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…

Study designs for identification of rare disease variants in complex diseases: the utility of family-based designs.

PubMed

Ionita-Laza, Iuliana; Ottman, Ruth

2011-11-01

The recent progress in sequencing technologies makes possible large-scale medical sequencing efforts to assess the importance of rare variants in complex diseases. The results of such efforts depend heavily on the use of efficient study designs and analytical methods. We introduce here a unified framework for association testing of rare variants in family-based designs or designs based on unselected affected individuals. This framework allows us to quantify the enrichment in rare disease variants in families containing multiple affected individuals and to investigate the optimal design of studies aiming to identify rare disease variants in complex traits. We show that for many complex diseases with small values for the overall sibling recurrence risk ratio, such as Alzheimer's disease and most cancers, sequencing affected individuals with a positive family history of the disease can be extremely advantageous for identifying rare disease variants. In contrast, for complex diseases with large values of the sibling recurrence risk ratio, sequencing unselected affected individuals may be preferable.

Health Systems Sustainability and Rare Diseases.

PubMed

Ferrelli, Rita Maria; De Santis, Marta; Egle Gentile, Amalia; Taruscio, Domenica

2017-01-01

The paper is addressing aspects of health system sustainability for rare diseases in relation to the current economic crisis and equity concerns. It takes into account the results of the narrative review carried out in the framework of the Joint Action for Rare Diseases (Joint RD-Action) "Promoting Implementation of Recommendations on Policy, Information and Data for Rare Diseases", that identified networks as key factors for health systems sustainability for rare diseases. The legal framework of European Reference Networks and their added value is also presented. Networks play a relevant role for health systems sustainability, since they are based upon, pay special attention to and can intervene on health systems knowledge development, partnership, organizational structure, resources, leadership and governance. Moreover, sustainability of health systems can not be separated from the analysis of the context and the action on it, including fiscal equity. As a result of the financial crisis of 2008, cuts of public health-care budgets jeopardized health equity, since the least wealthy suffered from the greatest health effects. Moreover, austerity policies affected economic growth much more adversely than previously believed. Therefore, reducing public health expenditure not only is going to jeopardise citizens' health, but also to hamper fair and sustainable development.

Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning

PubMed Central

Fakhro, Khalid A.; Choi, Murim; Ware, Stephanie M.; Belmont, John W.; Towbin, Jeffrey A.; Lifton, Richard P.; Khokha, Mustafa K.; Brueckner, Martina

2011-01-01

Dominant human genetic diseases that impair reproductive fitness and have high locus heterogeneity constitute a problem for gene discovery because the usual criterion of finding more mutations in specific genes than expected by chance may require extremely large populations. Heterotaxy (Htx), a congenital heart disease resulting from abnormalities in left-right (LR) body patterning, has features suggesting that many cases fall into this category. In this setting, appropriate model systems may provide a means to support implication of specific genes. By high-resolution genotyping of 262 Htx subjects and 991 controls, we identify a twofold excess of subjects with rare genic copy number variations in Htx (14.5% vs. 7.4%, P = 1.5 × 10−4). Although 7 of 45 Htx copy number variations were large chromosomal abnormalities, 38 smaller copy number variations altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated LR organizer (gastrocoel roof plate), a marked enrichment compared with 40 of 845 previously studied genes (sevenfold enrichment, P < 10−6). Morpholino knockdown in Xenopus of Htx candidates demonstrated that five (NEK2, ROCK2, TGFBR2, GALNT11, and NUP188) strongly disrupted both morphological LR development and expression of pitx2, a molecular marker of LR patterning. These effects were specific, because 0 of 13 control genes from rare Htx or control copy number variations produced significant LR abnormalities (P = 0.001). These findings identify genes not previously implicated in LR patterning. PMID:21282601

Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning.

PubMed

Fakhro, Khalid A; Choi, Murim; Ware, Stephanie M; Belmont, John W; Towbin, Jeffrey A; Lifton, Richard P; Khokha, Mustafa K; Brueckner, Martina

2011-02-15

Dominant human genetic diseases that impair reproductive fitness and have high locus heterogeneity constitute a problem for gene discovery because the usual criterion of finding more mutations in specific genes than expected by chance may require extremely large populations. Heterotaxy (Htx), a congenital heart disease resulting from abnormalities in left-right (LR) body patterning, has features suggesting that many cases fall into this category. In this setting, appropriate model systems may provide a means to support implication of specific genes. By high-resolution genotyping of 262 Htx subjects and 991 controls, we identify a twofold excess of subjects with rare genic copy number variations in Htx (14.5% vs. 7.4%, P = 1.5 × 10(-4)). Although 7 of 45 Htx copy number variations were large chromosomal abnormalities, 38 smaller copy number variations altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated LR organizer (gastrocoel roof plate), a marked enrichment compared with 40 of 845 previously studied genes (sevenfold enrichment, P < 10(-6)). Morpholino knockdown in Xenopus of Htx candidates demonstrated that five (NEK2, ROCK2, TGFBR2, GALNT11, and NUP188) strongly disrupted both morphological LR development and expression of pitx2, a molecular marker of LR patterning. These effects were specific, because 0 of 13 control genes from rare Htx or control copy number variations produced significant LR abnormalities (P = 0.001). These findings identify genes not previously implicated in LR patterning.

A comparison of interventional clinical trials in rare versus non-rare diseases: an analysis of ClinicalTrials.gov.

PubMed

Bell, Stuart A; Tudur Smith, Catrin

2014-11-26

To provide a comprehensive characterisation of rare disease clinical trials registered in ClinicalTrials.gov, and compare against characteristics of trials in non-rare diseases. Registry based study of ClinicalTrials.gov registration entries. The ClinicalTrials.gov registry comprised 133,128 studies registered to September 27, 2012. By annotating medical subject heading descriptors to condition terms we could identify rare and non-rare disease trials. A total of 24,088 Interventional trials registered after January 1, 2006, conducted in the United States, Canada and/or the European Union were categorised as rare or non-rare. Characteristics of the respective trials were extracted and summarised with comparative statistics calculated where appropriate. Characteristics of interventional trials reported in the database categorised by rare and non-rare conditions to allow comparison. Of the 24,088 trials categorised 2,759 (11.5%) were classified as rare disease trials and 21,329 (88.5%) related to non-rare conditions. Despite the limitations of the database we found that rare disease trials differed to non-rare disease trials across all characteristics that we examined. Rare disease trials enrolled fewer participants (median 29 vs. 62), were more likely to be single arm (63.0% vs. 29.6%), non-randomised (64.5% vs. 36.1%) and open label (78.7% vs. 52.2%). A higher proportion of rare disease trials were terminated early (13.7% vs. 6.3%) and proportionally fewer rare disease studies were actively pursuing, or waiting to commence, enrolment (15.9% vs. 38.5%). Rare disease interventional trials differ from those in non-rare conditions with notable differences in enrolment, design, blinding and randomisation. However, clinical trials should aim to implement the highest trial design standards possible, regardless of whether diseases are rare or not.

Adopting Quality Criteria for Websites Providing Medical Information About Rare Diseases.

PubMed

Pauer, Frédéric; Göbel, Jens; Storf, Holger; Litzkendorf, Svenja; Babac, Ana; Frank, Martin; Lührs, Verena; Schauer, Franziska; Schmidtke, Jörg; Biehl, Lisa; Wagner, Thomas Of; Ückert, Frank; Graf von der Schulenburg, Johann-Matthias; Hartz, Tobias

2016-08-25

The European Union considers diseases to be rare when they affect less than 5 in 10,000 people. It is estimated that there are between 5000 and 8000 different rare diseases. Consistent with this diversity, the quality of information available on the Web varies considerably. Thus, quality criteria for websites about rare diseases are needed. The objective of this study was to generate a catalog of quality criteria suitable for rare diseases. First, relevant certificates and quality recommendations for health information websites were identified through a comprehensive Web search. Second, all considered quality criteria of each certification program and catalog were examined, extracted into an overview table, and analyzed by thematic content. Finally, an interdisciplinary expert group verified the relevant quality criteria. We identified 9 quality certificates and criteria catalogs for health information websites with 304 single criteria items. Through this, we aggregated 163 various quality criteria, each assigned to one of the following categories: thematic, technical, service, content, and legal. Finally, a consensus about 13 quality criteria for websites offering medical information on rare diseases was determined. Of these categories, 4 (data protection concept, imprint, creation and updating date, and possibility to contact the website provider) were identified as being the most important for publishing medical information about rare diseases. The large number of different quality criteria appearing within a relatively small number of criteria catalogs shows that the opinion of what is important in the quality of health information differs. In addition, to define useful quality criteria for websites about rare diseases, which are an essential source of information for many patients, a trade-off is necessary between the high standard of quality criteria for health information websites in general and the limited provision of information about some rare diseases

E-Learning for Rare Diseases: An Example Using Fabry Disease.

PubMed

Cimmaruta, Chiara; Liguori, Ludovica; Monticelli, Maria; Andreotti, Giuseppina; Citro, Valentina

2017-09-24

Rare diseases represent a challenge for physicians because patients are rarely seen, and they can manifest with symptoms similar to those of common diseases. In this work, genetic confirmation of diagnosis is derived from DNA sequencing. We present a tutorial for the molecular analysis of a rare disease using Fabry disease as an example. An exonic sequence derived from a hypothetical male patient was matched against human reference data using a genome browser. The missense mutation was identified by running BlastX, and information on the affected protein was retrieved from the database UniProt. The pathogenic nature of the mutation was assessed with PolyPhen-2. Disease-specific databases were used to assess whether the missense mutation led to a severe phenotype, and whether pharmacological therapy was an option. An inexpensive bioinformatics approach is presented to get the reader acquainted with the diagnosis of Fabry disease. The reader is introduced to the field of pharmacological chaperones, a therapeutic approach that can be applied only to certain Fabry genotypes. The principle underlying the analysis of exome sequencing can be explained in simple terms using web applications and databases which facilitate diagnosis and therapeutic choices.

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

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

PubMed

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

2015-01-01

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. 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. 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. 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. 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.

Economic Modeling Considerations for Rare Diseases.

PubMed

Pearson, Isobel; Rothwell, Ben; Olaye, Andrew; Knight, Christopher

2018-05-01

To identify challenges that affect the feasibility and rigor of economic models in rare diseases and strategies that manufacturers have employed in health technology assessment submissions to demonstrate the value of new orphan products that have limited study data. Targeted reviews of PubMed, the National Institute for Health and Care Excellence's (NICE's) Highly Specialised Technologies (HST), and the Scottish Medicines Consortium's (SMC's) ultra-orphan submissions were performed. A total of 19 PubMed studies, 3 published NICE HSTs, and 11 ultra-orphan SMC submissions were eligible for inclusion. In rare diseases, a number of different factors may affect the model's ability to comply with good practice recommendations. Many products for the treatment of rare diseases have an incomplete efficacy and safety profile at product launch. In addition, there is often limited available natural history and epidemiology data. Information on the direct and indirect cost burden of an orphan disease also may be limited, making it difficult to estimate the potential economic benefit of treatment. These challenges can prevent accurate estimation of a new product's benefits in relation to costs. Approaches that can address such challenges include using patient and/or clinician feedback to inform model assumptions; data from disease analogues; epidemiological techniques, such as matching-adjusted indirect comparison; and long-term data collection. Modeling in rare diseases is often challenging; however, a number of approaches are available to support the development of model structures and the collation of input parameters and to manage uncertainty. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Towards efficiency in rare disease research: what is distinctive and important?

PubMed

Jia, Jinmeng; Shi, Tieliu

2017-07-01

Characterized by their low prevalence, rare diseases are often chronically debilitating or life threatening. Despite their low prevalence, the aggregate number of individuals suffering from a rare disease is estimated to be nearly 400 million worldwide. Over the past decades, efforts from researchers, clinicians, and pharmaceutical industries have been focused on both the diagnosis and therapy of rare diseases. However, because of the lack of data and medical records for individual rare diseases and the high cost of orphan drug development, only limited progress has been achieved. In recent years, the rapid development of next-generation sequencing (NGS)-based technologies, as well as the popularity of precision medicine has facilitated a better understanding of rare diseases and their molecular etiology. As a result, molecular subclassification can be identified within each disease more clearly, significantly improving diagnostic accuracy. However, providing appropriate care for patients with rare diseases is still an enormous challenge. In this review, we provide a brief introduction to the challenges of rare disease research and make suggestions on where and how our efforts should be focused.

Adopting Quality Criteria for Websites Providing Medical Information About Rare Diseases

PubMed Central

Göbel, Jens; Storf, Holger; Litzkendorf, Svenja; Babac, Ana; Frank, Martin; Lührs, Verena; Schauer, Franziska; Schmidtke, Jörg; Biehl, Lisa; Wagner, Thomas OF; Ückert, Frank; Graf von der Schulenburg, Johann-Matthias; Hartz, Tobias

2016-01-01

Background The European Union considers diseases to be rare when they affect less than 5 in 10,000 people. It is estimated that there are between 5000 and 8000 different rare diseases. Consistent with this diversity, the quality of information available on the Web varies considerably. Thus, quality criteria for websites about rare diseases are needed. Objective The objective of this study was to generate a catalog of quality criteria suitable for rare diseases. Methods First, relevant certificates and quality recommendations for health information websites were identified through a comprehensive Web search. Second, all considered quality criteria of each certification program and catalog were examined, extracted into an overview table, and analyzed by thematic content. Finally, an interdisciplinary expert group verified the relevant quality criteria. Results We identified 9 quality certificates and criteria catalogs for health information websites with 304 single criteria items. Through this, we aggregated 163 various quality criteria, each assigned to one of the following categories: thematic, technical, service, content, and legal. Finally, a consensus about 13 quality criteria for websites offering medical information on rare diseases was determined. Of these categories, 4 (data protection concept, imprint, creation and updating date, and possibility to contact the website provider) were identified as being the most important for publishing medical information about rare diseases. Conclusions The large number of different quality criteria appearing within a relatively small number of criteria catalogs shows that the opinion of what is important in the quality of health information differs. In addition, to define useful quality criteria for websites about rare diseases, which are an essential source of information for many patients, a trade-off is necessary between the high standard of quality criteria for health information websites in general and the limited

Rare deleterious mutations are associated with disease in bipolar disorder families.

PubMed

Rao, A R; Yourshaw, M; Christensen, B; Nelson, S F; Kerner, B

2017-07-01

Bipolar disorder (BD) is a common, complex and heritable psychiatric disorder characterized by episodes of severe mood swings. The identification of rare, damaging genomic mutations in families with BD could inform about disease mechanisms and lead to new therapeutic interventions. To determine whether rare, damaging mutations shared identity-by-descent in families with BD could be associated with disease, exome sequencing was performed in multigenerational families of the NIMH BD Family Study followed by in silico functional prediction. Disease association and disease specificity was determined using 5090 exomes from the Sweden-Schizophrenia (SZ) Population-Based Case-Control Exome Sequencing study. We identified 14 rare and likely deleterious mutations in 14 genes that were shared identity-by-descent among affected family members. The variants were associated with BD (P<0.05 after Bonferroni's correction) and disease specificity was supported by the absence of the mutations in patients with SZ. In addition, we found rare, functional mutations in known causal genes for neuropsychiatric disorders including holoprosencephaly and epilepsy. Our results demonstrate that exome sequencing in multigenerational families with BD is effective in identifying rare genomic variants of potential clinical relevance and also disease modifiers related to coexisting medical conditions. Replication of our results and experimental validation are required before disease causation could be assumed.

How rare bone diseases have informed our knowledge of complex diseases.

PubMed

Johnson, Mark L

2016-01-01

Rare bone diseases, generally defined as monogenic traits with either autosomal recessive or dominant patterns of inheritance, have provided a rich database of genes and associated pathways over the past 2-3 decades. The molecular genetic dissection of these bone diseases has yielded some major surprises in terms of the causal genes and/or involved pathways. The discovery of genes/pathways involved in diseases such as osteopetrosis, osteosclerosis, osteogenesis imperfecta and many other rare bone diseases have all accelerated our understanding of complex traits. Importantly these discoveries have provided either direct validation for a specific gene embedded in a group of genes within an interval identified through a complex trait genome-wide association study (GWAS) or based upon the pathway associated with a monogenic trait gene, provided a means to prioritize a large number of genes for functional validation studies. In some instances GWAS studies have yielded candidate genes that fall within linkage intervals associated with monogenic traits and resulted in the identification of causal mutations in those rare diseases. Driving all of this discovery is a complement of technologies such as genome sequencing, bioinformatics and advanced statistical analysis methods that have accelerated genetic dissection and greatly reduced the cost. Thus, rare bone disorders in partnership with GWAS have brought us to the brink of a new era of personalized genomic medicine in which the prevention and management of complex diseases will be driven by the molecular understanding of each individuals contributing genetic risks for disease.

The Problem of Rarity: Estimation of Prevalence in Rare Disease.

PubMed

Auvin, Stéphane; Irwin, John; Abi-Aad, Paul; Battersby, Alysia

2018-05-01

From a disease's first description to its wider recognition, factors such as changes over time in diagnostic criteria, available therapies, and subsequent mortality rates may influence diagnosed prevalence of rare diseases. To propose a novel methodology for estimating the true prevalence of rare diseases using current incidence adjusted to changing diagnostic practice over time. This article focuses on rare diseases whose diagnosis may have changed over time, and raises the hypothesis that prevalence calculated from current incidence may be higher than diagnosed prevalence, which may lag behind the current disease definition and diagnostic methods. A rare epileptic encephalopathy, Dravet syndrome (DS), is explored as an illustrative example. A targeted literature review was performed for DS to identify all reported incidence, prevalence, and mortality and depict how diagnostic practice has evolved over time. A conceptual model was developed to calculate prevalence derived from current incidence figures alone (incidence-derived prevalence) or incidence adjusted with factors that cause a diagnostic drag (diagnostic awareness-adjusted prevalence). We identified sufficient publications of incidence and prevalence to test the conceptual model. For pediatric patients with DS, diagnosed prevalence in the field (as reported in current literature) matches incidence-derived prevalence, whereas for adult patients, it is overestimated by incidence-derived prevalence, but not by diagnostic awareness-adjusted prevalence. Care should be taken with current incidence-derived prevalence figures to not overstate the prevalence in rare diseases, as methodological challenges in counting small populations, coupled with advances in rare disease discovery, may cause discrepancies. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

An overview of the impact of rare disease characteristics on research methodology.

PubMed

Whicher, Danielle; Philbin, Sarah; Aronson, Naomi

2018-01-19

About 30 million individuals in the United States are living with a rare disease, which by definition have a prevalence of 200,000 or fewer cases in the United States ([National Organization for Rare Disorders], [About NORD], [2016]). Disease heterogeneity and geographic dispersion add to the difficulty of completing robust studies in small populations. Improving the ability to conduct research on rare diseases would have a significant impact on population health. The purpose of this paper is to raise awareness of methodological approaches that can address the challenges to conducting robust research on rare diseases. We conducted a landscape review of available methodological and analytic approaches to address the challenges of rare disease research. Our objectives were to: 1. identify algorithms for matching study design to rare disease attributes and the methodological approaches applicable to these algorithms; 2. draw inferences on how research communities and infrastructure can contribute to the efficiency of research on rare diseases; and 3. to describe methodological approaches in the rare disease portfolio of the Patient-Centered Outcomes Research Institute (PCORI), a funder promoting both rare disease research and research infrastructure. We identified three algorithms for matching study design to rare disease or intervention characteristics (Gagne, et.al, BMJ 349:g6802, 2014); (Gupta, et.al, J Clin Epidemiol 64:1085-1094, 2011); (Cornu, et. al, Orphet J Rare Dis 8:48,2012) and summarized the applicable methodological and analytic approaches. From this literature we were also able to draw inferences on how an effective research infrastructure can set an agenda, prioritize studies, accelerate accrual, catalyze patient engagement and terminate poorly performing studies. Of the 24 rare disease projects in the PCORI portfolio, 11 are randomized controlled trials (RCTs) using standard designs. Thirteen are observational studies using case-control, prospective

Rare variants and autoimmune disease.

PubMed

Massey, Jonathan; Eyre, Steve

2014-09-01

The study of rare variants in monogenic forms of autoimmune disease has offered insight into the aetiology of more complex pathologies. Research in complex autoimmune disease initially focused on sequencing candidate genes, with some early successes, notably in uncovering low-frequency variation associated with Type 1 diabetes mellitus. However, other early examples have proved difficult to replicate, and a recent study across six autoimmune diseases, re-sequencing 25 autoimmune disease-associated genes in large sample sizes, failed to find any associated rare variants. The study of rare and low-frequency variation in autoimmune diseases has been made accessible by the inclusion of such variants on custom genotyping arrays (e.g. Immunochip and Exome arrays). Whole-exome sequencing approaches are now also being utilised to uncover the contribution of rare coding variants to disease susceptibility, severity and treatment response. Other sequencing strategies are starting to uncover the role of regulatory rare variation. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Economic aspects of rare diseases.

PubMed

Borski, Krzysztof

2015-01-01

Economic problems related to the prevention, diagnosis and treatment of rare diseases are presented paying particular attention to the costs of financing treatment, including the issue of its refund, which is a fundamental and difficult to solve economic problem of the health care system. Rare diseases, despite the low frequency of occurrence, together cover a large group of diseases being a serious medical, social and economic problem. The adoption of Polish National Plan for Rare Diseases resulting from the recommendations of the Council of the European Union, the extension of institutional activities related to the area of public health and social initiatives seeking innovative solutions to create a model of social support for patients and their families, with very high complexity of the issues regarding rare diseases, results in the need for a coherent, comprehensive, system operations and adoption of comprehensive solutions.

75 FR 47458 - TRICARE; Rare Diseases Definition

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-06

... TRICARE; Rare Diseases Definition AGENCY: Office of the Secretary, DoD. ACTION: Final rule. SUMMARY: 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...

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…

[SZCZECIN CITIZENS' KNOWLEDGE ABOUT RARE DISEASES].

PubMed

Walat, Anna; Skoczylas, Michal Marian; Welnicka, Agnieszka; Kulig, Malgorzata; Rodak, Przemyslaw; Walczak, Zuzanna; Jablońska, Agata

2014-01-01

The aim of the study was to assess knowledge about rare diseases among citizens of Szczecin (Poland). The study was performed by questioning 242 adult customers of Turzyn Shopping Centre in Szczecin (149 females and 93 males). The survey was conducted in the shopping mall on 23 February 2013 (control group) and during the celebration of Rare Disease Day and the 12th Polish Nationwide Cystic Fibrosis Week ("Dolina Mukolinków") on 2 March 2013 (research group). The research tool was a questionnaire devised by the authors and filled out by the writing authors interviewer's answers. In the study group more people knew about the existence of Rare Disease Day than in the control group (86.02% vs 57.72%, chi-square test χ2 > χ2(1); 0.001, p < 0.001), but there was no significant difference between knowledge of when Rare Disease Day is celebrated. The definition of rare diseases compatible with the definition of the European Commission's Health and Consumer Protection was reported only in the control group by 4 people. Examples of rare diseases were reported by 74.19% of the respondents in the study group and by 65.10% in the control group (more than 130 diseases were mentioned altogether). Usually, respondents mentioned fewer examples than were asked about in the questionnaire. The aim of Rare Disease Day was accurately specified by 86.02% of persons in the study group and 87.92% in the control group. Rare Disease Day personally concerns 30.11% of respondents in the study group and 10.07% of persons in the control group (OR = 3.85, 95% CI 0.9-3.6, χ2 > χ2(1); 0.001, p < 0.001). The respondents from the research group knew more about Rare Disease Day and defined the idea of it as closed in a significantly higher degree than the control group. There was no significant difference in the detailed knowledge about rare diseases in either group. This might indicate the need to educate society and patients, along with their families.

Pharmacotherapy challenges of Fontan-associated plastic bronchitis: a rare pediatric disease.

PubMed

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

2013-09-01

Pediatric pharmacotherapy is often challenging due to the paucity of available clinical data on the safety and efficacy of drugs 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 rare 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, a generally accepted effective pharmacotherapy regimen has yet to be 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 2-fold: 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 safe and effective drug regimens can be established, particularly for rare diseases. © 2013 Pharmacotherapy Publications, Inc.

RNF213 Rare Variants in Slovakian and Czech Moyamoya Disease Patients.

PubMed

Kobayashi, Hatasu; Brozman, Miroslav; Kyselová, Kateřina; Viszlayová, Daša; Morimoto, Takaaki; Roubec, Martin; Školoudík, David; Petrovičová, Andrea; Juskanič, Dominik; Strauss, Jozef; Halaj, Marián; Kurray, Peter; Hranai, Marián; Harada, Kouji H; Inoue, Sumiko; Yoshida, Yukako; Habu, Toshiyuki; Herzig, Roman; Youssefian, Shohab; Koizumi, Akio

2016-01-01

RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients.

RNF213 Rare Variants in Slovakian and Czech Moyamoya Disease Patients

PubMed Central

Kyselová, Kateřina; Viszlayová, Daša; Morimoto, Takaaki; Roubec, Martin; Školoudík, David; Petrovičová, Andrea; Juskanič, Dominik; Strauss, Jozef; Halaj, Marián; Kurray, Peter; Hranai, Marián; Harada, Kouji H.; Inoue, Sumiko; Yoshida, Yukako; Habu, Toshiyuki; Herzig, Roman; Youssefian, Shohab; Koizumi, Akio

2016-01-01

RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients. PMID:27736983

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…

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

PubMed

Putzeist, Michelle; Mantel-Teeuwisse, Aukje K; Wied, Christine C Gispen-de; Hoes, Arno W; Leufkens, Hubert G M; de Vrueh, Remco L A

2013-11-15

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). 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). 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 2.8, 95% CI 1.4-5.4). For only

What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants?

PubMed

Jeff, Janina M; Peloso, Gina M; Do, Ron

2016-04-01

Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease.

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

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

USDA-ARS?s Scientific Manuscript database

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...

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

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

DOE PAGES

Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; ...

2015-06-25

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 10,000more » 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.« less

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

[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.

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

Integrated rare variant-based risk gene prioritization in disease case-control sequencing studies.

