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Sample records for identify rare disease

  1. Identifying rare events in rare diseases.

    PubMed

    Attiyeh, Edward F; Maris, John M

    2015-04-15

    Utilizing genomic signatures from diagnostic tumor samples to forecast clinical behavior and response to therapy has long been a goal, and we are now poised to further refine how we can identify the relatively rare patients with aggressive neuroblastoma masquerading as patients with a more benign form of the disease. Clin Cancer Res; 21(8); 1782-5. ©2014 AACR. See related article by Oberthuer et al., p. 1904. PMID:25424848

  2. New Test Helps Identify Rare Genetic Diseases in Newborns

    MedlinePlus

    ... fullstory_159097.html New Test Helps Identify Rare Genetic Diseases in Newborns 'Next-generation gene sequencing' could ... greatly improve doctors' ability to quickly diagnose rare genetic diseases in newborns, researchers say. The new test ...

  3. New Test Helps Identify Rare Genetic Diseases in Newborns

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_159097.html New Test Helps Identify Rare Genetic Diseases in Newborns ' ... 31, 2016 MONDAY, May 30, 2016 (HealthDay News) -- New gene screening methods may greatly improve doctors' ability ...

  4. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases

    PubMed Central

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-01-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases. PMID:26924528

  5. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases.

    PubMed

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-03-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases. PMID:26924528

  6. The UK10K project identifies rare variants in health and disease

    PubMed Central

    2015-01-01

    The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. PMID:26367797

  7. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes

    PubMed Central

    Christodoulou, Katja; Wiskin, Anthony E; Gibson, Jane; Tapper, William; Willis, Claire; Afzal, Nadeem A; Upstill-Goddard, Rosanna; Holloway, John W; Simpson, Michael A; Beattie, R Mark; Collins, Andrew

    2013-01-01

    Background Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. Objective To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. Design DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. Results Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. Conclusion For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this

  8. RARE DISEASES LIST

    EPA Science Inventory

    The rare disease list includes rare diseases and conditions for which information requests have been made to the Office of Rare Diseases. A rare disease is defined as a disease or condition for which there are fewer than 200,000 affected persons alive in the United States. The Of...

  9. Not so Rare, Rare Diseases

    ERIC Educational Resources Information Center

    Waldman, H. Barry; Perlman, Steven P.; Munter, Beverly L.; Chaudhry, Ramiz A.

    2008-01-01

    A rare disease or condition is defined by federal legislation such that it: (1) affects less than 200,000 persons in the U.S.; or (2) affects more than 200,000 persons in the U.S. but for which there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered from…

  10. Rare Parotid Gland Diseases.

    PubMed

    Sanan, Akshay; Cognetti, David M

    2016-04-01

    The differential diagnosis for "rare" parotid gland diseases is broad and encompasses infectious, neoplastic, autoimmune, metabolic, and iatrogenic etiologies. The body of knowledge of parotid gland diseases has grown owing to advances in imaging and pathologic analysis and molecular technology. This article reviews rare parotid diseases, discussing the respective disease's clinical presentation, diagnosis, imaging, pathogenesis, treatment, and prognosis. PMID:26902981

  11. Rare Disorders and Diseases

    ERIC Educational Resources Information Center

    Umlauf, Mary; Monaco, Jana; FitzZaland, Mary; FitzZaland, Richard; Novitsky, Scott

    2008-01-01

    According to the National Organization for Rare Disorders (NORD), a rare or "orphan" disease affects fewer than 200,000 people in the United States. There are more than 6,000 rare disorders that, taken together, affect approximately 25 million Americans. "Exceptional Parent" ("EP") recognizes that when a disorder affects a child or adult, it…

  12. Collecting rare diseases

    PubMed Central

    Ekins, Sean

    2014-01-01

    This editorial introduces the F1000Research rare disease collection. It is common knowledge that for new treatments to be successful there has to be a partnership between the many interested parties such as the patient, advocate, disease foundations, the academic scientists, venture funding organizations, biotech companies, pharmaceutical companies, NIH, and the FDA. Our intention is to provide a forum for discussion and dissemination of any rare disease related topics that will advance scientific understanding and progress to treatments. PMID:25580231

  13. Rare Diseases Clinical Research Network

    MedlinePlus

    ... RDCRN? Aims of the Rare Diseases Clinical Research Network Contact Us RDCRN Members Login Accessibility Disclaimer The Rare Diseases Clinical Research Network is an initiative of the Office of Rare ...

  14. Ethical issues in rare diseases.

    PubMed

    Borski, Krzysztof

    2015-01-01

    Scientific, technical and medical advances continue to raise consequential ethical questions and dilemmas also in the field of rare diseases. Difficult and complex issues of medical ethics in rare diseases are presented and several different ethical problems, like those regarding inborn errors of metabolism, are discussed. PMID:26982768

  15. Detection of a Distinctive Genomic Signature in Rhabdoid Glioblastoma, A Rare Disease Entity Identified by Whole Exome Sequencing and Whole Transcriptome Sequencing123

    PubMed Central

    Koh, Youngil; Park, Inho; Sun, Chung-Hyun; Lee, Seungmook; Yun, Hongseok; Park, Chul-Kee; Park, Sung-Hye; Park, Joo Kyung; Lee, Se-Hoon

    2015-01-01

    We analyzed the genome of a rhabdoid glioblastoma (R-GBM) tumor, a very rare variant of GBM. A surgical specimen of R-GBM from a 20-year-old woman was analyzed using whole exome sequencing (WES), whole transcriptome sequencing (WTS), single nucleotide polymorphism array, and array comparative genomic hybridization. The status of gene expression in R-GBM tissue was compared with that of normal brain tissue and conventional GBM tumor tissue. We identified 23 somatic non-synonymous small nucleotide variants with WES. We identified the BRAF V600E mutation and possible functional changes in the mutated genes, ISL1 and NDRG2. Copy number alteration analysis revealed gains of chromosomes 3, 7, and 9. We found loss of heterozygosity and focal homozygous deletion on 9q21, which includes CDKN2A and CDKN2B. In addition, WTS revealed that CDK6, MET, EZH2, EGFR, and NOTCH1, which are located on chromosomes 7 and 9, were over-expressed, whereas CDKN2A/2B were minimally expressed. Fusion gene analysis showed 14 candidate genes that may be functionally involved in R-GBM, including TWIST2, and UPK3BL. The BRAF V600E mutation, CDKN2A/2B deletion, and EGFR/MET copy number gain were observed. These simultaneous alterations are very rarely found in GBM. Moreover, the NDRG2 mutation was first identified in this study as it has never been reported in GBM. We observed a unique genomic signature in R-GBM compared to conventional GBM, which may provide insight regarding R-GBM as a distinct disease entity among the larger group of GBMs. PMID:26310374

  16. [Adult-onset rare diseases].

    PubMed

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-01

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.). PMID:24566697

  17. A Network Approach to Rare Disease Modeling

    NASA Astrophysics Data System (ADS)

    Ghiassian, Susan; Rabello, Sabrina; Sharma, Amitabh; Wiest, Olaf; Barabasi, Albert-Laszlo

    2011-03-01

    Network approaches have been widely used to better understand different areas of natural and social sciences. Network Science had a particularly great impact on the study of biological systems. In this project, using biological networks, candidate drugs as a potential treatment of rare diseases were identified. Developing new drugs for more than 2000 rare diseases (as defined by ORPHANET) is too expensive and beyond expectation. Disease proteins do not function in isolation but in cooperation with other interacting proteins. Research on FDA approved drugs have shown that most of the drugs do not target the disease protein but a protein which is 2 or 3 steps away from the disease protein in the Protein-Protein Interaction (PPI) network. We identified the already known drug targets in the disease gene's PPI subnetwork (up to the 3rd neighborhood) and among them those in the same sub cellular compartment and higher coexpression coefficient with the disease gene are expected to be stronger candidates. Out of 2177 rare diseases, 1092 were found not to have any drug target. Using the above method, we have found the strongest candidates among the rest in order to further experimental validations.

  18. Resources, challenges and way forward in rare mitochondrial diseases research.

    PubMed

    Rajput, Neeraj Kumar; Singh, Vipin; Bhardwaj, Anshu

    2015-01-01

    Over 300 million people are affected by about 7000 rare diseases globally. There are tremendous resource limitations and challenges in driving research and drug development for rare diseases. Hence, innovative approaches are needed to identify potential solutions. This review focuses on the resources developed over the past years for analysis of genome data towards understanding disease biology especially in the context of mitochondrial diseases, given that mitochondria are central to major cellular pathways and their dysfunction leads to a broad spectrum of diseases. Platforms for collaboration of research groups, clinicians and patients and the advantages of community collaborative efforts in addressing rare diseases are also discussed. The review also describes crowdsourcing and crowdfunding efforts in rare diseases research and how the upcoming initiatives for understanding disease biology including analyses of large number of genomes are also applicable to rare diseases. PMID:26180633

  19. Resources, challenges and way forward in rare mitochondrial diseases research

    PubMed Central

    Rajput, Neeraj Kumar; Singh, Vipin; Bhardwaj, Anshu

    2015-01-01

    Over 300 million people are affected by about 7000 rare diseases globally. There are tremendous resource limitations and challenges in driving research and drug development for rare diseases. Hence, innovative approaches are needed to identify potential solutions. This review focuses on the resources developed over the past years for analysis of genome data towards understanding disease biology especially in the context of mitochondrial diseases, given that mitochondria are central to major cellular pathways and their dysfunction leads to a broad spectrum of diseases. Platforms for collaboration of research groups, clinicians and patients and the advantages of community collaborative efforts in addressing rare diseases are also discussed. The review also describes crowdsourcing and crowdfunding efforts in rare diseases research and how the upcoming initiatives for understanding disease biology including analyses of large number of genomes are also applicable to rare diseases. PMID:26180633

  20. Contraception, pregnancy and rare respiratory diseases.

    PubMed

    Lara, Beatriz; Fornet, Inocencia; Goya, María; López, Francisco; De Miguel, José Ramón; Molina, María; Morales, Pilar; Quintana, Esther; Salicrú, Sabina; Suárez, Elena; Usetti, Piedad; Zurbano, Felipe

    2012-10-01

    Three percent of rare diseases are pneumopathies. Improvements in survival and quality of life have led to a new situation where patients with rare respiratory diseases want to plan their reproductive lives. The intention of this review is to present the experience accumulated in the field of the reproductive health of these women. In several rare respiratory diseases, a genetic base has been identified. The combination of preimplantation genetic diagnosis, assisted reproduction and molecular biology techniques enable embryos to be studied genetically before being transplanted into the uterus. Therefore, the risk for transmitting a certain disease or chromosome alteration may be avoided in high-risk couples, and prenatal diagnoses may be done by chorionic villus sampling or amniocentesis. As a general rule, contraceptive methods should be personalized by evaluating the general state of female patients as well as their possibilities for pregnancy, complications and the future possibility of lung transplantation. In lymphangioleiomyomatosis and primary pulmonary hypertension, pregnancy is considered a contraindication. In the former, there is a very high risk for pneumothorax and loss of lung function. In the latter, mortality reaches 33%. In cystic fibrosis, it is estimated that each year 4% of patients become pregnant and there is no observed loss in lung function. There are special circumstances in childbirth that should be considered as well as specific anesthesia risks. The present review suggests that the decision about contraceptive methods, pregnancy as a contraindication or conditions for managing a pregnancy should be both individualized and multidisciplinary. PMID:22771004

  1. Genetic and Rare Diseases Information Center

    MedlinePlus

    ... and Students guides/pages/99/teachers-and-students Teaching Resources News 1 In The Spotlight News Archive ... about rare or genetic diseases in English or Spanish. text go Browse Diseases View diseases by alphabetical ...

  2. [Rare diseases from a life insurance perspective].

    PubMed

    Senn, A; Filzmaier, K

    2015-12-01

    A rare disease is defined as a disease that affects a maximum of 5 in 10,000 people. As of today there are roughly 7000 different rare diseases known. On account of this one can say that "rare diseases are rare, but people affected by them are common". For Germany this amounts to: 4 million people that are affected by a rare disease. Diagnosis, therapeutic options and prognosis have substantially improved for some of the rare diseases. Besides the general medical advances--especially in the area of genetics--this is also due to networking and sharing information by so-called Centres of Competence on a national and international scale. This results in a better medical care for the corresponding group of patients. Against this backdrop, the number of people applying for life assurance who are suffering from a complex or rare disease has risen steadily in the last years. Due to the scarce availability of data regarding long-term prognosis of many rare diseases, a biomathematical, medical and actuarial expertise on the part of the insurer is necessary in order to adequately assess the risk of mortality and morbidity. Furthermore there is quite a focus on the issue of rare diseases from not only politics but society as well. Therefore evidence based medical assessment by insurers is especially important in this group of applicants--thinking of legal compliance and reputational risk. PMID:26775306

  3. TRICARE; rare diseases definition. Final rule.

    PubMed

    2010-08-01

    This final rule revises the definition of rare diseases to adopt the definition of a rare disease as promulgated by the National Institutes of Health, Office of Rare Diseases. The rule modification will result in the definition used by the TRICARE program for a rare disease to be consistent with the definition used by the National Institutes of Health and the Food and Drug Administration. TRICARE has generally been applying the broader National Institutes of Health and Food and Drug Administration definitions when making coverage decisions for treatments; therefore, there will be no practical changes for beneficiaries. PMID:20690233

  4. [RARE DISEASES DTC: DIAGNOSIS, TREATMENT AND CARE].

    PubMed

    Mendlovic, Joseph; Barash, Hila; Yardeni, Hadar; Banet-Levi, Yonit; Yonath, Hagith; Raas-Rothschild, Annick

    2016-04-01

    Rare diseases are chronic, progressive genetic disorders, which affect around 6-8% of the general population, mainly children. Therefore, in Israel approximately 500,000 people are probably affected by a rare disease. In this article, we review some of the issues pertaining to rare diseases, such as the need for accurate diagnosis which is necessary not only for specific care and treatment but also for informed family planning. In addition, we review the impact of the activities of patients' organizations on the awareness of rare diseases and their involvement in the creation of the Orphan Drug Act, which was the leading point on the way to drug development worldwide. During the last few years networks for reaching leading specialists' opinions on the way to proper diagnosis were created. Thereafter, the next generation genetic technologies, such as exome sequencing, have been a revolution in terms of options and hope for patients with rare undiagnosed diseases. Patients with rare diseases and their families are a challenge to the health care system, not only in terms of diagnosis and therapy, but also in terms of special needs. In addition, deciphering molecular pathways of rare diseases might be the key for understanding molecular events involved in common disorders. We emphasize the duty to ensure appropriate capacity and equal access to follow-up and clinical management of patients with rare diseases in Israel. PMID:27323543

  5. 75 FR 47458 - TRICARE; Rare Diseases Definition

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-06

    ... Register (62 FR 627-631) clarifying the TRICARE exclusion of unproven drugs, devices and medical treatments... July 24, 2009 (74 FR 36639-36640). No comments were received on the proposed rule before the comment... promote research and collaboration on rare and orphan diseases. The Rare Diseases Act of 2002 (Pub. L....

  6. The Italian National Rare Diseases Registry

    PubMed Central

    Taruscio, Domenica; Kodra, Yllka; Ferrari, Gianluca; Vittozzi, Luciano

    2014-01-01

    Introduction Rare disease registries are a priority at European level and specific actions are being implemented by the European Commission to support their development. In Italy, a National Registry of rare diseases has been established in 2001 as a network of regional registries. The latter have gradually been established and the full coverage of the Italian territory was attained during 2011. Methods Here we describe the basic features of the National Registry of rare diseases; the activities carried out to promote consistent operations in the regional registries; and the overall quality and composition of the records collected. Results After a validation process, including removal of duplicate records, 110,841 records of patients with rare diseases, single and with group denominations, are stored in the National Registry of rare diseases. They correspond to the overall diagnoses communicated to national registry by regional registries up to 30 June 2012. The quality of the data collected by the the National Registry of rare diseases has been assessed with respect to completeness and consistency of procedures. Variables characterising case and diagnosis showed a very limited number of missing values. Records reported at least one case of 485 rare conditions. Discussion To date, the National Registry of rare diseases is a surveillance system with the main objective of producing epidemiologic evidence on rare diseases in Italy, and of supporting policy making and health services planning. Data quality still represents a limitation for any sound epidemiological estimate of rare diseases in Italy. However, improvements of the quality of collected data and the completeness of case notifications should be strengthened. PMID:24922301

  7. The European Union Committee of Experts on Rare Diseases: three productive years at the service of the rare disease community

    PubMed Central

    2014-01-01

    The European Union Committee of Experts on Rare Diseases was entrusted with aiding the European Commission in a number of tasks, ranging from the monitoring of initiatives, to recommending improvements and actions to be pursued in the future, in addition to helping strengthen liaison at both European and International levels in the field of rare diseases. The three-year mandate of the EUCERD drew to a close in July 2013 with an impressive record. The EUCERD has laid down the foundations for future work so as to continue to advance in the key areas that have been identified as of interest for the rare disease community at large: centres of expertise, European Reference Networks, patient registries and databases, newborn screening, and indicators for national rare disease plans/strategies. The work of the Committee should now be continued by the newly formed European Commission Expert Group on Rare Diseases. PMID:24580800

  8. Rare disease surveillance: An international perspective

    PubMed Central

    Elliott, Elizabeth J; Nicoll, Angus; Lynn, Richard; Marchessault, Victor; Hirasing, Remy; Ridley, Greta

    2001-01-01

    BACKGROUND: The International Network of Paediatric Surveillance Units (INoPSU) was established in 1998 and met formally for the first time in Ottawa, Ontario in June 2000. OBJECTIVES: To document the methodology and activities of existing national paediatric surveillance units; the formation of INoPSU; the diseases studied by INoPSU members; and the impact of such studies on education, public health and paediatric practice. METHODS: Directors of paediatric surveillance units in Australia, Britain, Canada, Germany, the Netherlands, Latvia, Malaysia, Papua New Guinea, New Zealand and Switzerland were asked to provide information on each unit’s affiliations, funding and staffing; the method of case ascertainment, the mailing list and response rates; and diseases studied. Original articles that reported data derived from units were identified by a search of an electronic database (MEDLINE), and additional information was obtained from units’ annual reports. RESULTS: Worldwide, 10 units (established from 1986 to 1997), use active national surveillance of more than 8500 clinicians each month to identify cases of rare or uncommon diseases in a childhood population (younger than 15 years of age) of over 47 million (monthly response rate 73% to 98%). By January 1999, units had initiated 147 studies on 103 different conditions, and 63 studies were completed. CONCLUSION: INoPSU enhances collaboration among units from four continents, providing a unique opportunity for simultaneous cross-sectional studies of rare diseases in populations with diverse geographical and ethnic characteristics. It facilitates the sharing of ideas regarding current methodology, ethics, the most appropriate means of evaluating units and their potential application. PMID:20084246

  9. Identifying rare variants associated with complex traits via sequencing

    PubMed Central

    Li, Bingshan; Liu, Dajiang J.; Leal, Suzanne M.

    2013-01-01

    Although genome-wide association studies have been successful in detecting associations with common variants, there is currently an increasing interest in identifying low frequency and rare variants associated with complex traits. Next-generation sequencing technologies make it feasible to survey the full spectrum of genetic variation in coding regions or the entire genome. Due to the low frequency of rare variants, coupled with allelic heterogeneity, however, the association analysis for rare variants is challenging and traditional methods are ineffective. Recently a battery of new statistical methods has been proposed for identifying rare variants associated with complex traits. These methods test for associations by aggregating multiple rare variants across a gene or a genomic region, or a group of variants in the genome. In this Unit, we describe key concepts for rare variant association for complex traits, survey some of the recent methods and discuss their statistical power under various scenarios, and provide practical guidance on analyzing next-generation sequencing data for identifying rare variants associated with complex traits. PMID:23853079

  10. Histamine: an undercover agent in multiple rare diseases?

    PubMed Central

    Pino-Ángeles, Almudena; Reyes-Palomares, Armando; Melgarejo, Esther; Sánchez-Jiménez, Francisca

    2012-01-01

    Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G-protein coupled receptors. Thus, histamine-related effects are the results of highly interconnected and tissue-specific signalling networks. Consequently, alterations in histamine-related factors could be an important part in the cause of multiple rare/orphan diseases. Bearing this hypothesis in mind, more than 25 rare diseases related to histamine physiopathology have been identified using a computationally assisted text mining approach. These newly integrated data will provide insight to elucidate the molecular causes of these rare diseases. The data can also help in devising new intervention strategies for personalized medicine for multiple rare diseases. PMID:22435405

  11. Histamine: an undercover agent in multiple rare diseases?

    PubMed

    Pino-Ángeles, Almudena; Reyes-Palomares, Armando; Melgarejo, Esther; Sánchez-Jiménez, Francisca

    2012-09-01

    Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G-protein coupled receptors. Thus, histamine-related effects are the results of highly interconnected and tissue-specific signalling networks. Consequently, alterations in histamine-related factors could be an important part in the cause of multiple rare/orphan diseases. Bearing this hypothesis in mind, more than 25 rare diseases related to histamine physiopathology have been identified using a computationally assisted text mining approach. These newly integrated data will provide insight to elucidate the molecular causes of these rare diseases. The data can also help in devising new intervention strategies for personalized medicine for multiple rare diseases. PMID:22435405

  12. Applying complement therapeutics to rare diseases.

    PubMed

    Reis, Edimara S; Mastellos, Dimitrios C; Yancopoulou, Despina; Risitano, Antonio M; Ricklin, Daniel; Lambris, John D

    2015-12-01

    Around 350 million people worldwide suffer from rare diseases. These may have a genetic, infectious, or autoimmune basis, and several include an inflammatory component. Launching of effective treatments can be very challenging when there is a low disease prevalence and limited scientific insights into the disease mechanisms. As a key trigger of inflammatory processes, complement has been associated with a variety of diseases and has become an attractive therapeutic target for conditions involving inflammation. In view of the clinical experience acquired with drugs licensed for the treatment of rare diseases such as hereditary angioedema and paroxysmal nocturnal hemoglobinuria, growing evidence supports the safety and efficacy of complement therapeutics in restoring immune balance and preventing aggravation of clinical outcomes. This review provides an overview of the candidates currently in the pharmaceutical pipeline with potential to treat orphan diseases and discusses the molecular mechanisms triggered by complement involved with the disease pathogenesis. PMID:26341313

  13. Collaboration for rare disease drug discovery research

    PubMed Central

    Litterman, Nadia K.; Rhee, Michele; Swinney, David C.; Ekins, Sean

    2014-01-01

    Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives. PMID:25685324

  14. Rare essentials: drugs for rare diseases as essential medicines.

    PubMed

    Stolk, Pieter; Willemen, Marjolein J C; Leufkens, Hubert G M

    2006-09-01

    Since 1977, the WHO Model List of Essential Medicines (EML), published by WHO, has provided advice for Member States that struggle to decide which pharmaceutical technologies should be provided to patients within their public health systems. Originating from outside WHO, an incentive system has been put in place by various governments for the development of medicines for rare diseases ("orphan drugs"). With progress in pharmaceutical research (e.g. drugs targeted for narrower indications), these medicines will feature more often on future public health agendas. However, when current definitions for selecting essential medicines are applied strictly, orphan drugs cannot be part of the WHO Essential Medicines Programme, creating the risk that WHO may lose touch with this field. In our opinion WHO should explicitly include orphan drugs in its policy sphere by composing a complementary Orphan Medicines Model List as an addition to the EML. This complementary list of "rare essentials" could aid policy-makers and patients in, for example, emerging countries to improve access to these drugs and stimulate relevant policies. Furthermore, inconsistencies in the current EML with regard to medicines for rare diseases can be resolved. In this paper we propose selection criteria for an Orphan Medicines Model List that could form a departure point for future work towards an extensive WHO Orphan Medicines Programme. PMID:17128345

  15. Families Seek a Greater Role in Search for Rare Disease Treatments

    ERIC Educational Resources Information Center

    Abbott, Natalie

    2011-01-01

    Of the nearly 7,000 rare diseases identified by the National Institutes of Health (NIH), only a few hundred currently have treatments. The development of therapies for rare diseases is often hampered by the special challenges of conducting the needed studies for rare disease drugs and medical devices, such as small numbers of patients and the fact…

  16. Clinical Trials for Rare Lung Diseases: Lessons from Lymphangioleiomyomatosis

    PubMed Central

    McCormack, Francis X.

    2010-01-01

    Abstract Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive neoplasm that causes gradual but often life-threatening cystic destruction of the lung. Advances in our understanding of the molecular and cellular pathogenesis have LAM have identified a number of promising targets for testing in therapeutic trials. However, the design, prioritization, organization, and implementation of clinical trials in rare lung diseases poses unique challenges, including geographically disperse populations, sluggish enrollment, off- label drug use, burdensome regulations, and paucity of validated surrogate endpoints. PMID:20235889

  17. New therapeutic targets in rare genetic skeletal diseases

    PubMed Central

    Briggs, Michael D; Bell, Peter A; Wright, Michael J; Pirog, Katarzyna A

    2015-01-01

    Introduction: Genetic skeletal diseases (GSDs) are a diverse and complex group of rare genetic conditions that affect the development and homeostasis of the skeleton. Although individually rare, as a group of related diseases, GSDs have an overall prevalence of at least 1 per 4,000 children. There are currently very few specific therapeutic interventions to prevent, halt or modify skeletal disease progression and therefore the generation of new and effective treatments requires novel and innovative research that can identify tractable therapeutic targets and biomarkers of these diseases. Areas covered: Remarkable progress has been made in identifying the genetic basis of the majority of GSDs and in developing relevant model systems that have delivered new knowledge on disease mechanisms and are now starting to identify novel therapeutic targets. This review will provide an overview of disease mechanisms that are shared amongst groups of different GSDs and describe potential therapeutic approaches that are under investigation. Expert opinion: The extensive clinical variability and genetic heterogeneity of GSDs renders this broad group of rare diseases a bench to bedside challenge. However, the evolving hypothesis that clinically different diseases might share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers. PMID:26635999

  18. AMPK As A Target in Rare Diseases.

    PubMed

    Cotán, David; Paz, Marina Villanueva; Alcocer-Gómez, Elizabet; Garrido-Maraver, Juan; Oropesa-Ávila, Manuel; de la Mata, Mario; Pavón, Ana Delgado; de Lavera, Isabel; Galán, Fernando; Ybot-González, Patricia; Sánchez-Alcázar, José A

    2016-01-01

    The AMP-activated protein kinase (AMPK) has emerged as an important sensor of signals that control cellular energy balance in all eukaryotes. AMPK is also involved in fatty acid oxidation, glucose transport, antioxidant defense, mitochondrial biogenesis and the modulation of inflammatory processes. The numerous roles of AMPK in cell physiological and pathological states justified the notable increase in the number of publications in previous years, with almost 1500 scientific articles relative to this kinase in 2014. Due to its role in maintaining energy balance, a dysfunction in AMPK signalling pathway may result in perturbations at the systemic level that contribute to the development of many disease conditions. Among them, more than 7000 poorly-known rare diseases are particularly of social and scientific interest because they are usually chronically debilitating or even lifethreatening and lack effective and safe treatment. Several authors have demonstrated AMPK alterations and the beneficial effect of treatments with drugs regulating AMPK activity in some of these low prevalence pathologies. Among these rare diseases in which AMPK can play an important pathological role are mitochondrial disorders, muscular dystrophies, cardiovascular diseases, neurodegenerative pathologies, or even some types of cancer for the importance of AMPK as a suppressor of cell proliferation. This review focuses on current knowledge about the pathophysiological roles of AMPK and future approaches as therapeutic targeting in rare diseases. PMID:26758671

  19. [Rare disease at a primary care facility].

