, Neonatal Neurology, Neurodegeneration and Neuroprotection, Epilepsy, Neuromuscular Diseases, Genetics, Developmental Neurology, and Infection-related inflammatory CNS diseases.
For further details

Rare Diseases Warsaw 2008: MPS and Rare Diseases Conference
Date: 3-5 October 2008
Venue: Warsaw, Poland

The purpose of the conference is to introduce aspects of treatment and specialised medical care for rare genetic diseases and to strengthen cooperation and the exchange of experience between scientific environments and government institutions, as well as patient associations from Central and Eastern Europe.
For further details

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

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

International Conference on Genetic and Molecular Basis of Rare Kidney Disorders
Date: 9-11 October 2008
Venue: Bergamo, Italy

This conference will bring together research geneticists, nephrologists, clinicians and experts from related specialties to discuss the latest findings on and around the core themes of rare kidney diseases. The speakers will cover a varieties of topics: glomerular filter structure and function in health and diseased states, genetic basis of glomerular diseases (focal and segmental glomerulosclerosis, hematuric syndromes, dense deposit disease), inherited disorders of tubular function, and renal developmental disorders. The Conference Keynote lecture will be delivered by Nobel Laureate professor Peter Agre, who will discuss the impact that the discovery of aquaporins has had on the understanding of physiologic and pathologic states.
For further details

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

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

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

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

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

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

Annual Meeting of the Italian Network for Promotion of Folic Acid and Prevention of Congenital Defects
Date: 17 October 2008
Venue: Rome, Italy

Current debate pivots on how to potentiate actions towards periconceptional supplementation, as well as on possible complementary strategies, such as nutritional education as well as generalised or facultative fortification. The principal issues discussed in this meeting relate to the risk-benefit analysis of prevention approaches using folic acid.
For further details

Dystonia Europe 2008
Date: 17-19 October 2008
Venue: Hamburg, Germany

This conference will provide a forum for discussion of the latest developments in clinical features, treatment and research of dystonia, with presentations from a broad range of leading experts from Europe and North America.
For further information

First Congress of the African Society for Immunodeficiencies
Date: 30 October-1 November 2008
Venue: Casablanca, Morocco

Organised by the African Society for Primary Immunodeficiencies in conjunction with the Moroccan Societies for Paediatrics and for Haematologies, themes to be explored during this congress include primary immunodeficiencies (PIDS) and the skin; PIDs and the lungs; PIDs and the adult patient; PIDS and lymphomas; PIDs and nutrition; and PIDs and vaccines.
For further information

ESF-UB Conference in Biomedicine: Biobanks
Date: 1-6 November 2008
Venue: Sant Feliu de Guixols, Spain

The ESF-UB Conference on Biobanks will be focused on providing an open forum of discussion on all aspects involved in the governance, management and use of human biobanks, technical solutions, ethical, legal, and social aspects, also providing participants with a broad overview of the existing models of biobanks and the international initiatives on population-based and disease-oriented biobanks. A limited number of grants are available for young researchers to cover the conference fee and possibly part of the travel costs.
For further information

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

Details to follow shortly.
For further information

International Symposium on Rare Diseases: Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies
Date: 16-18 November 2008
Venue: Valencia, Spain

The symposium will permit exploration of the state-of–the-art of neuromuscular diseases as a whole, including muscular dystrophies, mitochondrial disorders, peripheral neuropathies, spinal muscular atrophy, motoneurone disease and Friedreich ataxia, and will explore pathogenic mechanisms and molecular targets for the different diseases, as a forum for discussion of the rational basis of the new therapeutic approaches.
For further information

From Cardiac Remodelling to Biotherapies: Homage to Ketty Schwartz
Date: 29 November 2008
Venue: Paris, France

The programme will include cardiac phenotype and remodelling in cardiopathies; genetics and pathophysiology of cardiac diseases; and therapies of cardiac and skeletal muscle diseases.
For further information

8th Balkan Meeting on Human Genetics
Date: 14-18 May 2009
Venue: Cavtat, Croatia

"Rare diseases – public policy, research, diagnosis and management" is one of the topics featured in this conference. Deadline to submit an abstract is 20 January 2009.
For further information

7th World Congress on Melanoma
Date: 12-16 May 2009
Venue: Vienna, Austria

A joint meeting with the 5th Congress of the European Association of Dermato-Oncology. Clinicians and researchers will focus on the state of the art in prevention, recognition, and treatment of cutaneous neoplasms covering melanoma and non melanoma skin cancer as well as lymphomas and rare skin tumours. Deadline for submission of abstracts: 31 January, 2009.
For further information


Press & Publications
A method to capture the geographic distribution of rare disorders
An article in the free access International Journal of Health Geographics evaluates a method for detecting clustering for a rare disorder of unknown etiology. The sensitivity, specificity and probability of false positives were evaluated for the procedure, demonstrated on two regions, each of which had a five-year cohort of birth and cases of a rare developmental disorder. A procedure to characterize geographic distributions of rare disorders in cohorts concludes that “for truly exploratory research on a rare disorder, false positive clusters can cause costly diverted research efforts”. As the procedure described is able to limit false positives, 'crude' clusters can be identified, which can be investigated for demographic risk factors “to focus exploration for geographically-based environmental exposure on areas of otherwise unexplained raised incidence".

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