PubMed

Lin, Jhih-Rong; Zhang, Quanwei; Cai, Ying; Morrow, Bernice E; Zhang, Zhengdong D

2017-12-01

Rare variants of major effect play an important role in human complex diseases and can be discovered by sequencing-based genome-wide association studies. Here, we introduce an integrated approach that combines the rare variant association test with gene network and phenotype information to identify risk genes implicated by rare variants for human complex diseases. Our data integration method follows a 'discovery-driven' strategy without relying on prior knowledge about the disease and thus maintains the unbiased character of genome-wide association studies. Simulations reveal that our method can outperform a widely-used rare variant association test method by 2 to 3 times. In a case study of a small disease cohort, we uncovered putative risk genes and the corresponding rare variants that may act as genetic modifiers of congenital heart disease in 22q11.2 deletion syndrome patients. These variants were missed by a conventional approach that relied on the rare variant association test alone.

A Global Approach to Rare Diseases Research and Orphan Products Development: The International Rare Diseases Research Consortium (IRDiRC).

PubMed

Cutillo, Christine M; Austin, Christopher P; Groft, Stephen C

2017-01-01

Rare diseases present unique challenges to researchers due to the global distribution of patients, complexity and low prevalence of each disease, and limited availability of data. They are also overwhelming and costly for patients, their families, communities, and society. As such, global integration of rare diseases research is necessary to accelerate the understanding, diagnosis, and treatment of rare disorders. The International Rare Diseases Research Consortium (IRDiRC) was born out of that need for a coordinated international community. IRDiRC was launched in 2011 to facilitate cooperation and collaboration on a global scale among the many stakeholders active in rare diseases research to stimulate better coordination, and thereby maximize output of rare diseases research efforts around the world. Members include funders, academic researchers, companies, and patient advocacy organizations all of whom share the common goals and principles of IRDiRC. The overarching objectives of the Consortium are to contribute to the development of 200 new therapies and a means to diagnose most rare diseases, by 2020. As IRDiRC approaches the end of its fifth year, these initial objectives have been largely achieved and new partners from across the globe are joining. This presents the Consortium with the exciting opportunity to set new and even more ambitious goals for the next phase with the ultimate goal of improved health through faster and better diagnostic capabilities and novel therapies for people living with rare diseases and conditions throughout the world.

Rare lung disease research: strategies for improving identification and recruitment of research participants.

PubMed

Gupta, Samir; Bayoumi, Ahmed M; Faughnan, Marie E

2011-11-01

Research in rare lung diseases faces methodologic limitations by virtue of the small number of participants available to be studied. We explored several strategies that may improve researchers' ability to identify and recruit research participants with rare lung diseases. We provide an overview of strategies based on available evidence, previously used approaches, and reasoning. First, disease detection is generally poor and may be improved through strategies targeted at primary care practitioners or directly at patients, thus increasing the pool of patients available for research studies. Next, standardization of case definitions in rare lung diseases is often lacking, hindering research recruitment efforts because of confusion over appropriate recruitment criteria. Expert consensus statements can enhance both clinical care and research recruitment by standardizing definitions. Finally, recruitment strategies using rare lung disease registries, clinical research networks, novel Internet-based direct patient recruitment approaches, and patient organizations may facilitate recruitment of patients with rare lung diseases. In summary, although several strategies for improving the identification and recruitment of research participants with rare lung diseases have been proposed, published examples are few. Objective measurement and reporting of novel recruitment methods and collaboration among researchers facing the same limitations across various rare lung diseases are required. Advancements in this area are vital to the design and performance of much-needed robust clinical studies across the spectrum of rare lung diseases.

Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive.

PubMed

Taudien, Stefan; Lausser, Ludwig; Giamarellos-Bourboulis, Evangelos J; Sponholz, Christoph; Schöneweck, Franziska; Felder, Marius; Schirra, Lyn-Rouven; Schmid, Florian; Gogos, Charalambos; Groth, Susann; Petersen, Britt-Sabina; Franke, Andre; Lieb, Wolfgang; Huse, Klaus; Zipfel, Peter F; Kurzai, Oliver; Moepps, Barbara; Gierschik, Peter; Bauer, Michael; Scherag, André; Kestler, Hans A; Platzer, Matthias

2016-10-01

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity>75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease.

PubMed

Nho, Kwangsik; Horgusluoglu, Emrin; Kim, Sungeun; Risacher, Shannon L; Kim, Dokyoon; Foroud, Tatiana; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; Green, Robert C; Toga, Arthur W; Saykin, Andrew J

2016-08-12

Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics. A WGS data set (N = 815) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). A total of 839 rare variants (MAF < 1/√(2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ε4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1-42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness. This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD

Characteristics of rare disease marketing applications associated with FDA product approvals 2006-2010.

PubMed

Pariser, Anne R; Slack, Daniel J; Bauer, Larry J; Warner, Catherine A; Tracy, LaRee A

2012-08-01

New drug and biologic product marketing applications submitted to FDA's Center for Drug Evaluation and Research (CDER) between 2006 and 2010 were analyzed to identify rare disease application characteristics associated with higher approval rates. The results show that approval rates were similar for rare and common disease applications. Larger company size, prior regulatory experience and priority review designation were associated with higher approval rates. The study findings show that rare disease product development is feasible, and increased interactions between product developers and FDA in early investigational phases can facilitate product development. Published by Elsevier Ltd.

Rare Diseases on the Internet: An Assessment of the Quality of Online Information.

PubMed

Pauer, Frédéric; Litzkendorf, Svenja; Göbel, Jens; Storf, Holger; Zeidler, Jan; Graf von der Schulenburg, Johann-Matthias

2017-01-18

The importance of the Internet as a medium for publishing and sharing health and medical information has increased considerably during the last decade. Nonetheless, comprehensive knowledge and information are scarce and difficult to find, especially for rare diseases. Additionally, the quality of health or medical information about rare diseases is frequently difficult to assess for the patients and their family members. The aim of this study is to assess the quality of information on the Internet about rare diseases. Additionally, the study aims to evaluate if the quality of information on rare diseases varies between different information supplier categories. A total of 13 quality criteria for websites providing medical information about rare diseases were transferred to a self-disclosure questionnaire. Identified providers of information on the Internet about rare diseases were invited to fill out the questionnaire. The questionnaire contained questions about the information provider in general (eg, supplier category, information category, language, use of quality certificates, and target group) and about quality aspects that reflect the 13 quality criteria. Differences in subgroup analyses were performed using t tests. We identified 693 websites containing information about rare diseases. A total of 123 questionnaires (17.7%) were completely filled out by the information suppliers. For the remaining identified suppliers (570/693, 82.3%), the questionnaires were filled out by the authors based on the information available on their website. In many cases, the quality of websites was proportionally low. Furthermore, subgroup analysis showed no statistically significant differences between the quality of information provided by support group/patient organization compared to medical institution (P=.19). The quality of information by individuals (patient/relative) was significantly lower compared to information provided by support group/patient organization (P=.001

Rare diseases in Italy: analysis of the costs and pharmacotherapy.

PubMed

Petrelli, Fabio; Grappasonni, Iolanda; Kračmarová, Lenka; Cioffi, Pasquale; Tayebati, Seyed Khosrow; Esposito, Lucia

2013-08-01

Purpose of this research was to analyse the rare diseases drug supply paths in the Italian region of Campania (Health District 47 of the Local Medical Company Naples 1), with a particular focus on current regulations in this field, and quantify the economic incidence of such pathologies in each quarter of 2007 and 2008. Rare, or orphan, diseases are especially serious and onerous from every point of view. Patients meet significant difficulties in obtaining information and in identifying the most appropriate treatment path within the health care system. Pharmaceutical prescriptions were analysed in order to identify the number of patients for each pathology in each quarter of the years 2007 and 2008, the drugs used, the quantity of each drug, and the costs for treatments. Data show a significant increase of costs during each quarter of the year 2008, as well as from 2007 to 2008. In the absence of specific guidelines for the Campania Region, the Local Medical Company of Naples 1 has established a procedure for patients affected by rare diseases that enables them to receive at no cost products that otherwise would not be distributed for free by the health care system.

Respiratory diseases registries in the national registry of rare diseases.

PubMed

Lara Gallego, Beatriz; Abaitua Borda, Ignacio; Galán Gil, Genaro; Castillo Villegas, Diego; Casanova Espinosa, Álvaro; Cano Jiménez, Esteban; Ojanguren Arranz, Iñigo; Posada de la Paz, Manuel

2014-09-01

This report describes the general characteristics, objectives and organizational aspects of the registries of rare respiratory diseases included in the National Registry of Rare Diseases of the Research Institute for Rare Diseases (ISCIII), in order to publicize their existence and encourage the participation of professionals. Information is collected on the following conditions: alpha-1 antitrypsin deficiency, idiopathic tracheal stenosis, adult pulmonary Langerhans' cell histiocytosis, lymphangioleiomyomatosis, alveolar proteinosis, and sarcoidosis. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

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.

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

2014-06-05

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. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PhenomeCentral: A Portal for Phenotypic and Genotypic Matchmaking of Patients with Rare Genetic Diseases

PubMed Central

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

2017-01-01

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

Standardization of Questions in Rare Disease Registries: The PRISM Library Project.

PubMed

Richesson, Rachel Lynn; Shereff, Denise; Andrews, James Everett

2012-10-10

Patient registries are often a helpful first step in estimating the impact and understanding the etiology of rare diseases - both requisites for the development of new diagnostics and therapeutics. The value and utility of patient registries rely on the use of both well-constructed structured research questions and relevant answer sets accompanying them. There are currently no clear standards or specifications for developing registry questions, and there are no banks of existing questions to support registry developers. This paper introduces the [Rare Disease] PRISM (Patient Registry Item Specifications and Metadata for Rare Disease) project, a library of standardized questions covering a broad spectrum of rare diseases that can be used to support the development of new registries, including Internet-based registries. A convenience sample of questions was identified from well-established (>5 years) natural history studies in various diseases and from several existing registries. Face validity of the questions was determined by review by many experts (both terminology experts at the College of American Pathologists (CAP) and research and informatics experts at the University of South Florida (USF)) for commonality, clarity, and organization. Questions were re-worded slightly, as needed, to make the full semantics of the question clear and to make the questions generalizable to multiple diseases where possible. Questions were indexed with metadata (structured and descriptive information) using a standard metadata framework to record such information as context, format, question asker and responder, and data standards information. At present, PRISM contains over 2,200 questions, with content of PRISM relevant to virtually all rare diseases. While the inclusion of disease-specific questions for thousands of rare disease organizations seeking to develop registries would present a challenge for traditional standards development organizations, the PRISM library could

Standardization of Questions in Rare Disease Registries: The PRISM Library Project

PubMed Central

Shereff, Denise; Andrews, James Everett

2012-01-01

Background Patient registries are often a helpful first step in estimating the impact and understanding the etiology of rare diseases - both requisites for the development of new diagnostics and therapeutics. The value and utility of patient registries rely on the use of both well-constructed structured research questions and relevant answer sets accompanying them. There are currently no clear standards or specifications for developing registry questions, and there are no banks of existing questions to support registry developers. Objective This paper introduces the [Rare Disease] PRISM (Patient Registry Item Specifications and Metadata for Rare Disease) project, a library of standardized questions covering a broad spectrum of rare diseases that can be used to support the development of new registries, including Internet-based registries. Methods A convenience sample of questions was identified from well-established (>5 years) natural history studies in various diseases and from several existing registries. Face validity of the questions was determined by review by many experts (both terminology experts at the College of American Pathologists (CAP) and research and informatics experts at the University of South Florida (USF)) for commonality, clarity, and organization. Questions were re-worded slightly, as needed, to make the full semantics of the question clear and to make the questions generalizable to multiple diseases where possible. Questions were indexed with metadata (structured and descriptive information) using a standard metadata framework to record such information as context, format, question asker and responder, and data standards information. Results At present, PRISM contains over 2,200 questions, with content of PRISM relevant to virtually all rare diseases. While the inclusion of disease-specific questions for thousands of rare disease organizations seeking to develop registries would present a challenge for traditional standards development

Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

PubMed Central

Wangler, Michael F.; Yamamoto, Shinya; Chao, Hsiao-Tuan; Posey, Jennifer E.; Westerfield, Monte; Postlethwait, John; Hieter, Philip; Boycott, Kym M.; Campeau, Philippe M.; Bellen, Hugo J.

2017-01-01

Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies. PMID:28874452

Collaboration for rare disease drug discovery research.

PubMed

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.

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

Multiomics tools for the diagnosis and treatment of rare neurological disease.

PubMed

Crowther, L M; Poms, M; Plecko, Barbara

2018-05-01

Conventional workup of rare neurological disease is frequently hampered by diagnostic delay or lack of diagnosis. While biomarkers have been established for many neurometabolic disorders, improved methods are required for diagnosis of previously unidentified or underreported causes of rare neurological disease. This would result in a higher diagnostic yield and increased patient numbers required for interventional studies. Recent studies using next-generation sequencing and metabolomics have led to identification of novel disease-causing genes and biomarkers. This combined approach can assist in overcoming challenges associated with analyzing and interpreting the large amount of data obtained from each technique. In particular, metabolomics can support the pathogenicity of sequence variants in genes encoding enzymes or transporters involved in metabolic pathways. Moreover, metabolomics can show the broader perturbation caused by inborn errors of metabolism and identify a metabolic fingerprint of metabolic disorders. As such, using "omics" has great potential to meet the current needs for improved diagnosis and elucidation of rare neurological disease.

Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis

PubMed Central

Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

2017-01-01

In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients’ phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases. PMID:29854225

Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis.

PubMed

Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

2017-01-01

In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients' phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases.

An integrative, translational approach to understanding rare and orphan genetically based diseases

PubMed Central

Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

2013-01-01

PhenomeNet is an approach for integrating phenotypes across species and identifying candidate genes for genetic diseases based on the similarity between a disease and animal model phenotypes. In contrast to ‘guilt-by-association’ approaches, PhenomeNet relies exclusively on the comparison of phenotypes to suggest candidate genes, and can, therefore, be applied to study the molecular basis of rare and orphan diseases for which the molecular basis is unknown. In addition to disease phenotypes from the Online Mendelian Inheritance in Man (OMIM) database, we have now integrated the clinical signs from Orphanet into PhenomeNet. We demonstrate that our approach can efficiently identify known candidate genes for genetic diseases in Orphanet and OMIM. Furthermore, we find evidence that mutations in the HIP1 gene might cause Bassoe syndrome, a rare disorder with unknown genetic aetiology. Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases. PMID:23853703

Twenty-First Century Diseases: Commonly Rare and Rarely Common?

PubMed

Daunert, Sylvia; Sittampalam, Gurusingham Sitta; Goldschmidt-Clermont, Pascal J

2017-09-20

Alzheimer's drugs are failing at a rate of 99.6%, and success rate for drugs designed to help patients with this form of dementia is 47 times less than for drugs designed to help patients with cancers ( www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/2014 ). How can it be so difficult to produce a valuable drug for Alzheimer's disease? Each human has a unique genetic and epigenetic makeup, thus endowing individuals with a highly unique complement of genes, polymorphisms, mutations, RNAs, proteins, lipids, and complex sugars, resulting in distinct genome, proteome, metabolome, and also microbiome identity. This editorial is taking into account the uniqueness of each individual and surrounding environment, and stresses the point that a more accurate definition of a "common" disorder could be simply the amalgamation of a myriad of "rare" diseases. These rare diseases are being grouped together because they share a rather constant complement of common features and, indeed, generally respond to empirically developed treatments, leading to a positive outcome consistently. We make the case that it is highly unlikely that such treatments, despite their statistical success measured with large cohorts using standardized clinical research, will be effective on all patients until we increase the depth and fidelity of our understanding of the individual "rare" diseases that are grouped together in the "buckets" of common illnesses. Antioxid. Redox Signal. 27, 511-516.

On the Front Lines of Rare Disease Research

MedlinePlus

... Diseases On the Front Lines of Rare Disease Research Past Issues / Spring 2016 Table of Contents Dr. ... MedlinePlus magazine. Many people may not hear about research on rare diseases. Why is this research important ...

[Hungarian national plan and strategy for rare diseases].

PubMed

Kosztolányi, György

2014-03-02

The rarity of low prevalence diseases and the lack of information, research, diagnosis, treatment and expert availability may mean that the people affected do not benefit from the health resources and services they need. Rare diseases are considered to have little impact on society as a whole, yet they pose serious difficulties for sufferers and their families. By the end of the last century, two robust achievements in science and technology, i.e. the biotechnological and informatics revolutions, have created a real base for global approach to rare diseases by coordinating the capacities for health care, biomedical research and drug development and pooling the very limited resources available both nationally and transnationally. The European Commission has taken a number of actions which help patients and professionals to share expertise and information across borders with the objective of reducing the number of people suffering from these types of diseases. These actions together form the legal basis of the European Union policy on rare diseases. Orphan or rare diseases are now one of the priorities in the public health programmes in European Union. In 2009, the document "European Union Council Recommendation on an action in the field of rare diseases" was released with the main goal to provide national health authorities with supporting tools for the development and implementation of national plans and strategies for rare diseases by the end of 2013. This recommendation adopted by European Union Member States, allows common policy guidelines to be shared everywhere in Europe. By September 2013 the Hungarian National Plan for Rare Diseases, a health policy strategy until 2020 was finalized. The present report gives a short view on the document.

A rare duplication on chromosome 16p11.2 is identified in patients with psychosis in Alzheimer's disease.

PubMed

Zheng, Xiaojing; Demirci, F Yesim; Barmada, M Michael; Richardson, Gale A; Lopez, Oscar L; Sweet, Robert A; Kamboh, M Ilyas; Feingold, Eleanor

2014-01-01

Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis.

Cost of illness and economic evaluation in rare diseases.

PubMed

López-Bastida, Julio; Oliva-Moreno, Juan

2010-01-01

Rare diseases are a major cause of morbidity and mortality in high income countries and have major repercussions on individuals and health care systems. This chapter examines the health economy of rare diseases from two different perspectives: firstly, the study of the economic impact of rare diseases (Cost of Illness studies); and, secondly, cost-effectiveness evaluation, which evaluates both the costs and results of the health care technologies applied in rare diseases. From the point of view of economics, health resource allocation is based on the principle of scarcity, as there are not - and never will be- sufficient resources for all worthy objectives. Hence, policy makers should balance costs and health outcomes. Rare diseases may well represent a significant societal burden that should rightly receive appropriate prioritisation of health care resources. As new and seemingly expensive health care technologies are developed for rare diseases, it will become increasingly important to evaluate potential and real impact of these new technologies in both dimensions: social costs and health outcomes.

Establishing the role of rare coding variants in known Parkinson's disease risk loci.

PubMed

Jansen, Iris E; Gibbs, J Raphael; Nalls, Mike A; Price, T Ryan; Lubbe, Steven; van Rooij, Jeroen; Uitterlinden, André G; Kraaij, Robert; Williams, Nigel M; Brice, Alexis; Hardy, John; Wood, Nicholas W; Morris, Huw R; Gasser, Thomas; Singleton, Andrew B; Heutink, Peter; Sharma, Manu

2017-11-01

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks. Copyright © 2017 Elsevier Inc. All rights reserved.

eRAM: encyclopedia of rare disease annotations for precision medicine.

PubMed

Jia, Jinmeng; An, Zhongxin; Ming, Yue; Guo, Yongli; Li, Wei; Liang, Yunxiang; Guo, Dongming; Li, Xin; Tai, Jun; Chen, Geng; Jin, Yaqiong; Liu, Zhimei; Ni, Xin; Shi, Tieliu

2018-01-04

Rare diseases affect over a hundred million people worldwide, most of these patients are not accurately diagnosed and effectively treated. The limited knowledge of rare diseases forms the biggest obstacle for improving their treatment. Detailed clinical phenotyping is considered as a keystone of deciphering genes and realizing the precision medicine for rare diseases. Here, we preset a standardized system for various types of rare diseases, called encyclopedia of Rare disease Annotations for Precision Medicine (eRAM). eRAM was built by text-mining nearly 10 million scientific publications and electronic medical records, and integrating various data in existing recognized databases (such as Unified Medical Language System (UMLS), Human Phenotype Ontology, Orphanet, OMIM, GWAS). eRAM systematically incorporates currently available data on clinical manifestations and molecular mechanisms of rare diseases and uncovers many novel associations among diseases. eRAM provides enriched annotations for 15 942 rare diseases, yielding 6147 human disease related phenotype terms, 31 661 mammalians phenotype terms, 10,202 symptoms from UMLS, 18 815 genes and 92 580 genotypes. eRAM can not only provide information about rare disease mechanism but also facilitate clinicians to make accurate diagnostic and therapeutic decisions towards rare diseases. eRAM can be freely accessed at http://www.unimd.org/eram/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

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

Development of Korean Rare Disease Knowledge Base

PubMed Central

Seo, Heewon; Kim, Dokyoon; Chae, Jong-Hee; Kang, Hee Gyung; Lim, Byung Chan; Cheong, Hae Il

2012-01-01

Objectives Rare disease research requires a broad range of disease-related information for the discovery of causes of genetic disorders that are maladies caused by abnormalities in genes or chromosomes. A rarity in cases makes it difficult for researchers to elucidate definite inception. This knowledge base will be a major resource not only for clinicians, but also for the general public, who are unable to find consistent information on rare diseases in a single location. Methods We design a compact database schema for faster querying; its structure is optimized to store heterogeneous data sources. Then, clinicians at Seoul National University Hospital (SNUH) review and revise those resources. Additionally, we integrated other sources to capture genomic resources and clinical trials in detail on the Korean Rare Disease Knowledge base (KRDK). Results As a result, we have developed a Web-based knowledge base, KRDK, suitable for study of Mendelian diseases that commonly occur among Koreans. This knowledge base is comprised of disease summary and review, causal gene list, laboratory and clinic directory, patient registry, and so on. Furthermore, database for analyzing and giving access to human biological information and the clinical trial management system are integrated on KRDK. Conclusions We expect that KRDK, the first rare disease knowledge base in Korea, may contribute to collaborative research and be a reliable reference for application to clinical trials. Additionally, this knowledge base is ready for querying of drug information so that visitors can search a list of rare diseases that is relative to specific drugs. Visitors can have access to KRDK via http://www.snubi.org/software/raredisease/. PMID:23346478

State of rare disease management in Southeast Asia.

PubMed

Shafie, Asrul Akmal; Chaiyakunapruk, Nathorn; Supian, Azuwana; Lim, Jeremy; Zafra, Matt; Hassali, Mohamed Azmi Ahmad

2016-08-02

Rare diseases, also referred to as orphan diseases, are characterised by their low prevalence with majority of them are chronically debilitating and life threatening. Given the low prevalence and the widely dispersed but very small patient base for each disease, there may often be a disproportion in the availability of treatments and resources to manage patients, spur research and train experts. This is especially true in Southeast Asian countries that are currently in the process of implementing or revising their universal health coverage schemes. This paper aims to examine the status of rare disease management in Southeast Asian countries. It will serve as the basis for a more active discussion on how countries in the region can address an under-recognised rare disease burden and enhance national and regional capacities. The study consists of literature reviews and key stakeholders interviews in six focus countries, including the Philippines, Singapore, Malaysia, Indonesia, Vietnam, and Thailand and five countries as best practice, comprising of France, Canada, Australia, Taiwan, and South Korea. Rare disease management initiatives across each country were examined based on the World Health Organization's framework for action in strengthening health systems. The results suggest rare disease management remains challenging across Southeast Asia, as many of the focus countries face fundamental issues from basic healthcare systems to funding. Nonetheless, there are substantial improvement opportunities, including leveraging best practices from around the world and organising a multi-stakeholder and regional approach and strategy. Southeast Asian countries have made significant progress in the management of rare disease, but there remain key areas for substantial development opportunities.

Challenges in Research and Health Technology Assessment of Rare Disease Technologies: Report of the ISPOR Rare Disease Special Interest Group.

PubMed

Nestler-Parr, Sandra; Korchagina, Daria; Toumi, Mondher; Pashos, Chris L; Blanchette, Christopher; Molsen, Elizabeth; Morel, Thomas; Simoens, Steven; Kaló, Zoltán; Gatermann, Ruediger; Redekop, William

2018-05-01

Successful development of new treatments for rare diseases (RDs) and their sustainable patient access require overcoming a series of challenges related to research and health technology assessment (HTA). These impediments, which may be unique to RDs or also apply to common diseases but are particularly pertinent in RDs, are diverse and interrelated. To develop for the first time a catalog of primary impediments to RD research and HTA, and to describe the cause and effect of individual challenges. Challenges were identified by an international 22-person expert working group and qualitative outreach to colleagues with relevant expertise. A broad range of stakeholder perspectives is represented. Draft results were presented at annual European and North American International Society for Pharmacoeconomics and Outcomes Research (ISPOR) congresses, and written comments were received by the 385-strong ISPOR Rare Disease Review Group from two rounds of review. Findings were refined and confirmed via targeted literature search. Research-related challenges linked to the low prevalence of RDs were categorized into those pertaining to disease recognition and diagnosis, evaluation of treatment effect, and patient recruitment for clinical research. HTA-related challenges were classified into issues relating to the lack of a tailored HTA method for RD treatments and uncertainty for HTA agencies and health care payers. Identifying and highlighting diverse, but interrelated, key challenges in RD research and HTA is an essential first step toward developing implementable and sustainable solutions. A collaborative multistakeholder effort is required to enable faster and less costly development of safe, efficacious, and appropriate new RD therapies that offer value for money. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Large-scale computational drug repositioning to find treatments for rare diseases.

PubMed

Govindaraj, Rajiv Gandhi; Naderi, Misagh; Singha, Manali; Lemoine, Jeffrey; Brylinski, Michal

2018-01-01

Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed e MatchSite, a new computer program to compare drug-binding sites. In this study, e MatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

How important are rare variants in common disease?