    PubMed

    Ortega Calvo, M; García de la Corte, F; Iglesias Bonilla, P

    2007-11-01

    A pragmatic classification. Rare diseases (RD) might be a research target on primary care because their gift of scientific knowledge building. A rational scheme would be necessary for clinical and scientific findings. Retrospective long-term report of the most important RD achieved for a ten years period by a general practitioner at a non-urban primary care facility (Andalusia-Spain). Our results are classified as: a) rare adverse drug reactions (RADR); b) accurate RD diagnosis (RDD); and c) RD prevalence study (RDP). PMID:18275262

  20. Impact of rare diseases in oral health

    PubMed Central

    Molina-García, Ana; Castellanos-Cosano, Lizett; Posada-de la Paz, Manuel

    2016-01-01

    Background Rare diseases (RD) are those that present a lower prevalence than 5 cases per 10.000 population. The main objective of this review was to study the effect on oral health in rare diseases, while the secondary objective of the study is theme upgrade. Material and Methods Comparative observational case-control studies were analysed and a systematic review was conducted in PubMed. Each rare disease listed on the statistical data record of the Health Portal of the Ministry of Equality, Health and Social Policies Board of Andalusia was associated with “oral health”. The variables studied included dental, oral mucosa and occlusion alterations, oral pathologies (caries, periodontal disease) and other alterations (mouth breathing, parafunctional habits, etc). A bias analysis of the variable caries was conducted. Results Six RD were selected through our inclusion and exclusion criteria (hypogammaglobulinemia, Rett syndrome, Marfan syndrome, Prader-Willi syndrome, cystic fibrosis and Cri du chat syndrome) in a total of 8 publications, of which four trials were classified as high risk of bias and one of them as medium risk. There were not trials with low risk of bias. Conclusions The main statistically significant differences found by Syndrome compared to a control group were in Hypogammaglobulinemia with a greater tendency to enamel hypoplasia and dry mouth. The Rett syndrome had, as well, a greater tendency to an anterior open bite, ogival palate, bruxism, mouth breathing and tongue thrusting. Prader-Willi syndrome had a tendency of dental erosion, and Cri du chat syndrome showed a higher association to Tannerella forsythia. Key words:Rare diseases, oral health. PMID:27475682

  1. Massively parallel sequencing and rare disease

    PubMed Central

    Ng, Sarah B.; Nickerson, Deborah A.; Bamshad, Michael J.; Shendure, Jay

    2010-01-01

    Massively parallel sequencing has enabled the rapid, systematic identification of variants on a large scale. This has, in turn, accelerated the pace of gene discovery and disease diagnosis on a molecular level and has the potential to revolutionize methods particularly for the analysis of Mendelian disease. Using massively parallel sequencing has enabled investigators to interrogate variants both in the context of linkage intervals and also on a genome-wide scale, in the absence of linkage information entirely. The primary challenge now is to distinguish between background polymorphisms and pathogenic mutations. Recently developed strategies for rare monogenic disorders have met with some early success. These strategies include filtering for potential causal variants based on frequency and function, and also ranking variants based on conservation scores and predicted deleteriousness to protein structure. Here, we review the recent literature in the use of high-throughput sequence data and its analysis in the discovery of causal mutations for rare disorders. PMID:20846941

  2. The discovery of medicines for rare diseases

    PubMed Central

    Swinney, David C; Xia, Shuangluo

    2015-01-01

    There is a pressing need for new medicines (new molecular entities; NMEs) for rare diseases as few of the 6800 rare diseases (according to the NIH) have approved treatments. Drug discovery strategies for the 102 orphan NMEs approved by the US FDA between 1999 and 2012 were analyzed to learn from past success: 46 NMEs were first in class; 51 were followers; and five were imaging agents. First-in-class medicines were discovered with phenotypic assays (15), target-based approaches (12) and biologic strategies (18). Identification of genetic causes in areas with more basic and translational research such as cancer and in-born errors in metabolism contributed to success regardless of discovery strategy. In conclusion, greater knowledge increases the chance of success and empirical solutions can be effective when knowledge is incomplete. PMID:25068983

  3. Mast cell leukemia: an extremely rare disease.

    PubMed

    Lu, Dai-Yin; Gau, Jyh-Pyng; Hong, Ying-Chung; Liu, Chun-Yu; Yu, Yuan-Bin; Hsiao, Liang-Tsai; Liu, Jin-Hwang; Chen, Po-Min; Chiou, Tzeon-Jye; Tzeng, Cheng-Hwai

    2014-08-01

    Systemic mastocytosis is characterized by pathologic proliferation and accumulation of mast cells in at least one extracutaneous organ such as liver, spleen, bone marrow, or lymph nodes. The clinical features are highly variable depending on impairment of the involved organ systems. It often raises diagnostic challenges. Here we report a case of a 78-year-old patient with mast cell leukemia. The literature is reviewed regarding the diagnosis and updated management of this rare disease. PMID:25028296

  4. Marble Bone Disease: A Rare Bone Disorder

    PubMed Central

    Harinathbabu, Maheswari; Thillaigovindan, Ranjani; Prabhu, Geetha

    2015-01-01

    Osteopetrosis, or marble bone disease, is a rare skeletal disorder due to a defective function of the osteoclasts. This defect renders bones more susceptible to osteomyelitis due to decreased vascularity. This disorder is inherited as autosomal dominant and autosomal recessive. Healthcare professionals should urge these patients to maintain their oral health as well as general health, as this condition makes these patients more susceptible to frequent infections and fractures. This case report emphasizes the signs and symptoms of marble bone disease and presents clinical and radiographic findings.  PMID:26594603

  5. Funding resources for rare disease research.

    PubMed

    Stehr, F; Forkel, M

    2013-11-01

    Research is an expensive venture requiring multiple sources of funding for small projects that test new theories, large projects to make major advancements, training the next generation of researchers and facilitating meetings to share findings and support collaboration. For rare conditions, such as Batten disease, research funds can be difficult to find. To see how investigators supported their work in the past, we did a key word search of the Acknowledgement Section of peer-reviewed literature published in Batten disease in the last 6.5 years. Interestingly, we discovered 193 separate funding sources. The authors hope that, by showing where funds are available, we will enable Batten disease researchers to continue their pursuits and expand their studies; moving key findings from discovery to application phases. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease. PMID:23608548

  6. Social media methods for studying rare diseases.

    PubMed

    Schumacher, Kurt R; Stringer, Kathleen A; Donohue, Janet E; Yu, Sunkyung; Shaver, Ashley; Caruthers, Regine L; Zikmund-Fisher, Brian J; Fifer, Carlen; Goldberg, Caren; Russell, Mark W

    2014-05-01

    For pediatric rare diseases, the number of patients available to support traditional research methods is often inadequate. However, patients who have similar diseases cluster "virtually" online via social media. This study aimed to (1) determine whether patients who have the rare diseases Fontan-associated protein losing enteropathy (PLE) and plastic bronchitis (PB) would participate in online research, and (2) explore response patterns to examine social media's role in participation compared with other referral modalities. A novel, internet-based survey querying details of potential pathogenesis, course, and treatment of PLE and PB was created. The study was available online via web and Facebook portals for 1 year. Apart from 2 study-initiated posts on patient-run Facebook pages at the study initiation, all recruitment was driven by study respondents only. Response patterns and referral sources were tracked. A total of 671 respondents with a Fontan palliation completed a valid survey, including 76 who had PLE and 46 who had PB. Responses over time demonstrated periodic, marked increases as new online populations of Fontan patients were reached. Of the responses, 574 (86%) were from the United States and 97 (14%) were international. The leading referral sources were Facebook, internet forums, and traditional websites. Overall, social media outlets referred 84% of all responses, making it the dominant modality for recruiting the largest reported contemporary cohort of Fontan patients and patients who have PLE and PB. The methodology and response patterns from this study can be used to design research applications for other rare diseases. PMID:24733869

  7. Rare Disease Roadmap: Navigating the challenges and barriers to deliver improved outcomes for patients living with a Rare Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rare Disease registries have now been recognized as a global priority for progress in monitoring, documenting natural course, preventing and treating rare diseases. However, a disease registry is only one element of Rare Disease translational research. Here, we outline what we believe are ten key co...

  8. Rare lung diseases I--Lymphangioleiomyomatosis.

    PubMed

    Juvet, Stephen C; Hwang, David; Downey, Gregory P

    2006-10-01

    The present article is the first in a series that will review selected rare lung diseases. The objective of this series is to promote a greater understanding and awareness of these unusual conditions among respirologists. Each article will begin with a case that serves as a focal point for a discussion of the pathophysiology and management of the particular condition. The first article is on lymphangioleiomyomatosis (LAM); subsequent articles will focus on pulmonary alveolar proteinosis, alpha-1-antitrypsin deficiency and primary ciliary dyskinesia. LAM is a rare, progressive and (without intervention) often fatal interstitial lung disease that predominantly affects women of childbearing age. LAM is characterized by progressive interstitial infiltration of the lung by smooth muscle cells, resulting in diffuse cystic changes of the lung parenchyma. The molecular basis of this disorder has been delineated over the past five years and LAM is now known to be a consequence of mutations in the tuberous sclerosis genes. This knowledge, combined with advances in our understanding of the signalling pathways regulated by these genes, has given rise to potential molecular therapies that hold great promise for treating this devastating disease. PMID:17036091

  9. Melorheostosis – Case Report of Rare Disease

    PubMed Central

    Kumar, Rakesh; Sankhala, S.S.; Bijarnia, Isha

    2014-01-01

    Introduction: Melorheostosis(synonyms: candle bone disease, melting wax syndrome, Leri disease) is a rare chronic bone disorder, first described in 1922 by Leri and Joanny. Men and women are equally affected, and no hereditary features have been discovered. Onset is insidious, and most common symptom is pain. Most common part of bone is diaphysis of the long bone of lower limb rarely the axial skeleton. Classical radiological appearance of ’flowing hyperosteosis’ resembling hardened wax that has dripped down the side of a candle. Case Report: A 35 years old woman presented with left leg pain with mild swelling and limitation of knee movement. On examination non tender bony heard swelling, hyperpigmented and restriction of knee movement present. Plain radiographs showed extensive, dense, undulating or irregular cortical hyperostosis, resembling candle wax, extending along the length of bone. Pamidronate as well asanalgesic were given to the patient. Physiotherepy started for the deformity. Conclusion: Routine laboratory findings usually are normal. The exact cause remain unclear. There is no definite treatment available for this disease. Only symptomatic treatment improve the condition of the patients, more fruitful result obtain with pamidronate and physiotherapy. PMID:27298954

  10. Rare disease clinical trials: Power in numbers.

    PubMed

    Wicklund, Matthew P

    2016-08-01

    The limb-girdle muscular dystrophies (LGMDs) encompass a collection of genetic muscle diseases with proximal-predominant weakness of the limbs. Thirty-two of these disorders are named via the common nomenclature, including 8 autosomal-dominant (LGMD1A-H) and 24 autosomal-recessive (LGMD2A-X) disorders.(1) In addition, numerous other genetic muscle diseases, including Bethlem myopathy, dystrophinopathies, ryanodine receptor-associated myopathies, and many more, may clinically present with similar proximal-predominant weakness.(2) Therefore, current genetic testing panels targeting neuromuscular weakness frequently encompass >75 genes. These disorders are quite rare, each with minimum prevalence estimates of 0.01-0.60 cases per 100,000 persons.(3) LGMD2A (attributable to mutations in the gene for calpain-3) and LGMD2B (attributable to mutations in the gene for dysferlin) consistently are the 2 most prevalent LGMD subtypes in a variety of ethnic cohorts. PMID:27540592

  11. Rare disease research: Breaking the privacy barrier.

    PubMed

    Mascalzoni, Deborah; Paradiso, Angelo; Hansson, Matts

    2014-06-01

    Due to the few patients affected, rare disease research has to count on international registries to exist in order to produce significant research outputs. Data sharing of registries is therefore a unique resource to allow rare disease research to flourish and any lost data will jeopardize the quality of an already extremely difficult research. The rules usually applied to research such as the right to withdraw or the need for specific consent for every use of data can be detrimental in order to get effective results. Privacy rights regulated through traditional informed consent mechanisms have been regarded as a major barrier in order to effectively share data worldwide. Some authors argue that this barrier hampers results that could be beneficial to the patients so that another right will be overstated: the right to quality healthcare. We argue in this paper that privacy has been often interpreted just one-sided as the right to secrecy but it can entail another meaning: the right to manage one's own private sphere. Managing it pertains, not only to the right to deny access, but also to the right to grant access. At the same time research on patient participation and transparency shows that new forms of IT-based informed consent can provide a good balance between the right of individuals to be in control of their data and the opportunity for science to pursue international research. PMID:27275410

  12. Search for rare liver diseases: the case of glycosylation defects mimicking Wilson Disease.

    PubMed

    Socha, Piotr; Vajro, Pietro; Lefeber, Dirk; Adamowicz, Maciej; Tanner, Stuart

    2014-09-01

    Pediatric hepatology appears to be a very specific field of paediatrics which deals mainly with rare diseases although clinical features can be commonly found - like increased activity of transaminases. Some of these rare diseases like Wilson disease are commonly looked for and recently Wilsonian like phenotypes have been described which additionally presented with abnormal glycosylation of the plasma protein transferrin. In a subgroup of those patients with specific additional clinical symptoms (cleft uvula, low blood sugar, rhabdomyolysis and dilated cardiomyopathy) phosphoglucomutase 1 deficiency was identified. We recommend screening for abnormal glycosylation of the plasma protein transferrin in children with unexplained liver injury. PMID:24972800

  13. Bardet-Biedl syndrome: A rare genetic disease

    PubMed Central

    Valverde, Diana; Castro-Sánchez, Sheila; Álvarez-Satta, María

    2013-01-01

    Bardet-Biedl syndrome (BBS) is a rare multisystem genetic disease, with high phenotypic and genetic heterogeneity. Rod-cone dystrophy, obesity, polydactyly, hypogonadism, cognitive impairment and renal abnormalities have been established as primary features. There are 17 BBS genes (BBS1-BBS17) described to date, which explain 70–80% of the patients clinically diagnosed, therefore more BBS genes remain to be identified. BBS belongs to a group of diseases known as ciliopathies. In general, ciliopathies and BBS in particular share a partial overlapping phenotype that makes them complicated to diagnose. We present an up-to-date review including clinical, epidemiologic and genetic aspects of the syndrome.

  14. Towards government-funded special biomedical research programs to combat rare diseases in China.

    PubMed

    Chen, Kai; Yao, Lan; Liu, Zhiyong

    2015-04-01

    Rare diseases are rarely conditions that are often debilitating and even life-threatening, which was identified by the World Health Organization (WHO) with a prevalence of 0.65-1‰. 5,000-7,000 rare diseases are thought to exist, which account for around 10% of diseases for individuals worldwide. It is estimated that over 10 million people were patients with rare disease in China. During the past years, public awareness of rare diseases has in fact heightened with the launching of campaigns by patients' organizations and spontaneous efforts by members of the public, not only in developed countries and regions including United States of America (USA), the European Union (EU), and in Japan, but also in China. However, the features of missed or delayed diagnosis, shortage of effective drugs, and the high cost of currently available drugs for rare diseases make it an important public health issue and a challenge to medical care worldwide. To combat rare disease, the government should assume the responsibility of taking on the important task of promoting the sustained development of a system of medical care for and research into rare diseases. Government-funded special biomedical research programs in the USA, EU, and Japan may serve as a reference for China coping with rare diseases. The government-funded special biomedical research programs consisting of leading clinicians and researchers to enhance basic and applied research on rare diseases were expected to be launched in China. PMID:25902953

  15. Rare lung diseases II: Pulmonary alveolar proteinosis

    PubMed Central

    Juvet, Stephen C; Hwang, David; Waddell, Thomas K; Downey, Gregory P

    2008-01-01

    The present article is the second in a series on rare lung diseases. It focuses on pulmonary alveolar proteinosis (PAP), a disorder in which lipoproteinaceous material accumulates in the alveolar space. PAP was first described in 1958, and for many years the nature of the material accumulating in the lungs was unknown. Major insights into PAP have been made in the past decade, and these have led to the notion that PAP is an autoimmume disorder in which autoantibodies interfere with signalling through the granulocyte-macrophage colony-stimulating factor receptor, leading to macrophage and neutrophil dysfunction. This has spurred new therapeutic approaches to this disorder. The discussion of PAP will begin with a case report, then will highlight the classification of PAP and review recent insights into the pathogenesis of PAP. The approach to therapy and the prognosis of PAP will also be discussed. PMID:18551202

  16. A Rare Clinical Presentation of Darier's Disease

    PubMed Central

    Ferizi, Mybera; Begolli-Gerqari, Antigona; Luzar, Bostjan; Kurshumliu, Fisnik; Ferizi, Mergita

    2013-01-01

    Darier's disease, also known as keratosis follicularis or dyskeratosis follicularis, is a rare disorder of keratinization. It is an autosomal dominant genodermatosis with high penetrance and variable expressivity. Its manifestation appears as hyperkeratotic papules, primarily affecting seborrheic areas on the head, neck, and thorax and less frequently on the oral mucosa. When oral manifestations are present, the palatal and alveolar mucosae are primarily affected. They are usually asymptomatic and are discovered in routine dental examination. Histologically, the lesions are presented as suprabasal clefts in the epithelium with acantholytic and dyskeratotic cells represented by “corps ronds and grains”. This paper reports a case of a 53-year-old woman that was admitted to our clinic with more than 10-year history of keratotic papules, presented on the hands and feet, nose, ears, genitalia, and whitish lesions on palatal mucosae. PMID:23573430

  17. The Orphan Drug Act: Restoring the Mission to Rare Diseases.

    PubMed

    Daniel, Michael G; Pawlik, Timothy M; Fader, Amanda N; Esnaola, Nestor F; Makary, Martin A

    2016-04-01

    The Orphan Drug Act has fostered drug development for patients with rare cancers and other diseases; however, current data suggest that companies are gaming the system to use the law for mainstream drugs. We identify a pattern of pharmaceutical companies submitting drugs to the Food and Drug Administration (FDA) as orphan drugs but once approved, the drugs are used broadly off-label with the lucrative orphan drug protections and exclusivity benefits. Since the law was passed, the proportion of new FDA-approved drugs that were submitted as orphan drugs has increased with a peak last year of 41% of all FDA-approved drugs approved as orphan drugs. On the basis of the current data, we suggest that patients with rare cancers and other diseases may suffer due to dilution of the incentives and benefits. We propose reform to increase submission scrutiny, decrease benefits based on off-label use, and increase price transparency. PMID:26580246

  18. Genetic and Rare Diseases Information Center

    MedlinePlus

    ... GARD Information Specialists can provide you with current, reliable, and easy to understand information about rare or ... GARD provides the public with access to current, reliable, and easy-to-understand information about rare or ...

  19. [Rare diseases and their patient organization: the Hungarian Federation of People with Rare and Congenital Diseases].

    PubMed

    Pogány, Gábor

    2014-03-01

    The aim of the author is to discuss special issues of rare diseases, with emphasis on circumstances present in Hungary, including those leading to the foundation of the non-governmental organization, the Hungarian Federation of People with Rare and Congenital Diseases. The author briefly reviews the most important findings of current international surveys which have been performed with or without the involvement of member associations of the Hungarian Federation of People with Rare and Congenital Diseases. At the level of medical and social services in Hungary, it is still "incidental" to get to the appropriate expert or centre providing the diagnosis or treatment. It is difficult to find the still very few existing services due to the lack of suitable "pathways" and referrals. There are long delays in obtaining the first appointment, resulting in vulnerability and inequality along the regions. The overall consequence is the insufficiency or lack of access to medical and social services. There are also difficulties related to the supply of orphan medication and the long duration of hospitalization. At the level of patient organizations financial scarcity and uncertainty are typical, combined with inappropriate infrastructural background and human resources. The poor quality of organization of patient bodies along with insufficient cooperation among them are characteristic as well. The author concludes that a National Plan or Strategy is needed to improve the current fragmentation of services which would enable patients and health, social and educational professionals to provide and use the best care in the practice. This would ensure all patients with rare diseases to be diagnosed within a possible shortest time allowing access to the care and support needed in time resulting in a decrease in burden of families and society. PMID:24566696

  20. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

    PubMed

    Lange, Leslie A; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M; Smith, Joshua D; Turner, Emily H; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-Ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A; Holmen, Oddgeir L; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C; Correa, Adolfo; Griswold, Michael E; Jakobsdottir, Johanna; Smith, Albert V; Schreiner, Pamela J; Feitosa, Mary F; Zhang, Qunyuan; Huffman, Jennifer E; Crosby, Jacy; Wassel, Christina L; Do, Ron; Franceschini, Nora; Martin, Lisa W; Robinson, Jennifer G; Assimes, Themistocles L; Crosslin, David R; Rosenthal, Elisabeth A; Tsai, Michael; Rieder, Mark J; Farlow, Deborah N; Folsom, Aaron R; Lumley, Thomas; Fox, Ervin R; Carlson, Christopher S; Peters, Ulrike; Jackson, Rebecca D; van Duijn, Cornelia M; Uitterlinden, André G; Levy, Daniel; Rotter, Jerome I; Taylor, Herman A; Gudnason, Vilmundur; Siscovick, David S; Fornage, Myriam; Borecki, Ingrid B; Hayward, Caroline; Rudan, Igor; Chen, Y Eugene; Bottinger, Erwin P; Loos, Ruth J F; Sætrom, Pål; Hveem, Kristian; Boehnke, Michael; Groop, Leif; McCarthy, Mark; Meitinger, Thomas; Ballantyne, Christie M; Gabriel, Stacey B; O'Donnell, Christopher J; Post, Wendy S; North, Kari E; Reiner, Alexander P; Boerwinkle, Eric; Psaty, Bruce M; Altshuler, David; Kathiresan, Sekar; Lin, Dan-Yu; Jarvik, Gail P; Cupples, L Adrienne; Kooperberg, Charles; Wilson, James G; Nickerson, Deborah A; Abecasis, Goncalo R; Rich, Stephen S; Tracy, Russell P; Willer, Cristen J

    2014-02-01

    Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. PMID:24507775

  1. Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol

    PubMed Central

    Lange, Leslie A.; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M.; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M.; Smith, Joshua D.; Turner, Emily H.; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A.; Holmen, Oddgeir L.; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A.; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C.; Correa, Adolfo; Griswold, Michael E.; Jakobsdottir, Johanna; Smith, Albert V.; Schreiner, Pamela J.; Feitosa, Mary F.; Zhang, Qunyuan; Huffman, Jennifer E.; Crosby, Jacy; Wassel, Christina L.; Do, Ron; Franceschini, Nora; Martin, Lisa W.; Robinson, Jennifer G.; Assimes, Themistocles L.; Crosslin, David R.; Rosenthal, Elisabeth A.; Tsai, Michael; Rieder, Mark J.; Farlow, Deborah N.; Folsom, Aaron R.; Lumley, Thomas; Fox, Ervin R.; Carlson, Christopher S.; Peters, Ulrike; Jackson, Rebecca D.; van Duijn, Cornelia M.; Uitterlinden, André G.; Levy, Daniel; Rotter, Jerome I.; Taylor, Herman A.; Gudnason, Vilmundur; Siscovick, David S.; Fornage, Myriam; Borecki, Ingrid B.; Hayward, Caroline; Rudan, Igor; Chen, Y. Eugene; Bottinger, Erwin P.; Loos, Ruth J.F.; Sætrom, Pål; Hveem, Kristian; Boehnke, Michael; Groop, Leif; McCarthy, Mark; Meitinger, Thomas; Ballantyne, Christie M.; Gabriel, Stacey B.; O’Donnell, Christopher J.; Post, Wendy S.; North, Kari E.; Reiner, Alexander P.; Boerwinkle, Eric; Psaty, Bruce M.; Altshuler, David; Kathiresan, Sekar; Lin, Dan-Yu; Jarvik, Gail P.; Cupples, L. Adrienne; Kooperberg, Charles; Wilson, James G.; Nickerson, Deborah A.; Abecasis, Goncalo R.; Rich, Stephen S.; Tracy, Russell P.; Willer, Cristen J.; Gabriel, Stacey B.; Altshuler, David M.; Abecasis, Gonçalo R.; Allayee, Hooman; Cresci, Sharon; Daly, Mark J.; de Bakker, Paul I.W.; DePristo, Mark A.; Do, Ron; Donnelly, Peter; Farlow, Deborah N.; Fennell, Tim; Garimella, Kiran; Hazen, Stanley L.; Hu, Youna; Jordan, Daniel M.; Jun, Goo; Kathiresan, Sekar; Kang, Hyun Min; Kiezun, Adam; Lettre, Guillaume; Li, Bingshan; Li, Mingyao; Newton-Cheh, Christopher H.; Padmanabhan, Sandosh; Peloso, Gina; Pulit, Sara; Rader, Daniel J.; Reich, David; Reilly, Muredach P.; Rivas, Manuel A.; Schwartz, Steve; Scott, Laura; Siscovick, David S.; Spertus, John A.; Stitziel, Nathaniel O.; Stoletzki, Nina; Sunyaev, Shamil R.; Voight, Benjamin F.; Willer, Cristen J.; Rich, Stephen S.; Akylbekova, Ermeg; Atwood, Larry D.; Ballantyne, Christie M.; Barbalic, Maja; Barr, R. Graham; Benjamin, Emelia J.; Bis, Joshua; Boerwinkle, Eric; Bowden, Donald W.; Brody, Jennifer; Budoff, Matthew; Burke, Greg; Buxbaum, Sarah; Carr, Jeff; Chen, Donna T.; Chen, Ida Y.; Chen, Wei-Min; Concannon, Pat; Crosby, Jacy; Cupples, L. Adrienne; D’Agostino, Ralph; DeStefano, Anita L.; Dreisbach, Albert; Dupuis, Josée; Durda, J. Peter; Ellis, Jaclyn; Folsom, Aaron R.; Fornage, Myriam; Fox, Caroline S.; Fox, Ervin; Funari, Vincent; Ganesh, Santhi K.; Gardin, Julius; Goff, David; Gordon, Ora; Grody, Wayne; Gross, Myron; Guo, Xiuqing; Hall, Ira M.; Heard-Costa, Nancy L.; Heckbert, Susan R.; Heintz, Nicholas; Herrington, David M.; Hickson, DeMarc; Huang, Jie; Hwang, Shih-Jen; Jacobs, David R.; Jenny, Nancy S.; Johnson, Andrew D.; Johnson, Craig W.; Kawut, Steven; Kronmal, Richard; Kurz, Raluca; Lange, Ethan M.; Lange, Leslie A.; Larson, Martin G.; Lawson, Mark; Lewis, Cora E.; Levy, Daniel; Li, Dalin; Lin, Honghuang; Liu, Chunyu; Liu, Jiankang; Liu, Kiang; Liu, Xiaoming; Liu, Yongmei; Longstreth, William T.; Loria, Cay; Lumley, Thomas; Lunetta, Kathryn; Mackey, Aaron J.; Mackey, Rachel; Manichaikul, Ani; Maxwell, Taylor; McKnight, Barbara; Meigs, James B.; Morrison, Alanna C.; Musani, Solomon K.; Mychaleckyj, Josyf C.; Nettleton, Jennifer A.; North, Kari; O’Donnell, Christopher J.; O’Leary, Daniel; Ong, Frank; Palmas, Walter

    2014-01-01

    Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. PMID:24507775

  2. Pregnancy and Medically Assisted Conception in Rare Diseases

    ClinicalTrials.gov

    2016-06-23

    Rheumatoid Arthritis; Spondyloarthritis; Psoriatic Arthritis; Systemic Lupus Erythematosus; Antiphospholipid Syndrome; Sjogren Syndrome; Scleroderma; Myositis; Vasculitis; Mastocytosis; Various Autoimmune and/or Systemic and/or Rare Diseases

  3. Rare disease policies to improve care for patients in Europe.

    PubMed

    Rodwell, Charlotte; Aymé, Ségolène

    2015-10-01

    Rare diseases are those with a particularly low prevalence; in Europe, diseases are considered to be rare when they affect not more than 5 in 10000 persons in the European Union. The specificities of rare diseases make the area a veritable public health challenge: the limited number of patients and scarcity of knowledge and expertise single rare diseases out as a distinctive domain of high European added-value. The Orphan Medicinal Product Regulation of 1999 was the first European legislative text concerning rare diseases, followed by many initiatives, including recommendations by the Council of Ministers of the European Union in 2009. These initiatives contributed to the development of rare diseases policies at European and national level aimed at improving care for patients with rare diseases. A review of the political framework at European level and in European countries is provided to demonstrate how legislation has created a dynamic that is progressively improving care for patients with rare diseases. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". PMID:25725454

  4. Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy.

    PubMed

    Boon-Peng, Hoh; Mat Jusoh, Julia Ashazila; Marshall, Christian R; Majid, Fadhlina; Danuri, Norlaila; Basir, Fashieha; Thiruvahindrapuram, Bhooma; Scherer, Stephen W; Yusoff, Khalid

    2016-01-01

    Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, and a powerful predictor of adverse cardiovascular outcomes in the hypertensive patients. It has complex multifactorial and polygenic basis for its pathogenesis. We hypothesized that rare copy number variants (CNVs) contribute to the LVH pathogenesis in hypertensive patients. Copy number variants (CNV) were identified in 258 hypertensive patients, 95 of whom had LVH, after genotyping with a high resolution SNP array. Following stringent filtering criteria, we identified 208 rare, or private CNVs that were only present in our patients with hypertension related LVH. Preliminary findings from Gene Ontology and pathway analysis of this study confirmed the involvement of the genes known to be functionally involved in cardiac development and phenotypes, in line with previously reported transcriptomic studies. Network enrichment analyses suggested that the gene-set was, directly or indirectly, involved in the transcription factors regulating the "foetal cardiac gene programme" which triggered the hypertrophic cascade, confirming previous reports. These findings suggest that multiple, individually rare copy number variants altering genes may contribute to the pathogenesis of hypertension-related LVH. In summary, we have provided further supporting evidence that rare CNV could potentially impact this common and complex disease susceptibility with lower heritability. PMID:26930585

  5. Rare Copy Number Variants Identified Suggest the Regulating Pathways in Hypertension-Related Left Ventricular Hypertrophy

    PubMed Central

    Marshall, Christian R.; Majid, Fadhlina; Danuri, Norlaila; Basir, Fashieha; Thiruvahindrapuram, Bhooma; Scherer, Stephen W.; Yusoff, Khalid

    2016-01-01

    Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, and a powerful predictor of adverse cardiovascular outcomes in the hypertensive patients. It has complex multifactorial and polygenic basis for its pathogenesis. We hypothesized that rare copy number variants (CNVs) contribute to the LVH pathogenesis in hypertensive patients. Copy number variants (CNV) were identified in 258 hypertensive patients, 95 of whom had LVH, after genotyping with a high resolution SNP array. Following stringent filtering criteria, we identified 208 rare, or private CNVs that were only present in our patients with hypertension related LVH. Preliminary findings from Gene Ontology and pathway analysis of this study confirmed the involvement of the genes known to be functionally involved in cardiac development and phenotypes, in line with previously reported transcriptomic studies. Network enrichment analyses suggested that the gene-set was, directly or indirectly, involved in the transcription factors regulating the “foetal cardiac gene programme” which triggered the hypertrophic cascade, confirming previous reports. These findings suggest that multiple, individually rare copy number variants altering genes may contribute to the pathogenesis of hypertension-related LVH. In summary, we have provided further supporting evidence that rare CNV could potentially impact this common and complex disease susceptibility with lower heritability. PMID:26930585

  6. Mitigating false-positive associations in rare disease gene discovery.

    PubMed

    Akle, Sebastian; Chun, Sung; Jordan, Daniel M; Cassa, Christopher A

    2015-10-01

    Clinical sequencing is expanding, but causal variants are still not identified in the majority of cases. These unsolved cases can aid in gene discovery when individuals with similar phenotypes are identified in systems such as the Matchmaker Exchange. We describe risks for gene discovery in this growing set of unsolved cases. In a set of rare disease cases with the same phenotype, it is not difficult to find two individuals with the same phenotype that carry variants in the same gene. We quantify the risk of false-positive association in a cohort of individuals with the same phenotype, using the prior probability of observing a variant in each gene from over 60,000 individuals (Exome Aggregation Consortium). Based on the number of individuals with a genic variant, cohort size, specific gene, and mode of inheritance, we calculate a P value that the match represents a true association. A match in two of 10 patients in MECP2 is statistically significant (P = 0.0014), whereas a match in TTN would not reach significance, as expected (P > 0.999). Finally, we analyze the probability of matching in clinical exome cases to estimate the number of cases needed to identify genes related to different disorders. We offer Rare Disease Match, an online tool to mitigate the uncertainty of false-positive associations. PMID:26378430

  7. Information Supply Chain System for Managing Rare Infectious Diseases

    ERIC Educational Resources Information Center

    Gopalakrishna-Remani, Venugopal

    2012-01-01

    Timely identification and reporting of rare infectious diseases has important economic, social and health implications. In this study, we investigate how different stakeholders in the existing reporting system influence the timeliness in identification and reporting of rare infectious diseases. Building on the vision of the information supply…

  8. Leveraging Terminological Resources for Mapping between Rare Disease Information Sources

    PubMed Central

    Rance, Bastien; Snyder, Michelle; Lewis, Janine; Bodenreider, Olivier

    2015-01-01

    Background Rare disease information sources are incompletely and inconsistently cross-referenced to one another, making it difficult for information seekers to navigate across them. The development of such cross-references established manually by experts is generally labor intensive and costly. Objectives To develop an automatic mapping between two of the major rare diseases information sources, GARD and Orphanet, by leveraging terminological resources, especially the UMLS. Methods We map the rare disease terms from Orphanet and ORDR to the UMLS. We use the UMLS as a pivot to bridge between the rare disease terminologies. We compare our results to a mapping obtained through manually established cross-references to OMIM. Results Our mapping has a precision of 94%, a recall of 63% and an F1-score of 76%. Our automatic mapping should help facilitate the development of more complete and consistent cross-references between GARD and Orphanet, and is applicable to other rare disease information sources as well. PMID:23920611

  9. Computer-assisted initial diagnosis of rare diseases

    PubMed Central

    Piñol, Marc; Vilaplana, Jordi; Teixidó, Ivan; Cruz, Joaquim; Comas, Jorge; Vilaprinyo, Ester; Sorribas, Albert