PubMed

Saint Pierre, Aude; Génin, Emmanuelle

2014-09-01

Genome-wide association studies have uncovered hundreds of common genetic variants involved in complex diseases. However, for most complex diseases, these common genetic variants only marginally contribute to disease susceptibility. It is now argued that rare variants located in different genes could in fact play a more important role in disease susceptibility than common variants. These rare genetic variants were not captured by genome-wide association studies using single nucleotide polymorphism-chips but with the advent of next-generation sequencing technologies, they have become detectable. It is now possible to study their contribution to common disease by resequencing samples of cases and controls or by using new genotyping exome arrays that cover rare alleles. In this review, we address the question of the contribution of rare variants in common disease by taking the examples of different diseases for which some resequencing studies have already been performed, and by summarizing the results of simulation studies conducted so far to investigate the genetic architecture of complex traits in human. So far, empirical data have not allowed the exclusion of many models except the most extreme ones involving only a small number of rare variants with large effects contributing to complex disease. To unravel the genetic architecture of complex disease, case-control data will not be sufficient, and alternative study designs need to be proposed together with methodological developments. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Resequencing the susceptibility gene, ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases

PubMed Central

2014-01-01

Introduction The majority of the genetic variance of systemic lupus erythematosus (SLE) remains unexplained by the common disease-common variant hypothesis. Rare variants, which are not detectable by genome-wide association studies because of their low frequencies, are predicted to explain part of this ”missing heritability.” However, recent studies identifying rare variants within known disease-susceptibility loci have failed to show genetic associations because of their extremely low frequencies, leading to the questioning of the contribution of rare variants to disease susceptibility. A common (minor allele frequency = 17.4% in cases) nonsynonymous coding variant rs1143679 (R77H) in ITGAM (CD11b), which forms half of the heterodimeric integrin receptor, complement receptor 3 (CR3), is robustly associated with SLE and has been shown to impair CR3-mediated phagocytosis. Methods We resequenced ITGAM in 73 SLE cases and identified two previously unidentified, case-specific nonsynonymous variants, F941V and G1145S. Both variants were genotyped in 2,107 and 949 additional SLE cases, respectively, to estimate their frequencies in a disease population. An in vitro model was used to assess the impact of F941V and G1145S, together with two nonsynonymous ITGAM polymorphisms, A858V (rs1143683) and M441T (rs11861251), on CR3-mediated phagocytosis. A paired two-tailed t test was used to compare the phagocytic capabilities of each variant with that of wild-type CR3. Results Both rare variants, F941V and G1145S, significantly impair CR3-mediated phagocytosis in an in vitro model (61% reduction, P = 0.006; 26% reduction, P = 0.0232). However, neither of the common variants, M441T and A858V, had an effect on phagocytosis. Neither rare variant was observed again in the genotyping of additional SLE cases, suggesting that there frequencies are extremely low. Conclusions Our results add further evidence to the functional importance of ITGAM in SLE pathogenesis through impaired

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; Pankow, James S.; Pankratz, Nathan D.; Paul, Shom; Perez, Marco; Person, Sharina D.; Polak, Joseph; Post, Wendy S.; Psaty, Bruce M.; Quinlan, Aaron R.; Raffel, Leslie J.; Ramachandran, Vasan S.; Reiner, Alexander P.; Rice, Kenneth; Rotter, Jerome I.; Sanders, Jill P.; Schreiner, Pamela; Seshadri, Sudha; Shea, Steve; Sidney, Stephen; Silverstein, Kevin; Smith, Nicholas L.; Sotoodehnia, Nona; Srinivasan, Asoke; Taylor, Herman A.; Taylor, Kent; Thomas, Fridtjof; Tracy, Russell P.; Tsai, Michael Y.; Volcik, Kelly A.; Wassel, Chrstina L.; Watson, Karol; Wei, Gina; White, Wendy; Wiggins, Kerri L.; Wilk, Jemma B.; Williams, O. Dale; Wilson, Gregory; Wilson, James G.; Wolf, Phillip; Zakai, Neil A.; Hardy, John; Meschia, James F.; Nalls, Michael; Singleton, Andrew; Worrall, Brad; Bamshad, Michael J.; Barnes, Kathleen C.; Abdulhamid, Ibrahim; Accurso, Frank; Anbar, Ran; Beaty, Terri; Bigham, Abigail; Black, Phillip; Bleecker, Eugene; Buckingham, Kati; Cairns, Anne Marie; Caplan, Daniel; Chatfield, Barbara; Chidekel, Aaron; Cho, Michael; Christiani, David C.; Crapo, James D.; Crouch, Julia; Daley, Denise; Dang, Anthony; Dang, Hong; De Paula, Alicia; DeCelie-Germana, Joan; Drumm, Allen DozorMitch; Dyson, Maynard; Emerson, Julia; Emond, Mary J.; Ferkol, Thomas; Fink, Robert; Foster, Cassandra; Froh, Deborah; Gao, Li; Gershan, William; Gibson, Ronald L.; Godwin, Elizabeth; Gondor, Magdalen; Gutierrez, Hector; Hansel, Nadia N.; Hassoun, Paul M.; Hiatt, Peter; Hokanson, John E.; Howenstine, Michelle; Hummer, Laura K.; Kanga, Jamshed; Kim, Yoonhee; Knowles, Michael R.; Konstan, Michael; Lahiri, Thomas; Laird, Nan; Lange, Christoph; Lin, Lin; Lin, Xihong; Louie, Tin L.; Lynch, David; Make, Barry; Martin, Thomas R.; Mathai, Steve C.; Mathias, Rasika A.; McNamara, John; McNamara, Sharon; Meyers, Deborah; Millard, Susan; Mogayzel, Peter; Moss, Richard; Murray, Tanda; Nielson, Dennis; Noyes, Blakeslee; O’Neal, Wanda; Orenstein, David; O’Sullivan, Brian; Pace, Rhonda; Pare, Peter; Parker, H. Worth; Passero, Mary Ann; Perkett, Elizabeth; Prestridge, Adrienne; Rafaels, Nicholas M.; Ramsey, Bonnie; Regan, Elizabeth; Ren, Clement; Retsch-Bogart, George; Rock, Michael; Rosen, Antony; Rosenfeld, Margaret; Ruczinski, Ingo; Sanford, Andrew; Schaeffer, David; Sell, Cindy; Sheehan, Daniel; Silverman, Edwin K.; Sin, Don; Spencer, Terry; Stonebraker, Jackie; Tabor, Holly K.; Varlotta, Laurie; Vergara, Candelaria I.; Weiss, Robert; Wigley, Fred; Wise, Robert A.; Wright, Fred A.; Wurfel, Mark M.; Zanni, Robert; Zou, Fei; Nickerson, Deborah A.; Rieder, Mark J.; Green, Phil; Shendure, Jay; Akey, Joshua M.; Bustamante, Carlos D.; Crosslin, David R.; Eichler, Evan E.; Fox, P. Keolu; Fu, Wenqing; Gordon, Adam; Gravel, Simon; Jarvik, Gail P.; Johnsen, Jill M.; Kan, Mengyuan; Kenny, Eimear E.; Kidd, Jeffrey M.; Lara-Garduno, Fremiet; Leal, Suzanne M.; Liu, Dajiang J.; McGee, Sean; O’Connor, Timothy D.; Paeper, Bryan; Robertson, Peggy D.; Smith, Joshua D.; Staples, Jeffrey C.; Tennessen, Jacob A.; Turner, Emily H.; Wang, Gao; Yi, Qian; Jackson, Rebecca; Peters, Ulrike; Carlson, Christopher S.; Anderson, Garnet; Anton-Culver, Hoda; Assimes, Themistocles L.; Auer, Paul L.; Beresford, Shirley; Bizon, Chris; Black, Henry; Brunner, Robert; Brzyski, Robert; Burwen, Dale; Caan, Bette; Carty, Cara L.; Chlebowski, Rowan; Cummings, Steven; Curb, J. David; Eaton, Charles B.; Ford, Leslie; Franceschini, Nora; Fullerton, Stephanie M.; Gass, Margery; Geller, Nancy; Heiss, Gerardo; Howard, Barbara V.; Hsu, Li; Hutter, Carolyn M.; Ioannidis, John; Jiao, Shuo; Johnson, Karen C.; Kooperberg, Charles; Kuller, Lewis; LaCroix, Andrea; Lakshminarayan, Kamakshi; Lane, Dorothy; Lasser, Norman; LeBlanc, Erin; Li, Kuo-Ping; Limacher, Marian; Lin, Dan-Yu; Logsdon, Benjamin A.; Ludlam, Shari; Manson, JoAnn E.; Margolis, Karen; Martin, Lisa; McGowan, Joan; Monda, Keri L.; Kotchen, Jane Morley; Nathan, Lauren; Ockene, Judith; O’Sullivan, Mary Jo; Phillips, Lawrence S.; Prentice, Ross L.; Robbins, John; Robinson, Jennifer G.; Rossouw, Jacques E.; Sangi-Haghpeykar, Haleh; Sarto, Gloria E.; Shumaker, Sally; Simon, Michael S.; Stefanick, Marcia L.; Stein, Evan; Tang, Hua; Taylor, Kira C.; Thomson, Cynthia A.; Thornton, Timothy A.; Van Horn, Linda; Vitolins, Mara; Wactawski-Wende, Jean; Wallace, Robert; Wassertheil-Smoller, Sylvia; Zeng, Donglin; Applebaum-Bowden, Deborah; Feolo, Michael; Gan, Weiniu; Paltoo, Dina N.; Sholinsky, Phyliss; Sturcke, Anne

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

Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin.

PubMed

Manna, Raffaele; Cauda, Roberto; Feriozzi, Sandro; Gambaro, Giovanni; Gasbarrini, Antonio; Lacombe, Didier; Livneh, Avi; Martini, Alberto; Ozdogan, Huri; Pisani, Antonio; Riccio, Eleonora; Verrecchia, Elena; Dagna, Lorenzo

2017-10-01

Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6 months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings.

Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer.

PubMed

Mitsui, Jun; Fukuda, Yoko; Azuma, Kyo; Tozaki, Hirokazu; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Tsuji, Shoji

2010-07-01

We have recently found that multiple rare variants of the glucocerebrosidase gene (GBA) confer a robust risk for Parkinson disease, supporting the 'common disease-multiple rare variants' hypothesis. To develop an efficient method of identifying rare variants in a large number of samples, we applied multiplexed resequencing using a next-generation sequencer to identification of rare variants of GBA. Sixteen sets of pooled DNAs from six pooled DNA samples were prepared. Each set of pooled DNAs was subjected to polymerase chain reaction to amplify the target gene (GBA) covering 6.5 kb, pooled into one tube with barcode indexing, and then subjected to extensive sequence analysis using the SOLiD System. Individual samples were also subjected to direct nucleotide sequence analysis. With the optimization of data processing, we were able to extract all the variants from 96 samples with acceptable rates of false-positive single-nucleotide variants.

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

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

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

PubMed

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

2015-12-01

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.

Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

PubMed

Baynam, Gareth; Bowman, Faye; Lister, Karla; Walker, Caroline E; Pachter, Nicholas; Goldblatt, Jack; Boycott, Kym M; Gahl, William A; Kosaki, Kenjiro; Adachi, Takeya; Ishii, Ken; Mahede, Trinity; McKenzie, Fiona; Townshend, Sharron; Slee, Jennie; Kiraly-Borri, Cathy; Vasudevan, Anand; Hawkins, Anne; Broley, Stephanie; Schofield, Lyn; Verhoef, Hedwig; Groza, Tudor; Zankl, Andreas; Robinson, Peter N; Haendel, Melissa; Brudno, Michael; Mattick, John S; Dinger, Marcel E; Roscioli, Tony; Cowley, Mark J; Olry, Annie; Hanauer, Marc; Alkuraya, Fowzan S; Taruscio, Domenica; Posada de la Paz, Manuel; Lochmüller, Hanns; Bushby, Kate; Thompson, Rachel; Hedley, Victoria; Lasko, Paul; Mina, Kym; Beilby, John; Tifft, Cynthia; Davis, Mark; Laing, Nigel G; Julkowska, Daria; Le Cam, Yann; Terry, Sharon F; Kaufmann, Petra; Eerola, Iiro; Norstedt, Irene; Rath, Ana; Suematsu, Makoto; Groft, Stephen C; Austin, Christopher P; Draghia-Akli, Ruxandra; Weeramanthri, Tarun S; Molster, Caron; Dawkins, Hugh J S

2017-01-01

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy

Consensus on the criteria needed for creating a rare-disease patient registry. A Delphi study.

PubMed

Cavero-Carbonell, Clara; Gras-Colomer, Elena; Guaita-Calatrava, Rosana; López-Briones, Carmen; Amorós, Rubén; Abaitua, Ignacio; Posada, Manuel; Zurriaga, Oscar

2016-06-01

Patient registries (PRs) are important tools for public-health surveillance and rare-disease research. The purpose of this study is to identify the most important criteria for the creation of a rare-disease PR that could be used by public-health authorities to develop health policies. A consensus-development Delphi study was used, with participants selected for their expertize in rare diseases and registries. Participants were asked to complete a questionnaire on the most important criteria for creating PRs. Three rounds were performed. Agreement was reached on half the questions in the first round and on 89% of questions in the final round, with a total expert participation rate of around 60% by the final stage. This study made it possible to reach a broader consensus starting from experts' initial assessment of the features that should be considered for the creation of a rare-disease PR. The consensus method used made it possible to define the characteristics of a PR based on expert opinion within a rare-disease framework. This study may serve as a guide for helping other researchers plan and build a rare-disease PR. © The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Rare disease: a national survey of paediatricians' experiences and needs.

PubMed

Zurynski, Yvonne; Gonzalez, Aranzazu; Deverell, Marie; Phu, Amy; Leonard, Helen; Christodoulou, John; Elliott, Elizabeth

2017-01-01

To describe the experiences of Australian paediatricians while caring for children with rare diseases, and their educational and resource needs. A brief online survey was developed and deployed to a representative sample of 679 paediatricians from the Australian Paediatric Surveillance Unit database. Of the 679 paediatricians, 242 (36%) completed the survey. The respondents were representative of all states and territories of Australia, urban and rural regions, and hospital and private practice. Almost all respondents (93%) had seen children with one or more of >350 different rare diseases during their career; 74% had seen a new patient with rare disease in the last 6 months. The most common problems encountered while caring for patients were: diagnostic delays (65%), lack of available treatments (40%), clinical guidelines (36%) and uncertainty where to refer for peer support (35%). Few paediatricians said that rare diseases were adequately covered during university (40%) or the Fellowship of the Royal Australasian College of Physicians (50%) training, and 28% felt unprepared to care for patients with rare diseases. Paediatricians wanted lists of specialist referral services (82%) and online educational modules about rare diseases (78%) that could be accessed via one online portal that consolidated multiple resources. Smartphone applications on rare diseases were favoured by paediatricians aged <50 years and by female paediatricians. An online educational portal should be developed and maintained for accuracy and currency of information to support dissemination of rare disease guidelines, referral pathways and coordination services relevant to Australian paediatricians and other health professionals who care for children with rare diseases.

Rare disease: a national survey of paediatricians’ experiences and needs

PubMed Central

Zurynski, Yvonne; Gonzalez, Aranzazu; Deverell, Marie; Phu, Amy; Leonard, Helen; Christodoulou, John; Elliott, Elizabeth

2017-01-01

Objective To describe the experiences of Australian paediatricians while caring for children with rare diseases, and their educational and resource needs. Design A brief online survey was developed and deployed to a representative sample of 679 paediatricians from the Australian Paediatric Surveillance Unit database. Results Of the 679 paediatricians, 242 (36%) completed the survey. The respondents were representative of all states and territories of Australia, urban and rural regions, and hospital and private practice. Almost all respondents (93%) had seen children with one or more of >350 different rare diseases during their career; 74% had seen a new patient with rare disease in the last 6 months. The most common problems encountered while caring for patients were: diagnostic delays (65%), lack of available treatments (40%), clinical guidelines (36%) and uncertainty where to refer for peer support (35%). Few paediatricians said that rare diseases were adequately covered during university (40%) or the Fellowship of the Royal Australasian College of Physicians (50%) training, and 28% felt unprepared to care for patients with rare diseases. Paediatricians wanted lists of specialist referral services (82%) and online educational modules about rare diseases (78%) that could be accessed via one online portal that consolidated multiple resources. Smartphone applications on rare diseases were favoured by paediatricians aged <50 years and by female paediatricians. Conclusions An online educational portal should be developed and maintained for accuracy and currency of information to support dissemination of rare disease guidelines, referral pathways and coordination services relevant to Australian paediatricians and other health professionals who care for children with rare diseases. PMID:29637168

Post-approval Studies for Rare Disease Treatments and Orphan Drugs.

PubMed

Maier, William C; Christensen, Ronald A; Anderson, Patricia

2017-01-01

Drug development involves a multi-stage process of drug discovery, animal studies and human clinical trials to assess the safety and efficacy of new medications. Rare disease drug development involves a much smaller number of affected patients, a predominance of pediatric patients and more complicated disease presentation. Post-approval studies are designed to address several limitations associated with the rare disease clinical trials.National and international regulatory agencies in the US and Europe have adopted similar approaches to requirements post-approval data for rare diseases and orphan drug indications. The US FDA published guidance in 2011 and the European Medicines Agency in 2015.Post-approval studies for rare diseases include observational studies, pragmatic trials and randomized controlled studies. Observational studies include both original data collection studies and the use of secondary data (retrospective studies). Original data collection can address limitations of retrospective studies resulting from incomplete information in secondary data sources. Disease registries focus on detail about a broad range of patients with a rare disease while product-related registries focus on specific health care outcomes associated with a single product and may incorporate a comparator of an alternative therapy or therapies.Rare disease patients can be difficult to find and enroll in a registry using conventional physician based driven recruitment. The study process also needs to recognize changes in the patient's disease and lifestyle and adapt both the study design and methods over time. Many rare diseases have strong patient advocacy groups that can in aid the design and execution of rare disease registries.

Adapting Knowledge Translation Strategies for Rare Rheumatic Diseases.

PubMed

Cellucci, Tania; Lee, Shirley; Webster, Fiona

2016-08-01

Rare rheumatic diseases present unique challenges to knowledge translation (KT) researchers. There is often an urgent need to transfer knowledge from research findings into clinical practice to facilitate earlier diagnosis and better outcomes. However, existing KT frameworks have not addressed the specific considerations surrounding rare diseases for which gold standard evidence is not available. Several widely adopted models provide guidance for processes and problems associated with KT. However, they do not address issues surrounding creation or synthesis of knowledge for rare diseases. Additional problems relate to lack of awareness or experience in intended knowledge users, low motivation, and potential barriers to changing practice or policy. Strategies to address the challenges of KT for rare rheumatic diseases include considering different levels of evidence available, linking knowledge creation and transfer directly, incorporating patient and physician advocacy efforts to generate awareness of conditions, and selecting strategies to address barriers to practice or policy change.

Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

PubMed Central

Boucher, Gabrielle; Lo, Ken Sin; Rivas, Manuel A.; Stevens, Christine; Alikashani, Azadeh; Ladouceur, Martin; Ellinghaus, David; Törkvist, Leif; Goel, Gautam; Lagacé, Caroline; Annese, Vito; Bitton, Alain; Begun, Jakob; Brant, Steve R.; Bresso, Francesca; Cho, Judy H.; Duerr, Richard H.; Halfvarson, Jonas; McGovern, Dermot P. B.; Radford-Smith, Graham; Schreiber, Stefan; Schumm, Philip L.; Sharma, Yashoda; Silverberg, Mark S.; Weersma, Rinse K.; D'Amato, Mauro; Vermeire, Severine; Franke, Andre; Lettre, Guillaume; Xavier, Ramnik J.; Daly, Mark J.; Rioux, John D.

2013-01-01

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. PMID:24068945

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. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Paediatric genomics: diagnosing rare disease in children.

PubMed

Wright, Caroline F; FitzPatrick, David R; Firth, Helen V

2018-05-01

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition. However, making a molecular diagnosis with current technologies and knowledge is often still a challenge. Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows. This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease. Importantly, for affected families, a better understanding of the genetic basis of rare disease translates to more accurate prognosis, management, surveillance and genetic advice; stimulates research into new therapies; and enables provision of better support.

Knowledge-driven binning approach for rare variant association analysis: application to neuroimaging biomarkers in Alzheimer's disease.

PubMed

Kim, Dokyoon; Basile, Anna O; Bang, Lisa; Horgusluoglu, Emrin; Lee, Seunggeun; Ritchie, Marylyn D; Saykin, Andrew J; Nho, Kwangsik

2017-05-18

Rapid advancement of next generation sequencing technologies such as whole genome sequencing (WGS) has facilitated the search for genetic factors that influence disease risk in the field of human genetics. To identify rare variants associated with human diseases or traits, an efficient genome-wide binning approach is needed. In this study we developed a novel biological knowledge-based binning approach for rare-variant association analysis and then applied the approach to structural neuroimaging endophenotypes related to late-onset Alzheimer's disease (LOAD). For rare-variant analysis, we used the knowledge-driven binning approach implemented in Bin-KAT, an automated tool, that provides 1) binning/collapsing methods for multi-level variant aggregation with a flexible, biologically informed binning strategy and 2) an option of performing unified collapsing and statistical rare variant analyses in one tool. A total of 750 non-Hispanic Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort who had both WGS data and magnetic resonance imaging (MRI) scans were used in this study. Mean bilateral cortical thickness of the entorhinal cortex extracted from MRI scans was used as an AD-related neuroimaging endophenotype. SKAT was used for a genome-wide gene- and region-based association analysis of rare variants (MAF (minor allele frequency) < 0.05) and potential confounding factors (age, gender, years of education, intracranial volume (ICV) and MRI field strength) for entorhinal cortex thickness were used as covariates. Significant associations were determined using FDR adjustment for multiple comparisons. Our knowledge-driven binning approach identified 16 functional exonic rare variants in FANCC significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In addition, the approach identified 7 evolutionary conserved regions, which were mapped to FAF1, RFX7, LYPLAL1 and GOLGA3, significantly associated

Innovative measures to combat rare diseases in China: The national rare diseases registry system, larger-scale clinical cohort studies, and studies in combination with precision medicine research.

PubMed

Song, Peipei; He, Jiangjiang; Li, Fen; Jin, Chunlin

2017-02-01

China is facing the great challenge of treating the world's largest rare disease population, an estimated 16 million patients with rare diseases. One effort offering promise has been a pilot national project that was launched in 2013 and that focused on 20 representative rare diseases. Another government-supported special research program on rare diseases - the "Rare Diseases Clinical Cohort Study" - was launched in December 2016. According to the plan for this research project, the unified National Rare Diseases Registry System of China will be established as of 2020, and a large-scale cohort study will be conducted from 2016 to 2020. The project plans to develop 109 technical standards, to establish and improve 2 national databases of rare diseases - a multi-center clinical database and a biological sample library, and to conduct studies on more than 50,000 registered cases of 50 different rare diseases. More importantly, this study will be combined with the concept of precision medicine. Chinese population-specific basic information on rare diseases, clinical information, and genomic information will be integrated to create a comprehensive predictive model with a follow-up database system and a model to evaluate prognosis. This will provide the evidence for accurate classification, diagnosis, treatment, and estimation of prognosis for rare diseases in China. Numerous challenges including data standardization, protecting patient privacy, big data processing, and interpretation of genetic information still need to be overcome, but research prospects offer great promise.

Ethical aspects on rare diseases.

PubMed

Barrera, Luis A; Galindo, Gilberto Cely

2010-01-01

In this chapter we discuss several of the most relevant subjects related to ethics on Rare Diseases. Some general aspects are discussed such as the socio-psychological problems that confront the patients and their families that finally lead to marginalization and exclusion of patients affected by these diseases from the health programs, even in wealthy countries. Then we address problems related to diagnosis and some ethical aspects of newborn screening, prenatal, pre-implantation diagnosis and reference centers, as well as some conditions that should be met by the persons and institutions performing such tasks. Alternatives of solutions for the most critical situations are proposed. Subsequently the orphan drugs subject is discussed not only from the availability point of view, prizes, industrial practices, and purchasing power in developed and developing societies. The research related to rare disease in children and other especially vulnerable conditions, the need for informed consent, review boards or ethics comities, confidentiality of the information, biobanks and pharmacogenetics are discussed.

Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease.

PubMed

Sasaki, Mark M; Skol, Andrew D; Hungate, Eric A; Bao, Riyue; Huang, Lei; Kahn, Stacy A; Allan, James M; Brant, Steven R; McGovern, Dermot P B; Peter, Inga; Silverberg, Mark S; Cho, Judy H; Kirschner, Barbara S; Onel, Kenan

2016-01-01

Rare variants (<1%) likely contribute significantly to risk for common diseases such as inflammatory bowel disease (IBD) in specific patient subsets, such as those with high familiality. They are, however, extraordinarily challenging to identify. To discover candidate rare variants associated with IBD, we performed whole-exome sequencing on 6 members of a pediatric-onset IBD family with multiple affected individuals. To determine whether the variants discovered in this family are also associated with nonfamilial IBD, we investigated their influence on disease in 2 large case-control (CC) series. We identified 2 rare variants, rs142430606 and rs200958270, both in the established IBD-susceptibility gene IL17REL, carried by all 4 affected family members and their obligate carrier parents. We then demonstrated that both variants are associated with sporadic ulcerative colitis (UC) in 2 independent data sets. For UC in CC 1: rs142430606 (odds ratio [OR] = 2.99, Padj = 0.028; minor allele frequency [MAF]cases = 0.0063, MAFcontrols = 0.0021); rs200958270 (OR = 2.61, Padj = 0.082; MAFcases = 0.0045, MAFcontrols = 0.0017). For UC in CC 2: rs142430606 (OR = 1.94, P = 0.0056; MAFcases = 0.0071, MAFcontrols = 0.0045); rs200958270 (OR = 2.08, P = 0.0028; MAFcases = 0.0071, MAFcontrols = 0.0042). We discover in a family and replicate in 2 CC data sets 2 rare susceptibility variants for IBD, both in IL17REL. Our results illustrate that whole-exome sequencing performed on disease-enriched families to guide association testing can be an efficient strategy for the discovery of rare disease-associated variants. We speculate that rare variants identified in families and confirmed in the general population may be important modifiers of disease risk for patients with a family history, and that genetic testing of these variants may be warranted in this patient subset.

Reducing selection bias in case-control studies from rare disease registries.

PubMed

Cole, J Alexander; Taylor, John S; Hangartner, Thomas N; Weinreb, Neal J; Mistry, Pramod K; Khan, Aneal

2011-09-12

In clinical research of rare diseases, where small patient numbers and disease heterogeneity limit study design options, registries are a valuable resource for demographic and outcome information. However, in contrast to prospective, randomized clinical trials, the observational design of registries is prone to introduce selection bias and negatively impact the validity of data analyses. The objective of the study was to demonstrate the utility of case-control matching and the risk-set method in order to control bias in data from a rare disease registry. Data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were used as an example. A case-control matching analysis using the risk-set method was conducted to identify two groups of patients with type 1 Gaucher disease in the ICGG Gaucher Registry: patients with avascular osteonecrosis (AVN) and those without AVN. The frequency distributions of gender, decade of birth, treatment status, and splenectomy status were presented for cases and controls before and after matching. Odds ratios (and 95% confidence intervals) were calculated for each variable before and after matching. The application of case-control matching methodology results in cohorts of cases (i.e., patients with AVN) and controls (i.e., patients without AVN) who have comparable distributions for four common parameters used in subject selection: gender, year of birth (age), treatment status, and splenectomy status. Matching resulted in odds ratios of approximately 1.00, indicating no bias. We demonstrated bias in case-control selection in subjects from a prototype rare disease registry and used case-control matching to minimize this bias. Therefore, this approach appears useful to study cohorts of heterogeneous patients in rare disease registries.