    2016-01-01

    Introduction. Most documented rare diseases have genetic origin. Because of their low individual frequency, an initial diagnosis based on phenotypic symptoms is not always easy, as practitioners might never have been exposed to patients suffering from the relevant disease. It is thus important to develop tools that facilitate symptom-based initial diagnosis of rare diseases by clinicians. In this work we aimed at developing a computational approach to aid in that initial diagnosis. We also aimed at implementing this approach in a user friendly web prototype. We call this tool Rare Disease Discovery. Finally, we also aimed at testing the performance of the prototype. Methods. Rare Disease Discovery uses the publicly available ORPHANET data set of association between rare diseases and their symptoms to automatically predict the most likely rare diseases based on a patient’s symptoms. We apply the method to retrospectively diagnose a cohort of 187 rare disease patients with confirmed diagnosis. Subsequently we test the precision, sensitivity, and global performance of the system under different scenarios by running large scale Monte Carlo simulations. All settings account for situations where absent and/or unrelated symptoms are considered in the diagnosis. Results. We find that this expert system has high diagnostic precision (≥80%) and sensitivity (≥99%), and is robust to both absent and unrelated symptoms. Discussion. The Rare Disease Discovery prediction engine appears to provide a fast and robust method for initial assisted differential diagnosis of rare diseases. We coupled this engine with a user-friendly web interface and it can be freely accessed at http://disease-discovery.udl.cat/. The code and most current database for the whole project can be downloaded from https://github.com/Wrrzag/DiseaseDiscovery/tree/no_classifiers. PMID:27547534

  10. Computer-assisted initial diagnosis of rare diseases.

    PubMed

    Alves, Rui; Piñol, Marc; Vilaplana, Jordi; Teixidó, Ivan; Cruz, Joaquim; Comas, Jorge; Vilaprinyo, Ester; Sorribas, Albert; Solsona, Francesc

    2016-01-01

    Introduction. Most documented rare diseases have genetic origin. Because of their low individual frequency, an initial diagnosis based on phenotypic symptoms is not always easy, as practitioners might never have been exposed to patients suffering from the relevant disease. It is thus important to develop tools that facilitate symptom-based initial diagnosis of rare diseases by clinicians. In this work we aimed at developing a computational approach to aid in that initial diagnosis. We also aimed at implementing this approach in a user friendly web prototype. We call this tool Rare Disease Discovery. Finally, we also aimed at testing the performance of the prototype. Methods. Rare Disease Discovery uses the publicly available ORPHANET data set of association between rare diseases and their symptoms to automatically predict the most likely rare diseases based on a patient's symptoms. We apply the method to retrospectively diagnose a cohort of 187 rare disease patients with confirmed diagnosis. Subsequently we test the precision, sensitivity, and global performance of the system under different scenarios by running large scale Monte Carlo simulations. All settings account for situations where absent and/or unrelated symptoms are considered in the diagnosis. Results. We find that this expert system has high diagnostic precision (≥80%) and sensitivity (≥99%), and is robust to both absent and unrelated symptoms. Discussion. The Rare Disease Discovery prediction engine appears to provide a fast and robust method for initial assisted differential diagnosis of rare diseases. We coupled this engine with a user-friendly web interface and it can be freely accessed at http://disease-discovery.udl.cat/. The code and most current database for the whole project can be downloaded from https://github.com/Wrrzag/DiseaseDiscovery/tree/no_classifiers. PMID:27547534

  11. Identifying rare variants from exome scans: the GAW17 experience

    PubMed Central

    2011-01-01

    Genetic Analysis Workshop 17 (GAW17) provided a platform for evaluating existing statistical genetic methods and for developing novel methods to analyze rare variants that modulate complex traits. In this article, we present an overview of the 1000 Genomes Project exome data and simulated phenotype data that were distributed to GAW17 participants for analyses, the different issues addressed by the participants, and the process of preparation of manuscripts resulting from the discussions during the workshop. PMID:22373325

  12. Creating an effective clinical registry for rare diseases.

    PubMed

    D'Agnolo, Hedwig Ma; Kievit, Wietske; Andrade, Raul J; Karlsen, Tom Hemming; Wedemeyer, Heiner; Drenth, Joost Ph

    2016-06-01

    The exposure of clinicians to patients with rare gastrointestinal diseases is limited. This hurts clinical studies, which impedes accumulation of scientific knowledge on the natural disease course, treatment outcomes and prognosis in these patients. An excellent method to detect patterns on an aggregate level that would not be possible to discover in individual cases, is a registry study. This paper aims to describe a template to create a successful international registry for rare diseases. We focus mainly on rare hepatic diseases, but lessons from this paper serve other fields in medicine, as well. PMID:27403298

  13. Creating an effective clinical registry for rare diseases

    PubMed Central

    D’Agnolo, Hedwig MA; Kievit, Wietske; Andrade, Raul J; Karlsen, Tom Hemming; Wedemeyer, Heiner

    2015-01-01

    The exposure of clinicians to patients with rare gastrointestinal diseases is limited. This hurts clinical studies, which impedes accumulation of scientific knowledge on the natural disease course, treatment outcomes and prognosis in these patients. An excellent method to detect patterns on an aggregate level that would not be possible to discover in individual cases, is a registry study. This paper aims to describe a template to create a successful international registry for rare diseases. We focus mainly on rare hepatic diseases, but lessons from this paper serve other fields in medicine, as well. PMID:27403298

  14. Integrative analysis of independent transcriptome data for rare diseases

    PubMed Central

    Zhang, Zhe; Hailat, Zeyad; Falk, Marni J.; Chen, Xue–wen

    2016-01-01

    High–throughput technologies used to interrogate transcriptomes have been generating a great amount of publicly available gene expression data. For raw diseases that lack of clinical samples and research funding, there is a practical benefit to jointly analyze existing datasets commonly related to a specific rare disease. In this study, we collected a number of independently generated transcriptome data sets from four species: Human, Fly, Mouse and Worm. All data sets included samples with both normal and abnormal mitochondrial functions. We reprocessed each data set to standardize format, scale and gene annotation and used HomoloGene database to map genes between species. Standard procedure was also applied to compare gene expression profiles of normal and abnormal mitochondrial functions to identify differentially expressed genes. We further used meta–analysis and other integrative analyses to recognize patterns across data sets and species. Novel insights related to mitochondrial dysfunctions was revealed via these analyses, such as a group of genes consistently dysregulated by impaired mitochondrial function in multiple species. This study created a template for the study of rare diseases using genomic technologies and advanced statistical methods. All data and results generated by this study are freely available and stored at http://goo.gl/nOGWC2, to support further data mining. PMID:24981076

  15. Strategies for postmarketing surveillance of drugs for rare diseases.

    PubMed

    Kesselheim, A S; Gagne, J J

    2014-03-01

    Rare diseases are an important part of the public health, affecting 6-8% of the population, and drugs intended for rare diseases comprise the fastest growing subcategory of new drug approvals in the United States. However, clinical study of therapeutics in these populations is limited by the low prevalence of these diseases, and the natural history or pathogenesis of the disease may be poorly described. In addition, commonly used strategies for evaluation of postapproval safety and effectiveness, such as meta-analyses and review of spontaneous adverse event reports, may not be applicable. Alternative methodological approaches, including natural history studies, adaptive clinical trial designs, and epidemiological studies using patient-organized registries, show substantial promise for the study of rare disease therapeutics. Bayesian trials and distributed networks of large electronic databases are the most promising strategies for active and prospective monitoring of clinical interventions for rare diseases. PMID:24193169

  16. Rare inherited kidney diseases: challenges, opportunities, and perspectives

    PubMed Central

    Devuyst, Olivier; Knoers, Nine V A M; Remuzzi, Giuseppe; Schaefer, Franz

    2014-01-01

    At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease. These patients rarely die when their disease progresses and can remain alive for many years because of advances in organ-replacement therapy. However, these disorders substantially decrease their quality of life and have a large effect on health-care systems. Since the kidneys regulate essential homoeostatic processes, inherited kidney disorders have multisystem complications, which add to the usual challenges for rare disorders. In this review, we discuss the nature of rare inherited kidney diseases, the challenges they pose, and opportunities from technological advances, which are well suited to target the kidney. Mechanistic insights from rare disorders are relevant for common disorders such as hypertension, kidney stones, cardiovascular disease, and progression of chronic kidney disease. PMID:24856029

  17. Clinical Trials in Rare Disease: Challenges and Opportunities

    PubMed Central

    Augustine, Erika F.; Adams, Heather R.; Mink, Jonathan W.

    2014-01-01

    The neuronal ceroid lipofuscinoses constitute one of many groups of rare childhood diseases for which disease-modifying treatments are non-existent. Disease-specific barriers to therapeutic success include incomplete understanding of disease pathophysiology and limitations of treatments that cannot adequately cross the blood-brain barrier to access the central nervous system. Therapeutic development in the neuronal ceroid lipofuscinoses shares many challenges with other rare diseases, such as incomplete understanding of natural history to inform trial design, need for alternatives to the randomized controlled clinical trial, requirement for more sensitive outcome measures to quantify disease, limited access to resources required to mount a clinical trial (including funding), and difficulties of recruiting a small sample to participation. Solutions to these barriers will require multicenter collaboration, partnership with patient organizations, training a new generation of researchers interested in rare diseases, and leveraging existing resources. PMID:24014509

  18. Cold agglutinin disease in fibrolamellar hepatocellular carcinoma: a rare association with a rare cancer variant.

    PubMed

    Al-Matham, Khalid; Alabed, Iehab; Zaidi, Syed Z A; Qushmaq, Khalid A

    2011-01-01

    Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although it can occur secondary to lymphoproliferative disorders and autoimmune or infectious diseases, CAD is rarely reported as secondary to solid tumors. We report a case of a woman aged 18 years diagnosed with a well-differentiated hepatocellular carcinoma of the fibrolamellar subtype, who was shown to have CAD also. Her general condition, including CAD, improved after targeted therapy with sorafenib for the hepatocellular carcinoma and only conservative measures for the CAD that consisted of avoidance of cold. In summary, although it is an extremely rare association and less common than lymphoproliferative disorders, CAD can be associated with solid tumors. PMID:21293066

  19. Genotype-based databases for variants causing rare diseases.

    PubMed

    Lanthaler, Barbara; Wieser, Stefanie; Deutschmann, Andrea; Schossig, Anna; Fauth, Christine; Zschocke, Johannes; Witsch-Baumgartner, Martina

    2014-10-15

    Inherited diseases are the result of DNA sequence changes. In recessive diseases, the clinical phenotype results from the combined functional effects of variants in both copies of the gene. In some diseases there is often considerable variability of clinical presentation or disease severity, which may be predicted by the genotype. Additional effects may be triggered by environmental factors, as well as genetic modifiers which could be nucleotide polymorphisms in related genes, e.g. maternal ApoE or ABCA1 genotypes which may have an influence on the phenotype of SLOS individuals. Here we report the establishment of genotype variation databases for various rare diseases which provide individual clinical phenotypes associated with genotypes and include data about possible genetic modifiers. These databases aim to be an easy public access to information on rare and private variants with clinical data, which will facilitate the interpretation of genetic variants. The created databases include ACAD8 (isobutyryl-CoA dehydrogenase deficiency (IBD)), ACADSB (short-chain acyl-CoA dehydrogenase (SCAD) deficiency), AUH (3-methylglutaconic aciduria (3-MGCA)), DHCR7 (Smith-Lemli-Opitz syndrome), HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency), HSD17B10 (17-beta-hydroxysteroid dehydrogenase X deficiency), FKBP14 (Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss; EDSKMH) and ROGDI (Kohlschütter-Tönz syndrome). These genes have been selected because of our specific research interests in these rare and metabolic diseases. The aim of the database was to include all identified individuals with variants in these specific genes. Identical genotypes are listed multiple times if they were found in several patients, phenotypic descriptions and biochemical data are included as detailed as possible in view also of validating the proposed pathogenicity of these genotypes. For DHCR7 genetic modifier data (maternal APOE and ABCA1 genotypes) is

  20. Erdheim-Chester Disease: A Rare Presentation of a Rare Disease.

    PubMed

    Matzumura, Melissa; Arias-Stella, Javier; Novak, James E

    2016-01-01

    Erdheim-Chester disease (ECD) is a rare, xanthogranulomatous, non-Langerhans cell histiocytosis with frequent systemic involvement. Although the diagnosis is based on characteristic histological and radiological findings, its identification can be challenging because of its heterogeneous presentation. Osteosclerosis of long bones, often associated with bone pain, is the most common initial manifestation, followed by extraskeletal manifestations in approximately 50% of cases. There is no standard treatment for ECD, although recommendations have been made on the basis of small studies. A systematic approach to the diagnosis of ECD is important, because its manifestations may be life-threatening and may require specific management. We report an atypical presentation of ECD, with early cardiac, renal, and central nervous system involvement, and only late skeletal manifestations. PMID:27606325

  1. Menkes Kinky Hair Syndrome: A Rare Neurodegenerative Disease

    PubMed Central

    Gandhi, Rozil; Kakkar, Ritu; Rajan, Sajeev; Bhangale, Rashmi; Desai, Shrinivas

    2012-01-01

    Menkes kinky hair disease is a rare X-linked recessive disease nearly exclusively affecting males who present at 2-3 months of age due to abnormal functioning of copper-dependent enzymes due to deficiency of copper. Here, we describe a completely worked-up case of a 4-month-old male infant with very typical history and radiological features confirmed by biochemical and trichoanalysis. The initially seen asymmetric cortical and subcortical T2 hyperintensities in cerebral and cerebellar hemispheres converted into symmetrical diffuse cerebral and predominantly cerebellar atrophy with uniform loss of both white and grey matter on follow-up MRI. Also, subdural hemorrhages of various sizes and different stages and tortuosity of larger proximal intracranial vessels with distal narrowing were identified. Ours is a completely worked-up proven case of Menkes kinky hair disease (MKHD) with history, electroencephalography, biochemical, trichoanalysis, and MRI findings. This is a good teaching case and shows importance of clinical examination and biochemistry as complimentary to MRI. Tortuous intracranial arteries with blocked major vessels are found only in this disease, thus stressing the value of MR Angiography in these patients. PMID:22919529

  2. Mastoiditis--paleopathological evidence of a rarely reported disease.

    PubMed

    Flohr, Stefan; Schultz, Michael

    2009-03-01

    Since antibiotics have become available, mastoiditis has become a rare disease in modern Western societies. However, it is still common in developing countries. It can be hypothesized that in earlier historical and prehistoric times, mastoiditis must have posed a serious threat to people's lives, and that the prevalence of this disease is probably underrepresented in the paleopathological literature. The present study identifies pathological changes in the pneumatized cells of the mastoid process in human skeletal samples from two early medieval cemeteries from Germany (Dirmstein: n = 152 mastoids, Rhens: n = 71 mastoids), using macroscopic, endoscopic, low-power microscopic, scanning-electron and light microscopic techniques, and draws some epidemiological conclusions as to the frequency of the disease diagnosed in the archaeological samples. Osseous changes because of mastoiditis were diagnosed in 83.4% of the temporal bones. The frequency in the skeletal sample from Dirmstein was higher than in the sample from Rhens. In both populations, males were more often affected than females and older individuals more often than younger individuals. The high frequency of mastoiditis observed was most likely due to an accumulation of osseous changes during individual lifetimes and supports the hypothesis that mastoiditis was a serious health problem in pre-antibiotic times. It may be assumed that subclinical forms of mastoiditis and their osseous manifestations may even nowadays occur more often than was previously thought. It is suggested that the disease should be given more consideration in paleopathological investigations. PMID:18773457

  3. Contribution of Electronic Medical Records to the Management of Rare Diseases

    PubMed Central

    Bremond-Gignac, Dominique; Lewandowski, Elisabeth; Copin, Henri

    2015-01-01

    Purpose. Electronic health record systems provide great opportunity to study most diseases. Objective of this study was to determine whether electronic medical records (EMR) in ophthalmology contribute to management of rare eye diseases, isolated or in syndromes. Study was designed to identify and collect patients' data with ophthalmology-specific EMR. Methods. Ophthalmology-specific EMR software (Softalmo software Corilus) was used to acquire ophthalmological ocular consultation data from patients with five rare eye diseases. The rare eye diseases and data were selected and collected regarding expertise of eye center. Results. A total of 135,206 outpatient consultations were performed between 2011 and 2014 in our medical center specialized in rare eye diseases. The search software identified 29 congenital aniridia, 6 Axenfeld/Rieger syndrome, 11 BEPS, 3 Nanophthalmos, and 3 Rubinstein-Taybi syndrome. Discussion. EMR provides advantages for medical care. The use of ophthalmology-specific EMR is reliable and can contribute to a comprehensive ocular visual phenotype useful for clinical research. Conclusion. Routinely EMR acquired with specific software dedicated to ophthalmology provides sufficient detail for rare diseases. These software-collected data appear useful for creating patient cohorts and recording ocular examination, avoiding the time-consuming analysis of paper records and investigation, in a University Hospital linked to a National Reference Rare Center Disease. PMID:26539543

  4. FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project.

    PubMed

    Beaulieu, Chandree L; Majewski, Jacek; Schwartzentruber, Jeremy; Samuels, Mark E; Fernandez, Bridget A; Bernier, Francois P; Brudno, Michael; Knoppers, Bartha; Marcadier, Janet; Dyment, David; Adam, Shelin; Bulman, Dennis E; Jones, Steve J M; Avard, Denise; Nguyen, Minh Thu; Rousseau, Francois; Marshall, Christian; Wintle, Richard F; Shen, Yaoqing; Scherer, Stephen W; Friedman, Jan M; Michaud, Jacques L; Boycott, Kym M

    2014-06-01

    Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally. PMID:24906018

  5. Detecting Rare Disease-Causing Glitches

    MedlinePlus

    ... to other members. Instead of sequencing the entire human genome , which has 3 billion DNA base pairs, whole- ... Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Human Genome Research Institute (NHGRI), National Institute of Neurological Disorders ...

  6. New perspectives on rare connective tissue calcifying diseases.

    PubMed

    Rashdan, Nabil A; Rutsch, Frank; Kempf, Hervé; Váradi, András; Lefthériotis, Georges; MacRae, Vicky E

    2016-06-01

    Connective tissue calcifying diseases (CTCs) are characterized by abnormal calcium deposition in connective tissues. CTCs are caused by multiple factors including chronic diseases (Type II diabetes mellitus, chronic kidney disease), the use of pharmaceuticals (e.g. warfarin, glucocorticoids) and inherited rare genetic diseases such as pseudoxanthoma elasticum (PXE), generalized arterial calcification in infancy (GACI) and Keutel syndrome (KTLS). This review explores our current knowledge of these rare inherited CTCs, and highlights the most promising avenues for pharmaceutical intervention. Advancing our understanding of rare inherited forms of CTC is not only essential for the development of therapeutic strategies for patients suffering from these diseases, but also fundamental to delineating the mechanisms underpinning acquired chronic forms of CTC. PMID:26930168

  7. Rare variant mutations identified in pediatric patients with dilated cardiomyopathy.

    PubMed

    Rampersaud, Evadnie; Siegfried, Jill D; Norton, Nadine; Li, Duanxiang; Martin, Eden; Hershberger, Ray E

    2011-01-01

    Dilated cardiomyopathy (DCM) in infants and children can be partially explained by genetic cause but the catalogue of known genes is limited. We reviewed our database of 41 cases diagnosed with DCM before 18 years of age who underwent detailed clinical and genetic evaluation, and summarize here the evidence for mutations causing DCM in these cases from 15 genes (PSEN1, PSEN2, CSRP3, LBD3, MYH7, SCN5A, TCAP, TNNT2, LMNA, MYBPC3, MYH6, TNNC1, TNNI3, TPM1, and RBM20). Thirty-five of the 41 pediatric cases had relatives with adult-onset DCM. More males (66%) were found among children diagnosed after 1 year of age with DCM. Nineteen mutations in 9 genes were identified among 15 out of 41 patients; 3 patients (diagnosed at ages 2 weeks, 9 and 13 years) had multiple mutations. Of the 19 mutations identified in 12 families, mutations in TPM1 (32%) and TNNT2 (21%) were the most commonly found. Of the 6 patients diagnosed before 1 year of age, 3 had mutations in TPM1 (including a set of identical twins), 1 in TNNT2, 1 in MYH7, and 1 with multiple mutations (MYH7 and TNNC1). Most DCM was accompanied by advanced heart failure and need for cardiac transplantation. We conclude that in some cases pediatric DCM has a genetic basis, which is complicated by allelic and locus heterogeneity as seen in adult-onset DCM. We suggest that future prospective comprehensive family-based genetic studies of pediatric DCM are indicated to further define mutation frequencies in known genes and to discover novel genetic cause. PMID:21483645

  8. Rare variant mutations identified in pediatric patients with dilated cardiomyopathy

    PubMed Central

    Rampersaud, Evadnie; Siegfried, Jill D; Norton, Nadine; Li, Duanxiang; Martin, Eden; Hershberger, Ray E

    2010-01-01

    Dilated cardiomyopathy (DCM) in infants and children can be partially explained by genetic cause but the catalogue of known genes is limited. We reviewed our database of 41 cases diagnosed with DCM before 18 years of age who underwent detailed clinical and genetic evaluation, and summarize here the evidence for mutations causing DCM in these cases from 15 genes (PSEN1, PSEN2, CSRP3, LBD3, MYH7, SCN5A, TCAP, TNNT2, LMNA, MYBPC3, MYH6, TNNC1, TNNI3, TPM1, and RBM20). Thirty-five of the 41 pediatric cases had relatives with adult-onset DCM. More males (66%) were found among children diagnosed after 1 year of age with DCM. Nineteen mutations in 9 genes were identified among 15 out of 41 patients; 3 patients (diagnosed at ages 2 weeks, 9 and 13 years) had multiple mutations. Of the 19 mutations identified in 12 families, mutations in TPM1 (32%) and TNNT2 (21%) were the most commonly found. Of the 6 patients diagnosed before 1 year of age, 3 had mutations in TPM1 (including a set of identical twins), 1 in TNNT2, 1 in MYH7, and 1 with multiple mutations (MYH7 and TNNC1). Most DCM was accompanied by advanced heart failure and need for cardiac transplantation. We conclude that in some cases pediatric DCM has a genetic basis, which is complicated by allelic and locus heterogeneity as seen in adult-onset DCM. We suggest that future prospective comprehensive family-based genetic studies of pediatric DCM are indicated to further define mutation frequencies in known genes and to discover novel genetic cause. PMID:21483645

  9. Hirayama Disease with Periscapular Involvement: A Rare Association

    PubMed Central

    Holla, Vikram V.; Kumar, Sanjeev; Shukla, Rakesh

    2016-01-01

    Hirayama disease (HD) is a rare disease commonly seen in India and Japan typically presenting in adolescent age group with male predominance and asymmetrical distal pure motor, lower-motor neuron-type weakness. We report a patient of HD who had significant involvement of proximal periscapular muscles along with typical distal involvement. The patient also had scapular winging, which is rare in HD. He was treated conservatively with physiotherapy and hard cervical collar and is presently under follow-up during the static phase of disease.

  10. Rare inflammatory and hereditary connective tissue diseases.

    PubMed

    Klipple, G L; Riordan, K K

    1989-05-01

    Polyarteritis nodosa developing during gestation has an extremely grave prognosis. To an uncertain extent, this results from a delay in recognition and therapy. The diagnosis of PAN is complicated by the expanded differential of common conditions associated with pregnancy such as pre-eclampsia and toxemia which can present with similar symptoms and signs. On the other hand, the pregnant woman with known, quiescent disease has a much better prognosis with only one of four women experiencing exacerbation. In women with Behcet's disease, convincing reports of both pregnancy-related flares and remissions involving primarily mucocutaneous manifestations are found in the literature. Gestational exacerbation of the more serious manifestations including chorioretinitis, vasculitis and CNS disease does not appear to be a problem. Also, a significant effect on fetal development or survival is not evident. The pregnant woman with the Marfan syndrome and pre-existing cardiovascular disease, particularly dilatation of the aortic root, has a substantially increased risk of developing a major complication during gestation most commonly aortic aneurysm, dissection, rupture or insufficiency. Echocardiographic determination of the aortic root diameter is prognostic with a decreased risk at a diameter of 40 mm or less. A diameter of greater than 40 to 45 mm constitutes a significant contraindication to pregnancy. All pregnancies in patients with the Marfan syndrome are considered high risk and frequent evaluations and echocardiograms are required. The EDS patient is subject to a wide range of gestational complications resulting from the basic connective tissue defect manifested clinically by hyperextensible skin, joint hypermobility, connective tissue and vascular fragility, and poor wound healing. The most serious complications occur in type I EDS (gravis) and type IV (ecchymotic) and include extensive perineal tears and hematoma after vaginal delivery, uterine prolapse and rupture

  11. Translation of rare disease research into orphan drug development: disease matters.

    PubMed

    Heemstra, Harald E; van Weely, Sonja; Büller, Hans A; Leufkens, Hubert G M; de Vrueh, Remco L A

    2009-12-01

    More than 25 years of orphan drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an orphan drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current orphan drug legislation alone is not sufficient to stimulate orphan drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level. PMID:19818412

  12. Advances in Identifying Beryllium Sensitization and Disease

    PubMed Central

    Middleton, Dan; Kowalski, Peter

    2010-01-01

    Beryllium is a lightweight metal with unique qualities related to stiffness, corrosion resistance, and conductivity. While there are many useful applications, researchers in the 1930s and l940s linked beryllium exposure to a progressive occupational lung disease. Acute beryllium disease is a pulmonary irritant response to high exposure levels, whereas chronic beryllium disease (CBD) typically results from a hypersensitivity response to lower exposure levels. A blood test, the beryllium lymphocyte proliferation test (BeLPT), was an important advance in identifying individuals who are sensitized to beryllium (BeS) and thus at risk for developing CBD. While there is no true “gold standard” for BeS, basic epidemiologic concepts have been used to advance our understanding of the different screening algorithms. PMID:20195436

  13. Rare mutations associating with serum creatinine and chronic kidney disease.

    PubMed

    Sveinbjornsson, Gardar; Mikaelsdottir, Evgenia; Palsson, Runolfur; Indridason, Olafur S; Holm, Hilma; Jonasdottir, Aslaug; Helgason, Agnar; Sigurdsson, Snaevar; Jonasdottir, Adalbjorg; Sigurdsson, Asgeir; Eyjolfsson, Gudmundur Ingi; Sigurdardottir, Olof; Magnusson, Olafur Th; Kong, Augustine; Masson, Gisli; Sulem, Patrick; Olafsson, Isleifur; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F; Stefansson, Kari

    2014-12-20

    Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45 and SLC47A1) and two E3 ubiquitin ligases (RNF186 and RNF128). All the variants are within coding sequences and all but one are rare (MAF <2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease. PMID:25082825

  14. Dispelling myths about rare disease registry system development

    PubMed Central

    2013-01-01

    Rare disease registries (RDRs) are an essential tool to improve knowledge and monitor interventions for rare diseases. If designed appropriately, patient and disease related information captured within them can become the cornerstone for effective diagnosis and new therapies. Surprisingly however, registries possess a diverse range of functionality, operate in different, often-times incompatible, software environments and serve various, and sometimes incongruous, purposes. Given the ambitious goals of the International Rare Diseases Research Consortium (IRDiRC) by 2020 and beyond, RDRs must be designed with the agility to evolve and efficiently interoperate in an ever changing rare disease landscape, as well as to cater for rapid changes in Information Communication Technologies. In this paper, we contend that RDR requirements will also evolve in response to a number of factors such as changing disease definitions and diagnostic criteria, the requirement to integrate patient/disease information from advances in either biotechnology and/or phenotypying approaches, as well as the need to adapt dynamically to security and privacy concerns. We dispel a number of myths in RDR development, outline key criteria for robust and sustainable RDR implementation and introduce the concept of a RDR Checklist to guide future RDR development. PMID:24131574

  15. Rare Neurological Manifestation of Celiac Disease

    PubMed Central

    Rani, Uzma; Imdad, Aamer; Beg, Mirza

    2015-01-01

    Celiac disease (CD) is an immune-mediated disease characterized by permanent gastrointestinal tract sensitivity to gluten in genetically predisposed individuals. It has varied clinical manifestations, ranging from gastrointestinal to extraintestinal, including neurological, skin, reproductive and psychiatric symptoms, which makes its diagnosis difficult and challenging. Known neurological manifestations of CD include epilepsy with or without occipital calcification, attention deficit hyperactivity disorder and ataxia, headache, neuropathies and behavior disorders. We present the case of a 14-year-old female with headaches and blurred vision for 1 year; she was noted to have papilledema on ophthalmic examination with increased cerebrospinal fluid opening pressure on lumber puncture and was diagnosed as a case of pseudotumor cerebri (PTC). Meanwhile her workup for chronic constipation revealed elevated tissue transglutaminase IgA and antiendomysial IgA antibodies. Upper gastrointestinal endoscopy with duodenal biopsy confirmed the diagnosis of CD. The patient was started on a gluten-free diet, leading to resolution of not only gastrointestinal symptoms but also to almost complete resolution of symptoms of PTC. This report describes the correlation of CD and PTC as its neurological manifestation. PMID:26120302

  16. Pharmacotherapy Challenges of Fontan-Associated Plastic Bronchitis: A Rare Pediatric Disease

    PubMed Central

    Brooks, Kristina; Caruthers, Regine L.; Schumacher, Kurt R.; Stringer, Kathleen A.

    2013-01-01

    Pediatric pharmacotherapy is often challenging due to the paucity of available clinical data on the safety and efficacy of medications that are commonly used in children. This quandary is even more prevalent in children with rare diseases. Although extrapolations for dosing and administration are often made from available adult data with similar disease states, this translation becomes even more problematic in rare pediatric diseases. Understanding of disease pathophysiology is typically poor, and few, if any, effective therapies have been studied and identified. One condition that illustrates these issues is plastic bronchitis, a rare, most often pediatric disease that is characterized by the production of obstructive bronchial airway casts. This illness primarily occurs in children with congenital heart disease, often after palliative surgery. Plastic bronchitis is a highly clinically relevant and therapeutically challenging problem with a high mortality rate, and, to date, a generally accepted effective pharmacotherapy regimen has not been identified. Furthermore, the disease is ill defined, which makes timely identification and treatment of children with plastic bronchitis difficult. The pharmacotherapies currently used to manage this disease are largely anecdotal and vary between the use of macrolide antibiotics, mucolytics, bronchodilators, and inhaled fibrinolytics in a myriad of combinations. The purpose of this review is twofold: first, to highlight the dilemma of treating plastic bronchitis, and second, to bring attention to the continuing need for studies of drug therapies used in children so that safe and effective drug regimens can be established, particularly for rare diseases, which often have no treatment options. PMID:23686915

  17. Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Disease Research

    PubMed Central

    Newman, Samantha Kass; Jayanthan, Raj K.; Mitchell, Grant W.; Carreras Tartak, Jossie A.; Croglio, Michael P.; Suarez, Alexander; Liu, Amy Y.; Razzo, Beatrice M.; Oyeniran, Enny; Ruth, Jason R.; Fajgenbaum, David C.

    2015-01-01

    Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in “omics” technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN’s collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care. PMID:26604862

  18. A methodology for a minimum data set for rare diseases to support national centers of excellence for healthcare and research

    PubMed Central

    Choquet, Rémy; Maaroufi, Meriem; de Carrara, Albane; Messiaen, Claude; Luigi, Emmanuel; Landais, Paul

    2015-01-01

    Background Although rare disease patients make up approximately 6–8% of all patients in Europe, it is often difficult to find the necessary expertise for diagnosis and care and the patient numbers needed for rare disease research. The second French National Plan for Rare Diseases highlighted the necessity for better care coordination and epidemiology for rare diseases. A clinical data standard for normalization and exchange of rare disease patient data was proposed. The original methodology used to build the French national minimum data set (F-MDS-RD) common to the 131 expert rare disease centers is presented. Methods To encourage consensus at a national level for homogeneous data collection at the point of care for rare disease patients, we first identified four national expert groups. We reviewed the scientific literature for rare disease common data elements (CDEs) in order to build the first version of the F-MDS-RD. The French rare disease expert centers validated the data elements (DEs). The resulting F-MDS-RD was reviewed and approved by the National Plan Strategic Committee. It was then represented in an HL7 electronic format to maximize interoperability with electronic health records. Results The F-MDS-RD is composed of 58 DEs in six categories: patient, family history, encounter, condition, medication, and questionnaire. It is HL7 compatible and can use various ontologies for diagnosis or sign encoding. The F-MDS-RD was aligned with other CDE initiatives for rare diseases, thus facilitating potential interconnections between rare disease registries. Conclusions The French F-MDS-RD was defined through national consensus. It can foster better care coordination and facilitate determining rare disease patients’ eligibility for research studies, trials, or cohorts. Since other countries will need to develop their own standards for rare disease data collection, they might benefit from the methods presented here. PMID:25038198

  19. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

    ClinicalTrials.gov

    2016-09-01

    Rare Disorders; Undiagnosed Disorders; Disorders of Unknown Prevalence; Cornelia De Lange Syndrome; Prenatal Benign Hypophosphatasia; Perinatal Lethal Hypophosphatasia; Odontohypophosphatasia; Adult Hypophosphatasia; Childhood-onset Hypophosphatasia; Infantile Hypophosphatasia; Hypophosphatasia; Kabuki Syndrome; Bohring-Opitz Syndrome; Narcolepsy Without Cataplexy; Narcolepsy-cataplexy; Hypersomnolence Disorder; Idiopathic Hypersomnia Without Long Sleep Time; Idiopathic Hypersomnia With Long Sleep Time; Idiopathic Hypersomnia; Kleine-Levin Syndrome; Kawasaki Disease; Leiomyosarcoma; Leiomyosarcoma of the Corpus Uteri; Leiomyosarcoma of the Cervix Uteri; Leiomyosarcoma of Small Intestine; Acquired Myasthenia Gravis; Addison Disease; Hyperacusis (Hyperacousis); Juvenile Myasthenia Gravis; Transient Neonatal Myasthenia Gravis; Williams Syndrome; Lyme Disease; Myasthenia Gravis; Marinesco Sjogren Syndrome(Marinesco-Sjogren Syndrome); Isolated Klippel-Feil Syndrome; Frasier Syndrome; Denys-Drash Syndrome; Beckwith-Wiedemann Syndrome; Emanuel Syndrome; Isolated Aniridia; Beckwith-Wiedemann Syndrome Due to Paternal Uniparental Disomy of Chromosome 11; Beckwith-Wiedemann Syndrome Due to Imprinting Defect of 11p15; Beckwith-Wiedemann Syndrome Due to 11p15 Translocation/Inversion; Beckwith-Wiedemann Syndrome Due to 11p15 Microduplication; Beckwith-Wiedemann Syndrome Due to 11p15 Microdeletion; Axenfeld-Rieger Syndrome; Aniridia-intellectual Disability Syndrome; Aniridia - Renal Agenesis - Psychomotor Retardation; Aniridia - Ptosis - Intellectual Disability - Familial Obesity; Aniridia - Cerebellar Ataxia - Intellectual Disability; Aniridia - Absent Patella; Aniridia; Peters Anomaly - Cataract; Peters Anomaly; Potocki-Shaffer Syndrome; Silver-Russell Syndrome Due to Maternal Uniparental Disomy of Chromosome 11; Silver-Russell Syndrome Due to Imprinting Defect of 11p15; Silver-Russell Syndrome Due to 11p15 Microduplication; Syndromic Aniridia; WAGR Syndrome; Wolf

  20. The Matchmaker Exchange: a platform for rare disease gene discovery.

    PubMed

    Philippakis, Anthony A; Azzariti, Danielle R; Beltran, Sergi; Brookes, Anthony J; Brownstein, Catherine A; Brudno, Michael; Brunner, Han G; Buske, Orion J; Carey, Knox; Doll, Cassie; Dumitriu, Sergiu; Dyke, Stephanie O M; den Dunnen, Johan T; Firth, Helen V; Gibbs, Richard A; Girdea, Marta; Gonzalez, Michael; Haendel, Melissa A; Hamosh, Ada; Holm, Ingrid A; Huang, Lijia; Hurles, Matthew E; Hutton, Ben; Krier, Joel B; Misyura, Andriy; Mungall, Christopher J; Paschall, Justin; Paten, Benedict; Robinson, Peter N; Schiettecatte, François; Sobreira, Nara L; Swaminathan, Ganesh J; Taschner, Peter E; Terry, Sharon F; Washington, Nicole L; Züchner, Stephan; Boycott, Kym M; Rehm, Heidi L

    2015-10-01

    There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow. PMID:26295439

  1. A rare case of Weil's disease with alveolar haemorrhage

    PubMed Central

    Chakrabarti, Abhiram; Nandy, Manab; Pal, Dipankar; Mallik, Sudesna

    2014-01-01

    Leptospirosis, a disease of protean manifestations occurs sporadically throughout the year with a peak seasonal incidence during the rainy season mimicking other febrile viral illness. In the rare case, the disease leads to renal and hepatic involvement with hemorrhage which may be associated with multisystem organ dysfunction in form of pulmonary, cardiac and central nervous system, when it is known as Weil's disease. Rarely haemorrhagic manifestations are assosciated. Early diagnosis is important as sometimes the disease may be life threatening. Proper antibiotics results in dramatic improvement. We hereby presented a case that had clinical features of Weil's disease with cough, dyspnoea and haemoptysis. Leptospirosis was detected on ELISA testing. Patient was cured rapidly with antibiotics. PMID:25183149

  2. Ultra-rare Disease and Genomics-Driven Precision Medicine

    PubMed Central

    Lee, Sangmoon

    2016-01-01

    Since next-generation sequencing (NGS) technique was adopted into clinical practices, revolutionary advances in diagnosing rare genetic diseases have been achieved through translating genomic medicine into precision or personalized management. Indeed, several successful cases of molecular diagnosis and treatment with personalized or targeted therapies of rare genetic diseases have been reported. Still, there are several obstacles to be overcome for wider application of NGS-based precision medicine, including high sequencing cost, incomplete variant sensitivity and accuracy, practical complexities, and a shortage of available treatment options. PMID:27445646

  3. Bottlenecks in molecular testing for rare genetic diseases.

    PubMed

    Willems, Patrick J

    2008-06-01

    Despite the impressive progress in our understanding of the genetic causes of genetic diseases over the past decade, molecular diagnosis for rare genetic disorders is still in its infancy, being slow, expensive, unreliable, insufficient, and ill-organized in many countries. This leaves the gap between the hype of the current genomic research and the hope for a simple genetic diagnosis too large for patients and families affected with genetic disease. The bottlenecks in the molecular testing for rare genetic disorders are discussed below. PMID:18412107

  4. Communication strategies employed by rare disease patient organizations in Spain.

    PubMed

    Castillo-Esparcia, Antonio; López-Villafranca, Paloma

    2016-08-01

    The current study focuses on communication strategies employed by rare disease patient organizations. The aims of these organizations are: educate and inform the public about rare diseases, raise awareness of the problems related to rare diseases, and achieve social legitimacy in order give visibility to their demands. We analyzed the portrayal of rare disease and patient organizations by Spain's major media organizations in terms of circulation and viewership - the press (El País, El Mundo, La Vanguardia,ABC and El Periódico), radio (CadenaSer, Onda Cero, Cope and RNE), and television (Telecinco, Antena 3, La 1, La Sexta, Cuatro) -between 2012 and 2014.We then carried out a descriptive analysis of communication activities performed via the World Wide Web and social networks by 143 national organizations. Finally, we conducted a telephone questionnaire of a representative sample of 90 organizations in order to explore the association between media presence and funding and public image. The triangulation of quantitative and qualitative methods allowed us to meet the study's objectives. Increased visibility of the organizations afforded by an increase in the coverage of the topic by the medialed to an increase in membership - but not in donations - and increased awareness of these diseases. PMID:27557016

  5. Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

    PubMed Central

    Bogaerts, Jan; Sydes, Matthew R.; Keat, Nicola; McConnell, Andrea; Benson, Al; Ho, Alan; Roth, Arnaud; Fortpied, Catherine; Eng, Cathy; Peckitt, Clare; Coens, Corneel; Pettaway, Curtis; Arnold, Dirk; Hall, Emma; Marshall, Ernie; Sclafani, Francesco; Hatcher, Helen; Earl, Helena; Ray-Coquard, Isabelle; Paul, James; Blay, Jean-Yves; Whelan, Jeremy; Panageas, Kathy; Wheatley, Keith; Harrington, Kevin; Licitra, Lisa; Billingham, Lucinda; Hensley, Martee; McCabe, Martin; Patel, Poulam M.; Carvajal, Richard; Wilson, Richard; Glynne-Jones, Rob; McWilliams, Rob; Leyvraz, Serge; Rao, Sheela; Nicholson, Steve; Filiaci, Virginia; Negrouk, Anastassia; Lacombe, Denis; Dupont, Elisabeth; Pauporté, Iris; Welch, John J.; Law, Kate; Trimble, Ted; Seymour, Matthew

    2015-01-01

    Background The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. Settings The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. Results The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Interpretation Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. PMID:25542058

  6. PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases.

    PubMed

    Buske, Orion J; Girdea, Marta; Dumitriu, Sergiu; Gallinger, Bailey; Hartley, Taila; Trang, Heather; Misyura, Andriy; Friedman, Tal; Beaulieu, Chandree; Bone, William P; Links, Amanda E; Washington, Nicole L; Haendel, Melissa A; Robinson, Peter N; Boerkoel, Cornelius F; Adams, David; Gahl, William A; Boycott, Kym M; Brudno, Michael

    2015-10-01

    The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https://phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome or candidate genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on promising matches. PhenomeCentral incorporates data for over 1,000 patients with rare genetic diseases, contributed by the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, the EU Neuromics and ANDDIrare projects, as well as numerous independent clinicians and scientists. Though the majority of these records have associated exome data, most lack a molecular diagnosis. PhenomeCentral has already been used to identify causative mutations for several patients, and its ability to find matching patients and diagnose these diseases will grow with each additional patient that is entered. PMID:26251998

  7. Intracranial hydatid cyst: imaging findings of a rare disease.

    PubMed

    Taslakian, Bedros; Darwish, Houssein

    2016-01-01

    Hydatid disease (echinococcosis) is a worldwide zoonosis produced by the larval stage of the Echinococcus tapeworm. The disease is endemic in many parts of the world, particularly in the Middle East, Australia, New Zealand, South America and central and south Europe. Intracranial hydatid disease is considered a rare disease and may be sometimes very difficult to diagnose based on the clinical and laboratory findings. Therefore, it is important to be aware of the condition and the imaging findings even in the non-endemic parts of the world. We report the case of a 12-year-old boy who presented with headache and vomiting for a few months. The mass was totally excised, with no postoperative complications. We present MR spectroscopy (MRS) findings in this operatively proven case of hydatid cyst of the brain. We discuss imaging findings, in particular the findings on MRS, which is rarely reported in the literature. PMID:27620198

  8. Oophorovesicular-colonic fistula: a rare complication of Crohn's disease.

    PubMed

    Goldberg, S D; Gray, R R; Cadesky, K I; Mackenzie, R L

    1988-11-01

    Salpingitis and vesicular fistulas are rare complications of Crohn's disease. In this report the authors describe a case of oophorovesicular-colonic fistula secondary to Crohn's disease. The patient presented with bleeding from the bladder during menstruation, fecaluria and pneumaturia. A single-stage left salpingo-oophorectomy, sigmoid resection and repair of the fistula were carried out, with complete resolution of symptoms and preservation of fertility potential. PMID:3179852

  9. Children with Rare Chronic Skin Diseases: Hemangiomas and Epidermolysis Bullosa.

    ERIC Educational Resources Information Center

    Jones, Sheila Dove; Miller, Cynthia Dieterich

    The paper reports on studies involving children having the rare chronic skin diseases of hemangiomas and epidermolysis bullosa (characterized by easy blistering). One study compared the self-concept and psychosocial development of young (mean age 46 months) children (N=19) with hemangiomas with 19 children without hemangiomas. Findings indicated…

  10. Rare bone diseases and their dental, oral, and craniofacial manifestations.

    PubMed

    Foster, B L; Ramnitz, M S; Gafni, R I; Burke, A B; Boyce, A M; Lee, J S; Wright, J T; Akintoye, S O; Somerman, M J; Collins, M T

    2014-07-01

    Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690

  11. Rare Bone Diseases and Their Dental, Oral, and Craniofacial Manifestations

    PubMed Central

    Foster, B.L.; Ramnitz, M.S.; Gafni, R.I.; Burke, A.B.; Boyce, A.M.; Lee, J.S.; Wright, J.T.; Akintoye, S.O.; Somerman, M.J.; Collins, M.T.

    2014-01-01

    Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690

  12. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration

    PubMed Central

    Yu, Yi; Triebwasser, Michael P.; Wong, Edwin K. S.; Schramm, Elizabeth C.; Thomas, Brett; Reynolds, Robyn; Mardis, Elaine R.; Atkinson, John P.; Daly, Mark; Raychaudhuri, Soumya; Kavanagh, David; Seddon, Johanna M.

    2014-01-01

    We sequenced the whole exome of 35 cases and 7 controls from 9 age-related macular degeneration (AMD) families in whom known common genetic risk alleles could not explain their high disease burden and/or their early-onset advanced disease. Two families harbored novel rare mutations in CFH (R53C and D90G). R53C segregates perfectly with AMD in 11 cases (heterozygous) and 1 elderly control (reference allele) (LOD = 5.07, P = 6.7 × 10−7). In an independent cohort, 4 out of 1676 cases but none of the 745 examined controls or 4300 NHBLI Exome Sequencing Project (ESP) samples carried the R53C mutation (P = 0.0039). In another family of six siblings, D90G similarly segregated with AMD in five cases and one control (LOD = 1.22, P = 0.009). No other sample in our large cohort or the ESP had this mutation. Functional studies demonstrated that R53C decreased the ability of FH to perform decay accelerating activity. D90G exhibited a decrease in cofactor-mediated inactivation. Both of these changes would lead to a loss of regulatory activity, resulting in excessive alternative pathway activation. This study represents an initial application of the whole-exome strategy to families with early-onset AMD. It successfully identified high impact alleles leading to clearer functional insight into AMD etiopathogenesis. PMID:24847005

  13. Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration.

    PubMed

    Yu, Yi; Triebwasser, Michael P; Wong, Edwin K S; Schramm, Elizabeth C; Thomas, Brett; Reynolds, Robyn; Mardis, Elaine R; Atkinson, John P; Daly, Mark; Raychaudhuri, Soumya; Kavanagh, David; Seddon, Johanna M

    2014-10-01

    We sequenced the whole exome of 35 cases and 7 controls from 9 age-related macular degeneration (AMD) families in whom known common genetic risk alleles could not explain their high disease burden and/or their early-onset advanced disease. Two families harbored novel rare mutations in CFH (R53C and D90G). R53C segregates perfectly with AMD in 11 cases (heterozygous) and 1 elderly control (reference allele) (LOD = 5.07, P = 6.7 × 10(-7)). In an independent cohort, 4 out of 1676 cases but none of the 745 examined controls or 4300 NHBLI Exome Sequencing Project (ESP) samples carried the R53C mutation (P = 0.0039). In another family of six siblings, D90G similarly segregated with AMD in five cases and one control (LOD = 1.22, P = 0.009). No other sample in our large cohort or the ESP had this mutation. Functional studies demonstrated that R53C decreased the ability of FH to perform decay accelerating activity. D90G exhibited a decrease in cofactor-mediated inactivation. Both of these changes would lead to a loss of regulatory activity, resulting in excessive alternative pathway activation. This study represents an initial application of the whole-exome strategy to families with early-onset AMD. It successfully identified high impact alleles leading to clearer functional insight into AMD etiopathogenesis. PMID:24847005

  14. Identifying Mendelian disease genes with the Variant Effect Scoring Tool

    PubMed Central

    2013-01-01

    Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is

  15. Rare Diseases Leading to Childhood Glaucoma: Epidemiology, Pathophysiogenesis, and Management.

    PubMed

    Abdolrahimzadeh, Solmaz; Fameli, Valeria; Mollo, Roberto; Contestabile, Maria Teresa; Perdicchi, Andrea; Recupero, Santi Maria

    2015-01-01

    Noteworthy heterogeneity exists in the rare diseases associated with childhood glaucoma. Primary congenital glaucoma is mostly sporadic; however, 10% to 40% of cases are familial. CYP1B1 gene mutations seem to account for 87% of familial cases and 27% of sporadic cases. Childhood glaucoma is classified in primary and secondary congenital glaucoma, further divided as glaucoma arising in dysgenesis associated with neural crest anomalies, phakomatoses, metabolic disorders, mitotic diseases, congenital disorders, and acquired conditions. Neural crest alterations lead to the wide spectrum of iridocorneal trabeculodysgenesis. Systemic diseases associated with childhood glaucoma include the heterogenous group of phakomatoses where glaucoma is frequently encountered in the Sturge-Weber syndrome and its variants, in phakomatosis pigmentovascularis associated with oculodermal melanocytosis, and more rarely in neurofibromatosis type 1. Childhood glaucoma is also described in systemic disorders of mitotic and metabolic activity. Acquired secondary glaucoma has been associated with uveitis, trauma, drugs, and neoplastic diseases. A database research revealed reports of childhood glaucoma in rare diseases, which do not include glaucoma in their manifestation. These are otopalatodigital syndrome, complete androgen insensitivity, pseudotrisomy 13, Brachmann-de Lange syndrome, acrofrontofacionasal dysostosis, caudal regression syndrome, and Wolf-Hirschhorn syndrome. PMID:26451378

  16. Rare Diseases Leading to Childhood Glaucoma: Epidemiology, Pathophysiogenesis, and Management

    PubMed Central

    Abdolrahimzadeh, Solmaz; Fameli, Valeria; Mollo, Roberto; Contestabile, Maria Teresa; Perdicchi, Andrea; Recupero, Santi Maria

    2015-01-01

    Noteworthy heterogeneity exists in the rare diseases associated with childhood glaucoma. Primary congenital glaucoma is mostly sporadic; however, 10% to 40% of cases are familial. CYP1B1 gene mutations seem to account for 87% of familial cases and 27% of sporadic cases. Childhood glaucoma is classified in primary and secondary congenital glaucoma, further divided as glaucoma arising in dysgenesis associated with neural crest anomalies, phakomatoses, metabolic disorders, mitotic diseases, congenital disorders, and acquired conditions. Neural crest alterations lead to the wide spectrum of iridocorneal trabeculodysgenesis. Systemic diseases associated with childhood glaucoma include the heterogenous group of phakomatoses where glaucoma is frequently encountered in the Sturge-Weber syndrome and its variants, in phakomatosis pigmentovascularis associated with oculodermal melanocytosis, and more rarely in neurofibromatosis type 1. Childhood glaucoma is also described in systemic disorders of mitotic and metabolic activity. Acquired secondary glaucoma has been associated with uveitis, trauma, drugs, and neoplastic diseases. A database research revealed reports of childhood glaucoma in rare diseases, which do not include glaucoma in their manifestation. These are otopalatodigital syndrome, complete androgen insensitivity, pseudotrisomy 13, Brachmann-de Lange syndrome, acrofrontofacionasal dysostosis, caudal regression syndrome, and Wolf-Hirschhorn syndrome. PMID:26451378

  17. Improving translational studies: lessons from rare neuromuscular diseases

    PubMed Central

    Wells, Dominic

    2015-01-01

    ABSTRACT Animal models play a key role in the development of novel treatments for human disease. This is particularly true for rare diseases – defined as disorders that affect less than 1 in 2000 people in the human population – for which, very often, there are no effective methods of treatment. Pharmaceutical companies are increasingly focussing on the development of therapies for the more than 7000 rare diseases. Because the majority of these are the result of single gene disorders, the exceptional ability to manipulate the mouse genome means that many such studies will take place in the laboratory mouse. But how good are the mouse models and how useful are they in assessing the potential for translational medicine? In this Editorial, I will discuss current difficulties in translational research as well as examples of good laboratory practice and guidelines that are being implemented to improve the translational potential of animal studies in the field of neuromuscular rare diseases. This could represent a potentially useful approach for adoption by other disease fields to achieve a greater success rate in translational studies. PMID:26438690

  18. Diagnosis and management of rare congenital nonimmune hemolytic disease.

    PubMed

    Gallagher, Patrick G

    2015-01-01

    Rare, congenital nonimmune hemolytic disorders of the erythrocyte, although uncommon, are important causes of anemia in the child and adult. These are a heterogeneous group of diseases that disrupt normal erythrocyte structure and function in varying ways. Predominant are abnormalities of hemoglobin stability, defects of erythrocyte metabolism, and disorders of erythrocyte hydration. Unstable hemoglobinopathies may lead to chronic or episodic hemolysis. Perturbation of critical enzymes of the Embden-Meyerhof pathway lead to altered erythrocyte metabolism and chronic hemolysis. Disorders of erythrocyte hydration are an under-recognized cause of hemolytic anemia. Beyond pathophysiologic mechanisms of disease, clinical, laboratory, and genetic heterogeneity characterize this group of disorders. Often, they are underdiagnosed or misdiagnosed. This review discusses pathophysiology, inheritance, clinical findings, laboratory manifestations, and management considerations in several rare nonimmune hemolytic diseases including the unstable hemoglobins, disorders of erythrocyte metabolism, and abnormalities of erythrocyte hydration. PMID:26637748

  19. The Genetics of Ultra-Rare Renal Disease.

    PubMed

    Muff-Luett, Melissa; Nester, Carla M

    2016-03-01

    The complement-mediated renal diseases are a group of ultra-rare renal diseases that disproportionately affect children and young adults and frequently lead to irreversible renal failure. Genetic mutations in alternate pathway of complement genes are pathomechanistically involved in a significant number of these unique diseases. Here, we review our current understanding of the role of genetics in the primary complement-mediated renal diseases affecting children, with a focus on atypical hemolytic uremic syndrome and C3 glomerulopathy. Also, included is a brief discussion of the related diseases whose relationship to complement abnormality has been suspected but not yet confirmed. Advances in genetics have transformed both treatment and outcomes in these historically difficult to treat, highly morbid diseases. PMID:27617140

  20. Detection and Impact of Rare Regulatory Variants in Human Disease

    PubMed Central

    Li, Xin; Montgomery, Stephen B.

    2013-01-01

    Advances in genome sequencing are providing unprecedented resolution of rare and private variants. However, methods which assess the effect of these variants have relied predominantly on information within coding sequences. Assessing their impact in non-coding sequences remains a significant contemporary challenge. In this review, we highlight the role of regulatory variation as causative agents and modifiers of monogenic disorders. We further discuss how advances in functional genomics are now providing new opportunity to assess the impact of rare non-coding variants and their role in disease. PMID:23755067

  1. A rare case of Kussmaul Disease (Sialodochitis Fibrinosa)

    PubMed Central

    Ray, Amrita; Burgin, Sarah J.; Spector, Matthew E.

    2015-01-01

    Sialodochitis fibrinosa (or commonly known as Kussmaul Disease) is a rare salivary gland disease characterized by recurrent salivary gland swelling and pain as a result of mucofibrinous plugs. Typically patients have a history of multiply recurrent glandular swelling, dehydration and/or decreased salivary flow, thick secretions from Stensen’s or Wharton’s duct, and/or history of allergic diseases. Retention of mucofibrinous plugs may lead to acute suppurative parotitis and chronic sialadenitis ultimately. The diagnosis is one of exclusion, and treatment is based on symptomatology and largely supportive. PMID:26246913

  2. Chylomicron retention disease: A rare cause of chronic diarrhea.

    PubMed

    Ben Ameur, S; Aloulou, H; Jlidi, N; Kamoun, F; Chabchoub, I; Di Filippo, M; Sfaihi, L; Hachicha, M

    2016-07-01

    Chylomicron retention disease (CRD) is a rare autosomal recessive hereditary hypocholesterolemic disorder. The disease most frequently presents in infants and is characterized by a lipid malabsorption syndrome with steatorrhea, chronic diarrhea, and growth retardation. The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load. In this report, we describe the clinical, laboratory, and histological data as well as the molecular DNA analysis of a 12-month-old girl from Tunisia with CRD. The patient was treated with a low-fat diet and fat-soluble vitamin supplementation resulting in significant improvement. PMID:27266643

  3. Kullback-Leibler divergence for detection of rare haplotype common disease association.

    PubMed

    Lin, Shili

    2015-11-01

    Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single-nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haplotypes may shed light on the underlying disease causal mechanism, a feat unmatched by SNV-based collapsing methods. In recent years, data mining approaches have been adapted to detect rare haplotype association. However, as they rely on an assumed underlying disease model and require the specification of a null haplotype, results can be erroneous if such assumptions are violated. In this paper, we present a haplotype association method based on Kullback-Leibler divergence (hapKL) for case-control samples. The idea is to compare haplotype frequencies for the cases versus the controls by computing symmetrical divergence measures. An important property of such measures is that both the frequencies and logarithms of the frequencies contribute in parallel, thus balancing the contributions from rare and common, and accommodating both deleterious and protective, haplotypes. A simulation study under various scenarios shows that hapKL has well-controlled type I error rates and good power compared with existing data mining methods. Application of hapKL to age-related macular degeneration (AMD) shows a strong association of the complement factor H (CFH) gene with AMD, identifying several individual rare haplotypes with strong signals. PMID:25735482

  4. Socio-economic burden of rare diseases: A systematic review of cost of illness evidence.

    PubMed

    Angelis, Aris; Tordrup, David; Kanavos, Panos

    2015-07-01

    Cost-of-illness studies, the systematic quantification of the economic burden of diseases on the individual and on society, help illustrate direct budgetary consequences of diseases in the health system and indirect costs associated with patient or carer productivity losses. In the context of the BURQOL-RD project ("Social Economic Burden and Health-Related Quality of Life in patients with Rare Diseases in Europe") we studied the evidence on direct and indirect costs for 10 rare diseases (Cystic Fibrosis [CF], Duchenne Muscular Dystrophy [DMD], Fragile X Syndrome [FXS], Haemophilia, Juvenile Idiopathic Arthritis [JIA], Mucopolysaccharidosis [MPS], Scleroderma [SCL], Prader-Willi Syndrome [PWS], Histiocytosis [HIS] and Epidermolysis Bullosa [EB]). A systematic literature review of cost of illness studies was conducted using a keyword strategy in combination with the names of the 10 selected rare diseases. Available disease prevalence in Europe was found to range between 1 and 2 per 100,000 population (PWS, a sub-type of Histiocytosis, and EB) up to 42 per 100,000 population (Scleroderma). Overall, cost evidence on rare diseases appears to be very scarce (a total of 77 studies were identified across all diseases), with CF (n=29) and Haemophilia (n=22) being relatively well studied, compared to the other conditions, where very limited cost of illness information was available. In terms of data availability, total lifetime cost figures were found only across four diseases, and total annual costs (including indirect costs) across five diseases. Overall, data availability was found to correlate with the existence of a pharmaceutical treatment and indirect costs tended to account for a significant proportion of total costs. Although methodological variations prevent any detailed comparison between conditions and based on the evidence available, most of the rare diseases examined are associated with significant economic burden, both direct and indirect. PMID:25661982

  5. An innovative portal for rare genetic diseases research: the semantic Diseasecard.

    PubMed

    Lopes, Pedro; Oliveira, José Luís

    2013-12-01

    Advances in "omics" hardware and software technologies are bringing rare diseases research back from the sidelines. Whereas in the past these disorders were seldom considered relevant, in the era of whole genome sequencing the direct connections between rare phenotypes and a reduced set of genes are of vital relevance. This increased interest in rare genetic diseases research is pushing forward investment and effort towards the creation of software in the field, and leveraging the wealth of available life sciences data. Alas, most of these tools target one or more rare diseases, are focused solely on a single type of user, or are limited to the most relevant scientific breakthroughs for a specific niche. Furthermore, despite some high quality efforts, the ever-growing number of resources, databases, services and applications is still a burden to this area. Hence, there is a clear interest in new strategies to deliver a holistic perspective over the entire rare genetic diseases research domain. This is Diseasecard's reasoning, to build a true lightweight knowledge base covering rare genetic diseases. Developed with the latest semantic web technologies, this portal delivers unified access to a comprehensive network for researchers, clinicians, patients and bioinformatics developers. With in-context access covering over 20 distinct heterogeneous resources, Diseasecard's workspace provides access to the most relevant scientific knowledge regarding a given disorder, whether through direct common identifiers or through full-text search over all connected resources. In addition to its user-oriented features, Diseasecard's semantic knowledge base is also available for direct querying, enabling everyone to include rare genetic diseases knowledge in new or existing information systems. Diseasecard is publicly available at http://bioinformatics.ua.pt/diseasecard/. PMID:23973272

  6. Rare diseases: matching wheelchair users with rare metabolic, neuromuscular or neurological disorders to electric powered indoor/outdoor wheelchairs (EPIOCs)

    PubMed Central

    De Souza, Lorraine H.; Frank, Andrew O.