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

PubMed

Matsui, Akihiko

2013-02-01

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.

Next generation phenotyping using narrative reports in a rare disease clinical data warehouse.

PubMed

Garcelon, Nicolas; Neuraz, Antoine; Salomon, Rémi; Bahi-Buisson, Nadia; Amiel, Jeanne; Picard, Capucine; Mahlaoui, Nizar; Benoit, Vincent; Burgun, Anita; Rance, Bastien

2018-05-31

Secondary use of data collected in Electronic Health Records opens perspectives for increasing our knowledge of rare diseases. The clinical data warehouse (named Dr. Warehouse) at the Necker-Enfants Malades Children's Hospital contains data collected during normal care for thousands of patients. Dr. Warehouse is oriented toward the exploration of clinical narratives. In this study, we present our method to find phenotypes associated with diseases of interest. We leveraged the frequency and TF-IDF to explore the association between clinical phenotypes and rare diseases. We applied our method in six use cases: phenotypes associated with the Rett, Lowe, Silver Russell, Bardet-Biedl syndromes, DOCK8 deficiency and Activated PI3-kinase Delta Syndrome (APDS). We asked domain experts to evaluate the relevance of the top-50 (for frequency and TF-IDF) phenotypes identified by Dr. Warehouse and computed the average precision and mean average precision. Experts concluded that between 16 and 39 phenotypes could be considered as relevant in the top-50 phenotypes ranked by descending frequency discovered by Dr. Warehouse (resp. between 11 and 41 for TF-IDF). Average precision ranges from 0.55 to 0.91 for frequency and 0.52 to 0.95 for TF-IDF. Mean average precision was 0.79. Our study suggests that phenotypes identified in clinical narratives stored in Electronic Health Record can provide rare disease specialists with candidate phenotypes that can be used in addition to the literature. Clinical Data Warehouses can be used to perform Next Generation Phenotyping, especially in the context of rare diseases. We have developed a method to detect phenotypes associated with a group of patients using medical concepts extracted from free-text clinical narratives.

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

2014-02-06

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. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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

PubMed

Pogány, Gábor

2014-03-02

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.

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

Harmonising phenomics information for a better interoperability in the rare disease field.

PubMed

Maiella, Sylvie; Olry, Annie; Hanauer, Marc; Lanneau, Valérie; Lourghi, Halima; Donadille, Bruno; Rodwell, Charlotte; Köhler, Sebastian; Seelow, Dominik; Jupp, Simon; Parkinson, Helen; Groza, Tudor; Brudno, Michael; Robinson, Peter N; Rath, Ana

2018-02-07

HIPBI-RD (Harmonising phenomics information for a better interoperability in the rare disease field) is a three-year project which started in 2016 funded via the E-Rare 3 ERA-NET program. This project builds on three resources largely adopted by the rare disease (RD) community: Orphanet, its ontology ORDO (the Orphanet Rare Disease Ontology), HPO (the Human Phenotype Ontology) as well as PhenoTips software for the capture and sharing of structured phenotypic data for RD patients. Our project is further supported by resources developed by the European Bioinformatics Institute and the Garvan Institute. HIPBI-RD aims to provide the community with an integrated, RD-specific bioinformatics ecosystem that will harmonise the way phenomics information is stored in databases and patient files worldwide, and thereby contribute to interoperability. This ecosystem will consist of a suite of tools and ontologies, optimized to work together, and made available through commonly used software repositories. The project workplan follows three main objectives: The HIPBI-RD ecosystem will contribute to the interpretation of variants identified through exome and full genome sequencing by harmonising the way phenotypic information is collected, thus improving diagnostics and delineation of RD. The ultimate goal of HIPBI-RD is to provide a resource that will contribute to bridging genome-scale biology and a disease-centered view on human pathobiology. Achievements in Year 1. Copyright © 2018. Published by Elsevier Masson SAS.

China launched a pilot project to improve its rare disease healthcare levels.

PubMed

Cui, Yazhou; Zhou, Xiaoyan; Han, Jinxiang

2014-01-27

China is facing the great challenge of serving the world's largest rare disease population. It is necessary to develop a specific medical plan to increase the levels of optimal prevention, diagnosis and treatment of rare diseases under the existing clinical service structures in China. In 2013, China launched its first pilot project focused on 20 representative rare diseases. A national network including approximately 100 provincial or municipal medical centers has been established to enable collaboration on rare diseases across China. The main objectives for this project are to develop and apply medical guidelines and clinical pathways for rare diseases, to establish a rare disease patient registry and data repository system, and to promote molecular testing for rare genetic disorders. This project also emphasizes building close links among the collaborative network, clinicians on the frontlines in basic medical services institutions and rare disease patient organizations. Primarily, this project expects to develop an actionable medical services plan to increase the delivery of quality healthcare for individuals and families living with rare diseases in China within five years.

The European Union Policy in the Field of Rare Diseases.

PubMed

Moliner, Antoni Montserrat; Waligora, Jaroslaw

2017-01-01

Rare diseases, are defined by the European Union as life-threatening or chronically debilitating diseases with low prevalence (less than 5 per 10,000). The specificities of rare diseases - limited number of patients and scarcity of relevant knowledge and expertise - single them out as a unique domain of very high European added-value.The legal instruments at the disposal of the European Union, in terms of the Article 168 of the Treaties, are very limited. However a combination of instruments using the research and the pharmaceutical legal basis and an intensive and creative use of funding from the Health Programmes has permitted to create a solid basis that Member States have considered enough to put rare diseases in a privileged position in the health agenda.The adoption of the Commission Communication, in November 2008, and of the Council Recommendation, in June 2009, and in 2011 the adoption of the Directive on Cross-border healthcare., have created an operational framework to act in the field of rare disease with European coordination in several areas (classification and codification, European Reference Networks, orphan medicinal products, the Commission expert group on rare diseases, etc.).Rare diseases is an area with high and practical potential for the European cooperation.

Conceptualization and Implementation of the Central Information Portal on Rare Diseases: Protocol for a Qualitative Study

PubMed Central

Hartz, Tobias; Göbel, Jens; Storf, Holger; Pauer, Frédéric; Babac, Ana; Lührs, Verena; Bruckner-Tuderman, Leena; Schauer, Franziska; Schmidtke, Jörg; Biehl, Lisa; Wagner, TOF; Graf von der Schulenburg, J-Matthias; Frank, Martin

2018-01-01

Background Recently, public and political interest has focused on people living with rare diseases and their health concerns. Due to the large number of different types of rare diseases and the sizable number of patients, taking action to improve the life of those affected is gaining importance. In 2013, the federal government of Germany adopted a national action plan for rare diseases, including the call to establish a central information portal on rare diseases (Zentrales Informationsportal über seltene Erkrankungen, ZIPSE). Objective The objective of this study, therefore, was to conduct scientific research on how such a portal must be designed to meet the needs of patients, their families, and medical professionals, and to provide high-quality information for information seekers. Methods We chose a 3-step procedure to develop a needs-based prototype of a central information portal. In the first step, we determined the information needs of patients with rare diseases, their relatives, and health care professionals by means of qualitative interviews and their content-analytical evaluation. On the basis of this, we developed the basic structure of the portal. In the second step, we identified quality criteria for websites on rare diseases to ensure that the information linked with ZIPSE meets the quality demands. Therefore, we gathered existing criteria catalogs and discussed them in an expert workshop. In the third step, we implemented and tested the developed prototypical information portal. Results A portal page was configured and made accessible on the Web. The structure of ZIPSE was based on the findings from 108 qualitative interviews with patients, their relatives, and health care professionals, through which numerous information needs were identified. We placed particularly important areas of information, such as symptoms, therapy, research, and advisory services, on the start page. Moreover, we defined 13 quality criteria, referring to factors such as

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.

Rare essentials: drugs for rare diseases as essential medicines.

PubMed Central

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

2006-01-01

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

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

Leveraging terminological resources for mapping between rare disease information sources.

PubMed

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

2013-01-01

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. To develop an automatic mapping between two of the major rare diseases information sources, GARD and Orphanet, by leveraging terminological resources, especially the UMLS. 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. 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.

Evolutionary evidence of the effect of rare variants on disease etiology.

PubMed

Gorlov, I P; Gorlova, O Y; Frazier, M L; Spitz, M R; Amos, C I

2011-03-01

The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs. © 2010 John Wiley & Sons A/S.

[Introduction to Genetic/Rare Disease and the Application of Genetic Counseling].

PubMed

Chu, Shao-Yin; Weng, Chun-Ying

2017-10-01

Genetic disease or hereditary disease is a group of disorders that is caused by mutations in an individual's genome. The mutated genome or gene may be transmitted through the germ line during reproduction, causing certain recurrence risk in offspring and other family members. The heritability of these disorders is thus an important issue to deal with clinically. In Taiwan, a rare disease is defined as a disease that is prevalent in fewer than 1 in 10,000 individuals. As up to 80% of rare disease cases in Taiwan are genetic disease disorders, genetic disease may not rare. The pathophysiology of genetic/ rare disease is very complicated. Individual disorders may have their own unique mechanisms (such as Fragile X syndrome), with most of these mechanisms still unclear or unknown. The symptoms and signs of genetic/rare disease thus present the greatest variabilities and cause difficulties in making diagnoses. Most related patients may present multiple congenital anomalies, metabolic disorders, growth and developmental delays, defects in cognition, neuromuscular abnormalities, and defects in vision, hearing or other organ functions. Symptomatic and supportive treatment still comprise a major component of treatment of genetic/rare disease (with the exception of special formulae for several inborn errors of metabolic disease and enzyme replacement therapy in some lysosomal storage disease). Poor self-care ability is common and the burden on caregivers is huge. Most rare disease patients are treated using a comprehensive rehabilitation program that begins during very early childhood, receive individual educational programs, and are continuously monitored with regard to their growth, developmental, and nutritional status. Inter-professional patient care, genetic counseling, and the creation of family support networks play an important role in family management. Public awareness and the creation of appropriate social systems and resources allocation are mandatory for proper

[Healthcare services for people in Lower Saxony (Germany) suffering from a rare disease: Findings from a survey among medical professionals].

PubMed

Pauer, Frédéric; Pflaum, Uljana; Lührs, Verena; Frank, Martin; Graf von der Schulenburg, J-Matthias

2016-01-01

In the European Union, about 30 million people are affected by one of the 7,000 to 8,000 diseases being defined as rare. In Germany alone, an estimated 4 million people suffer from a rare disease. In many cases, therapeutic options and knowledge of specific rare diseases are strongly limited. The aim of this study was to identify the deficits and challenges confronting healthcare services for people suffering from a rare disease from the medical professional's perspective. As many as 530 medical professionals were invited to complete an online questionnaire, which was also available on the website of the General Medical Council of Lower Saxony. The questionnaire focused on questions in the following fields: structure of the medical care system; diagnosis and therapy; information sources and information exchange; and improvement of healthcare situation. Data were analyzed using IBM SPSS 22. We received 65 completed questionnaires. The evaluation indicates deficits in the medical services provided for people with a rare disease and shortcomings in the communication between clinical disciplines. In addition, diagnostic and therapeutic options are limited, and quality-tested information is rare. Many of the identified deficits have already been addressed in the German national plan of action for people affected by rare diseases. Furthermore, newly discovered deficits have been evaluated. The German government implemented healthcare structures to improve healthcare services for people with rare diseases. However, budget deficits for specialized structures have occurred inhibiting the expansion of healthcare services. Moreover, many patients need systemic treatment requiring the further development of interdisciplinary care. Copyright © 2016. Published by Elsevier GmbH.

Networking for rare diseases: a necessity for Europe.

PubMed

Aymé, S; Schmidtke, J

2007-12-01

Most rare diseases are life-threatening and chronically debilitating conditions, and the vast majority of them are genetically determined. Their individually low prevalence requires special combined efforts to address them so as to improve diagnosis, care and prevention. Though it is difficult to develop a public health policy specific to each rare disease, it is possible to have a global rather than a piecemeal approach in the areas of scientific and biomedical research, drug research and development, industry policy, information and training, social benefits, hospitalisation and outpatient care. In the recent past, several initiatives at EU and Member States levels have been taken and proved efficient in developing suitable solutions which are now having a positive impact on the quality of life of patients. These initiatives are presented here. They include the establishment of Orphanet, a database of rare diseases and orphan drugs providing an encyclopedia of rare diseases and a directory of associated expert services, the funding of research networks to boost the collaboration between research teams, as well as the funding of networks of clinical centres of reference to better serve the patients and contribute to developing clinical research.

Rare diseases in clinical endocrinology: a taxonomic classification system.

PubMed

Marcucci, G; Cianferotti, L; Beck-Peccoz, P; Capezzone, M; Cetani, F; Colao, A; Davì, M V; degli Uberti, E; Del Prato, S; Elisei, R; Faggiano, A; Ferone, D; Foresta, C; Fugazzola, L; Ghigo, E; Giacchetti, G; Giorgino, F; Lenzi, A; Malandrino, P; Mannelli, M; Marcocci, C; Masi, L; Pacini, F; Opocher, G; Radicioni, A; Tonacchera, M; Vigneri, R; Zatelli, M C; Brandi, M L

2015-02-01

Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.

Policy recommendations for rare disease centres of expertise.

PubMed

Syed, Ahmed M; Camp, Rob; Mischorr-Boch, Christina; Houÿez, Francois; Aro, Arja R

2015-10-01

Rare diseases are a serious public health concern and are a priority in the EU. This study aims to develop policy recommendations for rare disease centres of expertise (CoEs) in order to improve standards and quality of care. A modified 3-round Delphi technique was used. Participants included rare diseases patients, carers, patient representatives and healthcare professionals (HCPs) from CoEs in two countries-Denmark and the UK. The results suggest the need to make improvements within current CoE environments, access to CoEs and the need for coordination and cooperation of services within and outside CoEs. It is recommended that CoEs are not overly 'medicalised', while at the same time they should be established as research facilities. The importance of including patient representatives in CoE performance management was also highlighted. Raising awareness and provision of appropriate training amongst non-specialist HCPs is seen as a priority for early and correct diagnosis and ensuring high quality care. Similarly, provision of targeted information about patients' illness and care was considered essential along with access to social assistance within CoEs. Policy recommendations were developed in areas previously recognised as having gaps. Their implementation is expected to strengthen and improve current care provision for rare disease patients. In member states where national plans and strategies are being developed, it is recommended to replicate the methodological approach used in this study as it has proven to be a helpful tool in rare disease centres of expertise policy development. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

2016-09-02

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.

The importance of international collaboration for rare diseases research: a European perspective

PubMed Central

Julkowska, D; Austin, C P; Cutillo, C M; Gancberg, D; Hager, C; Halftermeyer, J; Jonker, A H; Lau, L P L; Norstedt, I; Rath, A; Schuster, R; Simelyte, E; van Weely, S

2017-01-01

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease. PMID:28440796

The importance of international collaboration for rare diseases research: a European perspective.

PubMed

Julkowska, D; Austin, C P; Cutillo, C M; Gancberg, D; Hager, C; Halftermeyer, J; Jonker, A H; Lau, L P L; Norstedt, I; Rath, A; Schuster, R; Simelyte, E; van Weely, S

2017-09-01

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

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…

Transposition and implementation of EU rare disease policy in Eastern Europe.

PubMed

Pejcic, Ana V; Iskrov, Georgi; Raycheva, Ralitsa; Stefanov, Rumen; Jakovljevic, Mihajlo Michael

2017-12-01

А series of European Union (EU) political decisions have made rare diseases one of the cornerstones of the common European health policy. Adopted in 2009, Council Recommendation on an action in the field of rare diseases aimed to serve as a policy-making guideline. However, the implementation report, which followed it, neither performed detailed cross-country comparison, nor assessed the impact of the policies. Areas covered: A 10-indicator set was elaborated to structure the review and to describe rare disease activities in 14 Eastern European countries. Expert commentary: Taking into account all indicators, EU member states outperform candidate and potential candidate countries in terms of rare disease policy planning and implementation. Hungary is the top performer, followed by Bulgaria and Czech Republic. Non-EU countries form the bottom tier, with Serbia being the best ranked among them. While EU adhesion is a major facilitator for planning and adopting rare disease policies, local stakeholders are the triggering factor for their successful implementation. European reference networks are likely to be the future of rare disease activities in the EU. They need to synchronize and closely collaborate with all important EU projects in the field of rare diseases if they are to achieve their objectives.

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.

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

Quantifying a rare disease in administrative data: the example of calciphylaxis.

PubMed

Nigwekar, Sagar U; Solid, Craig A; Ankers, Elizabeth; Malhotra, Rajeev; Eggert, William; Turchin, Alexander; Thadhani, Ravi I; Herzog, Charles A

2014-08-01

Calciphylaxis, a rare disease seen in chronic dialysis patients, is associated with significant morbidity and mortality. As is the case with other rare diseases, the precise epidemiology of calciphylaxis remains unknown. Absence of a unique International Classification of Diseases (ICD) code impedes its identification in large administrative databases such as the United States Renal Data System (USRDS) and hinders patient-oriented research. This study was designed to develop an algorithm to accurately identify cases of calciphylaxis and to examine its incidence and mortality. Along with many other diagnoses, calciphylaxis is included in ICD-9 code 275.49, Other Disorders of Calcium Metabolism. Since calciphylaxis is the only disorder listed under this code that requires a skin biopsy for diagnosis, we theorized that simultaneous application of code 275.49 and skin biopsy procedure codes would accurately identify calciphylaxis cases. This novel algorithm was developed using the Partners Research Patient Data Registry (RPDR) (n = 11,451 chronic hemodialysis patients over study period January 2002 to December 2011) using natural language processing and review of medical and pathology records (the gold-standard strategy). We then applied this algorithm to the USRDS to investigate calciphylaxis incidence and mortality. Comparison of our novel research strategy against the gold standard yielded: sensitivity 89.2%, specificity 99.9%, positive likelihood ratio 3,382.3, negative likelihood ratio 0.11, and area under the curve 0.96. Application of the algorithm to the USRDS identified 649 incident calciphylaxis cases over the study period. Although calciphylaxis is rare, its incidence has been increasing, with a major inflection point during 2006-2007, which corresponded with specific addition of calciphylaxis under code 275.49 in October 2006. Calciphylaxis incidence continued to rise even after limiting the study period to 2007 onwards (from 3.7 to 5.7 per 10

Common Elements in Rare Kidney Diseases: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

PubMed

Aymé, Ségolène; Bockenhauer, Detlef; Day, Simon; Devuyst, Olivier; Guay-Woodford, Lisa M; Ingelfinger, Julie R; Klein, Jon B; Knoers, Nine V A M; Perrone, Ronald D; Roberts, Julia; Schaefer, Franz; Torres, Vicente E; Cheung, Michael; Wheeler, David C; Winkelmayer, Wolfgang C

2017-10-01

Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare kidney diseases raise specific issues, as a group these rare diseases can have overlapping challenges in diagnosis and treatment. These challenges include small numbers of affected patients, unidentified causes of disease, lack of biomarkers for monitoring disease progression, and need for complex care. To address common clinical and patient issues among rare kidney diseases, the KDIGO Controversies Conference entitled, Common Elements in Rare Kidney Diseases, brought together a panel of multidisciplinary clinical providers and patient advocates to address five central issues for rare kidney diseases. These issues encompassed diagnostic challenges, management of kidney functional decline and progression of chronic kidney disease, challenges in clinical study design, translation of advances in research to clinical care, and provision of practical and integrated patient support. Thus, by a process of consensus, guidance for addressing these challenges was developed and is presented here. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Budgetary Impact of Medicinal Therapies for Rare Diseases in Bulgaria.

PubMed

Iskrov, Georgi G; Jakovljevic, Mihajlo Michael; Stefanov, Rumen S

2018-03-01

Rare diseases have been continually outlined as one of the causes for the National Health Insurance Fund's (NHIF) deficit spending in Bulgaria. To estimate the budgetary impact of rare disease medicinal therapies from NHIF perspective for 2014 and 2016. Budgetary impact of rare diseases is calculated as a percentage of NHIF total pharmaceutical spending. Total expenditure per ICD-10 code, mean annual number of patients reimbursed and mean annual cost per patient are analysed. Budgetary impact of rare diseases reached a plateau of about 9% of NHIF total pharmaceutical spending for 2014-2016. Mean number of patients reimbursed and mean annual cost per patient increased by median rates of 4.27% and 2.54%, respectively. Glycogen storage disease, neuropathic heredofamilial amyloidosis and C1 esterase inhibitor deficiency stood out, as they had the second, fourth and fifth most expensive medicinal treatment cost. While accounting for only 92 patients in 2016, these three conditions contributed for 22.89% of NHIF total expenditure on rare disease medicinal therapies. For comparison, coagulation defects, with the biggest total cost per indication, had a similar budgetary impact - 24.88%, but for 277 patients reimbursed. Our study does not support the concerns about uncontrolled growth of expenditures for rare disease medicinal therapies. Nevertheless, there is a need for enhanced post-marketing surveillance and performance-based payment of these treatments. Development, collection and analysis of local real-world data have been increasingly applied as a tool to advance these health policy goals.

An evaluation framework for funding drugs for rare diseases.

PubMed

Winquist, Eric; Bell, Chaim M; Clarke, Joe T R; Evans, Gerald; Martin, Janet; Sabharwal, Mona; Gadhok, Anita; Stevenson, Helen; Coyle, Doug

2012-01-01

For rare diseases it may be difficult to generate data from randomized trials to support funding of a drug. Enzyme replacement therapies for diseases of inherited metabolic enzyme deficiency provide an example of this dilemma. The Ontario Public Drug Programs convened the Drugs for Rare Diseases Working Group to develop a policy for assessing these drugs. The Drugs for Rare Diseases Working Group developed terms of reference expecting that the ideal policy product would be transparent and consistent and address unique aspects of the treatment of a specific rare condition while being adaptable to other dissimilar conditions. The perspective was that of a public payer addressing requests for funding generated for a specific drug, and included respect for the principles of "accountability for reasonableness" of Daniels and Sabin. A seven-step framework was developed and tested by using the case study of idursulfase for mucopolysaccharidosis II (Hunter disease). Estimation of clinical effectiveness was done by using decision modeling. The model developed informed funding recommendations and ultimately led to an agreement with the manufacturer allowing funding of idursulfase in Ontario. This policy framework attempts to address the policy challenges of funding drugs for rare diseases. The framework will be used to assess other drugs in future and will inevitably require modification with experience. It is hoped that it may be of value to other policymakers. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

A comprehensive global genotype-phenotype database for rare diseases.

PubMed

Trujillano, Daniel; Oprea, Gabriela-Elena; Schmitz, Yvonne; Bertoli-Avella, Aida M; Abou Jamra, Rami; Rolfs, Arndt

2017-01-01

The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. This database (CentoMD ® ) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool

Insights into rare diseases from social media surveys.

PubMed

Davies, William

2016-11-09

The internet, and social media platforms, are increasingly being used by substantial sectors of the worldwide population. By engaging effectively with online and social media, scientists and clinicians can obtain unprecedented access to relatively large cohorts of individuals with rare diseases, as well as their relatives, carers and professionals involved in their healthcare. Online surveys of these stakeholder groups may provide important new insights into rare conditions and their management relatively quickly and easily, with the possibility of rapid translation into healthcare interventions and policy. Here, I describe our recent positive experience with the online survey approach to a rare disease (X-linked ichthyosis), and review its advantages and limitations.

A rare disease in an atypical location-Kimura's Disease of the upper extremity.

PubMed

Lam, Alan Cheuk Si; Au Yeung, Rex Kwok Him; Lau, Vince Wing Hang

2015-12-01

Kimura's disease is a rare chronic inflammatory disorder predominantly affecting young Asian male patients, occurring mainly in the head and neck regions. Kimura's disease of the upper extremity is extremely rare, and previous case reports in the literature show similar imaging characteristics with consistent location at the medial epitrochlear region, predominantly with unilateral involvement. We present the first reported case of Kimura's disease affecting the anterolateral aspect of the upper arm, sparing the medial epitrochlear region, illustrating that with typical MR appearance and serology, the involvement of this rare disease in an atypical location still warrants consideration of this diagnosis. There was also bilateral asymmetrical involvement in our patient, suggesting the possibility of a propensity for Kimura's disease affecting the upper extremities to have bilateral involvement, which may necessitate imaging of the clinically asymptomatic contralateral limb in these patients for early lesion identification and treatment.

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

The supportive care needs of parents caring for a child with a rare disease: A scoping review.

PubMed

Pelentsov, Lemuel J; Laws, Thomas A; Esterman, Adrian J

2015-10-01

Parents caring for a child with a rare disease report unmet needs, the origins of which are varied and complex. Few studies have systematically attempted to identify the supportive care needs of parents with a child with a rare disease comprehensively. We have used the widely accepted Supportive Care Needs Framework (SCNF) as the structure for this review. The purpose of the current review was to identify the supportive care needs of parents with a child with a rare disease, irrespective of condition. We conducted a scoping study review comprising 29 studies (1990-2014) to identify and examine the research literature related to the supportive care needs of parents, and to compare these needs with the seven domains outlined in the SCNF. Most common needs cited were social needs (72% of papers), followed by informational needs (65% of papers) and emotional needs (62% of papers), with the most common parental needs overall being information about their child's disease, emotional stress, guilt and uncertainty about their child's future health care needs, parents own caring responsibilities and the need for more general support. A paucity of studies exists that explore the supportive care needs of parents of a child with a rare disease. The SCNF only partially reflects the breadth and type of needs of these parents, and a preliminary revised framework has been suggested. Further research is required in this area, particularly empirical research to amend or confirm the suggested new framework. Copyright © 2015 Elsevier Inc. All rights reserved.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Kyasanur Forest Disease (KFD): Rare Disease of Zoonotic Origin.

PubMed

Muraleedharan, M

2016-09-01

Kyasanur forest disease (KFD) is a rare tick borne zoonotic disease that causes acute febrile hemorrhagic illness in humans and monkeys especially in southern part of India. The disease is caused by highly pathogenic KFD virus (KFDV) which belongs to member of the genus Flavivirus and family Flaviviridae. The disease is transmitted to monkeys and humans by infective tick Haemaphysalisspinigera. Seasonal outbreaks are expected to occur during the months of January to June. The aim of this paper is to briefly summarize the epidemiology, mode of transmission of KFD virus, clinical findings, diagnosis, treatment, control and prevention of the disease..