    2016-01-01

    Abstract Purpose: To describe the clinical features of electric powered indoor/outdoor wheelchair (EPIOC) users with rare diseases (RD) impacting on EPIOC provision and seating. Method: Retrospective review by a consultant in rehabilitation medicine of electronic and case note records of EPIOC recipients with RDs attending a specialist wheelchair service between June 2007 and September 2008. Data were systematically extracted, entered into a database and analysed under three themes; demographic, diagnostic/clinical (including comorbidity and associated clinical features (ACFs) of the illness/disability) and wheelchair factors. Results: Fifty-four (27 male) EPIOC users, mean age 37.3 (SD 18.6, range 11–70) with RDs were identified and reviewed a mean of 64 (range 0–131) months after receiving their wheelchair. Diagnoses included 27 types of RDs including Friedreich’s ataxia, motor neurone disease, osteogenesis imperfecta, arthrogryposis, cerebellar syndromes and others. Nineteen users had between them 36 comorbidities and 30 users had 44 ACFs likely to influence the prescription. Tilt-in-space was provided to 34 (63%) users and specialised seating to 17 (31%). Four users had between them complex control or interfacing issues. Conclusions: The complex and diverse clinical problems of those with RDs present unique challenges to the multiprofessional wheelchair team to maintain successful independent mobility and community living.Implications for RehabilitationPowered mobility is a major therapeutic tool for those with rare diseases enhancing independence, participation, reducing pain and other clinical features.The challenge for rehabilitation professionals is reconciling the physical disabilities with the individual’s need for function and participation whilst allowing for disease progression and/or growth.Powered wheelchair users with rare diseases with a (kypho) scoliosis require a wheelchair system that balances spine stability and movement to maximise

  7. Limits on use of health economic assessments for rare diseases.

    PubMed

    Hyry, H I; Stern, A D; Cox, T M; Roos, J C P

    2014-03-01

    Funding of expensive treatments for rare (orphan) diseases is contentious. These agents fare poorly on 'efficiency' or health economic measures, such as the quality-adjusted life years, because of high cost and frequently poor gains in quality of life and survival. We show that cost-effectiveness assessments are flawed, and have only a limited role to play in reimbursement decisions for orphan drugs and beyond. PMID:24453281

  8. Violent death in a rare peroxisomal disease--Zellweger syndrome.

    PubMed

    Malinescu, Bogdan; Martius, Eliza; Pelin, Ana Maria

    2015-10-01

    Peroxisomal diseases are rare (1:50,000), genetically determined disorders (autosomal recessive), systemic, multiorgan illnesses with prominent involvement of the nervous system, caused either by the failure to form or to maintain the peroxisome, or by a defect in the function of a single or multiple peroxisomal enzymes. Peroxisomes contain approximately 50 enzymes which are responsible for many metabolic reactions, and play an important role in the oxidation of saturated very-long-chain fatty acids (VLCFA). The authors present the case of a Romanian boy, who died at the age of 1.6 of one of the peroxisomal diseases-Zellweger syndrome. Newborn infants with Zellweger syndrome have a typical dysmorphic facies, neonatal seizures, profound hypotonia, and eye abnormalities. Major abnormalities are present in the liver (fibrotic), kidney (cortical cysts), and brain (lipid-laden macrophages and histiocytes in cortical and periventricular areas, demyelination, centrosylvian polymicrogyria and pachygyria)-cerebro-hepato-renal syndrome (CHRS) (Zellweger). Infants with Zellweger syndrome rarely live more than a few months, but in this case the survival was longer, and the cause of death was not directly the peroxisomal disease but a violent cause of death-mechanical asphyxia with tracheo-bronchial food aspiration. The authors present the results of investigations carried out during the child's life, but also data collected at the autopsy and hystopathological postnecroptic investigations. By presenting this case, the authors wish to bring to your attention a rare pathology in forensic practice by the paradox of finding a common violent cause of death, asphyxia with food aspiration, in a rare metabolic-genetic disease, which is usually fatal by itself. PMID:26235911

  9. A Sporadic Case of Ichthyosis Curth Macklin: Rare Presentation of a Rare Disease.

    PubMed

    Mehta, Sharad; Agarwal, Uma Shankar; Agarwal, Nidheesh

    2015-01-01

    Ichthyosis hystrix is a rare autosomal dominant genodermatosis, characterized by persistent spiny hyperkeratotic scales which cover a significant part of the skin surface. Based on the pattern of distribution, five clinical variants namely Brocq type, Lambert type, Curth-Macklin type, Rheydt type and Bδfverstedt type have been described. We report the case of an 11-year-old male child with spiny, hyperkeratotic scales all over the body since birth with sparing of scalp and central part of the face. Palmoplantar keratoderma was also present. These clinical features are suggestive of Ichthyosis Curth Macklin, which has been typically described in families. However, family history was negative in our patient. The case is being reported on account of rarity of the disease, that too with a very rare sporadic presentation. PMID:26538731

  10. A Sporadic Case of Ichthyosis Curth Macklin: Rare Presentation of a Rare Disease

    PubMed Central

    Mehta, Sharad; Agarwal, Uma Shankar; Agarwal, Nidheesh

    2015-01-01

    Ichthyosis hystrix is a rare autosomal dominant genodermatosis, characterized by persistent spiny hyperkeratotic scales which cover a significant part of the skin surface. Based on the pattern of distribution, five clinical variants namely Brocq type, Lambert type, Curth-Macklin type, Rheydt type and Bδfverstedt type have been described. We report the case of an 11-year-old male child with spiny, hyperkeratotic scales all over the body since birth with sparing of scalp and central part of the face. Palmoplantar keratoderma was also present. These clinical features are suggestive of Ichthyosis Curth Macklin, which has been typically described in families. However, family history was negative in our patient. The case is being reported on account of rarity of the disease, that too with a very rare sporadic presentation. PMID:26538731

  11. Cost effective assay choice for rare disease study designs.

    PubMed

    Campbell, Desmond D; Porsch, Robert M; Cherny, Stacey S; Capra, Valeria; Merello, Elisa; De Marco, Patrizia; Sham, Pak C; Garcia-Barceló, Maria-Mercè

    2015-01-01

    High throughput assays tend to be expensive per subject. Often studies are limited not so much by the number of subjects available as by assay costs, making assay choice a critical issue. We have developed a framework for assay choice that maximises the number of true disease causing mechanisms 'seen', given limited resources. Although straightforward, some of the ramifications of our methodology run counter to received wisdom on study design. We illustrate our methodology with examples, and have built a website allowing calculation of quantities of interest to those designing rare disease studies. PMID:25648394

  12. THE RARE DISEASES CLINICAL RESEARCH NETWORK CONTACT REGISTRY UPDATE: FEATURES AND FUNCTIONALITY

    PubMed Central

    Richesson, Rachel; Sutphen, Rebecca; Shereff, Denise; Krischer, Jeff

    2013-01-01

    The Rare Diseases Clinical Research Network (RDCRN) Contact Registry has grown in size and scope since it was first reported in this journal in 2007. In this paper, we reflect on our seven years’ experience developing and expanding the RDCRN Contact Registry to include many more rare diseases. We present the functional and data requirements that motivated this registry, and the new features and policies that have been developed since. Given the high costs and long-term commitment required to build patient registries, the RDCRN Contact Registry experience represents a reasonable approach for identifying and cultivating potential research populations, with minimal resources and patient burden. The basic model of a patient-reported registry has not changed since our 2007 report, but the number of diseases has grown from 42 to 201, and the types of information that are exchanged with participants has expanded. A patient-directed information-sharing feature has been added to reduce barriers to communication between investigators and patients affected by rare and genetic diseases. As specific data and research needs arise, the Contact Registry can be leveraged to access needed data or to solicit patients for particular research opportunities. This multiple-disease registry is scalable, expandable, and standards-driven, and has become a model for clinical and translational research across rare and many other diseases. PMID:22405970

  13. Rare diseases with renal involvement in the Republic of Macedonia.

    PubMed

    Tasic, V; Lozanovski, V J; Danilovski, D; Laban, N; Pop-Jordanova, N; Polenakovic, M; Gucev, Z S

    2011-01-01

    Rare diseases (RDs) pose a significant set of problems for patients, since their disease and general social and health situation are often not recognized by the medical community and shunned by health insurance. The sheer number of RDs (5000-8000) and the number of patients (6-8% of the population) are challenging for every society. We wanted to get a better understanding of the rare diseases affecting the kidneys and urinary tract (RDAKUT) in the Republic of Macedonia and we investigated principally the PubMed Central articles of Macedonian medical professionals dealing with RDAKUT, but we also used information on RDAKUT from local sources. A significant number of RDs have been published, demonstrating the awareness and skill of Macedonian medical professionals despite pretty limited diagnostic facilities. We still feel that RDAKUT are underdiagnosed (e.g. Fabry's disease has not yet been reported), and that many patients with RDs have a long way to go before an accurate diagnosis. Increased awareness and ameliorated education are needed by the physicians; while health insurance must include RDAKUT covering their diagnosis and treatment costs. Neonatal screening for ~30 diseases (instead of just hypothyroidism) is also required. Patients' organizations exist and they are active in promoting their interests before of the health authorities. PMID:21822178

  14. Drug development for exceptionally rare metabolic diseases: challenging but not impossible

    PubMed Central

    2013-01-01

    Background We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Methods All metabolic diseases with a genetic cause and prevalence of less than 10 patients per 1 million of the population were selected from the ‘Orphanet database of Rare diseases’. The outcome of interest was the application for an orphan designation at FDA or EMA. The level of publicly available knowledge of the disease and drug candidate before an orphan designation application was defined as whether the physiological function corresponding with the pathologic gene and initiation of the pathophysiological pathway was known, whether an appropriate animal study was identified for the disease, whether preclinical proof of concept was ascertained and the availability of data in humans. Other determinants included in the study were metabolic disease class, the prevalence of the disease, prognosis and time of first description of the disease in the literature. Univariate relative risks (RRs) and 95% confidence intervals (CIs) of an orphan designation application were calculated for each of these determinants. In addition, a multivariate Cox regression analysis was conducted (Forward LR). Results In total, 166 rare metabolic genetic diseases were identified and included in the analysis. For only 42 (25%) of the diseases an orphan designation application was submitted at either FDA or EMA before January 2012. The multivariate analysis identified preclinical proof of concept of a potential medicinal product as major knowledge related determinant associated with an orphan designation application (RRadj 3.9, 95% CI 1.9-8.3) and confirmed that prevalence of the disease is also associated with filing an application for an orphan designation (RRadj 2

  15. The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease

    PubMed Central

    Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; Vasilevsky, Nicole; Baynam, Gareth; Zemojtel, Tomasz; Schriml, Lynn Marie; Kibbe, Warren Alden; Schofield, Paul N.; Beck, Tim; Vasant, Drashtti; Brookes, Anthony J.; Zankl, Andreas; Washington, Nicole L.; Mungall, Christopher J.; Lewis, Suzanna E.; Haendel, Melissa A.; Parkinson, Helen; Robinson, Peter N.

    2015-01-01

    The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. PMID:26119816

  16. The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease.

    PubMed

    Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; Vasilevsky, Nicole; Baynam, Gareth; Zemojtel, Tomasz; Schriml, Lynn Marie; Kibbe, Warren Alden; Schofield, Paul N; Beck, Tim; Vasant, Drashtti; Brookes, Anthony J; Zankl, Andreas; Washington, Nicole L; Mungall, Christopher J; Lewis, Suzanna E; Haendel, Melissa A; Parkinson, Helen; Robinson, Peter N

    2015-07-01

    The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. PMID:26119816

  17. Identifying Constraints to Potato System Sustainability: Diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four different potato cropping systems, designed to address specific management goals of soil conservation (SC), soil improvement (SI), disease suppression (DS), and a status quo (standard rotation) control (SQ), were evaluated for their effects on soilborne and foliar diseases of potato, as well as...

  18. Heavy and Light chain amyloidosois presenting as complete heart block: A rare presentation of a rare disease

    PubMed Central

    Priyamvada, P. S.; Morkhandikar, S.; Srinivas, B. H.; Parameswaran, S.

    2015-01-01

    Amyloidosis is an uncommon disease characterized by deposition of proteinaceous material in the extracellular matrix, which results from abnormal protein folding. Even though more than 25 precursor proteins are identified, majority of systemic amyloidosis results from deposition of abnormal immunoglobulin (Ig) light chains. In heavy chain amyloidosis (AH), deposits are derived from both heavy chain alone, whereas in heavy and light chain amyloidosis (AHL), the deposits are derived from Ig heavy chains and light chains. Both AH and AHL are extremely rare diseases. Here, we report an unusual presentation of IgG (lambda) AHL amyloidosis in the background of multiple myeloma, where the initial clinical presentation was complete heart block, which preceded the definitive diagnosis by 18 months. PMID:25838650

  19. On the Front Lines of Rare Disease Research | NIH MedlinePlus the Magazine

    MedlinePlus

    ... GARD. She also directs NCATS' Division of Clinical Innovation. She recently discussed rare diseases and ongoing research ... of Rare Diseases Research and Division of Clinical Innovation What motivated you to help explore research on ...

  20. A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese.

    PubMed

    Jiang, Teng; Tan, Lan; Chen, Qi; Tan, Meng-Shan; Zhou, Jun-Shan; Zhu, Xi-Chen; Lu, Huan; Wang, Hui-Fu; Zhang, Ying-Dong; Yu, Jin-Tai

    2016-06-01

    Two recent studies have identified that a rare coding variant (p.R47H) in exon 2 of triggering receptor expressed on myeloid cells 2 (TREM2) gene is associated with Alzheimer's disease (AD) susceptibility in Caucasians. This association was not successfully replicated in Han Chinese, where this variant was rare or even absent. Previously, we resequenced TREM2 exon 2 to investigate whether additional rare variants conferred risk to AD in our cohort. Although several new variants had been identified, none of them was significantly associated with disease susceptibility. Here, to test whether TREM2 is truly a susceptibility gene of AD in Han Chinese, we extend our previous study by sequencing the other four exons of TREM2 in 988 AD patients and 1,354 healthy controls. We provided the first evidence that a rare coding variant (p.H157Y) in TREM2 exon 3 conferred a considerable risk of AD in our cohort (Pcorrected = 0.02, odds ratio = 11.01, 95% confidence interval: 1.38-88.05). This finding indicates that rare coding variants of TREM2 may play an important role in AD in Han Chinese. PMID:27067662

  1. Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.

    PubMed

    Lionel, Anath C; Crosbie, Jennifer; Barbosa, Nicole; Goodale, Tara; Thiruvahindrapuram, Bhooma; Rickaby, Jessica; Gazzellone, Matthew; Carson, Andrew R; Howe, Jennifer L; Wang, Zhuozhi; Wei, John; Stewart, Alexandre F R; Roberts, Robert; McPherson, Ruth; Fiebig, Andreas; Franke, Andre; Schreiber, Stefan; Zwaigenbaum, Lonnie; Fernandez, Bridget A; Roberts, Wendy; Arnold, Paul D; Szatmari, Peter; Marshall, Christian R; Schachar, Russell; Scherer, Stephen W

    2011-08-10

    Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders. PMID:21832240

  2. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease.

    PubMed

    Schulte, Eva C; Fukumori, Akio; Mollenhauer, Brit; Hor, Hyun; Arzberger, Thomas; Perneczky, Robert; Kurz, Alexander; Diehl-Schmid, Janine; Hüll, Michael; Lichtner, Peter; Eckstein, Gertrud; Zimprich, Alexander; Haubenberger, Dietrich; Pirker, Walter; Brücke, Thomas; Bereznai, Benjamin; Molnar, Maria J; Lorenzo-Betancor, Oswaldo; Pastor, Pau; Peters, Annette; Gieger, Christian; Estivill, Xavier; Meitinger, Thomas; Kretzschmar, Hans A; Trenkwalder, Claudia; Haass, Christian; Winkelmann, Juliane

    2015-10-01

    Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD. PMID:25604855

  3. Anaemia in Waldmann's disease: A rare presentation of a rare disease.

    PubMed

    El-Etreby, Shahira A; Altonbary, Ahmed Y; Sorogy, Mohamed El; Elkashef, Wagdi; Mazroa, Jehan A; Bahgat, Monir H

    2015-05-16

    A 32-year-old female presented with 5-year history of iron deficiency anemia, marked pallor and edema of both lower limbs. Laboratory investigations including complete blood count, blood film, iron studies, lipid profile, ascitic fluid analysis, test of stool for occult blood and alpha 1 anti-trypsin. Upper, lower gastrointestinal (GIT) endoscopies, and enteroscopy were performed. Imaging techniques as abdominal ultrasonography and computed tomography were done. Echocardiography, lymph node biopsy and bone marrow examination were normal. The case was diagnosed as Waldmann's disease with protein losing enteropathy and recurrent GIT bleeding. Management started with low fat diet with medium chain triglyceride, octreotide 200 μg twice a day, tranexamic acid and blood transfusion. Then, exploratory laparotomy with pathological examination of resected segment was done when recurrent GIT bleeding occurred and to excluded malignant transformation. PMID:25992197

  4. Anaemia in Waldmann’s disease: A rare presentation of a rare disease

    PubMed Central

    El-Etreby, Shahira A; Altonbary, Ahmed Y; Sorogy, Mohamed El; Elkashef, Wagdi; Mazroa, Jehan A; Bahgat, Monir H

    2015-01-01

    A 32-year-old female presented with 5-year history of iron deficiency anemia, marked pallor and edema of both lower limbs. Laboratory investigations including complete blood count, blood film, iron studies, lipid profile, ascitic fluid analysis, test of stool for occult blood and alpha 1 anti-trypsin. Upper, lower gastrointestinal (GIT) endoscopies, and enteroscopy were performed. Imaging techniques as abdominal ultrasonography and computed tomography were done. Echocardiography, lymph node biopsy and bone marrow examination were normal. The case was diagnosed as Waldmann’s disease with protein losing enteropathy and recurrent GIT bleeding. Management started with low fat diet with medium chain triglyceride, octreotide 200 μg twice a day, tranexamic acid and blood transfusion. Then, exploratory laparotomy with pathological examination of resected segment was done when recurrent GIT bleeding occurred and to excluded malignant transformation. PMID:25992197

  5. Challenges and Opportunities in Rare Disease Drug Development.

    PubMed

    Smith, B P

    2016-10-01

    Each month, Clinical Pharmacology & Therapeutics focuses on a particular theme. Twice a year, the associate editors, editors, and staff get together to discuss journal business and spend time setting up the calendar of themes. Often, there are no experts among us to take on a particular topic that we have chosen. The consequence is that one or two of us take on the theme and then have a crash course to learn as much as they can about it in order to solicit meaningful articles. This month's theme on rare diseases is such a case. PMID:27612019

  6. A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing.

    PubMed

    Tada, Hayato; Kawashiri, Masa-Aki; Okada, Hirofumi; Endo, Saori; Toyoshima, Yuka; Konno, Tetsuo; Nohara, Atsushi; Inazu, Akihiro; Takao, Akira; Mabuchi, Hiroshi; Yamagishi, Masakazu; Hayashi, Kenshi

    2016-07-01

    Whole exome sequencing (WES) technologies have accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. We encountered a 13-year-old Japanese female initially diagnosed with familial hypercholesterolemia on the basis of clinical manifestations of severe hypercholesterolemia (initial LDL cholesterol=609 mg/dl at the age of one) and systemic intertriginous xanthomas with histories of recurrent self-limiting episodes of fever and arthritis. Both her phenotypes seemed to co-segregate in a recessive manner. We performed WES on this patient, who was considered a proband. Among 206,430 variants found in this individual, we found 18,220 nonsense, missense, or splice site variants, of which 3,087 were rare (minor allele frequency ≤ 0.01 or not reported) in 1000 Genome (Asian population). Filtering by assuming a recessive pattern of inheritance with the use of an in silico annotation prediction tool, we successfully narrowed down the candidates to the compound heterozygous mutations in the ABCG5 gene (c.1256G>A or p.Arg419His/c.1763-1G>A [splice acceptor site]) and to the double-compound heterozygous mutations in the MEFV gene (c.329T>C/C or p.Leu110Pro/c.442G>C/C or p.Glu148Val). The patient was genetically diagnosed with sitosterolemia and familial Mediterranean fever using WES for the first time. Such a comprehensive approach is useful for identifying causative mutations for multiple unrelated inheritable diseases. PMID:27170062

  7. A Rare SNP Identified a TCP Transcription Factor Essential for Tendril Development in Cucumber.

    PubMed

    Wang, Shenhao; Yang, Xueyong; Xu, Mengnan; Lin, Xingzhong; Lin, Tao; Qi, Jianjian; Shao, Guangjin; Tian, Nana; Yang, Qing; Zhang, Zhonghua; Huang, Sanwen

    2015-12-01

    Rare genetic variants are abundant in genomes but less tractable in genome-wide association study. Here we exploit a strategy of rare variation mapping to discover a gene essential for tendril development in cucumber (Cucumis sativus L.). In a collection of >3000 lines, we discovered a unique tendril-less line that forms branches instead of tendrils and, therefore, loses its climbing ability. We hypothesized that this unusual phenotype was caused by a rare variation and subsequently identified the causative single nucleotide polymorphism. The affected gene TEN encodes a TCP transcription factor conserved within the cucurbits and is expressed specifically in tendrils, representing a new organ identity gene. The variation occurs within a protein motif unique to the cucurbits and impairs its function as a transcriptional activator. Analyses of transcriptomes from near-isogenic lines identified downstream genes required for the tendril's capability to sense and climb a support. This study provides an example to explore rare functional variants in plant genomes. PMID:26597500

  8. [RENDU-OSLER DISEASE: A RARE CAUSE OF AMMONIA ENCEPHALOPATHY].

    PubMed

    Dumont, R; Loly, J-P; Delwaide, J; Louis, E

    2016-02-01

    Hereditary Hemorrhagic Telangiectasia (HHT) also known as Rendu-Osler disease is a group of related disorders inherited in an autosomal dominant fashion and characterized by the development of arteriovenous malformations (AVM) in the skin, mucous membranes, and/or internal organs such as the brain, lungs, and liver. The prevalence of liver involvement is clinically estimated between 8 and 31 percent. It can be revealed by the following clinical signs : ascites, edema of the lower extremities, abdominal pain, dyspnea, and, rarely, hepatic encephalopathy and gastrointestinal bleeding associated with portal hypertension. This case illustrates the highlight of liver damage revealed by an ammonia encephalopathy associated with iconographic anomalies on ultrasonography and magnetic resonance liver as part of Rendu-Osler disease. PMID:27141651

  9. Thymic neoplasm: a rare disease with a complex clinical presentation

    PubMed Central

    Rashid, Omar M.; Cassano, Anthony D.

    2013-01-01

    Thymic neoplasms constitute a broad category of rare lesions with a wide spectrum of pathologic characteristics and clinical presentations which therefore require a high index of suspicion to diagnose. The natural history of the disease is seldom predictable, anywhere from an indolent to an aggressively malignant course. Although the classification and staging of these lesions are complex and controversial, complete radical surgical resection remains the gold standard of therapy. Radiation and chemotherapy are important elements of the multimodality approach to treating these patients and it is important for thoracic surgeons to work closely with their colleagues in other disciplines in the management of and future research endeavors in thymic neoplasm. In this review, we discuss the evaluation of the patient with an anterior mediastinal mass, the classification and staging of thymic neoplasms, the role of surgery, radiation and chemotherapy in treating this disease, as well as future directions in research for novel targeted therapies. PMID:23585946

  10. Financing translation: analysis of the NCATS rare-diseases portfolio.

    PubMed

    Fagnan, David E; Yang, N Nora; McKew, John C; Lo, Andrew W

    2015-02-25

    The portfolio of the National Center for Advancing Translational Sciences (NCATS) rare-diseases therapeutic development program comprises 28 research projects initiated at the preclinical stage. Historical data reveal substantially lower costs and higher success rates but longer preclinical timelines for the NCATS projects relative to the industry averages for early-stage translational medical research and development (R&D) typically cited in literature. Here, we evaluate the potential risks and rewards of investing in a portfolio of rare-disease therapeutics. Using a "megafund" financing structure, NCATS data, and valuation estimates from a panel of industry experts, we simulate a hypothetical megafund in which senior and junior debt yielded 5 and 8%, respectively. The simulated expected return to equity was 14.7%, corresponding to a modified internal rate of return of 21.6%. These returns and the likelihood of private-sector funding can be enhanced through third-party funding guarantees from philanthropies, patient advocacy groups, and government agencies. PMID:25717096

  11. [Hope for patients with rare diseases--"orphan" drugs].

    PubMed

    Kuzelová, M; Kubácková, K; Palágyi, M; Smíd, M

    2006-01-01

    Rare diseases are defined as those affected less than five in every 10 000 person in European Union. The purpose of this paper is to present activities, which make possible to stimulate research development and marketing of appropriate medicine for tretment of rare disease, named "Orphan" medicinal products. EU "Orphan" medicinal products legislation which entered into force in April 2000 is described. Definition of "Orphan" medicinal products as well as the procedure of designation and placing the products into the Community register is presented. Those incentives to industry are described, which are already five years very well implemented oh the European level mostly on the pre-authorisation phase of "Orphan" medicinal products development, but also in the registration process as well as the post-authorisation phase. Finaly, the first twenty "Orphan" medicinal products, which have been given positive opinion in the Community for the grant of a marketing authorisation till April 2005 are mentioned in this work. The real availability of "Orphan" medicinal products in the particular EU member states is analysed. PMID:16639930

  12. Rare diseases, orphan drugs, and their regulation in Asia: Current status and future perspectives

    PubMed Central

    Song, Peipei; Gao, Jianjun; Inagaki, Yoshinori; Kokudo, Norihiro; Tang, Wei

    2012-01-01

    Summary Rare diseases are an important public health issue and a challenge to medical care. Specific legislation to encourage research of rare diseases and development of orphan drugs has been adopted in the United States (US), the European Union (EU), and elsewhere. In recent years, much progress has been made in some parts of Asia, including Japan, South Korea, and Taiwan, with the enactment of legislation and accompanying regulation of rare diseases and orphan drugs. China is also actively promoting the regulation of rare diseases and orphan drugs. We describe the current status of the regulation of rare diseases and orphan drugs in Asia and we comparatively analyze the regulation of rare diseases and orphan drugs worldwide in order to examine the challenges to and future perspectives on promoting research on rare diseases and development of orphan drugs in China and other Asian countries. PMID:25343064

  13. Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.

    PubMed

    Sirkis, Daniel W; Bonham, Luke W; Aparicio, Renan E; Geier, Ethan G; Ramos, Eliana Marisa; Wang, Qing; Karydas, Anna; Miller, Zachary A; Miller, Bruce L; Coppola, Giovanni; Yokoyama, Jennifer S

    2016-01-01

    Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression. PMID:27589997

  14. Retroperitoneal Castleman's disease with colon cancer. A rare association.

    PubMed

    Gómez-Raposo, César; Nistal, Manuel; De Castro Carpeño, Javier; Sosa Rotundo, Grevelyn; Belda-Iniesta, Cristóbal; Casado, Enrique; González Barón, Manuel

    2008-04-01

    Castleman's disease (CD) is a rare disorder of uncertain aetiology characterised by massive proliferation of lymphoid tissue usually localised as mediastinal masses, although abdominal involvement has been reported. Localised forms are usually associated with a good prognosis, but several more aggressive multifocal variants have been observed. Two different histologic subtypes have been described: the hyaline vascular type, more common in unicentric CD and usually asymptomatic, and the plasma cell form. Unicentric CD may be associated with an increased risk of lymphoma, but there was no reported increased risk of other malignancies. A patient with plasma cell subtype unicentric CD localised in retroperitoneum associated with an adenocarcinoma of ileocaecal valve and liver metastasis is reported. PMID:18411199

  15. Childhood-onset (Juvenile) Huntington's disease: A rare case report

    PubMed Central

    Patra, Kailash Chandra; Shirolkar, Mukund Sudhir

    2015-01-01

    Huntington's disease (HD) is a rare dominantly inherited neurodegenerative disorder characterized clinically by a combination of abnormal involuntary (choreic) movements, neuropsychiatric manifestations, and dementia. It is caused by an unstable CAG repeat expansion in the gene IT15 which encodes a Huntingtin protein. We present a case of a 9 year old boy who had developmental regression starting from the age of 8 years of age along with resistant seizures and signs of cerebellar involvement with absence of chorea and is on anticonvulsants, baclofen, and tetrabenzine. As is expected in a case of childhood-onset HD, our patient is rapidly deteriorating and is currently in the terminal phase of his illness along with resistant convulsions. PMID:26557176

  16. Putting A Face On Rare Diseases | NIH MedlinePlus the Magazine

    MedlinePlus

    ... Partners for Life." This slogan aligns with NCATS' philosophy that researchers must work closely with patients, families, ... for success in advancing rare diseases research. This philosophy has been put into practice in NCATS' Rare ...

  17. Study Provides Insights into Diagnosis, Treatment of Rare Immune Disease: Autoimmmune Lymphoproliferative Syndrome ...

    MedlinePlus

    ... Related Links​ ALPS Unit, Laboratory of Immunology Autoimmune Diseases Immune System Primary Immune Deficiency Diseases National Library of ... Study Provides Insights Into Diagnosis, Treatment of Rare Immune Disease NIH Scientists Report Findings From 20 Years of ...

  18. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

    PubMed

    Do, Ron; Stitziel, Nathan O; Won, Hong-Hee; Jørgensen, Anders Berg; Duga, Stefano; Angelica Merlini, Pier; Kiezun, Adam; Farrall, Martin; Goel, Anuj; Zuk, Or; Guella, Illaria; Asselta, Rosanna; Lange, Leslie A; Peloso, Gina M; Auer, Paul L; Girelli, Domenico; Martinelli, Nicola; Farlow, Deborah N; DePristo, Mark A; Roberts, Robert; Stewart, Alexander F R; Saleheen, Danish; Danesh, John; Epstein, Stephen E; Sivapalaratnam, Suthesh; Hovingh, G Kees; Kastelein, John J; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Shah, Svati H; Kraus, William E; Davies, Robert; Nikpay, Majid; Johansen, Christopher T; Wang, Jian; Hegele, Robert A; Hechter, Eliana; Marz, Winfried; Kleber, Marcus E; Huang, Jie; Johnson, Andrew D; Li, Mingyao; Burke, Greg L; Gross, Myron; Liu, Yongmei; Assimes, Themistocles L; Heiss, Gerardo; Lange, Ethan M; Folsom, Aaron R; Taylor, Herman A; Olivieri, Oliviero; Hamsten, Anders; Clarke, Robert; Reilly, Dermot F; Yin, Wu; Rivas, Manuel A; Donnelly, Peter; Rossouw, Jacques E; Psaty, Bruce M; Herrington, David M; Wilson, James G; Rich, Stephen S; Bamshad, Michael J; Tracy, Russell P; Cupples, L Adrienne; Rader, Daniel J; Reilly, Muredach P; Spertus, John A; Cresci, Sharon; Hartiala, Jaana; Tang, W H Wilson; Hazen, Stanley L; Allayee, Hooman; Reiner, Alex P; Carlson, Christopher S; Kooperberg, Charles; Jackson, Rebecca D; Boerwinkle, Eric; Lander, Eric S; Schwartz, Stephen M; Siscovick, David S; McPherson, Ruth; Tybjaerg-Hansen, Anne; Abecasis, Goncalo R; Watkins, Hugh; Nickerson, Deborah A; Ardissino, Diego; Sunyaev, Shamil R; O'Donnell, Christopher J; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar

    2015-02-01

    Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. PMID:25487149

  19. Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate.