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.

Incentives for Starting Small Companies Focused on Rare and Neglected Diseases

PubMed Central

Ekins, Sean; Wood, Jill

2015-01-01

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

Fungi associated with drug recalls and rare disease outbreaks.

PubMed

Ahearn, Donald G; Doyle Stulting, R

2014-11-01

Fungi rarely cause disease outbreaks associated with use of microbe-contaminated drugs. These rare episodes typically involve a restricted spectrum of common environmental species with relatively low virulence, rather than classical pathogens. Review of data involving over-the-counter contact lens solutions and prescription drug-related recalls revealed six episodes during the past decade with significant adverse health and financial impact (including loss of vision and death). Contaminations involved fungi mostly identified with the genera Aspergillus, Exserohilum, Fusarium, Paecilomyces, and Rhizopus. These organisms are noted for their capacity to produce resistant morphotypes (chlamydoconidia, ascospores) under various adverse conditions, generally with temperature survival/tolerances markedly in excess of maximal growth temperatures. High constituent levels of melanin, trehalose and heat-shock proteins facilitate differential survival of morphotypes following exposures to toxic chemicals and temperatures above 80 °C. Adverse environmental factors that induce resistant morphotypes are suggested to occur more readily in situ than during in vitro testing. Rare unexplained, sporadic drug contamination episodes with select thermotolerant fungi may relate, in part, to resistant dormant stages.

Alkaptonuria: An example of a "fundamental disease"--A rare disease with important lessons for more common disorders.

PubMed

Gallagher, James A; Dillon, Jane P; Sireau, Nicolas; Timmis, Oliver; Ranganath, Lakshminarayan R

2016-04-01

"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fostering collaborative research for rare genetic disease: the example of niemann-pick type C disease.

PubMed

Walkley, Steven U; Davidson, Cristin D; Jacoby, Jonathan; Marella, Philip D; Ottinger, Elizabeth A; Austin, Christopher P; Porter, Forbes D; Vite, Charles H; Ory, Daniel S

2016-12-01

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the "SOAR" mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders.

Perceived Benefits and Factors that Influence the Ability to Establish and Maintain Patient Support Groups in Rare Diseases: A Scoping Review.

PubMed

Delisle, Vanessa C; Gumuchian, Stephanie T; Rice, Danielle B; Levis, Alexander W; Kloda, Lorie A; Körner, Annett; Thombs, Brett D

2017-06-01

Support groups are an important resource for many people living with rare diseases. The perceived benefits of participating in support groups for people with rare diseases and factors that may influence the ability to successfully establish and maintain these groups are not well understood. Thus, the objective of this scoping review was to provide a mapping of the available evidence on the (1) benefits or perceived benefits of participating in rare disease support groups and (2) barriers and facilitators of establishing and maintaining these groups. CINAHL and PubMed were searched from January 2000 to August 2015, with no language restrictions. Publications that described the benefits or perceived benefits of participating in rare disease support groups or the barriers and facilitators of establishing and maintaining them were eligible for inclusion. Two investigators independently evaluated titles/abstracts and full-text publications for eligibility, and extracted data from each included publication. Ten publications were included in the scoping review. There was no trial evidence on support group benefits. All ten publications reported on the perceived benefits of participating in rare disease support groups. Three reported on barriers and facilitators of establishing and maintaining them. Overall, seven different perceived benefits of participating in rare disease support groups were identified: (1) meeting and befriending other people with the same rare disease and similar experiences; (2) learning about the disease and related treatments; (3) giving and receiving emotional support; (4) having a place to speak openly about the disease and one's feelings; (5) learning coping skills; (6) feeling empowered and hopeful; and (7) advocating to improve healthcare for other rare disease patients. Several facilitators (e.g., meeting via teleconference) and barriers (e.g., getting patients and/or family members to lead the group) of establishing and maintaining these

Study and analysis of the state of rare disease research in Shandong Province, China.

PubMed

Zhao, Heng; Cui, Yazhou; Zhou, Xiaoyan; Pang, Jingxiang; Zhang, Xiumei; Xu, Shuangqing; Han, Jinxiang

2012-11-01

As the world's most populous country, China has the world's largest number of rare disease groups in terms of prevalence. However, the country has no system of registering cases of most rare diseases, so there is very little documented information on the epidemiology of those diseases. The purpose of this study was to study the state of rare disease research and survey doctors in Shandong Province regarding their level of awareness of rare diseases. Types of rare diseases and numbers of cases were tallied and their geographical distribution over the decades was analyzed. Eight hundred and twenty-four doctors in tertiary hospitals and maternity and child care hospitals were surveyed by questionnaire. Data were descriptively analyzed and a map of disease distribution was created. Articles about rare diseases were retrieved from the Chinese Biomedical Literature Database to provide pertinent data. This study yielded 5,749 cases of 323 different types of rare diseases. The survey found that doctors lack awareness of research on rare diseases. An authoritative and information-rich platform for rare disease research is urgently needed. Key steps are to study epidemiological and statistical techniques and then obtain available data to provide a basis for the definition and regulation of rare diseases in China.

Study and analysis of the state of rare disease research in Shandong Province, China

PubMed Central

Zhao, Heng; Cui, Yazhou; Zhou, Xiaoyan; Pang, Jingxiang; Zhang, Xiumei; Xu, Shuangqing; Han, Jinxiang

2012-01-01

Summary As the world's most populous country, China has the world's largest number of rare disease groups in terms of prevalence. However, the country has no system of registering cases of most rare diseases, so there is very little documented information on the epidemiology of those diseases. The purpose of this study was to study the state of rare disease research and survey doctors in Shandong Province regarding their level of awareness of rare diseases. Types of rare diseases and numbers of cases were tallied and their geographical distribution over the decades was analyzed. Eight hundred and twenty-four doctors in tertiary hospitals and maternity and child care hospitals were surveyed by questionnaire. Data were descriptively analyzed and a map of disease distribution was created. Articles about rare diseases were retrieved from the Chinese Biomedical Literature Database to provide pertinent data. This study yielded 5,749 cases of 323 different types of rare diseases. The survey found that doctors lack awareness of research on rare diseases. An authoritative and information-rich platform for rare disease research is urgently needed. Key steps are to study epidemiological and statistical techniques and then obtain available data to provide a basis for the definition and regulation of rare diseases in China. PMID:25343091

A Rare Disease in Adult: Langerhans Cell Histiocytosis

PubMed Central

Berber, Ilhami; Erkurt, Mehmet Ali; Kuku, Irfan; Koroglu, Mustafa; Kaya, Emin; Unlu, Serkan

2013-01-01

Langerhans cell histiocytosis is a rare histiocytic disorder and has been diagnosed in all age groups, but is most common in children. This disease is very rare in adults. We presented a patient who was 62 years old man diagnosed langerhans cell histiocytosis. PMID:29147350

De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease.

PubMed

Takahashi, Shinichi; Andreoletti, Gaia; Chen, Rui; Munehira, Yoichi; Batra, Akshay; Afzal, Nadeem A; Beattie, R Mark; Bernstein, Jonathan A; Ennis, Sarah; Snyder, Michael

2017-01-26

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood. We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles. In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Biochemical assays revealed that all six rare HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity. Our results indicate that de novo and rare mutations in HSPA1L are associated with IBD and provide insights into the pathogenesis of IBD, and also expand our understanding of the roles of HSP70s in human disease.

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

PubMed

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.

Data Quality in Rare Diseases Registries.

PubMed

Kodra, Yllka; Posada de la Paz, Manuel; Coi, Alessio; Santoro, Michele; Bianchi, Fabrizio; Ahmed, Faisal; Rubinstein, Yaffa R; Weinbach, Jérôme; Taruscio, Domenica

2017-01-01

In the field of rare diseases, registries are considered power tool to develop clinical research, to facilitate the planning of appropriate clinical trials, to improve patient care and healthcare planning. Therefore high quality data of rare diseases registries is considered to be one of the most important element in the establishment and maintenance of a registry. Data quality can be defined as the totality of features and characteristics of data set that bear on its ability to satisfy the needs that result from the intended use of the data. In the context of registries, the 'product' is data, and quality refers to data quality, meaning that the data coming into the registry have been validated, and ready for use for analysis and research. Determining the quality of data is possible through data assessment against a number of dimensions: completeness, validity; coherence and comparability; accessibility; usefulness; timeliness; prevention of duplicate records. Many others factors may influence the quality of a registry: development of standardized Case Report Form and security/safety controls of informatics infrastructure. With the growing number of rare diseases registries being established, there is a need to develop a quality validation process to evaluate the quality of each registry. A clear description of the registry is the first step when assessing data quality or the registry evaluation system. Here we report a template as a guide for helping registry owners to describe their registry.

A framework to evaluate the effects of small area variations in healthcare infrastructure on diagnostics and patient outcomes of rare diseases based on administrative data.

PubMed

Stargardt, Tom; Schreyögg, Jonas

2012-05-01

Small area variations in healthcare infrastructure may result in differences in early detection and outcomes for patients with rare diseases. It is our aim to provide a framework for evaluating small area variations in healthcare infrastructure on the diagnostics and health outcomes of rare diseases. We focus on administrative data as it allows (a) for relatively large sample sizes even though the prevalence of rare diseases is very low, and (b) makes it possible to link information on healthcare infrastructure to morbidity, mortality, and utilization. For identifying patients with a rare disease in a database, a combination of different classification systems has to be used due to usually multiple diseases sharing one ICD code. Outcomes should be chosen that are (a) appropriate for the disease, (b) identifiable and reliably coded in the administrative database, and (c) observable during the limited time period of the follow-up. Risk adjustment using summary scores of disease-specific or comprehensive risk adjustment instruments might be preferable over empirical weights because of the lower number of variables needed. The proposed framework will help to identify differences in time to diagnosis and treatment outcomes across areas in the context of rare diseases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

From Common to Rare Variants: The Genetic Component of Alzheimer Disease.

PubMed

Nicolas, Gaël; Charbonnier, Camille; Campion, Dominique

2016-01-01

Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is

The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

PubMed Central

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.

2015-01-01

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

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

PubMed

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

2014-05-01

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.

The Rare Disease Bank of Japan: establishment, current status and future challenges.

PubMed

Tada, Mayako; Hirata, Makoto; Sasaki, Mitsuho; Sakate, Ryuichi; Kohara, Arihiro; Takahashi, Ichiro; Kameoka, Yosuke; Masui, Toru; Matsuyama, Akifumi

2018-04-02

Research on rare diseases cannot be performed without appropriate samples from patients with such diseases. Due to the limited number of such patients, securing biosamples of sufficient quality for extensive research is a challenge and represents an important barrier to the advancement of research on rare diseases. To tackle this problem, the Rare Disease Bank (RDB) was established in 2009 at the National Institute of Biomedical Innovation (NIBIO; currently, the National Institutes of Biomedical Innovation, Health and Nutrition in Japan). Since then, the RDB has focused on three objectives: (1) emphasizing the importance of collecting biosamples from patients with rare diseases, together with appropriate clinical information, from various medical facilities nationwide; (2) maintaining strict high-quality sample management standards; and (3) sharing biosamples with research scientists across Japan for the advancement of research on rare diseases. As of August 2017, the bank has collected 4147 biosamples from patients with rare diseases, including DNA, serum, plasma, and cell samples from various university hospitals and other medical institutions across the country, and provided various research institutions with 13,686 biosample aliquots from 2850 cases. In addition, the management committee has successfully established a bank system that provides high-quality biosamples together with the results of human leukocyte antigen analysis. It is anticipated that the RDB, through the collection and sharing of biosamples with the medical research community, will enhance the understanding, prevention, and treatment of rare diseases in Japan and the world at large.

Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies

PubMed Central

Ayoglu, Burcu; Chaouch, Amina; Lochmüller, Hanns; Politano, Luisa; Bertini, Enrico; Spitali, Pietro; Hiller, Monika; Niks, Eric H; Gualandi, Francesca; Pontén, Fredrik; Bushby, Kate; Aartsma-Rus, Annemieke; Schwartz, Elena; Le Priol, Yannick; Straub, Volker; Uhlén, Mathias; Cirak, Sebahattin; ‘t Hoen, Peter A C; Muntoni, Francesco; Ferlini, Alessandra; Schwenk, Jochen M; Nilsson, Peter; Al-Khalili Szigyarto, Cristina

2014-01-01

Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies. PMID:24920607

Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

PubMed Central

Prescott, Natalie J.; Lehne, Benjamin; Stone, Kristina; Lee, James C.; Taylor, Kirstin; Knight, Jo; Papouli, Efterpi; Mirza, Muddassar M.; Simpson, Michael A.; Spain, Sarah L.; Lu, Grace; Fraternali, Franca; Bumpstead, Suzannah J.; Gray, Emma; Amar, Ariella; Bye, Hannah; Green, Peter; Chung-Faye, Guy; Hayee, Bu’Hussain; Pollok, Richard; Satsangi, Jack; Parkes, Miles; Barrett, Jeffrey C.; Mansfield, John C.; Sanderson, Jeremy; Lewis, Cathryn M.; Weale, Michael E.; Schlitt, Thomas; Mathew, Christopher G.

2015-01-01

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis. PMID:25671699

Conceptualization and Implementation of the Central Information Portal on Rare Diseases: Protocol for a Qualitative Study.

PubMed

Litzkendorf, Svenja; Hartz, Tobias; Göbel, Jens; Storf, Holger; Pauer, Frédéric; Babac, Ana; Lührs, Verena; Bruckner-Tuderman, Leena; Schauer, Franziska; Schmidtke, Jörg; Biehl, Lisa; Wagner, Tof; Graf von der Schulenburg, J-Matthias; Frank, Martin

2018-05-11

Recently, public and political interest has focused on people living with rare diseases and their health concerns. Due to the large number of different types of rare diseases and the sizable number of patients, taking action to improve the life of those affected is gaining importance. In 2013, the federal government of Germany adopted a national action plan for rare diseases, including the call to establish a central information portal on rare diseases (Zentrales Informationsportal über seltene Erkrankungen, ZIPSE). The objective of this study, therefore, was to conduct scientific research on how such a portal must be designed to meet the needs of patients, their families, and medical professionals, and to provide high-quality information for information seekers. We chose a 3-step procedure to develop a needs-based prototype of a central information portal. In the first step, we determined the information needs of patients with rare diseases, their relatives, and health care professionals by means of qualitative interviews and their content-analytical evaluation. On the basis of this, we developed the basic structure of the portal. In the second step, we identified quality criteria for websites on rare diseases to ensure that the information linked with ZIPSE meets the quality demands. Therefore, we gathered existing criteria catalogs and discussed them in an expert workshop. In the third step, we implemented and tested the developed prototypical information portal. A portal page was configured and made accessible on the Web. The structure of ZIPSE was based on the findings from 108 qualitative interviews with patients, their relatives, and health care professionals, through which numerous information needs were identified. We placed particularly important areas of information, such as symptoms, therapy, research, and advisory services, on the start page. Moreover, we defined 13 quality criteria, referring to factors such as author information, creation date, and

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. © 2015 WILEY PERIODICALS, INC.

The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

DOE PAGES

Philippakis, Anthony A.; Azzariti, Danielle R.; Beltran, Sergi; ...

2015-09-17

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 amore » 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. In conclusion, 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.« less

The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Philippakis, Anthony A.; Azzariti, Danielle R.; Beltran, Sergi

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 amore » 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. In conclusion, 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.« less

FindZebra: a search engine for rare diseases.

PubMed

Dragusin, Radu; Petcu, Paula; Lioma, Christina; Larsen, Birger; Jørgensen, Henrik L; Cox, Ingemar J; Hansen, Lars Kai; Ingwersen, Peter; Winther, Ole

2013-06-01

The web has become a primary information resource about illnesses and treatments for both medical and non-medical users. Standard web search is by far the most common interface to this information. It is therefore of interest to find out how well web search engines work for diagnostic queries and what factors contribute to successes and failures. Among diseases, rare (or orphan) diseases represent an especially challenging and thus interesting class to diagnose as each is rare, diverse in symptoms and usually has scattered resources associated with it. We design an evaluation approach for web search engines for rare disease diagnosis which includes 56 real life diagnostic cases, performance measures, information resources and guidelines for customising Google Search to this task. In addition, we introduce FindZebra, a specialized (vertical) rare disease search engine. FindZebra is powered by open source search technology and uses curated freely available online medical information. FindZebra outperforms Google Search in both default set-up and customised to the resources used by FindZebra. We extend FindZebra with specialized functionalities exploiting medical ontological information and UMLS medical concepts to demonstrate different ways of displaying the retrieved results to medical experts. Our results indicate that a specialized search engine can improve the diagnostic quality without compromising the ease of use of the currently widely popular standard web search. The proposed evaluation approach can be valuable for future development and benchmarking. The FindZebra search engine is available at http://www.findzebra.com/. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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. Copyright © 2014 by the American Academy of Pediatrics.

Promoting innovation in small markets: Evidence from the market for rare and intractable diseases.

PubMed

Iizuka, Toshiaki; Uchida, Gyo

2017-07-01

In many medical care markets with limited profit potential, firms often have little incentive to innovate. These include the market for rare diseases, "neglected" tropical diseases, and personalized medicine. Governments and not-for-profit organizations promote innovation in such markets but empirical evidence on the policy effect is limited. We study this issue by analyzing the impact of a demand-side policy in Japan, which reduces the cost sharing of patients with some rare and intractable diseases and attempts to establish and promote the treatment of those diseases. Using clinical trials data taken from public registries, we identify the effect of the policy using a difference-in-difference approach. We find that the demand-side policy increased firms' incentive to innovate: firm-sponsored clinical trials increased 181% (0.16 per disease per year) when covered by the policy. This result indicates that the demand-side policy can be an important part of innovation policies in markets with limited profit potential. Copyright © 2017 Elsevier B.V. All rights reserved.

Mining with Rare Cases

NASA Astrophysics Data System (ADS)

Weiss, Gary M.

Rare cases are often the most interesting cases. For example, in medical diagnosis one is typically interested in identifying relatively rare diseases, such as cancer, rather than more frequently occurring ones, such as the common cold. In this chapter we discuss the role of rare cases in Data Mining. Specific problems associated with mining rare cases are discussed, followed by a description of methods for addressing these problems.

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.

Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease.

PubMed

Nho, Kwangsik; Kim, Sungeun; Horgusluoglu, Emrin; Risacher, Shannon L; Shen, Li; Kim, Dokyoon; Lee, Seunggeun; Foroud, Tatiana; Shaw, Leslie M; Trojanowski, John Q; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Weiner, Michael W; Green, Robert C; Toga, Arthur W; Saykin, Andrew J

2017-05-24

The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE's vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ 1-42 (p < 1.0 × 10 -3 ). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ 1-42 and neuroimaging biomarkers after adjusting for APOE genotype

Towards a framework for personalized healthcare: lessons learned from the field of rare diseases.

PubMed

Tambuyzer, Erik

2010-09-01

A large percentage of medicines do not work for the patient populations they are intended to treat. Increased knowledge regarding genomics and the underlying biological mechanism of diseases should help us be able to stratify patients into groups of likely responders and nonresponders, and to identify those patients for whom a treatment might do more harm than good. This article sets out different policy perspectives for the healthcare systems, and draws in on 25 years of particular experience from the rare disease and orphan drug field, to illuminate the pathway forward in relation to key implementation aspects of personalized healthcare. In principle, we submit that targeting medicines to preidentified groups for whom we can predict a beneficial outcome is a good thing for everyone - first of all for the patients, but also for all the other stakeholders, including payers, treating physicians and industry - because it has the potential to create sustainable and functioning healthcare systems directed to better health and prevention of disease. Personalized healthcare over time could also lead to shorter drug-development times because of lower rates of failure in late-stage drug development. Using orphan medicines to treat well-diagnosed patients suffering from a life-threatening or seriously debilitating rare disease, is an attempt to work according to these principles. As there is much that needs to be done to turn the promise into reality, we need to identify the barriers and challenges to transform the potential opportunities into real-life benefits, and what needs to be done in order to overcome them. Learning from the field of rare diseases and orphan drugs may provide, perhaps unexpectedly, some of the answers to public policy questions related to future (personalized) healthcare, but of course not all aspects, are common between the two fields.

Mapping rare and common causal alleles for complex human diseases

PubMed Central

Raychaudhuri, Soumya

2011-01-01

Advances in genotyping and sequencing technologies have revolutionized the genetics of complex disease by locating rare and common variants that influence an individual’s risk for diseases, such as diabetes, cancers, and psychiatric disorders. However, to capitalize on this data for prevention and therapies requires the identification of causal alleles and a mechanistic understanding for how these variants contribute to the disease. After discussing the strategies currently used to map variants for complex diseases, this Primer explores how variants may be prioritized for follow-up functional studies and the challenges and approaches for assessing the contributions of rare and common variants to disease phenotypes. PMID:21962507

An early examination of access to select orphan drugs treating rare diseases in health insurance exchange plans.

PubMed

Robinson, Sandy W; Brantley, Kelly; Liow, Christine; Teagarden, J Russell

2014-10-01

Patients with rare diseases often face significant health care access challenges, particularly since the number of available treatment options for rare diseases is limited. The implementation of health insurance exchanges promises improved access to health care. However, when purchasing a plan, patients with rare diseases need to consider multiple factors, such as insurance premium, access to providers, coverage of a specific medication or treatment, tier placement of drug, and out-of-pocket costs.  To provide an early snapshot of the exchange plan landscape from the perspective of patients with select rare diseases by evaluating the degree of access to medications in a subset of exchange plans based on coverage, tier placement, associated cost sharing, and utilization management (UM) applied.  The selection of drugs for this analysis began by identifying rare diseases with FDA-approved treatment options using the National Institutes of Health Office of Rare Diseases' webpage and further identification of a subset of drugs based on select criteria to ensure a varied sample, including the characteristics and prevalence of the condition. The medications were categorized based on whether alternative therapies have FDA approval for the same indication and whether there are comparators based on class or therapeutic area. The list was narrowed to 11 medications across 7 diseases, and the analysis was based on how these drugs are listed in exchange plan outpatient pharmacy benefit formularies. This analysis focused on 84 plans in 15 states with the highest expected exchange enrollment and included a variety of plan types to ensure that variability in the marketplace was represented. To best approximate plans that will have the greatest enrollment, the analysis focused on silver and bronze plan formularies because consumers in this market are expected to be sensitive to premiums. Data on drug coverage, tier placement, cost, and UM were collected from these plans

New insights into old methods for identifying causal rare variants.

PubMed

Wang, Haitian; Huang, Chien-Hsun; Lo, Shaw-Hwa; Zheng, Tian; Hu, Inchi

2011-11-29

The advance of high-throughput next-generation sequencing technology makes possible the analysis of rare variants. However, the investigation of rare variants in unrelated-individuals data sets faces the challenge of low power, and most methods circumvent the difficulty by using various collapsing procedures based on genes, pathways, or gene clusters. We suggest a new way to identify causal rare variants using the F-statistic and sliced inverse regression. The procedure is tested on the data set provided by the Genetic Analysis Workshop 17 (GAW17). After preliminary data reduction, we ranked markers according to their F-statistic values. Top-ranked markers were then subjected to sliced inverse regression, and those with higher absolute coefficients in the most significant sliced inverse regression direction were selected. The procedure yields good false discovery rates for the GAW17 data and thus is a promising method for future study on rare variants.

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

[Epidemiology of Imperfect Osteogenesis: a Rare Disease in the Valencia Region.

PubMed

Gimeno-Martos, Silvia; Pérez-Riera, Carlos; Guardiola-Vilarroig, Sandra; Cavero-Carbonell, Clara

2017-11-28

Osteogenesis imperfecta (OI) is a rare connective tissue and bone disease that results in a bone fragility of varying severity. The objective was to determine and describe the OI in the Valencia Region (VR) during the period 2004 to 2014. From the Rare Diseases Information System of the VR (SIER-CV) patients from 2004 to 2014 with the codes of the International Classification of Diseases for the OI were identified: 756.51 from the 9th Revision-Clinical Modification and Q78.0 from the 10th Revision. The information was validated by reviewing clinical documentation (mainly electronic health records) and a descriptive analysis of the confirmed cases (diagnosis of OI in the clinical documentation) was performed. 162 patients were identified with a code for OI. 145 of the 161 patients with available clinical documentation were confirmed as cases. The prevalence was 0.29 per 10.000 inhabitants. 93.1% were Spanish, 54.5% were women and they were treated in 25 different hospitals in the VR. The type of OI was known in the 26.4% of the cases and type I was the most common (9.7%). 6.2% of the patients died with an average death age of 60.8 years. 44.8% of patients received treatment with bisphosphonates and 10.4% had affected relatives. The real situation of the OI in the VR has been established, which will allow a better planning in the health actions to improve the quality of life of the affected ones and their families.

Unintended Effects of Orphan Product Designation for Rare Neurological Diseases

PubMed Central

Murphy, Sinéad M; Puwanant, Araya; Griggs, Robert C.

2012-01-01

Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits and, perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs; both for newly developed drugs and even for drugs which were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington’s disease, adrenocorticotropic hormone for infantile spasms and enzyme replacement therapy with alglucosidase alpha for Pompe’s disease we highlight these paradoxical effects. PMID:23109143

Delayed access to treatments for rare diseases: who's to blame?

PubMed

Feltmate, Karen; Janiszewski, Peter M; Gingerich, Sheena; Cloutier, Michael

2015-04-01

The development and commercialization of drugs for rare diseases, termed 'orphan drugs', has historically been economically unattractive. However, because of the introduction of legislation that provides financial and regulatory incentives for the development of orphan drugs, new developments are making their way through the regulatory approval processes. Unfortunately, delays in availability of new drugs for treating rare disease continue to persist. This paper reviews the approach of several regulatory jurisdictions to orphan drugs in an effort to determine their relative effectiveness in providing patient access. Generally speaking, regulatory authorities across jurisdictions have recognized the need to enhance timely access to safe, effective treatment for patients with rare diseases and have been able to shift the approval timelines for access to new care. The greater impediment to orphan drug access appears to be funding, particularly in publicly sponsored health-care systems. Redundancies in federal and provincial reviews of orphan drugs can result in significant delays in access to new drugs. Clearly, more must be done to accelerate access to the treatments so desperately needed by patients. Public payers must be held accountable for their process and decisions--especially for rare disease therapies. © 2015 Asian Pacific Society of Respirology.