    PubMed

    Aylward, Alana; Cai, Yi; Lee, Andrew; Blue, Elizabeth; Rabinowitz, Daniel; Haddad, Joseph

    2016-07-01

    Studies suggest that nonsyndromic cleft lip and palate (NSCLP) is polygenic with variable penetrance, presenting a challenge in identifying all causal genetic variants. Despite relatively high prevalence of NSCLP among Amerindian populations, no large whole exome sequencing (WES) studies have been completed in this population. Our goal was to identify candidate genes with rare genetic variants for NSCLP in a Honduran population using WES. WES was performed on two to four members of 27 multiplex Honduran families. Genetic variants with a minor allele frequency > 1% in reference databases were removed. Heterozygous variants consistent with dominant disease with incomplete penetrance were ascertained, and variants with predicted functional consequence were prioritized for analysis. Pedigree-specific P-values were calculated as the probability of all affected members in the pedigree being carriers, given that at least one is a carrier. Preliminary results identified 3,727 heterozygous rare variants; 1,282 were predicted to be functionally consequential. Twenty-three genes had variants of interest in ≥3 families, where some genes had different variants in each family, giving a total of 50 variants. Variant validation via Sanger sequencing of the families and unrelated unaffected controls excluded variants that were sequencing errors or common variants not in databases, leaving four genes with candidate variants in ≥3 families. Of these, candidate variants in two genes consistently segregate with NSCLP as a dominant variant with incomplete penetrance: ACSS2 and PHYH. Rare variants found at the same gene in all affected individuals in several families are likely to be directly related to NSCLP. PMID:27229527

  20. Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction

    PubMed Central

    Magnani, Jared W.; Brody, Jennifer A.; Prins, Bram P.; Arking, Dan E.; Lin, Honghuang; Yin, Xiaoyan; Liu, Ching-Ti; Morrison, Alanna C.; Zhang, Feng; Spector, Tim D.; Alonso, Alvaro; Bis, Joshua C.; Heckbert, Susan R.; Lumley, Thomas; Sitlani, Colleen M.; Cupples, L. Adrienne; Lubitz, Steven A.; Soliman, Elsayed Z.; Pulit, Sara L.; Newton-Cheh, Christopher; O'Donnell, Christopher J.; Ellinor, Patrick T.; Benjamin, Emelia J.; Muzny, Donna M.; Gibbs, Richard A.; Santibanez, Jireh; Taylor, Herman A.; Rotter, Jerome I.; Lange, Leslie A.; Psaty, Bruce M.; Jackson, Rebecca; Rich, Stephen S.; Boerwinkle, Eric; Jamshidi, Yalda; Sotoodehnia, Nona

    2014-01-01

    Background The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to further characterize the contribution of rare and common coding variation in SCN5A to cardiac conduction. Methods and Results In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study (CHARGE), we performed targeted exonic sequencing of SCN5A (n=3699, European-ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, NHLBI’s Exome Sequencing Project (ESP, n=607) and the UK10K (n=1275) and by examining ESP African-ancestry participants (N=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African-ancestry participants (P=1.3×10−3). Three common variants were associated with PR and/or QRS interval duration among European-ancestry participants and one among African-ancestry participants. These included two well-known missense variants; rs1805124 (H558R) was associated with PR and QRS shortening in European-ancestry participants (P=6.25×10−4 and P=5.2×10−3 respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10−3). Among European-ancestry participants, two novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10−7 and P=2.69×10−4 respectively), and rs6599230 was associated with PR shortening (P=2.67×10−5). Conclusions By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction. PMID:24951663

  1. The Spectrum of Caregiving in Palliative Care for Serious, Advanced, Rare Diseases: Key Issues and Research Directions.

    PubMed

    Adams, Lynn S; Miller, Jeri L; Grady, Patricia A

    2016-07-01

    Rare diseases are often life-limiting conditions, the majority of which require constant caregiving needs. The realization of a spectrum of palliative care throughout the trajectory of rare diseases could ensure individualized and caregiver-focused approaches to the care of patients and families. In June 2015, the National Institute of Nursing Research (NINR), the lead institute at the National Institutes of Health for end-of-life research, in conjunction with the National Center for Advancing Translational Sciences, Office of Rare Diseases Research (ORDR) held an interdisciplinary workshop on the unique challenges of caregiving and palliative care in adult and pediatric rare diseases. The panel identified gaps in current knowledge, and afforded suggestions for research opportunities in palliative care science to improve the care of individuals with serious, advanced, rare diseases and their caregivers. This meeting provided an in-depth opportunity to incorporate new concepts into palliative and end-of-life care for individuals with a range of rare diseases and their caregivers. This report presents a summary of the workshop. PMID:27249541

  2. A population-based registry as a source of health indicators for rare diseases: the ten-year experience of the Veneto Region’s rare diseases registry

    PubMed Central

    2014-01-01

    Background Although rare diseases have become a major public health issue, there is a paucity of population-based data on rare diseases. The aim of this epidemiological study was to provide descriptive figures referring to a sizable group of unrelated rare diseases. Methods Data from the rare diseases registry established in the Veneto Region of north-east Italy (population 4,900,000), referring to the years from 2002 to 2012, were analyzed. The registry is based on a web-based system accessed by different users. Cases are enrolled by two different sources: clinicians working at Centers of expertise officially designated to diagnose and care patients with rare diseases and health professionals working in the local health districts. Deaths of patients are monitored by Death Registry. Results So far, 19,547 patients with rare diseases have been registered, and 23% of them are pediatric cases. The overall raw prevalence of the rare diseases monitored in the population under study is 33.09 per 10,000 inhabitants (95% CI 32.56-33.62), whilst the overall incidence is 3.85 per 10,000 inhabitants (95% CI 3.67-4.03). The most commonly-recorded diagnoses belong to the following nosological groups: congenital malformations (Prevalence: 5.45/10,000), hematological diseases (4.83/10,000), ocular disorders (4.47/10,000), diseases of the nervous system (3.51/10,000), and metabolic disorders (2,95/10,000). Most of the deaths in the study population occur among pediatric patients with congenital malformations, and among adult cases with neurological diseases. Rare diseases of the central nervous system carry the highest fatality rate (71.36/1,000). Rare diseases explain 4.2% of general population Years of Life Lost (YLLs), comparing to 1.2% attributable to infectious diseases and 2.6% to diabetes mellitus. Conclusions Our estimates of the burden of rare diseases at population level confirm that these conditions are a relevant public health issue. Our snapshot of their epidemiology

  3. Current progress in the management of rare diseases and orphan drugs in China

    PubMed Central

    Gong, Shiwei; Jin, Si

    2012-01-01

    Summary Currently, the issues of how to treat rare diseases and to improve accessibility to orphan drugs are arousing more and more concerns in China. Here we describe the push and pull incentive policies for rare diseases and orphan drugs and analyze the coverage and reimbursement level of rare diseases in the current Chinese medical insurance system. Three key obstacle factors that hinder Chinese patients' accessibility to timely drug treatment are summarized. Based on a comprehensive analysis, the measures of orphan drugs legislation, incentive mechanism, supply mechanism, and reimbursement mechanism are urgently expected to be established with the purpose of improving healthcare for patients with rare diseases in China. PMID:25343073

  4. Common and Rare Variant Association Study for Plasma Lipids and Coronary Artery Disease.

    PubMed

    Tada, Hayato; Kawashiri, Masa-Aki; Konno, Tetsuo; Yamagishi, Masakazu; Hayashi, Kenshi

    2016-03-01

    Blood lipid levels are highly heritable and modifiable risk factors for coronary artery disease (CAD), and are the leading cause of death worldwide. These facts have motivated human genetic association studies that have the substantial potential to define the risk factors that are causal and to identify pathways and therapeutic targets for lipids and CAD.The success of the HapMap project that provided an extensive catalog of human genetic variations and the development of microarray based genotyping chips (typically containing variations with allele frequencies >5%) facilitated common variant association study (CVAS; formerly termed genome-wide association study, GWAS) identifying disease-associated variants in a genome-wide manner. To date, 157 loci associated with blood lipids and 46 loci with CAD have been successfully identified, accounting for approximately 12%-14% of heritability for lipids and 10% of heritability for CAD. However, there is yet a major challenge termed "missing heritability problem," namely the observation that loci detected by CVAS explain only a small fraction of the inferred genetic variations. To explain such missing portions, focuses in genetic association studies have shifted from common to rare variants. However, it is challenging to apply rare variant association study (RVAS) in an unbiased manner because such variants typically lack the sufficient number to be identified statistically.In this review, we provide a current understanding of the genetic architecture mostly derived from CVAS, and several updates on the progress and limitations of RVAS for lipids and CAD. PMID:26347050

  5. A RARE COMPLICATION OF A RARE DISEASE; STROKE DUE TO RELAPSING POLYCHONDRITIS.

    PubMed

    Çoban, Eda Kiliç; Xanmemmedov, Elmir; Çolak, Melek; Soysal, Aysun

    2015-11-30

    Relapsing polychondritis (RP) is an episodic and progressive inflammatory disease of cartilaginous structures. Its diagnosis is based primarily on clinical features such as laboratory parameters, biopsy. Neurological complications occur in 3% of the cases and are classified as an important cause of death. The cranial nerve disorders are most common but hemiplegia, ataxia, myelitis, polyneuritis, seizures, confusion, hallucination and headache can also happen. The aetiology of central nervous system involvement is still unknown. Moreover stroke has rarely reported in these patients. The diagnosis of stroke is challenging because of its rarity among these patients. Perhaps vasculitis is the common underlying mechanism. Also meningitis and encephalitis can occur during the course of RP. A 44 year-old woman was admitted with uncontemplated left hemiparesis, redness, swelling, and tenderness of the metacarpophalangeal and interphalangeal joints of the right hand and the cartilaginous portion. White blood cell count, C-reactive protein and the erythrocyte sedimentation rate were elevated. Vasculitis biomarkers were normal in our patient. Carotid and vertebral artery doppler ultrasonography, cranial and cervical MR Angiography were normal. Echocardiography showed a mild mitral valve prolapse and regurgitation. Our patient had the history of auricular polychondritis but she had not been diagnosed. Hemiparesis was her first neurological manifestation that led her to doctors for diagnosis. Our patient fulfilled the criteria of RP so no biopsy was needed. She was treated with oral prednisolone (80 mg/day) and aspirin (300 mg/day) and now she is on 10 mg prednisolone and 150 mg azathioprine. Two months later her physical and neurological symptoms returned to normal. PMID:26821518

  6. Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death

    PubMed Central

    Campuzano, Oscar; Sanchez-Molero, Olallo; Mademont-Soler, Irene; Riuró, Helena; Allegue, Catarina; Coll, Monica; Pérez-Serra, Alexandra; Mates, Jesus; Picó, Ferran; Iglesias, Anna; Brugada, Ramon

    2015-01-01

    A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death. PMID:26516846

  7. Chronic Granulomatous Disease: Lessons from a Rare Disorder

    PubMed Central

    Segal, B H; Veys, P; Malech, H; Cowan, M J

    2010-01-01

    Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with x-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mould-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT) although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures and use of reduced toxicity conditioning have resulted in EFS of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of GVHD and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells. PMID:21195301

  8. Common and Rare Genetic Variants Associated With Alzheimer's Disease.

    PubMed

    Marei, Hany E; Althani, Asmaa; Suhonen, Jaana; El Zowalaty, Mohamed E; Albanna, Mohammad A; Cenciarelli, Carlo; Wang, Tengfei; Caceci, Thomas

    2016-07-01

    Alzheimer's disease (AD) is one of the most devastating disorders. Despite the continuing increase of its incidence among aging populations, no effective cure has been developed mainly due to difficulties in early diagnosis of the disease before damaging of the brain, and the failure to explore its complex underlying molecular mechanisms. Recent technological advances in genome-wide association studies (GWAS) and high throughput next generation whole genome, and exome sequencing had deciphered many of AD-related loci, and discovered single nucleotide polymorphisms (SNPs) that are associated with altered AD molecular pathways. Highlighting altered molecular pathways linked to AD pathogenesis is crucial to identify novel diagnostic and therapeutic AD targets. J. Cell. Physiol. 231: 1432-1437, 2016. © 2015 Wiley Periodicals, Inc. PMID:26496533

  9. [Erythropoietic protoporphyria. A rare differential diagnosis among photosensitive diseases].

    PubMed

    Schiekofer, C; Vogt, T; Reichrath, J

    2012-12-01

    A 31-year-old woman presented with recurrent swelling, burning, prickling and itching of the arms and the hands which appeared after UV exposure in the summer. Simultaneously she often had chills, malaise, nausea and circulatory problems lasting for hours. She did not have erythema or wheals. She had been seen by a number of specialties but to no avail. Her deceased mother suffered from the same symptoms. On presentation she had no skin lesions. Laboratory testing showed a dramatic increase in total protoporphyrin, enabling us to diagnose erythropoietic protoporphyria. This is a rare, genetic metabolic disturbance in hematopoiesis, whose true prevalence is probably underestimated. Because of abnormal or absent function of ferrochelatase, protoporphyrin accumulates in blood, erythrocytes and tissue usually causing photosensitivity as the first clinical symptom. The prognosis depends on the severity of liver involvement. Because of the marked restrictions on activity, especially in avoiding UV exposition, the quality of life of the patients and their families are strongly influenced. The odyssey of our patient and her mother in finding a diagnosis demonstrates impressively that the EPP is an important photosensitizing disease which must not be forgotten. PMID:22802217

  10. Encapsulating peritoneal sclerosis—a rare but devastating peritoneal disease

    PubMed Central

    Moinuddin, Zia; Summers, Angela; Van Dellen, David; Augustine, Titus; Herrick, Sarah E.

    2015-01-01

    Encapsulating peritoneal sclerosis (EPS) is a devastating but, fortunately, rare complication of long-term peritoneal dialysis. The disease is associated with extensive thickening and fibrosis of the peritoneum resulting in the formation of a fibrous cocoon encapsulating the bowel leading to intestinal obstruction. The incidence of EPS ranges between 0.7 and 3.3% and increases with duration of peritoneal dialysis therapy. Dialysis fluid is hyperosmotic, hyperglycemic, and acidic causing chronic injury and inflammation in the peritoneum with loss of mesothelium and extensive tissue fibrosis. The pathogenesis of EPS, however, still remains uncertain, although a widely accepted hypothesis is the “two-hit theory,” where, the first hit is chronic peritoneal membrane injury from long standing peritoneal dialysis followed by a second hit such as an episode of peritonitis, genetic predisposition and/or acute cessation of peritoneal dialysis, leading to EPS. Recently, EPS has been reported in patients shortly after transplantation suggesting that this procedure may also act as a possible second insult. The process of epithelial–mesenchymal transition of mesothelial cells is proposed to play a central role in the development of peritoneal sclerosis, a common characteristic of patients on dialysis, however, its importance in EPS is less clear. There is no established treatment for EPS although evidence from small case studies suggests that corticosteroids and tamoxifen may be beneficial. Nutritional support is essential and surgical intervention (peritonectomy and enterolysis) is recommended in later stages to relieve bowel obstruction. PMID:25601836

  11. A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency

    NASA Astrophysics Data System (ADS)

    Artyomov, Maxim; Meissner, Alex; Chakraborty, Arup

    2010-03-01

    Most cells in an organism have the same DNA. Yet, different cell types express different proteins and carry out different functions. This is because of epigenetic differences; i.e., DNA in different cell types is packaged distinctly, making it hard to express certain genes while facilitating the expression of others. During development, upon receipt of appropriate cues, pluripotent embryonic stem cells differentiate into diverse cell types that make up the organism (e.g., a human). There has long been an effort to make this process go backward -- i.e., reprogram a differentiated cell (e.g., a skin cell) to pluripotent status. Recently, this has been achieved by transfecting certain transcription factors into differentiated cells. This method does not use embryonic material and promises the development of patient-specific regenerative medicine, but it is inefficient. The mechanisms that make reprogramming rare, or even possible, are poorly understood. We have developed the first computational model of transcription factor-induced reprogramming. Results obtained from the model are consistent with diverse observations, and identify the rare pathways that allow reprogramming to occur. If validated, our model could be further developed to design optimal strategies for reprogramming and shed light on basic questions in biology.

  12. DNA bar coding and pyrosequencing to identify rare HIV drug resistance mutations.

    PubMed

    Hoffmann, Christian; Minkah, Nana; Leipzig, Jeremy; Wang, Gary; Arens, Max Q; Tebas, Pablo; Bushman, Frederic D

    2007-01-01

    Treatment of HIV-infected individuals with antiretroviral agents selects for drug-resistant mutants, resulting in frequent treatment failures. Although the major antiretroviral resistance mutations are routinely characterized by DNA sequencing, treatment failures are still common, probably in part because undetected rare resistance mutations facilitate viral escape. Here we combined DNA bar coding and massively parallel pyrosequencing to quantify rare drug resistance mutations. Using DNA bar coding, we were able to analyze seven viral populations in parallel, overall characterizing 118 093 sequence reads of average length 103 bp. Analysis of a control HIV mixture showed that resistance mutations present as 5% of the population could be readily detected without false positive calls. In three samples of multidrug-resistant HIV populations from patients, all the drug-resistant mutations called by conventional analysis were identified, as well as four additional low abundance drug resistance mutations, some of which would be expected to influence the response to antiretroviral therapy. Methods for sensitive characterization of HIV resistance alleles have been reported, but only the pyrosequencing method allows all the positions at risk for drug resistance mutations to be interrogated deeply for many HIV populations in a single experiment. PMID:17576693

  13. From disease to treatment: from rare skeletal disorders to treatments for osteoporosis.

    PubMed

    Appelman-Dijkstra, Natasha M; Papapoulos, Socrates E

    2016-06-01

    During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis. PMID:26892377

  14. Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

    PubMed

    Cappi, C; Brentani, H; Lima, L; Sanders, S J; Zai, G; Diniz, B J; Reis, V N S; Hounie, A G; Conceição do Rosário, M; Mariani, D; Requena, G L; Puga, R; Souza-Duran, F L; Shavitt, R G; Pauls, D L; Miguel, E C; Fernandez, T V

    2016-01-01

    Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular

  15. Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

    PubMed Central

    Cappi, C; Brentani, H; Lima, L; Sanders, S J; Zai, G; Diniz, B J; Reis, V N S; Hounie, A G; Conceição do Rosário, M; Mariani, D; Requena, G L; Puga, R; Souza-Duran, F L; Shavitt, R G; Pauls, D L; Miguel, E C; Fernandez, T V

    2016-01-01

    Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular

  16. SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis.

    PubMed

    Graham, Rondell P; Dina, Michelle A; Howe, Sarah C; Butz, Malinda L; Willkomm, Kurt S; Murray, David L; Snyder, Melissa R; Rumilla, Kandelaria M; Halling, Kevin C; Highsmith, W Edward

    2015-11-01

    Genetic α-1 antitrypsin (AAT) deficiency is characterized by low serum AAT levels and the identification of causal mutations or an abnormal protein. It needs to be distinguished from deficiency because of nongenetic causes, and diagnostic delay may contribute to worse patient outcome. Current routine clinical testing assesses for only the most common mutations. We wanted to determine the proportion of unexplained cases of AAT deficiency that harbor causal mutations not identified through current standard allele-specific genotyping and isoelectric focusing (IEF). All prospective cases from December 1, 2013, to October 1, 2014, with a low serum AAT level not explained by allele-specific genotyping and IEF were assessed through full-gene sequencing with a direct sequencing method for pathogenic mutations. We reviewed the results using American Council of Medical Genetics criteria. Of 3523 cases, 42 (1.2%) met study inclusion criteria. Pathogenic or likely pathogenic mutations not identified through clinical testing were detected through full-gene sequencing in 16 (38%) of the 42 cases. Rare mutations not detected with current allele-specific testing and IEF underlie a substantial proportion of genetic AAT deficiency. Full-gene sequencing, therefore, has the ability to improve accuracy in the diagnosis of AAT deficiency. PMID:26321041

  17. A Rare Mechanism of Hyponatremia in HIV Disease

    PubMed Central

    Madariaga, Hector; Kumar, Aswini; Khanna, Apurv

    2015-01-01

    Patient: Male, 25 Final Diagnosis: Corticosteroid reistance Symptoms: Weakness Medication: — Clinical Procedure: Diagnosis Specialty: Nephrology Objective: Unusual clinical course Background: Hyponatremia is the most common disorder of body fluid and electrolyte balance in clinical practice. It is associated with increased morbidity, mortality, and length of hospital stay. Little is known about the relationship between hyponatremia and HIV disease. It is thought that hyponatremia in HIV is associated with a syndrome of inappropriate ADH secretion (SIADH), volume depletion, and adrenal insufficiency. Another common association is with Pneumocystis jirovecii (PCP). In early 1990s, there were several reports linking hyponatremia and HIV disease. It was found that these patients with acquired immune deficiency syndrome (AIDS) had abnormal adrenal cortical function. Additionally, these patients showed an abnormally elevated baseline cortisol level and a blunted response to cosyntropin. Case Report: Here, we present the case of an HIV patient presenting with hyponatremia and a physical examination suggestive of hypovolemia. Laboratory tests revealed urinary loss of sodium in the setting of normal serum cortisol level. The patient responded well to the administration of a mineralocorticoid hormone. Conclusions: Glucocorticoid resistance is an unusual cause of hyponatremia, and needs to be identified and treated accordingly. PMID:26436215

  18. Orphan Products: Hope for People with Rare Diseases

    MedlinePlus

    ... drug manufacturers rarely could make a profit from marketing drugs to such small groups. Consequently, the prescription ... research, and a seven-year period of exclusive marketing given to the first sponsor of an orphan- ...

  19. Congenital labial mucocele: rare presentation of a common disease.

    PubMed

    Silva, Igor Henrique; Cardoso, Samantha; Carvalho, Camila Nunes; Carvalho, Alessandra Albuquerque Tavares; Leão, Jair Carneiro; Gueiros, Luiz Alcino

    2016-01-01

    Oral mucoceles are common lesions characterized by accumulation of mucus following rupture of a minor salivary gland duct. However, congenital mucoceles are a rare and distinctive oral condition observed in newborns. This case report details the features of a congenital labial nodule diagnosed as congenital mucocele. These lesions are rare in the oral cavity and should be diagnosed in the delivery room, but many cases are referred for further evaluation. Management is simple, and recurrence is not expected. PMID:26943092

  20. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases.

    PubMed

    Chen, Rong; Shi, Lisong; Hakenberg, Jörg; Naughton, Brian; Sklar, Pamela; Zhang, Jianguo; Zhou, Hanlin; Tian, Lifeng; Prakash, Om; Lemire, Mathieu; Sleiman, Patrick; Cheng, Wei-Yi; Chen, Wanting; Shah, Hardik; Shen, Yulan; Fromer, Menachem; Omberg, Larsson; Deardorff, Matthew A; Zackai, Elaine; Bobe, Jason R; Levin, Elissa; Hudson, Thomas J; Groop, Leif; Wang, Jun; Hakonarson, Hakon; Wojcicki, Anne; Diaz, George A; Edelmann, Lisa; Schadt, Eric E; Friend, Stephen H

    2016-05-01

    Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations in afflicted individuals. Here we describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes led to the identification of 13 adults harboring mutations for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. Our findings demonstrate the promise of broadening genetic studies to systematically search for well individuals who are buffering the effects of rare, highly penetrant, deleterious mutations. They also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies. PMID:27065010

  1. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

    PubMed

    Cruchaga, Carlos; Karch, Celeste M; Jin, Sheng Chih; Benitez, Bruno A; Cai, Yefei; Guerreiro, Rita; Harari, Oscar; Norton, Joanne; Budde, John; Bertelsen, Sarah; Jeng, Amanda T; Cooper, Breanna; Skorupa, Tara; Carrell, David; Levitch, Denise; Hsu, Simon; Choi, Jiyoon; Ryten, Mina; Hardy, John; Ryten, Mina; Trabzuni, Daniah; Weale, Michael E; Ramasamy, Adaikalavan; Smith, Colin; Sassi, Celeste; Bras, Jose; Gibbs, J Raphael; Hernandez, Dena G; Lupton, Michelle K; Powell, John; Forabosco, Paola; Ridge, Perry G; Corcoran, Christopher D; Tschanz, Joann T; Norton, Maria C; Munger, Ronald G; Schmutz, Cameron; Leary, Maegan; Demirci, F Yesim; Bamne, Mikhil N; Wang, Xingbin; Lopez, Oscar L; Ganguli, Mary; Medway, Christopher; Turton, James; Lord, Jenny; Braae, Anne; Barber, Imelda; Brown, Kristelle; Passmore, Peter; Craig, David; Johnston, Janet; McGuinness, Bernadette; Todd, Stephen; Heun, Reinhard; Kölsch, Heike; Kehoe, Patrick G; Hooper, Nigel M; Vardy, Emma R L C; Mann, David M; Pickering-Brown, Stuart; Brown, Kristelle; Kalsheker, Noor; Lowe, James; Morgan, Kevin; David Smith, A; Wilcock, Gordon; Warden, Donald; Holmes, Clive; Pastor, Pau; Lorenzo-Betancor, Oswaldo; Brkanac, Zoran; Scott, Erick; Topol, Eric; Morgan, Kevin; Rogaeva, Ekaterina; Singleton, Andrew B; Hardy, John; Kamboh, M Ilyas; St George-Hyslop, Peter; Cairns, Nigel; Morris, John C; Kauwe, John S K; Goate, Alison M

    2014-01-23

    Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex

  2. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    2014-01-01

    Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex

  3. Genetic risk factors for the development of allergic disease identified by genome-wide association

    PubMed Central

    Portelli, M A; Hodge, E; Sayers, I

    2015-01-01

    An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential

  4. Research on economy and social exclusion: China dolls and rare diseases

    PubMed Central

    Matsui, Akihiko

    2013-01-01

    Summary The second workshop on “Research on Economy And Social Exclusion (REASE)” was held in the University of Tokyo on January 26, 2013. Focusing on rare diseases and disorders in China, three speakers from China introduced the current status of rare diseases and the challenge of support organizations for patients with rare disease and disorders in China, and especially pointed out some important issues associated with rare diseases and disorders in China. From the viewpoint of economics, this paper discusses some of the important issues of rare diseases and disorders in China raised in this workshop, especially from the aspects of economy of scale and orphan drugs, and the emergence of stigma from discrimination. It was shown that international coordination and cooperation are called for in order to give a proper incentive to the drug industries to create new drugs for rare diseases, and suggested that an important step toward inclusion is to reduce stigma by making rare diseases visible as much as possible. PMID:25343098

  5. Exercise-induced haemoptysis as a rare presentation of a rare lung disease.

    PubMed

    Mihalek, Andrew D; Haney, Carissa; Merino, Maria; Roy-Chowdhuri, Sinchita; Moss, Joel; Olivier, Kenneth N

    2016-09-01

    Amyloid primarily affecting the lungs is a seldom seen clinical entity. This case discusses the work-up of a patient presenting with exercise-induced haemoptysis and diffuse cystic lung disease on radiographic imaging. The common clinical and radiographic findings of diffuse cystic lung diseases as well as a brief overview of pulmonary amyloid are presented. PMID:27272655

  6. Gene Therapy for Rare Diseases: Summary of a National Institutes of Health Workshop, September 13, 2012

    PubMed Central

    O'Reilly, Marina; Kohn, Donald B.; Bartlett, Jeffrey; Benson, Janet; Brooks, Philip J.; Byrne, Barry J.; Camozzi, Carlos; Cornetta, Kenneth; Crystal, Ronald G.; Fong, Yuman; Gargiulo, Linda; Gopal-Srivastava, Rashmi; High, Katherine A.; Jacobson, Samuel G.; Jambou, Robert C.; Montgomery, Maureen; Rosenthal, Eugene; Samulski, R. Jude; Skarlatos, Sonia I.; Sorrentino, Brian; Wilson, James M.; Xie, Yun

    2013-01-01

    Abstract Gene therapy has shown clinical efficacy for several rare diseases, using different approaches and vectors. The Gene Therapy for Rare Diseases workshop, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities and Office of Rare Diseases Research, brought together investigators from different disciplines to discuss the challenges and opportunities for advancing the field including means for enhancing data sharing for preclinical and clinical studies, development and utilization of available NIH resources, and interactions with the U.S. Food and Drug Administration. PMID:23517518

  7. Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A "Rare" Manifestation in a "Rare" Disease.

    PubMed

    Fierabracci, Alessandra

    2016-01-01

    Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome. PMID:27420045

  8. Estimating Genetic Effects and Quantifying Missing Heritability Explained by Identified Rare-Variant Associations

    PubMed Central

    Liu, Dajiang J.; Leal, Suzanne M.

    2012-01-01

    Next-generation sequencing has led to many complex-trait rare-variant (RV) association studies. Although single-variant association analysis can be performed, it is grossly underpowered. Therefore, researchers have developed many RV association tests that aggregate multiple variant sites across a genetic region (e.g., gene), and test for the association between the trait and the aggregated genotype. After these aggregate tests detect an association, it is only possible to estimate the average genetic effect for a group of RVs. As a result of the "winner’s curse," such an estimate can be biased. Although for common variants one can obtain unbiased estimates of genetic parameters by analyzing a replication sample, for RVs it is desirable to obtain unbiased genetic estimates for the study where the association is identified. This is because there can be substantial heterogeneity of RV sites and frequencies even among closely related populations. In order to obtain an unbiased estimate for aggregated RV analysis, we developed bootstrap-sample-split algorithms to reduce the bias of the winner’s curse. The unbiased estimates are greatly important for understanding the population-specific contribution of RVs to the heritability of complex traits. We also demonstrate both theoretically and via simulations that for aggregate RV analysis the genetic variance for a gene or region will always be underestimated, sometimes substantially, because of the presence of noncausal variants or because of the presence of causal variants with effects of different magnitudes or directions. Therefore, even if RVs play a major role in the complex-trait etiologies, a portion of the heritability will remain missing, and the contribution of RVs to the complex-trait etiologies will be underestimated. PMID:23022102

  9. New Viruses Identified in Fig Trees Exhibiting Fig Mosaic Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fig mosaic disease has been known for decades, but the causal agent has been elusive. Here we present data on the incidence of at least four new viruses isolated from fig trees exhibiting mosaic symptoms. One of the viruses is closely related to the recently identified European mountain ash ringspo...