Reconstructing normality following the diagnosis of a childhood chronic disease: does "rare" make a difference?

PubMed

Germeni, Evi; Vallini, Isabella; Bianchetti, Mario G; Schulz, Peter J

2018-04-01

Living with a childhood chronic disease can be challenging, especially if the diagnosis involves a rare condition. This study sought to elucidate how the diagnosis of a rare disease, as compared to a common, chronic condition, may influence maternal experiences of childhood illness. We conducted face-to-face, semi-structured interviews with 26 mothers of children treated in a pediatric hospital in the province of Lecco, Italy. Half of the participants had a child diagnosed with Bartter syndrome (BS), and the rest had a child suffering from celiac disease (CD). Interviews were recorded, transcribed, and analyzed using an inductive thematic approach. We identified three main themes from the analysis of our data: (1) disrupted normality and the need to know, (2) reconstructing normality, and (3) acting "normal." Although most participants experienced the disclosure of diagnosis as a relief, processes that facilitated normality reconstruction in celiac families, notably access to appropriate information, social support, and personal contact with comparison others, were found to be important stressors for mothers living with BS. This comparative qualitative study provides evidence on how well-known problems associated with the rarity of childhood diseases impact on families' efforts to cope with the illness and regain a sense of normality. What is Known: • Families living with a rare disease have been found to experience a range of common problems, directly linked to the rarity of these pathologies. What is New: • Maximization of both emotional and instrumental social support, through provision of appropriate information or establishment of disease-specific support groups, could greatly contribute to rare disease families' efforts to cope with childhood illness and regain a sense of normality.

Important role of translational science in rare disease innovation, discovery, and drug development.

PubMed

Pariser, Anne R; Gahl, William A

2014-08-01

Rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science. Most rare diseases are genetic disorders or atypical manifestations of infectious, immunologic, or oncologic diseases; they all provide opportunities to study extremes of human pathology and provide insight into both normal and aberrant physiology. Recently, drug development has become increasingly focused on classifying diseases largely on genetic grounds; this has allowed the identification of molecularly defined targets and the development of targeted therapies. Clinical trials are now focusing on progressively smaller subgroups within both common and rare disease populations, often based on genetic tests or biomarkers. Drug developers, researchers, and regulatory agencies face a variety of challenges throughout the life cycle of drug research and development for rare diseases. These include the small numbers of patients available for study, lack of knowledge of the disease's natural history, incomplete understanding of the basic mechanisms causing the disorder, and variability in disease severity, expression, and course. Traditional approaches to rare disease clinical research have not kept pace with advances in basic science, and increased attention to translational science is needed to address these challenges, especially diagnostic testing, registries, and novel trial designs.

A powerful team: the family physician advocating for patients with a rare disease.

PubMed

Dudding-Byth, Tracy

2015-09-01

Rare diseases are characteristically difficult to diagnose and for the majority, there are no effective treatments or evidence-based management guidelines. Although it is unrealistic to expect family physicians to recognise the wide clinical spectrum of rare diseases, their longitudinal and holistic approach to medicine place them in a unique position to consider the possibility of a rare disease. This article outlines the challenges faced by the rare disease community, and the role of the primary care physician to advocate for answers as their patients transition through the healthcare system. The road to the diagnosis of a rare disease can test the doctor-patient relationship. Patients often struggle for answers and family physicians are stymied by a lack of information. At the same time, the availability of cyber-based health information and online rare-disease patient groups has led to the emergence of the 'expert' patient, who seeks a collaborative and empowering relationship with their physician. Following diagnosis, the family physician plays a crucial part in providing continuity of care, advocating access to expert healthcare, coordinating complex management and becoming a source of psychological support.

The Quality of Rare Disease Registries: Evaluation and Characterization.

PubMed

Coi, Alessio; Santoro, Michele; Villaverde-Hueso, Ana; Lipucci Di Paola, Michele; Gainotti, Sabina; Taruscio, Domenica; Posada de la Paz, Manuel; Bianchi, Fabrizio

2016-01-01

The focus on the quality of the procedures for data collection, storing, and analysis in the definition and implementation of a rare disease registry (RDR) is the basis for developing a valid and long-term sustainable tool. The aim of this study was to provide useful information for characterizing a quality profile for RDRs using an analytical approach applied to RDRs participating in the European Platform for Rare Disease Registries 2011-2014 (EPIRARE) survey. An indicator of quality was defined by choosing a small set of quality-related variables derived from the survey. The random forest method was used to identify the variables best defining a quality profile for RDRs. Fisher's exact test was employed to assess the association with the indicator of quality, and the Cochran-Armitage test was used to check the presence of a linear trend along different levels of quality. The set of variables found to characterize high-quality RDRs focused on ethical and legal issues, governance, communication of activities and results, established procedures to regulate access to data and security, and established plans to ensure long-term sustainability. The quality of RDRs is usually associated with a good oversight and governance mechanism and with durable funding. The results suggest that RDRs would benefit from support in management, information technology, epidemiology, and statistics. © 2016 S. Karger AG, Basel.

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

Prospects of Pluripotent and Adult Stem Cells for Rare Diseases.

PubMed

García-Castro, Javier; Singeç, Ilyas

2017-01-01

Rare diseases are highly diverse and complex regarding molecular underpinning and clinical manifestation and afflict millions of patients worldwide. The lack of appropriate model systems with face and construct validity and the limited availability of live tissues and cells from patients has largely hampered the understanding of underlying disease mechanisms. As a consequence, there are no adequate treatment options available for the vast majority of rare diseases. Over the last decade, remarkable progress in pluripotent and adult stem cell biology and the advent of powerful genomic technologies opened up exciting new avenues for the investigation, diagnosis, and personalized therapy of intractable human diseases. Utilizing the entire range of available stem cell types will continue to cross-fertilize different research areas and leverage the investigation of rare diseases based on evidence-based medicine. Standardized cell engineering and manufacturing from inexhaustible stem cell sources should lay the foundation for next-generation drug discovery and cell therapies that are broadly applicable in regenerative medicine. In this chapter we discuss how patient- and disease-specific iPS cells as well as adult stem cells are changing the pace of biomedical research and the translational landscape.

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. © International & American Associations for Dental Research.

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

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways.

PubMed

Giacopuzzi, Edoardo; Gennarelli, Massimo; Minelli, Alessandra; Gardella, Rita; Valsecchi, Paolo; Traversa, Michele; Bonvicini, Cristian; Vita, Antonio; Sacchetti, Emilio; Magri, Chiara

2017-01-01

Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically

[Court-ordered access to treatment of rare genetic diseases: Fabry Disease in the state of Rio Grande do Sul, Brazil].

PubMed

Sartori Junior, Dailor; Leivas, Paulo Gilberto Cogo; Souza, Mônica Vinhas de; Krug, Bárbara Corrêa; Balbinotto, Giacomo; Schwartz, Ida Vanessa Doederlein

2012-10-01

Court-ordered access to high-cost drugs for rare genetic diseases, such as Fabry Disease (alpha-galactosidase-A deficiency), is a growing phenomenon as yet lacking systematic study. An observational, cross-sectional and retrospective study was conducted to characterize the lawsuits related to access to treatment for Fabry Disease by Enzyme Replacement Therapy in the State of Rio Grande do Sul prior to 2007. The study identified 13 lawsuits and 17 plaintiffs, 11 requesting alfa and 6 betagalsidase. The State of RS, the Federal Government, and 5 municipalities figured as defendants, in the form of joinder of parties or otherwise. There were 13 requests for interlocutory relief of which 12 were granted, and 2 sentences were handed down, both favorable. "Risk of death" was alleged by doctors in 4 prescriptions and by lawyers in the 13 lawsuits. The data suggest the lack of discussions combining aspects of medical efficacy and safety, cost-effectiveness, economic impact, and legal and constitutional arguments, which requires a specific policy for rare genetic diseases to standardize access to treatment.

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

A comparative study of European rare disease and orphan drug markets.

PubMed

Denis, Alain; Mergaert, Lut; Fostier, Christel; Cleemput, Irina; Simoens, Steven

2010-10-01

This article aims to compare regulatory aspects of rare disease and orphan drug markets in Belgium, France, Italy, the Netherlands, Sweden and the United Kingdom. Information was derived from the international literature, analysis of legal texts, and a survey completed by national experts. These countries adopted varying approaches towards regulating rare disease and orphan drug markets and, hence, the availability, pricing and reimbursement of orphan drugs vary between countries. Strategies to keep down prices include public procurement in Sweden, profit controls in the United Kingdom, and price comparisons with other countries. To gain reimbursement, the cost-effectiveness and/or budget impact of orphan drugs is considered in some countries. Other societal considerations, such as whether the drug treats a life-threatening disease, are sometimes taken into account. Extensive government intervention exists in rare disease and orphan drug markets in the countries studied. Our recommendations are to define priorities for research on rare diseases and orphan drugs at the European level, to set up disease and patient registries with a view to investigating the long-term effectiveness and cost-effectiveness of orphan drugs, to assess the profitability of orphan drugs, and to take into account societal considerations when evaluating orphan drugs. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Sustainable rare diseases business and drug access: no time for misconceptions.

PubMed

Rollet, Pierrick; Lemoine, Adrien; Dunoyer, Marc

2013-07-23

Legislative incentives enacted in Europe through the Regulation (EC) No. 141/2000 to incentivize orphan drug development have over the last 12 years constituted a powerful impetus toward R&D directed at the rare diseases population. However, despite therapeutic promises contained in these projects and significant economic impact linked to burgeoning R&D expenditures, the affordability and value of OMPs has become a topic of health policy debate in Europe fueled by the perception that OMPs have high acquisition costs, and by misconceptions around pricing dynamics and rare-diseases business models. In order to maintain sustainable patient access to new and innovative therapies, it is essential to address these misconceptions, and to ensure the successful continuation of a dynamic OMPs R&D within rare-diseases public health policy. Misconceptions abound regarding the pricing of rare diseases drugs and reflect a poor appreciation of the R&D model and the affordability and value of OMPs. Simulation of potential financial returns of small medium sized rare diseases companies focusing on high priced drugs show that their economic returns are likely to be close to their cost of capital. Research in rare diseases is a challenging endeavour characterised by high fixed costs in which companies accrue substantial costs for several years before potentially generating returns from the fruits of their investments. Although heavily dependent upon R&D capabilities of each individual company or R&D organization, continuous flow of R&D financial investment should allow industry to increasingly include efficiencies in research and development in cost considerations to its customers. Industry should also pro-actively work on facilitating development of a specific value based pricing approach to help understanding what constitute value in rare diseases. Policy makers must reward innovation based upon unmet need and patient outcome. Broader understanding by clinicians, the public, and

Sustainable rare diseases business and drug access: no time for misconceptions

PubMed Central

2013-01-01

Legislative incentives enacted in Europe through the Regulation (EC) No. 141/2000 to incentivize orphan drug development have over the last 12 years constituted a powerful impetus toward R&D directed at the rare diseases population. However, despite therapeutic promises contained in these projects and significant economic impact linked to burgeoning R&D expenditures, the affordability and value of OMPs has become a topic of health policy debate in Europe fueled by the perception that OMPs have high acquisition costs, and by misconceptions around pricing dynamics and rare-diseases business models. In order to maintain sustainable patient access to new and innovative therapies, it is essential to address these misconceptions, and to ensure the successful continuation of a dynamic OMPs R&D within rare-diseases public health policy. Misconceptions abound regarding the pricing of rare diseases drugs and reflect a poor appreciation of the R&D model and the affordability and value of OMPs. Simulation of potential financial returns of small medium sized rare diseases companies focusing on high priced drugs show that their economic returns are likely to be close to their cost of capital. Research in rare diseases is a challenging endeavour characterised by high fixed costs in which companies accrue substantial costs for several years before potentially generating returns from the fruits of their investments. Although heavily dependent upon R&D capabilities of each individual company or R&D organization, continuous flow of R&D financial investment should allow industry to increasingly include efficiencies in research and development in cost considerations to its customers. Industry should also pro-actively work on facilitating development of a specific value based pricing approach to help understanding what constitute value in rare diseases. Policy makers must reward innovation based upon unmet need and patient outcome. Broader understanding by clinicians, the public, and

[Scurvy. A rare differential diagnosis of rheumatic diseases].

PubMed

Hofheinz, K; Ganzleben, I; Schliep, S; Wacker, J; Schett, G; Manger, B

2016-03-01

In December 2014 a patient presented to our clinic with the clinical symptoms of vasculitis. However, treatment with glucocorticoids did not lead to any improvement; therefore, the differential diagnostics were extended to other indications and ultimately led to the diagnosis of scurvy. This article describes the clinical picture of scurvy and its relationship to rheumatic diseases based on a clinical case and additional information from the literature. Differences and similarities with important rheumatological disease symptoms are presented. Scurvy is a rare hypovitaminosis disease which can be manifested in different forms. In addition to vasculitis the symptoms can also resemble arthritis and hemarthrosis is a typical finding. These symptoms can be accompanied by unspecific manifestations, such as muscle pain and due to impaired collagen synthesis characteristic features, such as corkscrew hair can be observed. The causal therapy of scurvy is substitution of ascorbic acid. Scurvy is a rare differential diagnosis in the context of rheumatic diseases. The indications for scurvy can be a lack of response to immunosuppressive and immunomodulatory drugs as well as individual symptoms, such as corkscrew hair.

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

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

PubMed

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

2015-02-01

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. 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 randomized--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. 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. 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. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Moyamoya disease as a rare cause of ischaemic stroke--case report].

PubMed

Kułakowska, Alina; Kapica-Topczewska, Katarzyna; Borowik, Helena; Drozdowski, Wiesław

2009-10-01

Moyamoya disease is a rare, progressive disease of the vessels diagnosed according to characteristic abnormalities of brain arteries in the angiography. The incidence of moyamoya disease in Europe is lower than in Asia and its clinical course in European population is probably different from Asiatic (older age of onset and rare incidence of hemorrhagic strokes). Two young patients were diagnosed as moyamoya disease on the basis of clinical symptoms (ischaemic stroke) and results of brain vessels' angiography, which documented an occlusion of both internal carotid arteries above branching-off the ocular arteries in the first patient and stenosis of distal internal carotid arteries and proximal medial and anterior cerebral arteries in the second one. Both patients are under control of the Neurological Outpatient Department and their neurological state is stable. Despite that moyamoya disease is a rare cause of ischaemic stroke, it should be always considered as one of etiologic factors, especially in young patients.

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.

Tissue Chips to aid drug development and modeling for rare diseases

PubMed Central

Low, Lucie A.; Tagle, Danilo A.

2016-01-01

Introduction The technologies used to design, create and use microphysiological systems (MPS, “tissue chips” or “organs-on-chips”) have progressed rapidly in the last 5 years, and validation studies of the functional relevance of these platforms to human physiology, and response to drugs for individual model organ systems, are well underway. These studies are paving the way for integrated multi-organ systems that can model diseases and predict drug efficacy and toxicology of multiple organs in real-time, improving the potential for diagnostics and development of novel treatments of rare diseases in the future. Areas covered This review will briefly summarize the current state of tissue chip research and highlight model systems where these microfabricated (or bioengineered) devices are already being used to screen therapeutics, model disease states, and provide potential treatments in addition to helping elucidate the basic molecular and cellular phenotypes of rare diseases. Expert opinion Microphysiological systems hold great promise and potential for modeling rare disorders, as well as for their potential use to enhance the predictive power of new drug therapeutics, plus potentially increase the statistical power of clinical trials while removing the inherent risks of these trials in rare disease populations. PMID:28626620

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

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model.

PubMed

Bellgard, Matthew I; Napier, Kathryn R; Bittles, Alan H; Szer, Jeffrey; Fletcher, Sue; Zeps, Nikolajs; Hunter, Adam A; Goldblatt, Jack

2018-02-01

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Review of 11 national policies for rare diseases in the context of key patient needs.

PubMed

Dharssi, Safiyya; Wong-Rieger, Durhane; Harold, Matthew; Terry, Sharon

2017-03-31

Rare diseases collectively exert a global public health burden in the severity of their manifestations and the total number of people they afflict. For many patients, considerable barriers exist in terms of access to appropriate care, delayed diagnosis and limited or non-existing treatment options. Motivated by these challenges, the rare disease patient community has played a critical role, elevating the patient voice and mobilizing legislation to support the development of programs that address the needs of patients with rare diseases.The US Orphan Drug Act of 1983 served as a key milestone in this journey, providing a roadmap for other countries to introduce and implement similar orphan drug legislation; more recently, the European Union (EU) has gone further to encourage the widespread adoption and implementation of rare disease plans or strategies designed to more adequately address the comprehensive needs of patients with rare diseases. Despite these legislative efforts and the growing contributions of patient advocacy groups in moving forward implementation and adoption of rare disease programs, gaps still exist across the policy landscape for several countries. To gain deeper insights into the challenges and opportunities to address key needs of rare disease patients, it is critical to define the current status of rare disease legislation and policy across a geographically and economically diverse selection of countries. We analyzed the rare disease policy landscape across 11 countries: Germany, France, the United Kingdom, Canada, Bulgaria, Turkey, Argentina, Mexico, Brazil, China, and Taiwan. The status and implementation of policy was evaluated for each country in the context of key patient needs across 5 dimensions: improving coordination of care, diagnostic resources, access to treatments, patient awareness and support, and promoting innovative research. Our findings highlight the continuing role of the patient community in driving the establishment and

CEMARA: a Web dynamic application within a N-tier architecture for rare diseases.

PubMed

Messiaen, Claude; Le Mignot, Loïc; Rath, Ana; Richard, Jean-Baptiste; Dufour, Eric; Ben Said, Mohamed; Jais, Jean-Philippe; Verloes, Alain; Le Merrer, Martine; Bodemer, Christine; Baujat, Geneviève; Gerard-Blanluet, Marion; Bourdon-Lanoy, Eva; Salomon, Rémi; Ayme, Ségolène; Landais, Paul

2008-01-01

Rare diseases include a group of conditions characterized by a prevalence lower than 5 per 10,000 in the community. In France, any rare disease affects less than 30,000 patients and often much less. Three to 4% of children and 6% of the population in Europe are affected. It is a true public health stake since most diseases do not have any curative treatment. In France, the Ministry of Health has initiated a National Rare Diseases Plan. Twenty five out of 132 labelled Reference Centres (RC) decided to share a common Information System named CEMARA. It is dedicated to collect continuous and complete records of all patients presenting with a rare disease, and their follow-up. The main objective of CEMARA is to contribute to the missions of the RC regarding the registration and description of their activities, coordination of the network of their correspondents, organization of the follow-up of rare diseases, and analysis of the epidemiological patterns. A description of CEMARA is provided as well as its cooperation with Orphanet and Genatlas, and a presentation of 11803 current records collected by more than 300 health care professionals belonging to more than 70 sites.

Rare diseases, rare presentations: recognizing atypical inherited kidney disease phenotypes in the age of genomics.

PubMed

Ars, Elisabet; Torra, Roser

2017-10-01

A significant percentage of adults (10%) and children (20%) on renal replacement therapy have an inherited kidney disease (IKD). The new genomic era, ushered in by the next generation sequencing techniques, has contributed to the identification of new genes and facilitated the genetic diagnosis of the highly heterogeneous IKDs. Consequently, it has also allowed the reclassification of diseases and has broadened the phenotypic spectrum of many classical IKDs. Various genetic, epigenetic and environmental factors may explain 'atypical' phenotypes. In this article, we examine different mechanisms that may contribute to phenotypic variability and also provide case examples that illustrate them. The aim of the article is to raise awareness, among nephrologists and geneticists, of rare presentations that IKDs may show, to facilitate diagnosis.

Research Registries: A Tool to Advance Understanding of Rare Neuro-Ophthalmic Diseases

PubMed Central

Blankshain, Kimberly D; Moss, Heather E

2016-01-01

Background Medical research registries (MRR) are organized systems used to collect, store and analyze patient information. They are important tools for medical research with particular application to the study of rare diseases, including those seen in neuro-ophthalmic practice. Evidence Acquisition Evidence for this review was gathered from the writers’ experiences creating a comprehensive neuro-ophthalmology registry and review of the literature. Results MRR are typically observational and prospective databases of de-identified patient information. The structure is flexible and can accommodate a focus on specific diseases or treatments, surveillance of patient populations, physician quality improvement, or recruitment for future studies. They are particularly useful for the study of rare diseases. They can be integrated into the hierarchy of medical research at many levels provided their construction is well organized and they have several key characteristics including an easily manipulated database, comprehensive information on carefully selected patients and comply with human subjects regulations. MRR pertinent to neuro-ophthalmology include the UIC neuro-ophthalmology registry, Susac Syndrome Registry, Intracranial Hypertension Registry as well as larger scale patient outcome registries being developed by professional societies. Conclusion Medical research registries have a variety of forms and applications. With careful planning and clear goals, they are flexible and powerful research tools that can support multiple different study designs, and through this have the potential to advance understanding and care of neuro-ophthalmic diseases. PMID:27389624

Research Registries: A Tool to Advance Understanding of Rare Neuro-Ophthalmic Diseases.

PubMed

Blankshain, Kimberly D; Moss, Heather E

2016-09-01

Medical research registries (MRR) are organized systems used to collect, store, and analyze patient information. They are important tools for medical research with particular application to the study of rare diseases, including those seen in neuro-ophthalmic practice. Evidence for this review was gathered from the writers' experiences creating a comprehensive neuro-ophthalmology registry and review of the literature. MRR are typically observational and prospective databases of de-identified patient information. The structure is flexible and can accommodate a focus on specific diseases or treatments, surveillance of patient populations, physician quality improvement, or recruitment for future studies. They are particularly useful for the study of rare diseases. They can be integrated into the hierarchy of medical research at many levels provided their construction is well organized and they have several key characteristics including an easily manipulated database, comprehensive information on carefully selected patients, and comply with human subjects regulations. MRR pertinent to neuro-ophthalmology include the University of Illinois at Chicago neuro-ophthalmology registry, Susac Syndrome Registry, Intracranial Hypertension Registry, and larger-scale patient outcome registries being developed by professional societies. MRR have a variety of forms and applications. With careful planning and clear goals, they are flexible and powerful research tools that can support multiple different study designs, and this can provide the potential to advance understanding and care of neuro-ophthalmic diseases.

Rare neurological diseases: a Pandora's box for neurology (an European and Italian perspective).

PubMed

Federico, A

2013-02-01

Rare neurological diseases are a heterogeneous group of disorders mainly affecting the central and peripheral nervous systems and muscle, representing almost 50% of all rare diseases; this means that neurologists are among the main specialists involved in their diagnosis and research. However, the classical interest of neurologists is primarily directed towards the more common diseases such as dementia, multiple sclerosis, headache, epilepsy and stroke, while avoiding the follow-up of rare neurological diseases that have, taken altogether, had such a major impact on health systems in Europe as well as in other countries around the world. Rare diseases are also considered 'orphan' diseases, as only a few of them have treatments. In Europe as in the USA in recent years, considerable interest has been generated by these disorders, thereby stimulating more specific programs of care and management. In fact, the difficulty of diagnosis and the need for super-specialization in this field has led to the organization of dedicated centers in different countries to collect patients' data within a network for diagnosis, treatment and research. The present report describes our experience in Siena with such a reference center for these disorders and their diagnosis and treatment, and also includes a discussion of the organization of care for rare neurological diseases in Europe and Italy. Finally, this report also covers the new initiative of the Italian Neurological Society to promote an information center for rare neurological diseases to disseminate information and knowledge to all neurologists working in this field. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

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

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; 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

2014-01-23

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

Orphan Products: Hope for People with Rare Diseases

MedlinePlus

... of Rare Diseases, encourages people to use the Internet to find information, he also warns that it ... remedies and miracle cures being touted over the Internet," he says. Too often misleading or inaccurate information ...

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. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

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

PubMed Central

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

2015-01-01

ABSTRACT 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

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. Copyright © 2013 Elsevier B.V. All rights reserved.

Generic Substitution of Orphan Drugs for the Treatment of Rare Diseases: Exploring the Potential Challenges.

PubMed

Di Paolo, Antonello; Arrigoni, Elena

2018-03-01

Generic drugs are important components of measures introduced by healthcare regulatory authorities to reduce treatment costs. In most patients and conditions the switch from a branded drug to its generic counterpart is performed with no major complications. However, evidence from complex diseases suggests that generic substitution requires careful evaluation in some settings and that current bioequivalence criteria may not always be adequate for establishing the interchangeability of branded and generic products. Rare diseases, also called orphan diseases, are a group of heterogeneous diseases that share important characteristics: in addition to their scarcity, most are severe, chronic, highly debilitating, and often present in early childhood. Finding a treatment for a rare disease is challenging. Thanks to incentives that encourage research and development programs in rare diseases, several orphan drugs are currently available. The elevated cost of orphan drugs is a highly debated issue and a cause of limited access to treatment for many patients. As patent protection and the exclusivity period of several orphan drugs will expire soon, generic versions of orphan drugs should reach the market shortly, with great expectations about their impact on the economic burden of rare diseases. However, consistent with other complex diseases, generic substitution may require thoughtful considerations and may be even contraindicated in some rare conditions. This article provides an overview of rare disease characteristics, reviews reports of problematic generic substitution, and discusses why generic substitution of orphan drugs may be challenging and should be undertaken carefully in rare disease patients.

Pooled-DNA Sequencing for Elucidating New Genomic Risk Factors, Rare Variants Underlying Alzheimer's Disease.

PubMed

Jin, Sheng Chih; Benitez, Bruno A; Deming, Yuetiva; Cruchaga, Carlos

2016-01-01

Analyses of genome-wide association studies (GWAS) for complex disorders usually identify common variants with a relatively small effect size that only explain a small proportion of phenotypic heritability. Several studies have suggested that a significant fraction of heritability may be explained by low-frequency (minor allele frequency (MAF) of 1-5 %) and rare-variants that are not contained in the commercial GWAS genotyping arrays (Schork et al., Curr Opin Genet Dev 19:212, 2009). Rare variants can also have relatively large effects on risk for developing human diseases or disease phenotype (Cruchaga et al., PLoS One 7:e31039, 2012). However, it is necessary to perform next-generation sequencing (NGS) studies in a large population (>4,000 samples) to detect a significant rare-variant association. Several NGS methods, such as custom capture sequencing and amplicon-based sequencing, are designed to screen a small proportion of the genome, but most of these methods are limited in the number of samples that can be multiplexed (i.e. most sequencing kits only provide 96 distinct index). Additionally, the sequencing library preparation for 4,000 samples remains expensive and thus conducting NGS studies with the aforementioned methods are not feasible for most research laboratories.The need for low-cost large scale rare-variant detection makes pooled-DNA sequencing an ideally efficient and cost-effective technique to identify rare variants in target regions by sequencing hundreds to thousands of samples. Our recent work has demonstrated that pooled-DNA sequencing can accurately detect rare variants in targeted regions in multiple DNA samples with high sensitivity and specificity (Jin et al., Alzheimers Res Ther 4:34, 2012). In these studies we used a well-established pooled-DNA sequencing approach and a computational package, SPLINTER (short indel prediction by large deviation inference and nonlinear true frequency estimation by recursion) (Vallania et al., Genome Res

Linking rare and common disease: mapping clinical disease-phenotypes to ontologies in therapeutic target validation.