  10. Patient Identified Disease Burden in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Johnson, Nicholas E; Quinn, Christine; Eastwood, Eileen; Tawil, Rabi; Heatwole, Chad R

    2013-01-01

    Introduction The multitude of symptoms associated with facioscapulohumeral muscular dystrophy (FSHD) disease burden are of varying importance. The extent of these symptoms and their cumulative effect on the FSHD population is unknown. Methods We conducted interviews with adult FSHD patients to identify which symptoms have the greatest effect on their lives. Each interview was recorded, transcribed, coded, and analyzed using a qualitative framework technique, triangulation, and 3-investigator consensus approach. Results 1375 quotes were obtained through 20 patient interviews. 251 symptoms of importance were identified representing 14 themes of FSHD disease burden. Symptoms associated with mobility impairment, activity limitation, and social role limitation were most frequently mentioned by participants. Conclusions There are multiple themes and symptoms, some previously under-recognized, that play a key role in FSHD disease burden. PMID:23225386

  11. Fragile X syndrome as a rare disease in China — Therapeutic challenges and opportunities

    PubMed Central

    Jin, Xiaowei; Chen, Li

    2015-01-01

    Summary Recognized as the most common inherited from of intellectual disability (ID) and the most common known monogenic cause of autism spectrum disorders (ASD), Fragile X syndrome (FXS) is identified as an unmet medical need for the development of personalized medicine and targeted therapeutics for neurodevelopment disorders as a result of improved understanding of the genetic and cellular mechanisms. Consequently promising pharmacological targets have emerged from basic and translational research, are now being pursued by global pharmaceutical and biotech companies in early proof-of-concept clinical trials. With the world's largest rare disease population, China potentially has a large number of FXS patients, many of whom are under-diagnosed or even misdiagnosed, barely with any treatment. In spite of improved awareness of FXS in recent years, big gaps still exist between China and developed countries in multiple aspects. With increased public awareness, strong government support and investment, coupled with an increasingly large number of Western-trained experienced researchers engaging in new drug discovery and development, China has the potential to become an important player in the discovery of effective diagnostics and treatments for a rare disease like FXS. PMID:25674387

  12. Improving the informed consent process in international collaborative rare disease research: effective consent for effective research.

    PubMed

    Gainotti, Sabina; Turner, Cathy; Woods, Simon; Kole, Anna; McCormack, Pauline; Lochmüller, Hanns; Riess, Olaf; Straub, Volker; Posada, Manuel; Taruscio, Domenica; Mascalzoni, Deborah

    2016-08-01

    The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia - a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects. PMID:26860059

  13. Evaluation of participant recruitment methods to a rare disease online registry.

    PubMed

    Johnson, Kimberly J; Mueller, Nancy L; Williams, Katherine; Gutmann, David H

    2014-07-01

    Internet communication advances provide new opportunities to assemble individuals with rare diseases to online patient registries from wide geographic areas for research. However, there is little published information on the efficacy of different recruitment methods. Here we describe recruitment patterns and the characteristics of individuals with the self-identified autosomal dominant genetic disorder neurofibromatosis type 1 (NF1) who participated in an online patient registry during the 1-year period from 1/1/2012 to 12/31/2012. We employed four main mechanisms to alert potential participants to the registry: (1) Facebook and Google advertising, (2) government and academic websites, (3) patient advocacy groups, and (4) healthcare providers. Participants reported how they first heard about the registry through an online questionnaire. During the 1-year period, 880 individuals participated in the registry from all 50 U.S. States, the District of Columbia, Puerto Rico, and 39 countries. Facebook and Google were reported as referral sources by the highest number of participants (n=550, 72% Facebook), followed by healthcare providers (n=74), and government and academic websites (n=71). The mean participant age was 29±18 years and most participants reported White race (73%) and female sex (62%) irrespective of reported referral source. Internet advertising, especially through Facebook, resulted in efficient enrollment of large numbers of individuals with NF1. Our study demonstrates the potential utility of this approach to assemble individuals with a rare disease from across the world for research studies. PMID:24700441

  14. Fragile X syndrome as a rare disease in China - Therapeutic challenges and opportunities.

    PubMed

    Jin, Xiaowei; Chen, Li

    2015-02-01

    Recognized as the most common inherited from of intellectual disability (ID) and the most common known monogenic cause of autism spectrum disorders (ASD), Fragile X syndrome (FXS) is identified as an unmet medical need for the development of personalized medicine and targeted therapeutics for neurodevelopment disorders as a result of improved understanding of the genetic and cellular mechanisms. Consequently promising pharmacological targets have emerged from basic and translational research, are now being pursued by global pharmaceutical and biotech companies in early proof-of-concept clinical trials. With the world's largest rare disease population, China potentially has a large number of FXS patients, many of whom are under-diagnosed or even misdiagnosed, barely with any treatment. In spite of improved awareness of FXS in recent years, big gaps still exist between China and developed countries in multiple aspects. With increased public awareness, strong government support and investment, coupled with an increasingly large number of Western-trained experienced researchers engaging in new drug discovery and development, China has the potential to become an important player in the discovery of effective diagnostics and treatments for a rare disease like FXS. PMID:25674387

  15. Improving the informed consent process in international collaborative rare disease research: effective consent for effective research

    PubMed Central

    Gainotti, Sabina; Turner, Cathy; Woods, Simon; Kole, Anna; McCormack, Pauline; Lochmüller, Hanns; Riess, Olaf; Straub, Volker; Posada, Manuel; Taruscio, Domenica; Mascalzoni, Deborah

    2016-01-01

    The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia – a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects. PMID:26860059

  16. Extramammary Paget's disease of the oral tissues-literature review and a rare case report.

    PubMed

    Kennedy, Hana; Kunjur, Jayanth; Amarasinghe, Kavita; Smith, Graham

    2016-01-01

    Extramammary Paget's disease (EMPD) is a rare, cutaneous adenocarcinoma in situ characterized by a chronic eczema-like rash of the anogenital regions. It is usually slow growing, locally invasive and presents mainly with pruritis. Extremely rare in the oral tissues, here we present a case of EMPD of the hard palate and a review of the existing literature base. PMID:27587306

  17. Extramammary Paget's disease of the oral tissues—literature review and a rare case report

    PubMed Central

    Kennedy, Hana; Kunjur, Jayanth; Amarasinghe, Kavita; Smith, Graham

    2016-01-01

    Extramammary Paget's disease (EMPD) is a rare, cutaneous adenocarcinoma in situ characterized by a chronic eczema-like rash of the anogenital regions. It is usually slow growing, locally invasive and presents mainly with pruritis. Extremely rare in the oral tissues, here we present a case of EMPD of the hard palate and a review of the existing literature base. PMID:27587306

  18. A Rare Case of Azathioprine-Induced Sweet's Syndrome in a Patient with Crohn's Disease.

    PubMed

    Ben Salem, Chaker; Salem, Chaker B; Larif, Sofiene; Fathallah, Neila; Slim, Raoudha; Aounallah, Amina; Sakhri, Jaballah; Hmouda, Houssem

    2015-01-01

    Sweet's syndrome has been reported in association with inflammatory diseases such as Crohn's disease. It has also been reported in association with several drugs. Here, we report a rare case of Sweet's syndrome induced by azathioprine in a patient with Crohn's disease. PMID:26219289

  19. Identifying Rare FHB-Resistant Segregants in Intransigent Backcross and F2 Winter Wheat Populations

    PubMed Central

    Clark, Anthony J.; Sarti-Dvorjak, Daniela; Brown-Guedira, Gina; Dong, Yanhong; Baik, Byung-Kee; Van Sanford, David A.

    2016-01-01

    Fusarium head blight (FHB), caused mainly by Fusarium graminearum Schwabe [telomorph: Gibberella zeae Schwein.(Petch)] in the US, is one of the most destructive diseases of wheat (Triticum aestivum L. and T. durum L.). Infected grain is usually contaminated with deoxynivalenol (DON), a serious mycotoxin. The challenge in FHB resistance breeding is combining resistance with superior agronomic and quality characteristics. Exotic QTL are widely used to improve FHB resistance. Success depends on the genetic background into which the QTL are introgressed, whether through backcrossing or forward crossing; QTL expression is impossible to predict. In this study four high-yielding soft red winter wheat breeding lines with little or no scab resistance were each crossed to a donor parent (VA01W-476) with resistance alleles at two QTL: Fhb1 (chromosome 3BS) and QFhs.nau-2DL (chromosome 2DL) to generate backcross and F2 progeny. F2 individuals were genotyped and assigned to 4 groups according to presence/ absence of resistance alleles at one or both QTL. The effectiveness of these QTL in reducing FHB rating, incidence, index, severity, Fusarium-damaged kernels (FDK) and DON, in F2-derived lines was assessed over 2 years. Fhb1 showed an average reduction in DON of 17.5%, and conferred significant resistance in 3 of 4 populations. QFhs.nau-2DL reduced DON 6.7% on average and conferred significant resistance in 2 of 4 populations. The combination of Fhb1 and QFhs.nau-2DL resistance reduced DON 25.5% across all populations. Double resistant lines had significantly reduced DON compared to double susceptible lines in 3 populations. Backcross derived progeny were planted in replicated yield trials (2011 and 2012) and in a scab nursery in 2012. Several top yielding lines performed well in the scab nursery, with acceptable DON concentrations, even though the average effect of either QTL in this population was not significant. Population selection is often viewed as an “all or nothing

  20. Identifying Rare FHB-Resistant Segregants in Intransigent Backcross and F2 Winter Wheat Populations.

    PubMed

    Clark, Anthony J; Sarti-Dvorjak, Daniela; Brown-Guedira, Gina; Dong, Yanhong; Baik, Byung-Kee; Van Sanford, David A

    2016-01-01

    Fusarium head blight (FHB), caused mainly by Fusarium graminearum Schwabe [telomorph: Gibberella zeae Schwein.(Petch)] in the US, is one of the most destructive diseases of wheat (Triticum aestivum L. and T. durum L.). Infected grain is usually contaminated with deoxynivalenol (DON), a serious mycotoxin. The challenge in FHB resistance breeding is combining resistance with superior agronomic and quality characteristics. Exotic QTL are widely used to improve FHB resistance. Success depends on the genetic background into which the QTL are introgressed, whether through backcrossing or forward crossing; QTL expression is impossible to predict. In this study four high-yielding soft red winter wheat breeding lines with little or no scab resistance were each crossed to a donor parent (VA01W-476) with resistance alleles at two QTL: Fhb1 (chromosome 3BS) and QFhs.nau-2DL (chromosome 2DL) to generate backcross and F2 progeny. F2 individuals were genotyped and assigned to 4 groups according to presence/ absence of resistance alleles at one or both QTL. The effectiveness of these QTL in reducing FHB rating, incidence, index, severity, Fusarium-damaged kernels (FDK) and DON, in F2-derived lines was assessed over 2 years. Fhb1 showed an average reduction in DON of 17.5%, and conferred significant resistance in 3 of 4 populations. QFhs.nau-2DL reduced DON 6.7% on average and conferred significant resistance in 2 of 4 populations. The combination of Fhb1 and QFhs.nau-2DL resistance reduced DON 25.5% across all populations. Double resistant lines had significantly reduced DON compared to double susceptible lines in 3 populations. Backcross derived progeny were planted in replicated yield trials (2011 and 2012) and in a scab nursery in 2012. Several top yielding lines performed well in the scab nursery, with acceptable DON concentrations, even though the average effect of either QTL in this population was not significant. Population selection is often viewed as an "all or nothing

  1. Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes.

    PubMed

    Lavezzo, Marcelo Mendes; Sakata, Viviane Mayumi; Morita, Celso; Rodriguez, Ever Ernesto Caso; Abdallah, Smairah Frutuoso; da Silva, Felipe T G; Hirata, Carlos Eduardo; Yamamoto, Joyce Hisae

    2016-01-01

    Vogt-Koyanagi-Harada disease (VKHD) is a rare granulomatous inflammatory disease that affects pigmented structures, such as eye, inner ear, meninges, skin and hair. This disease is mainly a Th1 lymphocyte mediated aggression to melanocytes after a viral trigger in the presence of HLA-DRB1*0405 allele. The absence of ocular trauma or previous intraocular surgery sets VKHD appart from sympathetic ophthalmia, its main differential diagnosis. The disease has an acute onset of bilateral blurred vision with hyperemia preceded by flu-like symptoms. The acute uveitic stage is characterized by a diffuse choroiditis with serous retinal detachment and optic disc hyperemia and edema. Fluorescein angiography in this phase demonstrates multiple early hyperfluorescent points. After the acute uveitic stage, ocular and integumentary system pigmentary changes may appear. Ocular findings may be accompanied by lymphocytic meningitis, hearing impairment and/or tinnitus in a variable proportion of patients. Prompt diagnosis followed by early, aggressive and long-term treatment with high-dose corticosteroids is most often ensued by good visual outcomes. However, some patients may experience chronic uveal inflammation with functional eye deterioration. The current review discusses the general features of VKHD, including epidemiology, classification into categories, differential diagnosis and current therapeutic approaches. PMID:27008848

  2. Intestinal Ultrasound in Rare Gastrointestinal Diseases, Update, Part 2.

    PubMed

    Dietrich, C F; Lembcke, B; Jenssen, C; Hocke, M; Ignee, A; Hollerweger, A

    2015-10-01

    Intestinal ultrasound has become an established and valid diagnostic method for inflammatory bowel disease, diverticulitis, appendicitis, bowel obstruction, perforation and intussusception. However, little is known about sonographic findings in other rarer intestinal diseases. Ultrasound may display the transformation of the intestinal wall from a normal to a pathological state both in inflammatory and neoplastic disease. Besides demonstrating the transmural aspect, it also shows the mesenteric reaction as well as complications such as fistula, abscesses, stenosis, or ileus. Furthermore, in some diseases intestinal ultrasound may serve as a diagnostic clue if typical patterns of the bowel wall and impaired peristalsis can be demonstrated. This may lead to an important reduction of invasive and expensive (follow-up) procedures. The information gained by ultrasound regarding intestinal disease, however, is as important and valid as e. g. in case of focal lesions of the liver. Serving as tertiary referral centers for a broad spectrum of intestinal diseases, we therefore report some aspects of ultrasound in patients with less often recognized diseases. The article is divided into two parts, the first focusing on examination techniques, infectious diseases and celiac sprue and the second on hereditary, vascular and neoplastic diseases and varia. PMID:26091002

  3. Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

    PubMed

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei-Hsin; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez-Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel; Van Broeckhoven, Christine

    2015-12-01

    Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. PMID:26411346

  4. Phenotype with a side of genotype, please: Patients, parents and priorities in rare genetic disease

    PubMed Central

    Collins, Christy

    2016-01-01

    As the parent and caregiver of a child with an ultra-rare disease and advocate for others with the same condition, I discuss the importance of phenotyping in rare disease research. I emphasize the need for more clinical geneticists, deeper and more intentional integration of clinical genetics in complex patient care, and a greater appreciation of patients and families as an informational resource. PMID:27047761

  5. A Novel Approach for Identifying Causal Models of Complex Diseases from Family Data

    PubMed Central

    Park, Leeyoung; Kim, Ju H.

    2015-01-01

    Causal models including genetic factors are important for understanding the presentation mechanisms of complex diseases. Familial aggregation and segregation analyses based on polygenic threshold models have been the primary approach to fitting genetic models to the family data of complex diseases. In the current study, an advanced approach to obtaining appropriate causal models for complex diseases based on the sufficient component cause (SCC) model involving combinations of traditional genetics principles was proposed. The probabilities for the entire population, i.e., normal–normal, normal–disease, and disease–disease, were considered for each model for the appropriate handling of common complex diseases. The causal model in the current study included the genetic effects from single genes involving epistasis, complementary gene interactions, gene–environment interactions, and environmental effects. Bayesian inference using a Markov chain Monte Carlo algorithm (MCMC) was used to assess of the proportions of each component for a given population lifetime incidence. This approach is flexible, allowing both common and rare variants within a gene and across multiple genes. An application to schizophrenia data confirmed the complexity of the causal factors. An analysis of diabetes data demonstrated that environmental factors and gene–environment interactions are the main causal factors for type II diabetes. The proposed method is effective and useful for identifying causal models, which can accelerate the development of efficient strategies for identifying causal factors of complex diseases. PMID:25701286

  6. Unilateral sudden hearing loss: a rare symptom of Moyamoya disease.

    PubMed

    Gül, Fatih; Berçin, Sami; Müderris, Togay; Yalçıner, Gökhan; Ünal, Özkan; Kırış, Muzaffer

    2016-01-01

    A 38-year-old female patient experienced a sudden onset of unilateral sensorineural hearing loss due to Moyamoya disease. A detailed summary of audiological and neurological findings indicated that the sudden hearing loss might be due to Moyamoya disease resulting in occlusion of posterior and middle cerebral arteries. Intravenous prednisolone and trimetazidine dihydrochloride may improve hearing thresholds and speech understanding. To our knowledge, this is the first article in the literature reporting a case of sudden hearing loss as the first manifestation of Moyamoya disease in a young adult. PMID:26890714

  7. Incentives for Starting Small Companies Focused on Rare and Neglected Diseases.

    PubMed

    Ekins, Sean; Wood, Jill

    2016-04-01

    Starting biotech or pharmaceutical companies is traditionally thought to be based around a scientist, their technology platform or a clinical candidate spun out from another company. Between us we have taken a different approach and formed two small early stage companies after initially leveraging the perspective of a parent with a child with a life-threatening rare disease. Phoenix Nest ( http://www.phoenixnestbiotech.com/ ) was co-founded to work on treatments for Sanfilippo syndrome a devastating neurodegenerative lysosomal storage disorder. In the space of just over 3 years we have built up collaborations with leading scientists in academia and industry and been awarded multiple NIH small business grants. The second company, Collaborations Pharmaceuticals Inc. ( http://www.collaborationspharma.com/ ) was founded to address some of the other 7000 or so rare diseases as well as neglected infectious diseases. The Rare Pediatric Disease Priority Review Voucher is likely the most important incentive for companies working on rare diseases with very small populations. This may also be partially responsible for the recent acquisitions of rare disease companies with late stage candidates. Lessons learned in the process of starting our companies are that rare disease parents or patients can readily partner with a scientist and fund research through NIH grants rather than venture capital or angel investors initially. This process may be slow so patience and perseverance is key. We would encourage other pharmaceutical scientists to meet rare disease parents, patients or advocates and work with them to further the science on their diseases and create a source of future drugs. PMID:26666772

  8. Harnessing genomics to identify environmental determinants of heritable disease

    PubMed Central

    Yauk, Carole Lyn; Argueso, J. Lucas; Auerbach, Scott S.; Awadalla, Philip; Davis, Sean R.; DeMarini, David M.; Douglas, George R.; Dubrova, Yuri E.; Elespuru, Rosalie K.; Glover, Thomas W.; Hales, Barbara F.; Hurles, Matthew E.; Klein, Catherine B.; Lupski, James R.; Manchester, David K.; Marchetti, Francesco; Montpetit, Alexandre; Mulvihill, John J.; Robaire, Bernard; Robbins, Wendie A.; Rouleau, Guy A.; Shaughnessy, Daniel T.; Somers, Christopher M.; Taylor, James G.; Trasler, Jacquetta; Waters, Michael D.; Wilson, Thomas E.; Witt, Kristine L.; Bishop, Jack B.

    2012-01-01

    Next-generation sequencing technologies can now be used to directly measure heritable de novo DNA sequence mutations in humans. However, these techniques have not been used to examine environmental factors that induce such mutations and their associated diseases. To address this issue, a working group on environmentally induced germline mutation analysis (ENIGMA) met in October 2011 to propose the necessary foundational studies, which include sequencing of parent–offspring trios from highly exposed human populations, and controlled dose–response experiments in animals. These studies will establish background levels of variability in germline mutation rates and identify environmental agents that influence these rates and heritable disease. Guidance for the types of exposures to examine come from rodent studies that have identified agents such as cancer chemotherapeutic drugs, ionizing radiation, cigarette smoke, and air pollution as germ-cell mutagens. Research is urgently needed to establish the health consequences of parental exposures on subsequent generations. PMID:22935230

  9. A literature based method for identifying gene-disease connections.

    PubMed

    Adamic, Lada A; Wilkinson, Dennis; Huberman, Bernardo A; Adar, Eytan

    2002-01-01

    We present a statistical method that can swiftly identify, from the literature, sets of genes known to be associated with given diseases. It offers a comprehensive way to treat alias symbols, a statistical method for computing the relevance of the gene to the query, and a novel way to disambiguate gene symbols from other abbreviations. The method is illustrated by finding genes related to breast cancer. PMID:15838128

  10. Osler-Weber-Rendu disease: A rare cause of recurrent hemoptysis

    PubMed Central

    Khoja, Amir M; Jalan, Rahul K; Jain, Dheeraj L; Kajale, Omkar V

    2016-01-01

    Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia, is a rare autosomal dominant condition causing systemic fibrovascular dysplasia. It has an incidence of 1-2/100,000. Phenotypic variation is extreme ranging from asymptomatic to severely symptomatic, from cases with no or few mucocutaneous lesions to those with diffuse cutaneous telangiectasia. We discuss a case of Osler-Weber-Rendu disease causing diffuse cutaneous telangiectasia and hemoptysis. The patient presented with complaints of hemoptysis and was extensively examined and investigated before being diagnosed with Osler-Weber-Rendu disease. We successfully managed the patient's hemoptysis by bronchial artery embolization. This case emphasizes the need for careful examination and investigation and to consider such rare diseases when all the common causes of hemoptysis are ruled out. An early and proper diagnosis will lead to more effective management of such a rare disease with few treatment options available. PMID:27185997

  11. Osler-Weber-Rendu disease: A rare cause of recurrent hemoptysis.

    PubMed

    Khoja, Amir M; Jalan, Rahul K; Jain, Dheeraj L; Kajale, Omkar V

    2016-01-01

    Osler-Weber-Rendu disease, also known as hereditary hemorrhagic telangiectasia, is a rare autosomal dominant condition causing systemic fibrovascular dysplasia. It has an incidence of 1-2/100,000. Phenotypic variation is extreme ranging from asymptomatic to severely symptomatic, from cases with no or few mucocutaneous lesions to those with diffuse cutaneous telangiectasia. We discuss a case of Osler-Weber-Rendu disease causing diffuse cutaneous telangiectasia and hemoptysis. The patient presented with complaints of hemoptysis and was extensively examined and investigated before being diagnosed with Osler-Weber-Rendu disease. We successfully managed the patient's hemoptysis by bronchial artery embolization. This case emphasizes the need for careful examination and investigation and to consider such rare diseases when all the common causes of hemoptysis are ruled out. An early and proper diagnosis will lead to more effective management of such a rare disease with few treatment options available. PMID:27185997

  12. Oral health and oromotor function in rare diseases--a database study.

    PubMed

    Sjögreen, Lotta; Andersson-Norinder, Jan; Bratel, John

    2015-01-01

    The aim was to study oral health and oromotor function in individuals with rare diseases. A disease is defined as rare when it affects no more than 100 individuals per million population and leads to a marked degree of disability. An affected nervous or musculoskeletal system, cognitive impairment, neuropsychiatric disorders and craniofacial malformations are common in rare diseases and may all be risk factors for oral health and oromotor function. In 1996-2008, 1,703 individuals with 169 rare diseases, aged 3-67 years, answered a questionnaire about general health, oral health and orofacial function and 1,614 participated in a clinical examination. A control group of 135 healthy children, aged 3-14 years, was also included in the study. Oral health was examined by a dentist and oromotor function by a speech-language pathologist. The participants with rare diseases were recruited via family programmes, referrals to the clinic and research projects, while the controls were randomly selected from a Swedish municipality. In the diagnosis group, 40% had moderate or severe problems coping with dental treatment, 43% were receiving specialised dental care. Difficulties related to tooth brushing were common compared with the controls. Approximately two thirds of the study group and the control group were caries free. Frontal open bite, long face and high palate were common in individuals with rare diseases compared with controls. Oromotor impairment was a frequent finding (43%) and was absent among the controls. There was a significant correlation between oromotor impairment and certain structural deviations and oral-health issues. Compared with healthy controls, individuals with rare diseases often have difficulty coping with dental treatment and managing tooth brushing. Dysmorphology and oromotor dysfunction are frequent findings in this population and they often require extra prophylactic dental care and access to specialised dental care in order to prevent oral disease

  13. Comparison of statistical tests for disease association with rare variants.

    PubMed

    Basu, Saonli; Pan, Wei

    2011-11-01

    In anticipation of the availability of next-generation sequencing data, there is increasing interest in investigating association between complex traits and rare variants (RVs). In contrast to association studies for common variants (CVs), due to the low frequencies of RVs, common wisdom suggests that existing statistical tests for CVs might not work, motivating the recent development of several new tests for analyzing RVs, most of which are based on the idea of pooling/collapsing RVs. However, there is a lack of evaluations of, and thus guidance on the use of, existing tests. Here we provide a comprehensive comparison of various statistical tests using simulated data. We consider both independent and correlated rare mutations, and representative tests for both CVs and RVs. As expected, if there are no or few non-causal (i.e. neutral or non-associated) RVs in a locus of interest while the effects of causal RVs on the trait are all (or mostly) in the same direction (i.e. either protective or deleterious, but not both), then the simple pooled association tests (without selecting RVs and their association directions) and a new test called kernel-based adaptive clustering (KBAC) perform similarly and are most powerful; KBAC is more robust than simple pooled association tests in the presence of non-causal RVs; however, as the number of non-causal CVs increases and/or in the presence of opposite association directions, the winners are two methods originally proposed for CVs and a new test called C-alpha test proposed for RVs, each of which can be regarded as testing on a variance component in a random-effects model. Interestingly, several methods based on sequential model selection (i.e. selecting causal RVs and their association directions), including two new methods proposed here, perform robustly and often have statistical power between those of the above two classes. PMID:21769936

  14. Oral manifestations of epidermolysis bullosa dystrophica: a rare genetic disease

    PubMed Central

    Parushetti, Anita Dundappa; Agrawal, Jiwanasha Manish; Nanjannawar, Lalita Girish; Agrawal, Manish Suresh

    2013-01-01

    Epidermolysis bullosa (EB) constitutes a group of phenotypically diverse genodermatoses, which manifests with blistering and erosions of the skin and mucous membranes as the unifying diagnostic feature. It is an acquired disease or inherited as either autosomal-dominant or recessive with an incidence of 1/50 000. The prominent clinical characteristic of the disease is the development of bullae or vesicles in mucosa or skin in response to minor trauma. It is a chronic mechanobullous disease characterised by auto antibodies against Type VII collagen. This paper documents a case of a man diagnosed with dominant dystrophic EB; describing the measures that dentists and healthcare providers should adopt in order to provide a safe and effective dental treatment. Early prevention protocols for these patients have also been discussed. PMID:23349175

  15. Extra Mammary Paget's Disease: A Rare Case Report

    PubMed Central

    Sardesai, Vidyadhar R; Agarwal, Trupti D; Sakhalkar, Sarita P

    2015-01-01

    Extramammary Paget's disease is a marginated plaque resembling Paget's disease but occurring in anogenital area, axilla or most commonly on the vulva. A 62-year-old postmenopausal woman presented with extremely pruritic plaque on the perineal skin which progressed gradually over 3 years and did not respond to any topical/systemic steroids, antibiotics, and antifungals. Examination revealed 7 × 8 cm. hypertrophic, verrucous plaque with erosions, and crusts at places. There was no evidence of visceral malignancy. Biopsy showed Paget's cells which were positive for Periodic Acid Schiff and alcian blue stain. Surgical excision was done considering the premalignant potential. PMID:25657432

  16. [Q fever : A rare differential diagnosis of granulomatous disease].

    PubMed

    Hippe, S; Kellner, N; Seliger, G; Wiechmann, V; Grünewald, T

    2016-05-01

    Q fever is a worldwide distributed zoonotic disease with a mostly benign course, which regularly reoccurs in Germany. This report is about a patient with sporadic serologically proven Q fever, which also showed typical histopathological findings with nonspecific granulomatous hepatitis, usually seen in acute disease. The bone marrow biopsy revealed so-called doughnut granulomas, which are not pathognomonic but a typical finding in Q fever. This case report impressively underlines that the histomorphological findings can make a decisive contribution to the clarification by extended differential diagnostics, even though it plays a subordinate role in the routine diagnostics of disseminated Q fever. PMID:26919849

  17. Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases.

    PubMed

    Heidari, Moones; Gerami, Sam H; Bassett, Brianna; Graham, Ross M; Chua, Anita C G; Aryal, Ritambhara; House, Michael J; Collingwood, Joanna F; Bettencourt, Conceição; Houlden, Henry; Ryten, Mina; Olynyk, John K; Trinder, Debbie; Johnstone, Daniel M; Milward, Elizabeth A

    2016-01-01

    We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders. PMID:27500074

  18. Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases

    PubMed Central

    Heidari, Moones; Gerami, Sam H.; Bassett, Brianna; Graham, Ross M.; Chua, Anita C.G.; Aryal, Ritambhara; House, Michael J.; Collingwood, Joanna F.; Bettencourt, Conceição; Houlden, Henry; Ryten, Mina; Olynyk, John K.; Trinder, Debbie; Johnstone, Daniel M.; Milward, Elizabeth A.