PubMed

Sarntivijai, Sirarat; Vasant, Drashtti; Jupp, Simon; Saunders, Gary; Bento, A Patrícia; Gonzalez, Daniel; Betts, Joanna; Hasan, Samiul; Koscielny, Gautier; Dunham, Ian; Parkinson, Helen; Malone, James

2016-01-01

The Centre for Therapeutic Target Validation (CTTV - https://www.targetvalidation.org/) was established to generate therapeutic target evidence from genome-scale experiments and analyses. CTTV aims to support the validity of therapeutic targets by integrating existing and newly-generated data. Data integration has been achieved in some resources by mapping metadata such as disease and phenotypes to the Experimental Factor Ontology (EFO). Additionally, the relationship between ontology descriptions of rare and common diseases and their phenotypes can offer insights into shared biological mechanisms and potential drug targets. Ontologies are not ideal for representing the sometimes associated type relationship required. This work addresses two challenges; annotation of diverse big data, and representation of complex, sometimes associated relationships between concepts. Semantic mapping uses a combination of custom scripting, our annotation tool 'Zooma', and expert curation. Disease-phenotype associations were generated using literature mining on Europe PubMed Central abstracts, which were manually verified by experts for validity. Representation of the disease-phenotype association was achieved by the Ontology of Biomedical AssociatioN (OBAN), a generic association representation model. OBAN represents associations between a subject and object i.e., disease and its associated phenotypes and the source of evidence for that association. The indirect disease-to-disease associations are exposed through shared phenotypes. This was applied to the use case of linking rare to common diseases at the CTTV. EFO yields an average of over 80% of mapping coverage in all data sources. A 42% precision is obtained from the manual verification of the text-mined disease-phenotype associations. This results in 1452 and 2810 disease-phenotype pairs for IBD and autoimmune disease and contributes towards 11,338 rare diseases associations (merged with existing published work [Am J Hum Genet

Development of the parental needs scale for rare diseases: a tool for measuring the supportive care needs of parents caring for a child with a rare disease.

PubMed

Pelentsov, Lemuel J; Fielder, Andrea L; Laws, Thomas A; Esterman, Adrian J

2016-01-01

Children and families affected by rare diseases have received scant consideration from the medical, scientific, and political communities, with parents' needs especially having received little attention. Affected parents often have limited access to information and support and appropriate health care services. While scales to measure the needs of parents of children with chronic illnesses have been developed, there have been no previous attempts to develop a scale to assess the needs of parents of children with rare diseases. To develop a scale for measuring the supportive care needs of parents of children with rare diseases. A total of 301 responses to our Parental Needs Survey were randomly divided into two halves, one for exploratory factor analysis and the other for confirmatory factor analysis (CFA). After removing unsuitable items, exploratory factor analysis was undertaken to determine the factor structure of the data. CFA using structural equation modeling was then undertaken to confirm the factor structure. Seventy-two items were entered into the CFA, with a scree plot showing a likely four-factor solution. The results provided four independent subscales of parental needs: Understanding the disease (four items); Working with health professionals (four items); Emotional issues (three items); and Financial needs (three items). The structural equation modeling confirmed the suitability of the four-factor solution and demonstrated that the four subscales could be added to provide an overall scale of parental need. This is the first scale developed to measure the supportive care needs of parents of children with rare diseases. The scale is suitable for use in surveys to develop policy, in individual clinical assessments, and, potentially, for evaluating new programs. Measuring the supportive care needs of parents caring for a child with a rare disease will hopefully lead to better physical and psychological health outcomes for parents and their affected

Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.

PubMed

Chen, Rui; Davis, Lea K; Guter, Stephen; Wei, Qiang; Jacob, Suma; Potter, Melissa H; Cox, Nancy J; Cook, Edwin H; Sutcliffe, James S; Li, Bingshan

2017-01-01

Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs ( FOXP1 and KDM5B ). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission

Improving the analysis of composite endpoints in rare disease trials.

PubMed

McMenamin, Martina; Berglind, Anna; Wason, James M S

2018-05-22

Composite endpoints are recommended in rare diseases to increase power and/or to sufficiently capture complexity. Often, they are in the form of responder indices which contain a mixture of continuous and binary components. Analyses of these outcomes typically treat them as binary, thus only using the dichotomisations of continuous components. The augmented binary method offers a more efficient alternative and is therefore especially useful for rare diseases. Previous work has indicated the method may have poorer statistical properties when the sample size is small. Here we investigate small sample properties and implement small sample corrections. We re-sample from a previous trial with sample sizes varying from 30 to 80. We apply the standard binary and augmented binary methods and determine the power, type I error rate, coverage and average confidence interval width for each of the estimators. We implement Firth's adjustment for the binary component models and a small sample variance correction for the generalized estimating equations, applying the small sample adjusted methods to each sub-sample as before for comparison. For the log-odds treatment effect the power of the augmented binary method is 20-55% compared to 12-20% for the standard binary method. Both methods have approximately nominal type I error rates. The difference in response probabilities exhibit similar power but both unadjusted methods demonstrate type I error rates of 6-8%. The small sample corrected methods have approximately nominal type I error rates. On both scales, the reduction in average confidence interval width when using the adjusted augmented binary method is 17-18%. This is equivalent to requiring a 32% smaller sample size to achieve the same statistical power. The augmented binary method with small sample corrections provides a substantial improvement for rare disease trials using composite endpoints. We recommend the use of the method for the primary analysis in relevant rare

Can the EVIDEM Framework Tackle Issues Raised by Evaluating Treatments for Rare Diseases: Analysis of Issues and Policies, and Context-Specific Adaptation.

PubMed

Wagner, Monika; Khoury, Hanane; Willet, Jacob; Rindress, Donna; Goetghebeur, Mireille

2016-03-01

The multiplicity of issues, including uncertainty and ethical dilemmas, and policies involved in appraising interventions for rare diseases suggests that multicriteria decision analysis (MCDA) based on a holistic definition of value is uniquely suited for this purpose. The objective of this study was to analyze and further develop a comprehensive MCDA framework (EVIDEM) to address rare disease issues and policies, while maintaining its applicability across disease areas. Specific issues and policies for rare diseases were identified through literature review. Ethical and methodological foundations of the EVIDEM framework v3.0 were systematically analyzed from the perspective of these issues, and policies and modifications of the framework were performed accordingly to ensure their integration. Analysis showed that the framework integrates ethical dilemmas and issues inherent to appraising interventions for rare diseases but required further integration of specific aspects. Modification thus included the addition of subcriteria to further differentiate disease severity, disease-specific treatment outcomes, and economic consequences of interventions for rare diseases. Scoring scales were further developed to include negative scales for all comparative criteria. A methodology was established to incorporate context-specific population priorities and policies, such as those for rare diseases, into the quantitative part of the framework. This design allows making more explicit trade-offs between competing ethical positions of fairness (prioritization of those who are worst off), the goal of benefiting as many people as possible, the imperative to help, and wise use of knowledge and resources. It also allows addressing variability in institutional policies regarding prioritization of specific disease areas, in addition to existing uncertainty analysis available from EVIDEM. The adapted framework measures value in its widest sense, while being responsive to rare disease

[Central information portal on rare diseases : Implementation of quality- and needs-oriented information management].

PubMed

Litzkendorf, Svenja; Pauer, Frédéric; Zeidler, Jan; Göbel, Jens; Storf, Holger; Graf von der Schulenburg, J-Matthias

2017-05-01

A central information portal on rare diseases (ZIPSE) has been conceptualized and implemented that allows patients, relatives and health care professionals to access quality-assured information. For this purpose, quality criteria have been developed specifically for rare diseases. At the same time, the information basis should take into account the specific needs of those interested. The needs of patients and relatives regarding online-based information are analyzed. Based on this, we examined to what extent the information basis, which is available according to the ZIPSE quality criteria, can cover these needs. If necessary, measures have to be developed to ensure quality- as well as needs-oriented information management. Qualitative interviews with patients and relatives were conducted, which were then evaluated using content analysis. Subsequently, a quantitative evaluation of the information on rare diseases in the portal was made. The research addresses how many websites do not fulfil the quality criteria, from which group of provider these websites originate and which criteria are not fulfilled. This is followed by a comparison of the quantitative and qualitative results. When looking for information on the Internet, the websites of self-help groups represent a significant source. These are perceived as very trustworthy and in the later course of the disease, offer detailed information on important information areas. Information websites from self-help groups, however, often do not meet quality requirements. Therefore, a transparent representation is made regarding the quality of the ZIPSE information pages. Pages that are not quality-assured can be actively requested, but will be clearly identified.

[Acute renal failure: a rare presentation of Addison's disease].

PubMed

Salhi, Houda

2016-01-01

Addison's disease is a rare condition. Its onset of symptoms most often is nonspecific contributing to a diagnostic and therapeutic delay. Acute renal failure can be the first manifestation of this disease. We report the case of a patient with Addison's disease who was initially treated for acute renal failure due to multiple myeloma and whose diagnosis was adjusted thereafter. Patient's condition dramatically improved after treatment with intravenous rehydration; injectable hydrocortisone.

[Cœliac disease: a rare cause of recurrent miscarriages].

PubMed

Kehila, Mehdi; Hmid, Rim Ben; Godcha, Imene; Abouda, Hassine Saber; Boujomaa, Oueslati; Chanoufi, Mohamed Badis

2016-01-01

Cœliac disease is an autoimmune disorder associated with Gluten intolerance resulting in progressive destruction of the villi of the small intestine. Symptoms are very diverse and can occur at any age. Abortive illness is a rare symptom leading to the detection of cœliac disease. We report the case of a patient with a history of 12 consecutive miscarriages whose etiology was finally related to cœliac disease.

[Hyperlipoproteinemia and dyslipidemia as rare diseases. Diagnostics and treatment].

PubMed

Češka, Richard; Štulc, Tomáš; Votavová, Lucie; Schwarzová, Lucie; Vaclová, Martina; Freiberger, Tomáš

Hyperlipoproteinemia (HLP) and dyslipidemia (DLP) are of course mainly perceived as diseases of common incidence and are typically seen as the greatest risk factors (RF) in the context of the pandemic of cardiovascular diseases. This is certainly true and HLP or DLP overall affect tens of percents of adults. However we cannot overlook the fact that disorders (mostly congenital) of lipid metabolism exist which, though not formally defined as such, amply satisfy the conditions for classification as rare diseases. Our account only includes a brief overview of the rare HLPs based on the dominant disorder of lipid metabolism, i.e. we shall mention the rare primary forms of hypercholesterolemia, primary forms of hypertriglyceridemia and the rare primary combined forms of HLP. In recent years an amazing progress has been reached relating to these diseases, in particular in the area of exact identification of the genetic defect and the mechanism of defect formation, however each of these diseases would require a separate article, though outside the field of clinical internal medicine. Therefore we shall discuss homozygous familial hypercholesterolemia (FH) in greater depth, partially also the "severe" form of heterozygous FH and in the following part the lipoprotein lipase deficiency; that means, diseases which present an extreme and even fatal risk for their carriers at a young age, but on the other hand, new therapeutic possibilities are offered within their treatment. An internist then should be alert to the suspicion that the described diseases may be involved, know about their main symptoms, where to refer the patient and how to treat them. Also dysbetalipoproteinemia (or type III HLP) will be briefly mentioned. Homozygous FH occurs with the frequency of 1 : 1 000 000 (maybe even more frequently, 1 : 160 000), it is characterized by severe isolated hypercholesterolemia (overall cholesterol typically equal to 15 mmol/l or more), xanthomatosis and first of all by

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL).

PubMed

Annemans, Lieven; Aymé, Ségolène; Le Cam, Yann; Facey, Karen; Gunther, Penilla; Nicod, Elena; Reni, Michele; Roux, Jean-Louis; Schlander, Michael; Taylor, David; Tomino, Carlo; Torrent-Farnell, Josep; Upadhyaya, Sheela; Hutchings, Adam; Le Dez, Lugdivine

2017-03-10

Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure

Microphysiological Systems (Tissue Chips) and their Utility for Rare Disease Research.

PubMed

Low, Lucie A; Tagle, Danilo A

2017-01-01

The scientific and technological development of microphysiological systems (MPS) modeling organs-on-chips, or "tissue chips" (TCs), has progressed rapidly over the past decade. Stem cell research and microfluidic concepts have combined to lead to the development of microphysiological platforms representing an ever-expanding list of different human organ systems. In the context of rare diseases, these bioengineered microfluidics platforms hold promise for modeling of disorders and could prove useful in the screening and efficacy testing of existing therapeutics. Additionally, they have the potential for replacing and refining animal use for new drugs and clinical treatments, or could even act as surrogate human systems for testing of new therapeutics in the future, which could be particularly useful in populations of rare disease sufferers. This chapter will discuss the current state of tissue chip research, and challenges facing the field. Additionally, we will discuss how these devices are being used to model basic cellular and molecular phenotypes of rare diseases, holding promise to provide new tools for understanding of disease pathologies and screening and efficacy testing of potential therapeutics for drug discovery.

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

PubMed

Aung, Tin; Ozaki, Mineo; Lee, Mei Chin; Schlötzer-Schrehardt, Ursula; Thorleifsson, Gudmar; Mizoguchi, Takanori; Igo, Robert P; Haripriya, Aravind; Williams, Susan E; Astakhov, Yury S; Orr, Andrew C; Burdon, Kathryn P; Nakano, Satoko; Mori, Kazuhiko; Abu-Amero, Khaled; Hauser, Michael; Li, Zheng; Prakadeeswari, Gopalakrishnan; Bailey, Jessica N Cooke; Cherecheanu, Alina Popa; Kang, Jae H; Nelson, Sarah; Hayashi, Ken; Manabe, Shin-Ichi; Kazama, Shigeyasu; Zarnowski, Tomasz; Inoue, Kenji; Irkec, Murat; Coca-Prados, Miguel; Sugiyama, Kazuhisa; Järvelä, Irma; Schlottmann, Patricio; Lerner, S Fabian; Lamari, Hasnaa; Nilgün, Yildirim; Bikbov, Mukharram; Park, Ki Ho; Cha, Soon Cheol; Yamashiro, Kenji; Zenteno, Juan C; Jonas, Jost B; Kumar, Rajesh S; Perera, Shamira A; Chan, Anita S Y; Kobakhidze, Nino; George, Ronnie; Vijaya, Lingam; Do, Tan; Edward, Deepak P; de Juan Marcos, Lourdes; Pakravan, Mohammad; Moghimi, Sasan; Ideta, Ryuichi; Bach-Holm, Daniella; Kappelgaard, Per; Wirostko, Barbara; Thomas, Samuel; Gaston, Daniel; Bedard, Karen; Greer, Wenda L; Yang, Zhenglin; Chen, Xueyi; Huang, Lulin; Sang, Jinghong; Jia, Hongyan; Jia, Liyun; Qiao, Chunyan; Zhang, Hui; Liu, Xuyang; Zhao, Bowen; Wang, Ya-Xing; Xu, Liang; Leruez, Stéphanie; Reynier, Pascal; Chichua, George; Tabagari, Sergo; Uebe, Steffen; Zenkel, Matthias; Berner, Daniel; Mossböck, Georg; Weisschuh, Nicole; Hoja, Ursula; Welge-Luessen, Ulrich-Christoph; Mardin, Christian; Founti, Panayiota; Chatzikyriakidou, Anthi; Pappas, Theofanis; Anastasopoulos, Eleftherios; Lambropoulos, Alexandros; Ghosh, Arkasubhra; Shetty, Rohit; Porporato, Natalia; Saravanan, Vijayan; Venkatesh, Rengaraj; Shivkumar, Chandrashekaran; Kalpana, Narendran; Sarangapani, Sripriya; Kanavi, Mozhgan R; Beni, Afsaneh Naderi; Yazdani, Shahin; Lashay, Alireza; Naderifar, Homa; Khatibi, Nassim; Fea, Antonio; Lavia, Carlo; Dallorto, Laura; Rolle, Teresa; Frezzotti, Paolo; Paoli, Daniela; Salvi, Erika; Manunta, Paolo; Mori, Yosai; Miyata, Kazunori; Higashide, Tomomi; Chihara, Etsuo; Ishiko, Satoshi; Yoshida, Akitoshi; Yanagi, Masahide; Kiuchi, Yoshiaki; Ohashi, Tsutomu; Sakurai, Toshiya; Sugimoto, Takako; Chuman, Hideki; Aihara, Makoto; Inatani, Masaru; Miyake, Masahiro; Gotoh, Norimoto; Matsuda, Fumihiko; Yoshimura, Nagahisa; Ikeda, Yoko; Ueno, Morio; Sotozono, Chie; Jeoung, Jin Wook; Sagong, Min; Park, Kyu Hyung; Ahn, Jeeyun; Cruz-Aguilar, Marisa; Ezzouhairi, Sidi M; Rafei, Abderrahman; Chong, Yaan Fun; Ng, Xiao Yu; Goh, Shuang Ru; Chen, Yueming; Yong, Victor H K; Khan, Muhammad Imran; Olawoye, Olusola O; Ashaye, Adeyinka O; Ugbede, Idakwo; Onakoya, Adeola; Kizor-Akaraiwe, Nkiru; Teekhasaenee, Chaiwat; Suwan, Yanin; Supakontanasan, Wasu; Okeke, Suhanya; Uche, Nkechi J; Asimadu, Ifeoma; Ayub, Humaira; Akhtar, Farah; Kosior-Jarecka, Ewa; Lukasik, Urszula; Lischinsky, Ignacio; Castro, Vania; Grossmann, Rodolfo Perez; Sunaric Megevand, Gordana; Roy, Sylvain; Dervan, Edward; Silke, Eoin; Rao, Aparna; Sahay, Priti; Fornero, Pablo; Cuello, Osvaldo; Sivori, Delia; Zompa, Tamara; Mills, Richard A; Souzeau, Emmanuelle; Mitchell, Paul; Wang, Jie Jin; Hewitt, Alex W; Coote, Michael; Crowston, Jonathan G; Astakhov, Sergei Y; Akopov, Eugeny L; Emelyanov, Anton; Vysochinskaya, Vera; Kazakbaeva, Gyulli; Fayzrakhmanov, Rinat; Al-Obeidan, Saleh A; Owaidhah, Ohoud; Aljasim, Leyla Ali; Chowbay, Balram; Foo, Jia Nee; Soh, Raphael Q; Sim, Kar Seng; Xie, Zhicheng; Cheong, Augustine W O; Mok, Shi Qi; Soo, Hui Meng; Chen, Xiao Yin; Peh, Su Qin; Heng, Khai Koon; Husain, Rahat; Ho, Su-Ling; Hillmer, Axel M; Cheng, Ching-Yu; Escudero-Domínguez, Francisco A; González-Sarmiento, Rogelio; Martinon-Torres, Frederico; Salas, Antonio; Pathanapitoon, Kessara; Hansapinyo, Linda; Wanichwecharugruang, Boonsong; Kitnarong, Naris; Sakuntabhai, Anavaj; Nguyn, Hip X; Nguyn, Giang T T; Nguyn, Trình V; Zenz, Werner; Binder, Alexander; Klobassa, Daniela S; Hibberd, Martin L; Davila, Sonia; Herms, Stefan; Nöthen, Markus M; Moebus, Susanne; Rautenbach, Robyn M; Ziskind, Ari; Carmichael, Trevor R; Ramsay, Michele; Álvarez, Lydia; García, Montserrat; González-Iglesias, Héctor; Rodríguez-Calvo, Pedro P; Fernández-Vega Cueto, Luis; Oguz, Çilingir; Tamcelik, Nevbahar; Atalay, Eray; Batu, Bilge; Aktas, Dilek; Kasım, Burcu; Wilson, M Roy; Coleman, Anne L; Liu, Yutao; Challa, Pratap; Herndon, Leon; Kuchtey, Rachel W; Kuchtey, John; Curtin, Karen; Chaya, Craig J; Crandall, Alan; Zangwill, Linda M; Wong, Tien Yin; Nakano, Masakazu; Kinoshita, Shigeru; den Hollander, Anneke I; Vesti, Eija; Fingert, John H; Lee, Richard K; Sit, Arthur J; Shingleton, Bradford J; Wang, Ningli; Cusi, Daniele; Qamar, Raheel; Kraft, Peter; Pericak-Vance, Margaret A; Raychaudhuri, Soumya; Heegaard, Steffen; Kivelä, Tero; Reis, André; Kruse, Friedrich E; Weinreb, Robert N; Pasquale, Louis R; Haines, Jonathan L; Thorsteinsdottir, Unnur; Jonasson, Fridbert; Allingham, R Rand; Milea, Dan; Ritch, Robert; Kubota, Toshiaki; Tashiro, Kei; Vithana, Eranga N; Micheal, Shazia; Topouzis, Fotis; Craig, Jamie E; Dubina, Michael; Sundaresan, Periasamy; Stefansson, Kari; Wiggs, Janey L; Pasutto, Francesca; Khor, Chiea Chuen

2017-07-01

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10 -14 ) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10 -8 ). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon.

PubMed

Xu, Bin; Scognamiglio, Theresa; Cohen, Perry R; Prasad, Manju L; Hasanovic, Adnan; Tuttle, Robert Michael; Katabi, Nora; Ghossein, Ronald A

2017-07-01

Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAF V600E -positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases. Copyright © 2017 Elsevier Inc. All rights reserved.

New and evolving rare diseases research programs at the National Institutes of Health.

PubMed

Groft, S C; Rubinstein, Y R

2013-01-01

Research emphasis on rare diseases and orphan products remains a major focus of the research Institutes and Centers of National Institutes of Health (NIH). NIH provides more than USD 31 billion annually in biomedical research and research support. This research is the basis of many of the health advances in rare and common diseases. Numerous efforts and a major emphasis by the public and private sector initiatives have resulted in an increase of interventions and diagnostics for rare diseases. Newer translational research programs provide a more systematic and coordinated approach to rare diseases research and orphan products development. The approach that is offered requires extensive public-private partnerships with the pharmaceutical industry, contract research organizations, philanthropic foundations, medical and scientific advisory boards, patient advocacy groups, the academic research community, research and regulatory scientists, government funding agencies, and the public. Each program is unique and requires lengthy planning and collaborative efforts to reach programmatic goals. © 2013 S. Karger AG, Basel.

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

Database for Parkinson Disease Mutations and Rare Variants

DTIC Science & Technology

2016-09-01

AWARD NUMBER: W81XWH-14-1-0097 TITLE: “ Database for Parkinson Disease Mutations and Rare Variants” PRINCIPAL INVESTIGATOR: JEFFERY M. VANCE...TO THE ABOVE ADDRESS. 1. REPORT DATE September 2016 2. REPORT TYPE FINAL 3. DATES COVERED 1 Jul 2014 – 30 Jun 2016 4. TITLE AND SUBTITLE Database ...For Parkinson Disease (PD) specifically, the variant databases currently available are incomplete, don’t assess impact and/or are not equipped to

Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers.

PubMed

Morel, T; Aymé, S; Cassiman, D; Simoens, S; Morgan, M; Vandebroek, M

2016-05-26

Rare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context. A mixed-methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents. Final study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk. This is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed

PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.

PubMed

Miller, Patricia A; Mulla, Sohail M; Adams-Webber, Thomasin; Sivji, Yasmin; Guyatt, Gordon H; Johnston, Bradley C

2016-01-01

To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research.

Turning the Unknown into Known: Data Mining Is Increasingly Used to Prospect for Rare-Disease Biology and Treatments.

PubMed

Mertz, Leslie

2017-01-01

Taken as a whole, rare diseases are not very rare. Even though a rare disease by definition is one that affects fewer than 200,000 Americans or fewer than one in 2,000 Europeans at any time, when rare diseases are considered together, they affect some 350 million people worldwide, or about 5% of the population (Figure 1). What is even more alarming is that 7,800 of the approximately 8,000 known rare diseases have no treatments available. It's not that rare diseases are harder to treat than more widespread illnesses. Rather, compared to more common disorders, rare diseases simply do not draw the same level of attention from granting agencies, pharmaceutical companies, medical professionals, and researchers, so they languish in the shadows.

Bridging the Gap between Health and Social Care for Rare Diseases: Key Issues and Innovative Solutions.

PubMed

Castro, Raquel; Senecat, Juliette; de Chalendar, Myriam; Vajda, Ildikó; Dan, Dorica; Boncz, Béata

2017-01-01

Bridging the gaps between health and social care for rare diseases is not only necessary but crucial to increase the life expectancy, quality of life and autonomy of people living with a rare disease, supporting them in the full realisation of their fundamental human rights.The complexity of rare diseases, their strong relation to disability and the current unmet social and daily life needs of people living with a rare disease must not be underestimated and require urgent attention from all stakeholders involved in care provision, from healthcare to social and community services.The Commission Expert Group Recommendations to Support the Incorporation of Rare Diseases into Social Services and Policies, adopted unanimously in April 2016, by the representatives of European Member States and the other rare disease stakeholders, clearly set the tone for the need to promote measures that facilitate multidisciplinary, holistic, continuous, person-centred and participative care provision to people living with rare diseases.These recommendations, sided by other recent policy developments at European and national levels, represent an important policy step into approaching rare diseases' complex challenges in regards to holistic care provision.Innovative approaches aiming at bridging the gap between health, social and community service and support providers are currently being developed and tested in different European countries: standards of care, networks of expertise, case management services, one-stop-shop services, amongst others.These ongoing pilot approaches, presented in this chapter, have the power to inspire future policies and the effective and efficient implementation of holistic care pathways for people living with a rare disease, bringing about significant changes for patients, carers, care providers, competent authorities and the society at large.Nonetheless, the challenges to fully address this issue remain numerous and other key issues will also need to be

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

PubMed

van Karnebeek, Clara D M; Houben, Roderick F A; Lafek, Mirafe; Giannasi, Wynona; Stockler, Sylvia

2012-07-23

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. 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. 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 tool is designed to motivate health care

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

The ethical framework for performing research with rare inherited neurometabolic disease patients.