    2016-01-01

    ABSTRACT We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe−/−xTfr2mut mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family ‘neurodegeneration with brain iron accumulation’ (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders. PMID:27500074

  19. A rare cause of secondary amyloidosis: common variable immunodeficiency disease.

    PubMed

    Kadiroğlu, Ali Kemal; Yıldırım, Yaşar; Yılmaz, Zülfükar; Kayabaşı, Hasan; Avcı, Yahya; Yıldırım, M Serdar; Yılmaz, M Emin

    2012-01-01

    The common variable immunodeficiency disease (CVID) is the most common symptomatic primary antibody deficiency. It is the most frequently observed cause of panhypogammaglobulinemia in adults. Here, we present a case of systemic amyloidosis that developed secondary to the common variable immunodeficiency disease causing recurrent infections in a young female patient. A 24-year-old female patient, who was under treatment at the gynecology and obstetrics clinic for pelvic inflammatory disease, was referred to our clinic when she was observed to have swellings in her legs, hands, and face. She had proteinuria at a rate of 3.5 gr/day, and her serum albumin was 1.5 gr/dl. The levels of immunoglobulins are IgG: 138 mg/dl, IgA: 22,6 mg/dl, and IgM: 16,8 mg/dl. The renal USG revealed that the kidneys were observed to be enlarged. Since the patient had recurrent infections, hypogammaglobulinemia, nephrotic range proteinuria, and enlarged kidneys in the renal USG, she was thought to have type AA amyloidosis and therefore underwent a renal biopsy. The kidney biopsy revealed amyloid (+). So the patient was diagnosed with AA type of amyloidosis secondary to common variable immunodeficiency disease. A treatment regimen (an ACE inhibitor and a statin) with monthly administration of intravenous immunoglobulin was started. PMID:24558615

  20. Orphan drugs for rare diseases: is it time to revisit their special market access status?

    PubMed

    Simoens, Steven; Cassiman, David; Dooms, Marc; Picavet, Eline

    2012-07-30

    Orphan drugs are intended for diseases with a very low prevalence, and many countries have implemented legislation to support market access of orphan drugs. We argue that it is time to revisit the special market access status of orphan drugs. Indeed, evidence suggests that there is no societal preference for treating rare diseases. Although society appears to assign a greater value to severity of disease, this criterion is equally relevant to many common diseases. Furthermore, the criterion of equity in access to treatment, which underpins orphan drug legislation, puts more value on health improvement in rare diseases than in common diseases and implies that population health is not maximized. Finally, incentives for the development, pricing and reimbursement of orphan drugs have created market failures, including monopolistic prices and the artificial creation of rare diseases. We argue that, instead of awarding special market access status to orphan drugs, there is scope to optimize research and development (R&D) of orphan drugs and to control prices of orphan drugs by means of, for example, patent auctions, advance purchase commitments, pay-as-you-go schemes and dose-modification studies. Governments should consider carefully the right incentive strategy for R&D of orphan drugs in rare diseases. PMID:22747423

  1. A Rare Consequence of Chronic Graft Versus Host Disease - Peyronie's Disease

    PubMed Central

    Jain, Natasha A; Venkatesan, Krishnan; Anandi, Prathima; Ito, Sawa; Kumar, Dhruv; Lu, Kit; Battiwalla, Minoo; Barrett, A. John

    2015-01-01

    Chronic graft versus host disease (GvHD) after allogeneic stem cell transplantation (SCT) may involve any organ system, but male genital involvement is rare. Peyronie’s Disease (PD) is an acquired, localized fibrotic disorder of the tunica albuginea, which leads to penile deformity, pain, and eventually to erectile dysfunction. We report the case of a 52 year old African American male with Acute Myeloid Leukemia who underwent human leucocyte antigen (HLA) matched sibling allogeneic peripheral blood SCT. His post transplant course was complicated by development of acute and multi-organ chronic GvHD requiring prolonged immunosuppression. He developed progressive dorsal curvature of the penis with erections within 1 year of ultra low dose interleukin -2 (IL2) treatment for his chronic GvHD but concealed symptoms for several months. Color Doppler Duplex ultrasound evaluation of the erect penis revealed a 75-degree curvature and appropriate hemodynamic response to prostaglandin injection. He underwent successful incision and grafting of the penile plaque. There is no significant residual curvature and is now able to engage in intercourse. A strong temporal association between GVHD (or its treatment) and Peyronie's is documented here. Awareness of the possible link between PD and chronic GVHD is required in this era of rapid growth in numbers of SCT. PMID:26770907

  2. Rare diseases: the bane of modern society and the quest for cures.

    PubMed

    Azie, N; Vincent, J

    2012-08-01

    The enormous progress in the development of drugs for rare diseases may be attributed to advances in genomic technology, molecular profiling, improved target and biomarker selection, an improved understanding of the natural history and pathophysiology of several orphan diseases, use of integrated quantitative analysis techniques in drug development, and a favorable regulatory climate, but major challenges still remain. Most rare diseases manifest during childhood; about 30% of affected children die before their fifth birthday, and the health and economic burden on survivors can be tremendous. PMID:22814654

  3. Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

    PubMed Central

    Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-01-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity. PMID:26175648

  4. Rare coding variants in Phospholipase D3 (PLD3) confer risk for Alzheimer's disease

    PubMed Central

    Cruchaga, Carlos; Benitez, Bruno A.; Cai, Yefei; Guerreiro, Rita; Harari, Oscar; Norton, Joanne; Budde, John; Bertelsen, Sarah; Jeng, Amanda T.; Cooper, Breanna; Skorupa, Tara; Carrell, David; Levitch, Denise; Hsu, Simon; Choi, Jiyoon; Ryten, Mina; Sassi, Celeste; Bras, Jose; Gibbs, Raphael J.; Hernandez, Dena G.; Lupton, Michelle K.; Powell, John; Forabosco, Paola; Ridge, Perry G.; Corcoran, Christopher D.; Tschanz, JoAnn T.; Norton, Maria C.; Munger, Ronald G.; Schmutz, Cameron; Leary, Maegan; Demirci, F. Yesim; Bamne, Mikhil N.; Wang, Xingbin; Lopez, Oscar L.; Ganguli, Mary; Medway, Christopher; Turton, James; Lord, Jenny; Braae, Anne; Barber, Imelda; Brown, Kristelle; Pastor, Pau; Lorenzo-Betancor, Oswaldo; Brkanac, Zoran; Scott, Erick; Topol, Eric; Morgan, Kevin; Rogaeva, Ekaterina; Singleton, Andy; Hardy, John; Kamboh, M. Ilyas; George-Hyslop, Peter St; Cairns, Nigel; Morris, John C.; Kauwe, John S.K.; Goate, Alison M.

    2014-01-01

    Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits. PMID

  5. Emphysematous Cystitis: A Rare Disease of Genito-Urinary System

    PubMed Central

    Singh, Shilpi; Jehangir, Waqas; Littlefield, Jay; Hanna, George; Bowling, Gretchen; Yousif, Abdalla; Middleton, John R

    2015-01-01

    Context: Emphysematous cystitis (EC) is a rare infection of the urinary tract that results in gas production in the bladder. It is more common in diabetic and female patients, and can be associated with more serious complications, including pyelonephritis. Case Report: We describe a case of recurrent bacterial cystitis caused by Escherichia coli (E. coli). An incidental finding in our patient of pneumaturia on computed tomography (CT) scan prompted further work-up. Differential diagnoses for pneumaturia include infection, trauma, and fistula, most commonly colovesicular. The patient history ruled out trauma and CT scanning ruled out a fistula; culture of the urine then showed a bacterial load greater than 100,000 E. coli/mL. The patient was then diagnosed with EC. She was treated with ceftriaxone and released in stable condition. Conclusion: The literature was scarce when it came to diagnoses of EC based on bacterial load. We present this case to increase health care providers' awareness of recurrent EC with a urine culture bacterial load greater than 100,000 E. coli/mL. PMID:26258082

  6. Dyskeratosis Congenita Without Oral Involvement: A Rare Hereditary Disease

    PubMed Central

    Jamshidi, Kioumars; Pourazizi, Mohsen; Abtahi-Naeini, Bahareh

    2015-01-01

    Dyskeratosis congenita (DC) is a rare, progressive, multi-system, inherited disorder of telomere biology, first described in 1906 as the Zinsser–Engman–Cole syndrome. The condition presents with the classic triad of nail dystrophy, reticulate skin pigmentation, and oral leukoplakia. Variable somatic abnormalities may be present; these include pulmonary, gastrointestinal, genitourinary, cerebral, and dental complications. Pancytopenia eventually develops, progressing to bone marrow failure. In our patient, the progression of DC did not follow the "classic triad" typically seen in the condition. Here we report the case of a 27-year-old male who had features consistent with this syndrome but who had a normal oral cavity associated with aplastic anemia for which longstanding nail dystrophy and reticular pigmentation were the dominant clinical features. The patient was advised to avoid smoking and severe exposure to the sun, and to return regularly for follow-up. Because all symptoms of this disorder are not necessarily seen collectively in any one patient, physicians should consider it as a probability in all patients showing signs of reticular hyperpigmentation, especially accompanied by aplastic anemia. Our report emphasizes the fact that not all components of the syndrome need to be present and in all cases of genodermatosis, pleomorphism may be expected with variable clinical manifestations. Even though many variants have been described in literature, sparing of the oral cavity as in our patient is extremely uncommon. Therefore, physicians should be aware of the mucocutaneous manifestation of DC and its diagnosis and refer the patient for better evaluation. PMID:26171129

  7. Castleman Disease: A Rare Condition with Endocrine Manifestations

    PubMed Central

    Correa, Ricardo

    2015-01-01

    Castleman disease (CD) most commonly affects lymphoid tissues in the thorax, abdomen, pelvis, and neck. Extralymphatic tissues, such as lacrimal glands, lung, pancreas, larynx, parotid, meninges, and even muscles, have also been reported as sites. The etiology is unknown and its incidence has not been reported in the literature. Castleman disease can be classified clinically into a unicentric or multicentric form, depending on the number of lymph nodes involved, and histologically into a hyaline vascular variant, plasma cell, mixed cellular, or plasmablastic variant. The disease has a predominantly inflammatory background, reflected in high levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The role of cytokines in CD explains the clinical presentation. The clinical scenario varies widely, based mainly on the histologic type. Unicentric CD usually presents without symptomatology, whereas multicentric manifests with fatigue, abdominal or thoracic pain, cytopenias, and/or B- symptoms (10% weight loss in the last six months, nocturnal diaphoresis, and fever). The endocrinopathy has a wide range of manifestations, affecting either the pituitary or other target organs. Achieving the diagnosis is complicated and there is no laboratory or imaging pathognomonic for this disease. The gold standard is an excisional biopsy from an affected lymph node. The treatment depends on the type of CD. Unicentric CD has a good response to excisional surgery. However, in multicentric CD (MCD), surgery may provide transient relief of symptoms but with a rebound effect, so it is not considered a good method. The use of chemotherapy, monoclonal antibodies, glucocorticoids, and thalidomide has shown some improvement in MCD.  PMID:26719823

  8. Tackling rare diseases at European level: why do we need a harmonized framework?

    PubMed

    Taruscio, Domenica; Trama, Annalisa; Stefanov, Rumen

    2007-01-01

    Since 1999 the European Commission has gradually developed a proactive approach towards rare diseases (RD). Despite the progress made over the last years, a comprehensive and evidence based approach is still missing in many EU Member States (MS), leading to an incomplete and often inadequate framework to address rare diseases. Healthcare systems in EU MS differ to great extent among countries in respect to their organization and funding. In general, they are not ready to face the specific problems and needs of people with rare diseases for possible prevention, timely diagnosis, adequate treatment and rehabilitation. Access to new advanced treatment and approved orphan drugs by EMEA is also a big challenge for many MS. A public health approach is needed to properly tackle rare diseases. It is a while that the idea of a comprehensive approach addressing the different challenges of rare diseases is under discussion. In our opinion, the first step to build a comprehensive approach is to properly plan the activities to undertake accordingly to needs, gaps and resources available in a Country. It is therefore important to develop a strategic plan. Adopting a strategic planning approach to rare diseases implies taking advantage of ongoing actions and building on it to adjust, re-orient or expand the response. So far only France has developed a national strategic plan for rare diseases, Bulgaria is in the process of approving its national plan for RD and Spain is in the process of developing it. In this context, considering the importance of developing national plans for RD, it would be very useful to develop recommendations for RD national plan development in order to provide an instrument to support Countries in designing their national plans. The three MS initiatives presented in this paper confirmed the availability of great experiences and expertises among many EU MS and supported the idea that all these different experiences available at the EU level should form the

  9. Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

    PubMed Central

    Daoud, Hussein; Luco, Stephanie M.; Li, Rui; Bareke, Eric; Beaulieu, Chandree; Jarinova, Olga; Carson, Nancy; Nikkel, Sarah M.; Graham, Gail E.; Richer, Julie; Armour, Christine; Bulman, Dennis E.; Chakraborty, Pranesh; Geraghty, Michael; Lines, Matthew A.; Lacaze-Masmonteil, Thierry; Majewski, Jacek; Boycott, Kym M.; Dyment, David A.

    2016-01-01

    Background: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. Methods: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children’s Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype–phenotype correlations. Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys–Drash syndrome. Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU. PMID:27241786

  10. Cold agglutinin disease in sepsis: A rare entity.

    PubMed

    Garg, Ravinder; Kukar, Neetu; Bajwa, Sukhminder Jit Singh; Kaur, Shaminder

    2015-06-01

    Cold agglutinin disease (CAgD) is a type of autoimmune hemolytic anemia which generally occurs in adults and is characterized by the presence of IgM antibodies directed against polysaccharide antigens on red blood cell surface. A 16-year-old male, having clinical picture of sepsis and anemia, presented to the Emergency Department of our Institute in an Hemodynamically unstable condition. Investigation profile revealed hemolysis due to CAgD, which responded to corticosteroids, antibiotics and supportive treatment. This case highlights the importance of recognizing this entity in such type of cases presenting with sepsis and anemia. PMID:26229347

  11. Identifying Symptom Patterns in People Living With HIV Disease.

    PubMed

    Wilson, Natalie L; Azuero, Andres; Vance, David E; Richman, Joshua S; Moneyham, Linda D; Raper, James L; Heath, Sonya L; Kempf, Mirjam-Colette

    2016-01-01

    Symptoms guide disease management, and patients frequently report HIV-related symptoms, but HIV symptom patterns reported by patients have not been described in the era of improved antiretroviral treatment. The objectives of our study were to investigate the prevalence and burden of symptoms in people living with HIV and attending an outpatient clinic. The prevalence, burden, and bothersomeness of symptoms reported by patients in routine clinic visits during 2011 were assessed using the 20-item HIV Symptom Index. Principal component analysis was used to identify symptom clusters and relationships between groups using appropriate statistic techniques. Two main clusters were identified. The most prevalent and bothersome symptoms were muscle aches/joint pain, fatigue, and poor sleep. A third of patients had seven or more symptoms, including the most burdensome symptoms. Even with improved antiretroviral drug side-effect profiles, symptom prevalence and burden, independent of HIV viral load and CD4+ T cell count, are high. PMID:26790340

  12. Kikuchi-Fujimoto Disease, the Masquerading Menace: A Rare Case Report

    PubMed Central

    Kataria, Rohit; Rao, Pankaj; Kachhawa, Dilip; Jain, Vinod K; Tuteja, Rajat K; Vijayvargiya, Manish

    2016-01-01

    Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare, benign, self-limiting disease with unknown etiology characterized by regional lymphadenopathy. A 30-year-old female presented with fever, weakness, multiple joint pain, oral ulcers, erythematous facial rashes, hemorrhagic crusting on both lips, and cervical lymphadenopathy of 2-month duration. Clinically, the disease was mimicking systemic lupus erythematosus, but immunofluorescence was negative for it. Lymph node biopsy suggested a diagnosis of KFD. PMID:27293275

  13. On the Identifiability of Transmission Dynamic Models for Infectious Diseases.

    PubMed

    Lintusaari, Jarno; Gutmann, Michael U; Kaski, Samuel; Corander, Jukka

    2016-03-01

    Understanding the transmission dynamics of infectious diseases is important for both biological research and public health applications. It has been widely demonstrated that statistical modeling provides a firm basis for inferring relevant epidemiological quantities from incidence and molecular data. However, the complexity of transmission dynamic models presents two challenges: (1) the likelihood function of the models is generally not computable, and computationally intensive simulation-based inference methods need to be employed, and (2) the model may not be fully identifiable from the available data. While the first difficulty can be tackled by computational and algorithmic advances, the second obstacle is more fundamental. Identifiability issues may lead to inferences that are driven more by prior assumptions than by the data themselves. We consider a popular and relatively simple yet analytically intractable model for the spread of tuberculosis based on classical IS6110 fingerprinting data. We report on the identifiability of the model, also presenting some methodological advances regarding the inference. Using likelihood approximations, we show that the reproductive value cannot be identified from the data available and that the posterior distributions obtained in previous work have likely been substantially dominated by the assumed prior distribution. Further, we show that the inferences are influenced by the assumed infectious population size, which generally has been kept fixed in previous work. We demonstrate that the infectious population size can be inferred if the remaining epidemiological parameters are already known with sufficient precision. PMID:26739450

  14. Eosinophilic Esophagitis: The "Not-So-Rare" Disease.

    PubMed

    Goh, Vi Lier

    2016-02-01

    Eosinophilic esophagitis (EoE) is a relatively newly described disorder with increasing incidence. Patients with EoE may present at all ages from childhood through adulthood. Presenting symptoms may vary from feeding refusal, gagging, and/or vomiting in the younger population, dysphagia, chest pain, and abdominal pain in adolescents, as well as emergent food impactions. However, there are strict diagnostic criteria that must be met to make the diagnosis. Specifically, the diagnosis of EoE requires at least 15 eosinophils per high-powered field in the esophageal biopsies and symptoms of esophageal dysfunction after other causes, such as gastroesophageal reflux disease and proton pump inhibitor-responsive esophageal eosinophilia, have been ruled out. Common treatments include diet modifications and/or topical corticosteroids. PMID:26878186

  15. Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-05-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  16. Mastocytosis: a paradigmatic example of a rare disease with complex biology and pathology

    PubMed Central

    Valent, Peter

    2013-01-01

    Mastocytosis is a rare disease characterized by abnormal expansion and accumulation of tissue mast cells (MC) in one or multiple organs. In most adult patients, systemic mastocytosis (SM) is diagnosed. Based on histopathological findings and organ damage, SM is divided into indolent SM (ISM), smoldering SM (SSM), SM with an associated hematologic non-MC-lineage disease (SM-AHNMD), aggressive SM (ASM), and MC leukemia (MCL). The clinical course and prognosis vary greatly among these groups of patients. In all variants of SM and most patients, neoplastic cells display the KIT mutation D816V. This suggests that additional KIT-independent molecular defects cause progression. Indeed, additional oncogenic lesions, including RAS- and TET2 mutations, have recently been identified in advanced SM. In patients with SM-AHNMD, such additional lesions are often detectable in the ‘AHNMD-component’ of the disease. Clinically relevant symptoms of SM result from i) malignant MC infiltration and the subsequent organ damage seen in advanced SM and/or ii) the release of pro-inflammatory and vasoactive mediators from MC, found in all disease-variants. Therapy of SM has to be adjusted to the individual situation in each patient. In ISM, the aim is to control mediator release and mediator effects. In advanced SM, a major goal is to control MC expansion by using conventional drugs or novel targeted drugs directed against mutant forms of KIT and/or other pro-oncogenic kinase-targets. In rapidly progressing ASM, MCL and drug-resistant AHNMD, chemotherapy and subsequent stem cell transplantation has to be considered. PMID:23593539

  17. Normalized rare earth elements in water, sediments, and wine: identifying sources and environmental redox conditions

    USGS Publications Warehouse

    Piper, David Z.; Bau, Michael

    2013-01-01

    The concentrations of the rare earth elements (REE) in surface waters and sediments, when normalized on an element-by-element basis to one of several rock standards and plotted versus atomic number, yield curves that reveal their partitioning between different sediment fractions and the sources of those fractions, for example, between terrestrial-derived lithogenous debris and seawater-derived biogenous detritus and hydrogenous metal oxides. The REE of ancient sediments support their partitioning into these same fractions and further contribute to the identification of the redox geochemistry of the sea water in which the sediments accumulated. The normalized curves of the REE that have been examined in several South American wine varietals can be interpreted to reflect the lithology of the bedrock on which the vines may have been grown, suggesting limited fractionation during soil development.

  18. Rare Mendelian Primary Immunodeficiency diseases associated to impaired NF-κB signaling

    PubMed Central

    Paciolla, Mariateresa; Pescatore, Alessandra; Conte, Matilde Immacolata; Esposito, Elio; Incoronato, Mariarosaria; Lioi, Maria Brigida; Fusco, Francesca; Ursini, Matilde Valeria

    2015-01-01

    Mendelian Primary Immunodeficiency Diseases (MPIDs) are rare disorders affecting distinct constituents of the innate and adaptive immune system. Although they are genetically heterogeneous a substantial group of MPIDs is due to mutations in genes affecting the NF-κB transcription pathway, essential for cell proliferation, cell survival, and involved in innate immunity and in inflammation. Many of these genes encode for crucial regulatory components of NF-κB pathway and their mutations are associated with immunological and developmental signs somehow overlapping in patients with MPIDs. At present nine different MPIDs listed in the OMIM are caused by mutations in at least nine different genes strictly involved in the NF-κB pathway that result in defects in immune responses. We will report here on the distinct function of each causative gene, on the impaired NF-κB step and more in general on the molecular mechanisms underlining the pathogenesis of the disease. Overall, the MPIDs affecting NF-κB signalosome require a careful integrated diagnosis and appropriate genetic tests to be molecularly identified. Their discovery at an ever-increasing rate will help to establish common therapeutic strategy for a subclass of immunodeficient patients. PMID:25764117

  19. A novel rare copy number variant of the ABCF1 gene identified among dengue fever patients from Peninsular Malaysia.

    PubMed

    Hoh, B P; Sam, S S; Umi, S H; Mahiran, M; Nik Khairudin, N Y; Rafidah Hanim, S; Abubakar, S

    2014-01-01

    Copy number variation (CNV) is a form of genetic variation in addition to single nucleotide polymorphisms. The significance of CNV in the manifestation of a number of diseases is only recently receiving considerable attention. We genotyped 163 dengue patients from Peninsular Malaysia for genes possibly linked to dengue infection using quantitative real-time PCR. Here, we report a serendipitous discovery of a novel rare CNV of the ABCF1 gene among the dengue patients. Among these patients, two had a gain of 1 copy (CN = 3) and one had lost 1 copy (CN = 1), indicating that a rare CNV of the ABCF1 gene was detected among dengue patients from Peninsular Malaysia. Although the gene is suspected to regulate inflammatory responses and pathogen-induced cytokine storm, its relevance to dengue requires further investigation. PMID:24634119

  20. Identifying rare FHB-resistant transgressive segregants in intransigent backcross and F2 winter wheat populations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fusarium head blight (FHB), caused mainly by Fusarium graminearum Schwabe [telomorph: Gibberella zeae Schwein.(Petch)] in the US, is one of the most destructive diseases of wheat (Triticum aestivum L. and T. durum L.). FHB-infected grain is usually contaminated with deoxynivalenol (DON) a mycotoxin ...

  1. Wide disparity of clinical genetics services and EU rare disease research funding across Europe.

    PubMed

    Lynch, Sally Ann; Borg, Isabella

    2016-04-01

    The origins of clinical genetics services vary throughout Europe with some emerging from paediatric medicine and others from an academic laboratory setting. In 2011, the cross-border patients' rights directive recommended the creation of European Research Networks (ERNs) to improve patient care throughout EU. In 2013, the EU recommendation on the care for rare diseases came into place. The process of designating EU centres of expertise in rare diseases is being implemented to allow centres to enter ERNs. Hence, this is an opportune time to reflect on the current status of genetic services and research funding throughout Europe as 80 % of rare diseases have a genetic origin. Our aims were to determine (a) whether EU countries are prepared in terms of appropriate clinical genetic staffing to fulfil the European Union Committee of Experts on Rare Diseases (EUCERD) criteria that will allow national centres to be designated as centres of expertise, (b) which EU countries are successful in grant submissions to EU rare disease research funding and (c) country of origin of researchers from the EU presenting their research work as a spoken presentation at the European Society of Human Genetics annual conference. Our results show there is wide disparity of staffing levels per head of population in clinical genetics units throughout Europe. EU rare disease research funding is not being distributed equitably and the opportunity to present research is skewed with many countries not achieving spoken presentations despite abstract submissions. Inequity in the care of patients with rare diseases exists in Europe. Many countries will struggle to designate centres of expertise as their staffing mix and levels will not meet the EUCERD criteria which may prevent them from entering ERNs. The establishment of a small number of centres of expertise centrally, which is welcome, should not occur at the expense of an overall improvement in EU rare disease patient care. Caution should be

  2. Profound biotinidase deficiency: a rare disease among native Swedes.

    PubMed

    Ohlsson, Annika; Guthenberg, Claes; Holme, Elisabeth; von Döbeln, Ulrika

    2010-12-01

    Biotinidase deficiency is an autosomal recessive metabolic disorder included in many newborn screening programmes. Prior to the introduction of screening for biotinidase deficiency in Sweden in 2002, the disorder was almost unknown, with only one case diagnosed clinically. Biotinidase activity was measured in dried blood spots with a semiquantitative method using biotin-6-amidoquinoline as substrate. The cutoff value was set at 25% (later lowered to 20%) of the mean activity of all samples measured on that day. The disorder was confirmed by quantitative determination of biotinidase activity in plasma and DNA analyses. Over a period of 6 years, 13 patients were identified among 637,452 screened newborns and 5,068 adoptive/immigrant children. None of the patients had clinical symptoms at the time of diagnosis. Six patients had profound biotinidase deficiency, with an activity of 0-5% of normal in plasma. Four of these patients were born to parents who were first cousins of Middle Eastern or African origin. Eighteen gene alterations were identified, nine of which have not previously been described: seven mutations p.L83S (c.248T > C), p.R148H (c.443G > A), p.N202I (c.605A > T), p.I255T (c.764T > C), p.N402S (c.1205A > G), p.L405P (c.1214T > C), p.G445R (c.1333G > A) and two silent mutations p.L71L (c.211C > T) and p.L215L (c.645C > T). The predicted severity of the novel mutations was analyzed by sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), predicting p.L83S, p.L405P and p.G445R as severe mutations. Due to the high rate of immigrants since 1990 from non-Nordic countries, the incidence of biotinidase deficiency is similar to that found in many other Western countries. PMID:20224900

  3. A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease

    PubMed Central

    Kun-Rodrigues, Celia; Ganos, Christos; Guerreiro, Rita; Schneider, Susanne A.; Schulte, Claudia; Lesage, Suzanne; Darwent, Lee; Holmans, Peter; Singleton, Andrew; Bhatia, Kailash; Bras, Jose

    2015-01-01

    Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent–child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein–protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes. PMID:26362251

  4. A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease.

    PubMed

    Kun-Rodrigues, Celia; Ganos, Christos; Guerreiro, Rita; Schneider, Susanne A; Schulte, Claudia; Lesage, Suzanne; Darwent, Lee; Holmans, Peter; Singleton, Andrew; Bhatia, Kailash; Bras, Jose

    2015-12-01

    Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes. PMID:26362251

  5. Network motif-based method for identifying coronary artery disease

    PubMed Central

    LI, YIN; CONG, YAN; ZHAO, YUN

    2016-01-01

    The present study aimed to develop a more efficient method for identifying coronary artery disease (CAD) than the conventional method using individual differentially expressed genes (DEGs). GSE42148 gene microarray data were downloaded, preprocessed and screened for DEGs. Additionally, based on transcriptional regulation data obtained from ENCODE database and protein-protein interaction data from the HPRD, the common genes were downloaded and compared with genes annotated from gene microarrays to screen additional common genes in order to construct an integrated regulation network. FANMOD was then used to detect significant three-gene network motifs. Subsequently, GlobalAncova was used to screen differential three-gene network motifs between the CAD group and the normal control data from GSE42148. Genes involved in the differential network motifs were then subjected to functional annotation and pathway enrichment analysis. Finally, clustering analysis of the CAD and control samples was performed based on individual DEGs and the top 20 network motifs identified. In total, 9,008 significant three-node network motifs were detected from the integrated regulation network; these were categorized into 22 interaction modes, each containing a minimum of one transcription factor. Subsequently, 1,132 differential network motifs involving 697 genes were screened between the CAD and control group. The 697 genes were enriched in 154 gene ontology terms, including 119 biological processes, and 14 KEGG pathways. Identifying patients with CAD based on the top 20 network motifs provided increased accuracy compared with the conventional method based on individual DEGs. The results of the present study indicate that the network motif-based method is more efficient and accurate for identifying CAD patients than the conventional method based on individual DEGs. PMID:27347046

  6. The treatable intellectual disability APP www.treatable-id.org: A digital tool to enhance diagnosis & care for rare diseases

    PubMed Central

    2012-01-01

    Background Intellectual disability (ID) is a devastating and frequent condition, affecting 2-3% of the population worldwide. Early recognition of treatable underlying conditions drastically improves health outcomes and decreases burdens to patients, families and society. Our systematic literature review identified 81 such inborn errors of metabolism, which present with ID as a prominent feature and are amenable to causal therapy. The WebAPP translates this knowledge of rare diseases into a diagnostic tool and information portal. Methods & results Freely available as a WebAPP via http://www.treatable-id.org and end 2012 via the APP store, this diagnostic tool is designed for all specialists evaluating children with global delay / ID and laboratory scientists. Information on the 81 diseases is presented in different ways with search functions: 15 biochemical categories, neurologic and non-neurologic signs & symptoms, diagnostic investigations (metabolic screening tests in blood and urine identify 65% of all IEM), therapies & effects on primary (IQ/developmental quotient) and secondary outcomes, and available evidence For each rare condition a ‘disease page’ serves as an information portal with online access to specific genetics, biochemistry, phenotype, diagnostic tests and therapeutic options. As new knowledge and evidence is gained from expert input and PubMed searches this tool will be continually updated. The WebAPP is an integral part of a protocol prioritizing treatability in the work-up of every child with global delay / ID. A 3-year funded study will enable an evaluation of its effectiveness. Conclusions For rare diseases, a field for which financial and scientific resources are particularly scarce, knowledge translation challenges are abundant. With this WebAPP technology is capitalized to raise awareness for rare treatable diseases and their common presenting clinical feature of ID, with the potential to improve health outcomes. This innovative digital

  7. What is known on angiogenesis-related rare diseases? A systematic review of literature

    PubMed Central

    Rodríguez-Caso, Luis; Reyes-Palomares, Armando; Sánchez-Jiménez, Francisca; Quesada, Ana R; Medina, Miguel Ángel

    2012-01-01

    Angiogenesis, the formation of new vessels from pre-existing ones, is essential during ontogenetic development and is related to many important physio-pathological processes in the adult. In fact, a persistent and deregulated angiogenesis is a required event for many diseases and pathological situations, including cancer progression and metastasis. Some rare diseases are also angiogenesis-related pathologies. However, there is a lack of an exhaustive review on the topic. The main purpose of this work is to carry out a systematic review of literature to determine what (and how much) scientific information concerning angiogenesis-related rare diseases can be extracted from available sources. After exhaustive searches in bibliographic databases, preselected data were filtered by selecting only those articles on rare diseases with an Orpha number hosted in the Orphanet web. The selected bibliographic references were further curated manually. With the 187 selected references, a critical reading and analysis was carried out allowing for an identification and classification of angiogenesis-related rare diseases, the involved genes and the drugs available for their treatment, all on the basis of the information available in Orphanet database. PMID:22882737

  8. A journey of hope: lessons learned from studies on rare diseases and orphan drugs.

    PubMed

    Wästfelt, M; Fadeel, B; Henter, J-I

    2006-07-01

    Rare diseases are frequently life-threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or 'orphaned' by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review. PMID:16789973

  9. A modular approach to disease registry design: successful adoption of an internet-based rare disease registry.

    PubMed

    Bellgard, Matthew I; Macgregor, Andrew; Janon, Fred; Harvey, Adam; O'Leary, Peter; Hunter, Adam; Dawkins, Hugh

    2012-10-01

    There is a need to develop Internet-based rare disease registries to support health care stakeholders to deliver improved quality patient outcomes. Such systems should be architected to enable multiple-level access by a range of user groups within a region or across regional/country borders in a secure and private way. However, this functionality is currently not available in many existing systems. A new approach to the design of an Internet-based architecture for disease registries has been developed for patients with clinical and genetic data in geographical disparate locations. The system addresses issues of multiple-level access by key stakeholders, security and privacy. The system has been successfully adopted for specific rare diseases in Australia and is open source. The results of this work demonstrate that it is feasible to design an open source Internet-based disease registry system in a scalable and customizable fashion and designed to facilitate interoperability with other systems. PMID:22753342

  10. [Clinical picture of Hartnup disease. Without urine amino acids or any other identified metabolic disorder (a new entity)].

    PubMed

    Da Gloria, E R; Assunção, J G; Costa, M A

    1990-01-01

    Harthnup disease clinical picture without aminoaciduria or other identified metabolic disturb (New entity?). The authors present a patient with clinical picture superposed to the Hartnup disease's, a rare, autosomic and recessive metabolic disturbance, characterized by typical aminoaciduria consequent to tryptophan and other neutral aminoacids defective transport by jejunal mucous membrane and renal tubules, clinically expressed by photosensitive pellagra-like dermatitis, mental retardation and intermittent cerebellar ataxia. The laboratorial results did not confirm Hartnup aminoaciduria nor other identified metabolic change that justify his clinical manifestations. PMID:2077308