PubMed

Giannuzzi, Viviana; Devlieger, Hugo; Margari, Lucia; Odlind, Viveca Lena; Ragab, Lamis; Bellettato, Cinzia Maria; D'Avanzo, Francesca; Lampe, Christina; Cassis, Linda; Cortès-Saladelafont, Elisenda; Cazorla, Ángels Garcia; Barić, Ivo; Cvitanović-Šojat, Ljerka; Fumić, Ksenija; Dali, Christine I; Bartoloni, Franco; Bonifazi, Fedele; Scarpa, Maurizio; Ceci, Adriana

2017-03-01

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families. Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and

Telephone health services in the field of rare diseases: a qualitative interview study examining the needs of patients, relatives, and health care professionals in Germany.

PubMed

Babac, Ana; Frank, Martin; Pauer, Frédéric; Litzkendorf, Svenja; Rosenfeldt, Daniel; Lührs, Verena; Biehl, Lisa; Hartz, Tobias; Storf, Holger; Schauer, Franziska; Wagner, Thomas O F; Graf von der Schulenburg, J-Matthias

2018-02-09

Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians. In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for. Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling-in particular, differential diagnostics-and referrals. Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

PubMed

Phillips, Dawn; Leiro, Beth

2018-05-01

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution. Gross and fine motor skills, communication, cognition, and independence in activities of daily living vary by age, and it may be difficult to distinguish between treatment effect and change due to developmental maturation. Asfotase alfa was granted breakthrough therapy designation and subsequently approved for the treatment of hypophosphatasia (HPP; a genetic metabolic musculoskeletal disorder) and is used in this discussion to illustrate COA selection in a pediatric rare disease. Multiple COAs with normative data in HPP clinical trials for asfotase alfa are presented. The assessment instruments included the Bayley Scales of Infant and Toddler Development-Third Edition, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, the Childhood Health Assessment Questionnaire, the Pediatric Outcomes Data Collection Instrument, handheld dynamometry, the 6-minute walk test, and the Modified Performance-Oriented Mobility Assessment-Gait scale. Multiple end points were required to adequately capture the impact of asfotase alfa treatment on the multiple systems affected in HPP. These data illustrate the importance of using multiple COAs that provide normative data and to use COAs early in the drug development process for rare pediatric disease. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Utilising family-based designs for detecting rare variant disease associations.

PubMed

Preston, Mark D; Dudbridge, Frank

2014-03-01

Rare genetic variants are thought to be important components in the causality of many diseases but discovering these associations is challenging. We demonstrate how best to use family-based designs to improve the power to detect rare variant disease associations. We show that using genetic data from enriched families (those pedigrees with greater than one affected member) increases the power and sensitivity of existing case-control rare variant tests. However, we show that transmission- (or within-family-) based tests do not benefit from this enrichment. This means that, in studies where a limited amount of genotyping is available, choosing a single case from each of many pedigrees has greater power than selecting multiple cases from fewer pedigrees. Finally, we show how a pseudo-case-control design allows a greater range of statistical tests to be applied to family data. © 2014 The Authors. Annals of Human Genetics published by John Wiley & Sons Ltd/University College London.

Hemizygous Fabry disease associated with membranous nephropathy: A rare case report
.

PubMed

Zhou, Wenyan; Ni, Zhaohui; Zhang, Minfang

2018-05-24

Fabry disease may coexist with various glomerular diseases, including IgA nephropathy, focal segmental glomerulosclerosis, etc. In this study, we report a rare case of Fabry disease associated with membranous nephropathy (MN). A 30-year-old man with nephrotic proteinuria, normal renal function, and no other extrarenal manifestations underwent a renal biopsy in February 2017. Light microscopy and immunofluorescence indicated MN (stage 1). Under an electron microscope, there were subepithelial electron-dense deposits and abundant zebra bodies in podocytes. Both the findings of low-activity α-galactosidase A (α-Gal A, GLA) and base deletion in exon 7 of the GLA gene (GLA-E07.1286_*7 del, a newly reported mutation) confirmed that this patient was simultaneously afflicted with Fabry disease. This case report is an important reminder of the role of kidney biopsy, especially electron microscopy, as an indicator of Fabry disease and its rare coexistence with MN.
.

Conception of an Expert Advisory Board for the European Reference Network for Rare Respiratory Diseases.

PubMed

Walther, Désirée; Steinmann, Olivia; Schaefer, Johanna; Wagner, Thomas O F; Storf, Holger

2018-01-01

Due to low prevalence of rare diseases and lack of expertise, patients suffering rare diseases are challenged with finding experts that are specialized and experienced in treating their conditions and get qualified answers. To address this issue, the approach of an interactive platform was made, which should allow affected patients or physicians the possibility to ask experts their specific questions to gather and improve their knowledge about their condition. This paper introduces the pan-European Internet platform EXABO, an Expert Advisory Board, which is developed within the framework of the European Reference Network for rare respiratory diseases (ERN-LUNG). The purpose of establishing this platform is initially dedicated to rare respiratory diseases in whole Europe, whilst the set-up is however, planned to be a generic tool for additional diseases or groups of diseases. This paper gives an overview of the concept and planning of the EXABO platform and shows how the platform is to be implemented.

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

PubMed Central

Permuth, Jennifer B.; Pirie, Ailith; Ann Chen, Y.; Lin, Hui-Yi; Reid, Brett M.; Chen, Zhihua; Monteiro, Alvaro; Dennis, Joe; Mendoza-Fandino, Gustavo; Anton-Culver, Hoda; Bandera, Elisa V.; Bisogna, Maria; Brinton, Louise; Brooks-Wilson, Angela; Carney, Michael E.; Chenevix-Trench, Georgia; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; D’Aloisio, Aimee A.; Anne Doherty, Jennifer; Earp, Madalene; Edwards, Robert P.; Fridley, Brooke L.; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Goodman, Marc T.; Gronwald, Jacek; Hogdall, Estrid; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Karlan, Beth Y.; Kelemen, Linda E.; Kjaer, Suzanne K.; Kraft, Peter; Le, Nhu D.; Levine, Douglas A.; Lissowska, Jolanta; Lubinski, Jan; Matsuo, Keitaro; Menon, Usha; Modugno, Rosemary; Moysich, Kirsten B.; Nakanishi, Toru; Ness, Roberta B.; Olson, Sara; Orlow, Irene; Pearce, Celeste L.; Pejovic, Tanja; Poole, Elizabeth M.; Ramus, Susan J.; Anne Rossing, Mary; Sandler, Dale P.; Shu, Xiao-Ou; Song, Honglin; Taylor, Jack A.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tworoger, Shelley S.; Webb, Penelope M.; Wentzensen, Nicolas; Wilkens, Lynne R.; Winham, Stacey; Woo, Yin-Ling; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Phelan, Catherine M.; Schildkraut, Joellen M.; Berchuck, Andrew; Goode, Ellen L.; Pharoah, Paul D. P.; Sellers, Thomas A.

2016-01-01

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 − 7). One of the most significant signals (Pall histologies = 1.01 × 10 − 13;Pserous = 3.54 × 10 − 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified ‘best hit’ (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 − 5 > P≥5.0 ×10 − 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 − 5; PSKAT-o = 9.23 × 10 − 4) and KRT13 (PAML = 1.67 × 10 − 4; PSKAT-o = 1.07 × 10 − 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

PubMed

Permuth, Jennifer B; Pirie, Ailith; Ann Chen, Y; Lin, Hui-Yi; Reid, Brett M; Chen, Zhihua; Monteiro, Alvaro; Dennis, Joe; Mendoza-Fandino, Gustavo; Anton-Culver, Hoda; Bandera, Elisa V; Bisogna, Maria; Brinton, Louise; Brooks-Wilson, Angela; Carney, Michael E; Chenevix-Trench, Georgia; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; D'Aloisio, Aimee A; Anne Doherty, Jennifer; Earp, Madalene; Edwards, Robert P; Fridley, Brooke L; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Goodman, Marc T; Gronwald, Jacek; Hogdall, Estrid; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kjaer, Suzanne K; Kraft, Peter; Le, Nhu D; Levine, Douglas A; Lissowska, Jolanta; Lubinski, Jan; Matsuo, Keitaro; Menon, Usha; Modugno, Rosemary; Moysich, Kirsten B; Nakanishi, Toru; Ness, Roberta B; Olson, Sara; Orlow, Irene; Pearce, Celeste L; Pejovic, Tanja; Poole, Elizabeth M; Ramus, Susan J; Anne Rossing, Mary; Sandler, Dale P; Shu, Xiao-Ou; Song, Honglin; Taylor, Jack A; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tworoger, Shelley S; Webb, Penelope M; Wentzensen, Nicolas; Wilkens, Lynne R; Winham, Stacey; Woo, Yin-Ling; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Phelan, Catherine M; Schildkraut, Joellen M; Berchuck, Andrew; Goode, Ellen L; Pharoah, Paul D P; Sellers, Thomas A

2016-08-15

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10  -   7 ). One of the most significant signals (P all histologies  =   1.01 × 10  -   13 ;P serous  =   3.54 × 10  -   14 ) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r 2  =   0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10  -   5  >   P≥5.0 ×10  -   7 ) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (P AML  =   3.23 × 10  -   5 ; P SKAT-o  =   9.23 × 10  -   4 ) and KRT13 (P AML  =   1.67 × 10  -   4 ; P SKAT-o  =   1.07 × 10  -   5 ), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed

[Huntington's Disease in Balearic Islands Population-Based Registry of Rare Diseases: Prevalence and Mortality during the Period 2010-2013. Spain].

PubMed

Cáffaro Rovira, Mercedes; Salom Castell, M Magdalena

2017-02-16

Huntington's disease is a hereditary disease with low prevalence. The low frequency of Huntington's disease leads to its inclusion as one of the pathologies in the Registry of Rare Diseases. The Balearic Islands Population-based Registry of Rare Diseases began in 2010. Previously, there had been no prevalence or mortality data for Huntington's disease in the Balearic Islands. The aim of this study was to determine the prevalence and mortality of Huntington's disease in the Balearic Islands between 2010 and 2013. The data sources were the Balearic Islands Population-based Registry of Rare Diseases, from which the diagnosed cases were obtained; the Balearic Islands Mortality Register, from which the deceased cases were obtained; the Balearic Islands Health Service, from which the number of Health Cards was obtained; and the National Institute for Statistics, from which population data were obtained. Prevalence and mortality rates were calculated. The Balearic Islands Population-based Registry of Rare Diseases registered 27 cases of Huntington's disease between 2010-2013. 63% of these were women. The period prevalence rate was 2.6 per 100,000 and the period mortality rate was 1.1 per 100,000. Menorca was the island with the highest rates, the prevalence rate was 5,9 per 100,000 and the mortality rate was 2,1 per 100,000. Prevalence and mortality of Huntington's disease in the Balearic Islands are low compared to similar areas.

[An ophthalmologic diagnostic error leading to a rare systemic diagnosis: Erdheim-Chester disease].

PubMed

Gilles, M; Alberti, N; Seguy, C; Leger, F; Frulio, N; Pechmeja, J; Longueville, E; Korobelnik, J-F

2014-05-01

Erdheim-Chester disease is a rare systemic disease. The diagnosis is difficult due to significant clinical and morphological polymorphism. Orbital involvement is rare, but constitutes a classic means of detection. We report the case of a 60-year-old man, who consulted for evaluation of bilateral retro-orbital tumors. These tumors had been discovered on head CT two years previously during work-up of proptosis. Two biopsies were performed. The first one revealed polymorphous inflammatory tissue. The second one revealed intense granulomatous reaction, rich in non-specific foamy histiocytes. Thoracic-abdominal-pelvic CT scan detected peri-aortic and retroperitoneal infiltration. The association of these signs pointed to a diagnosis of Erdheim-Chester disease, confirmed by the re-examination of the histological samples. Erdheim-Chester disease is a rare non-Langerhans histiocytosis with a specific tropism for perivascular and fatty connective tissue. The cause is not known. The diagnosis of this systemic disease is histological. In the case of bilateral intra-orbital tumors, the diagnosis of Erdheim-Chester disease must be considered. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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

2015-12-07

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. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.

Towards the automated generation of expert profiles for rare diseases through bibliometric analysis.

PubMed

Pflugrad, Andreas; Jurkat-Rott, Karin; Lehmann-Horn, Frank; Bernauer, Jochen

2014-01-01

For patients suffering from rare diseases it is often hard to find an expert clinician. Existing registries rely on manual registration procedures and cannot easily be kept up to date. A prototype data collection system for discovering experts on rare diseases using MEDLINE has been successfully deployed. Initial manual analyses demonstrate proof of concept and deliver promising results. Examining the associations between authors, diseases and MeSH-Terms is expected to open up a variety of possibilities beyond expert discovery.

Giant pseudoaneurysm of the left ventricular outflow tract: a rare disease.

PubMed

Acioli Pereira, Larissa; Fontes Gontijo, Paula; Alcântara Farran, Jorge; Palandri Chagas, Antonio Carlos; Romano, Edson Renato; Bento de Souza, Luis Carlos

2013-06-01

Pseudoaneurysm of the left ventricular outflow tract (LVOT) is a rare disease with high morbidity and mortality, resulting from left ventricular damage due to myocardial infarction, infective endocarditis or surgical trauma. A case of giant pseudoaneurysm of the LVOT, even more rarely reported in the literature, is described. The lesion was detected 12 years after aortic valve replacement for infective endocarditis in a young patient, a former intravenous drug user. As it is an uncommon disease, little is known about its clinical presentation and treatment. Copyright © 2011 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Practical aspects of recruitment and retention in clinical trials of rare genetic diseases: the phenylketonuria (PKU) experience.

PubMed

DeWard, Stephanie J; Wilson, Ashley; Bausell, Heather; Volz, Ashley S; Mooney, Kimberly

2014-02-01

Bringing treatments for rare genetic diseases to patients requires clinical research. Despite increasing activism from patient support and advocacy groups to increase access to clinical research studies, connecting rare disease patients with the clinical research opportunities that may help them has proven challenging. Chief among these challenges are the low incidence of these diseases resulting in a very small pool of known patients with a particular disease, difficulty of diagnosing rare genetic diseases, logistical issues such as long distances to the nearest treatment center, and substantial disease burden leading to loss of independence. Using clinical studies of phenylketonuria as an example, this paper discusses how, based on the authors' collective experience, partnership among clinicians, patients, study coordinators, genetic counselors, dietitians, industry, patient support groups, and families can help overcome the challenges of recruiting and retaining patients in rare disease clinical trials. We discuss specific methods of collaboration, communication, and education as part of a long-term effort to build a community committed to advancing the medical care of patients with rare genetic diseases. By talking to patients and families regularly about research initiatives and taking steps to make study participation as easy as possible, rare disease clinic staff can help ensure adequate study enrollment and successful study completion.

[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.

Characterization of a rare Unverricht-Lundborg disease mutation.

PubMed

Duarte, Ana Joana; Ribeiro, Diogo; Chaves, João; Amaral, Olga

2015-09-01

Cystatin B (CSTB) gene mutations cause Unverricht-Lundborg disease (ULD), a rare form of myoclonic epilepsy. The previous identification of a Portuguese patient, homozygous for a unique splicing defect (c.66G > A; p.Q22Q), provided awareness regarding the existence of variant forms of ULD. In this work we aimed at the characterization of this mutation at the population level and at the cellular level. The cellular fractionation studies here carried out showed mislocalization of the protein and add to the knowledge on this disease.

Drug discovery and development for rare genetic disorders.

PubMed

Sun, Wei; Zheng, Wei; Simeonov, Anton

2017-09-01

Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated. © 2017 Wiley Periodicals, Inc.

Key outcomes from stakeholder workshops at a symposium to inform the development of an Australian national plan for rare diseases.

PubMed

Molster, Caron; Youngs, Leanne; Hammond, Emma; Dawkins, Hugh

2012-08-10

Calls have been made for governments to adopt a cohesive approach to rare diseases through the development of national plans. At present, Australia does not have a national plan for rare diseases. To progress such a plan an inaugural Australian Rare Diseases Symposium was held in Western Australia in April 2011. This paper describes the key issues identified by symposium attendees for the development of a national plan, compares these to the content of EUROPLAN and national plans elsewhere and discusses how the outcomes might be integrated for national planning. The symposium was comprised of a series of plenary sessions followed by workshops. The topics covered were; 1) Development of national plans for rare diseases; 2) Patient empowerment; 3) Patient care, support and management; 4) Research and translation; 5) Networks, partnerships and collaboration. All stakeholders within the rare diseases community were invited to participate, including: people affected by rare diseases such as patients, carers, and families; clinicians and allied health practitioners; social and disability services; researchers; patient support groups; industry (e.g. pharmaceutical, biotechnology and medical device companies); regulators and policy-makers. All of these stakeholder groups were represented at the symposium. Workshop participants indicated the need for a national plan, a national peak body, a standard definition of 'rare diseases', education campaigns, lobbying of government, research infrastructure, streamlined whole-of-lifetime service provision, case co-ordination, early diagnosis, support for health professionals and dedicated funding. These findings are consistent with frameworks and initiatives being undertaken internationally (such as EUROPLAN), and with national plans in other countries. This implies that the development of an Australian national plan could plausibly draw on frameworks for plan development that have been proposed for use in other jurisdictions. The

NGS Technologies as a Turning Point in Rare Disease Research, Diagnosis and Treatment

PubMed Central

Fernández-Marmiesse, Ana; Gouveia, Sofía; Couce, María L.

2018-01-01

Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Aus-tralian population have a rare disease. Rare diseases are thus a common problem for clini-cians and account for enormous healthcare costs worldwide due to the difficulty of establish-ing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedent-ed, simple way of discovering novel disease-associated genes. We focus particularly on meta-bolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide pheno-typic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the sec-ond part of the review, we look at the limitations and challenges of NGS, including determina-tion of variant causality, the loss of variants in coding and non-coding regions, and the detec-tion of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future. PMID:28721829

NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment.

PubMed

Fernandez-Marmiesse, Ana; Gouveia, Sofia; Couce, Maria L

2018-01-30

Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Australian population have a rare disease. Rare diseases are thus a common problem for clinicians and account for enormous healthcare costs worldwide due to the difficulty of establishing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedented, simple way of discovering novel disease-associated genes. We focus particularly on metabolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide phenotypic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the second part of the review, we look at the limitations and challenges of NGS, including determination of variant causality, the loss of variants in coding and non-coding regions, and the detection of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer's disease.

PubMed

Bonham, Luke W; Sirkis, Daniel W; Fan, Jia; Aparicio, Renan E; Tse, Marian; Ramos, Eliana Marisa; Wang, Qing; Coppola, Giovanni; Rosen, Howard J; Miller, Bruce L; Yokoyama, Jennifer S

2017-02-01

Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer's disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD. We characterized this variant using biochemical cell surface expression assays and found that it significantly altered cell surface expression of the TREM2 protein. Together these data provide evidence that the A192T variant in TREM2 could contribute risk for AD. This study underscores the increasingly recognized role of immune-related processes in AD and highlights the importance of including diverse populations in research to identify genetic variation that contributes risk for AD and other neurodegenerative disorders.

Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases

PubMed Central

Shi, Liang; Cui, Yazhou; Luan, Jing; Zhou, Xiaoyan; Han, Jinxiang

2016-01-01

Summary Rare diseases with a low prevalence are a key public health issue because the causes of those diseases are difficult to determine and those diseases lack a clearly established or curative treatment. Thus, investigating the molecular mechanisms that underlie the pathology of rare diseases and facilitating the development of novel therapies using disease models is crucial. Human induced pluripotent stem cells (iPSCs) are well suited to modeling rare diseases since they have the capacity for self-renewal and pluripotency. In addition, iPSC technology provides a valuable tool to generate patient-specific iPSCs. These cells can be differentiated into cell types that have been affected by a disease. These cells would circumvent ethical concerns and avoid immunological rejection, so they could be used in cell replacement therapy or regenerative medicine. To date, human iPSCs could have been generated from multiple donor sources, such as skin, adipose tissue, and peripheral blood. However, these cells are obtained via invasive procedures. In contrast, several groups of researchers have found that urine may be a better source for producing iPSCs from normal individuals or patients. This review discusses urinary iPSC (UiPSC) as a candidate for modeling rare diseases. Cells obtained from urine have overwhelming advantages compared to other donor sources since they are safely, affordably, and frequently obtained and they are readily obtained from patients. The use of iPSC-based models is also discussed. UiPSCs may prove to be a key means of modeling rare diseases and they may facilitate the treatment of those diseases in the future. PMID:27672542

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.

Linked Registries: Connecting Rare Diseases Patient Registries through a Semantic Web Layer

PubMed Central

González-Castro, Lorena; Carta, Claudio; van der Horst, Eelke; Lopes, Pedro; Kaliyaperumal, Rajaram; Thompson, Mark; Thompson, Rachel; Queralt-Rosinach, Núria; Lopez, Estrella; Wood, Libby; Robertson, Agata; Lamanna, Claudia; Gilling, Mette; Orth, Michael; Merino-Martinez, Roxana; Taruscio, Domenica; Lochmüller, Hanns

2017-01-01

Patient registries are an essential tool to increase current knowledge regarding rare diseases. Understanding these data is a vital step to improve patient treatments and to create the most adequate tools for personalized medicine. However, the growing number of disease-specific patient registries brings also new technical challenges. Usually, these systems are developed as closed data silos, with independent formats and models, lacking comprehensive mechanisms to enable data sharing. To tackle these challenges, we developed a Semantic Web based solution that allows connecting distributed and heterogeneous registries, enabling the federation of knowledge between multiple independent environments. This semantic layer creates a holistic view over a set of anonymised registries, supporting semantic data representation, integrated access, and querying. The implemented system gave us the opportunity to answer challenging questions across disperse rare disease patient registries. The interconnection between those registries using Semantic Web technologies benefits our final solution in a way that we can query single or multiple instances according to our needs. The outcome is a unique semantic layer, connecting miscellaneous registries and delivering a lightweight holistic perspective over the wealth of knowledge stemming from linked rare disease patient registries. PMID:29214177

Linked Registries: Connecting Rare Diseases Patient Registries through a Semantic Web Layer.

PubMed

Sernadela, Pedro; González-Castro, Lorena; Carta, Claudio; van der Horst, Eelke; Lopes, Pedro; Kaliyaperumal, Rajaram; Thompson, Mark; Thompson, Rachel; Queralt-Rosinach, Núria; Lopez, Estrella; Wood, Libby; Robertson, Agata; Lamanna, Claudia; Gilling, Mette; Orth, Michael; Merino-Martinez, Roxana; Posada, Manuel; Taruscio, Domenica; Lochmüller, Hanns; Robinson, Peter; Roos, Marco; Oliveira, José Luís

2017-01-01

Patient registries are an essential tool to increase current knowledge regarding rare diseases. Understanding these data is a vital step to improve patient treatments and to create the most adequate tools for personalized medicine. However, the growing number of disease-specific patient registries brings also new technical challenges. Usually, these systems are developed as closed data silos, with independent formats and models, lacking comprehensive mechanisms to enable data sharing. To tackle these challenges, we developed a Semantic Web based solution that allows connecting distributed and heterogeneous registries, enabling the federation of knowledge between multiple independent environments. This semantic layer creates a holistic view over a set of anonymised registries, supporting semantic data representation, integrated access, and querying. The implemented system gave us the opportunity to answer challenging questions across disperse rare disease patient registries. The interconnection between those registries using Semantic Web technologies benefits our final solution in a way that we can query single or multiple instances according to our needs. The outcome is a unique semantic layer, connecting miscellaneous registries and delivering a lightweight holistic perspective over the wealth of knowledge stemming from linked rare disease patient registries.

A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?

PubMed

Rath, Ana; Salamon, Valérie; Peixoto, Sandra; Hivert, Virginie; Laville, Martine; Segrestin, Berenice; Neugebauer, Edmund A M; Eikermann, Michaela; Bertele, Vittorio; Garattini, Silvio; Wetterslev, Jørn; Banzi, Rita; Jakobsen, Janus C; Djurisic, Snezana; Kubiak, Christine; Demotes-Mainard, Jacques; Gluud, Christian

2017-11-22

Evidence-based clinical practice is challenging in all fields, but poses special barriers in the field of rare diseases. The present paper summarises the main barriers faced by clinical research in rare diseases, and highlights opportunities for improvement. Systematic literature searches without meta-analyses and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. Barriers specific to rare diseases comprise the difficulty to recruit participants because of rarity, scattering of patients, limited knowledge on natural history of diseases, difficulties to achieve accurate diagnosis and identify patients in health information systems, and difficulties choosing clinically relevant outcomes. Evidence-based clinical practice for rare diseases should start by collecting clinical data in databases and registries; defining measurable patient-centred outcomes; and selecting appropriate study designs adapted to small study populations. Rare diseases constitute one of the most paradigmatic fields in which multi-stakeholder engagement, especially from patients, is needed for success. Clinical research infrastructures and expertise networks offer opportunities for establishing evidence-based clinical practice within rare diseases.

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. © 2012 Wiley Periodicals, Inc.

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. Copyright © 2015, American Association for the Advancement of Science.

Sequencing ASMT identifies rare mutations in Chinese Han patients with autism.

PubMed

Wang, Lifang; Li, Jun; Ruan, Yanyan; Lu, Tianlan; Liu, Chenxing; Jia, Meixiang; Yue, Weihua; Liu, Jing; Bourgeron, Thomas; Zhang, Dai

2013-01-01

Melatonin is involved in the regulation of circadian and seasonal rhythms and immune function. Prior research reported low melatonin levels in autism spectrum disorders (ASD). ASMT located in pseudo-autosomal region 1 encodes the last enzyme of the melatonin biosynthesis pathway. A previous study reported an association between ASD and single nucleotide polymorphisms (SNPs) rs4446909 and rs5989681 located in the promoter of ASMT. Furthermore, rare deleterious mutations were identified in a subset of patients. To investigate the association between ASMT and autism, we sequenced all ASMT exons and its neighboring region in 398 Chinese Han individuals with autism and 437 healthy controls. Although our study did not detect significant differences of genotypic distribution and allele frequencies of the common SNPs in ASMT between patients with autism and healthy controls, we identified new rare coding mutations of ASMT. Among these rare variants, 4 were exclusively detected in patients with autism including a stop mutation (p.R115W, p.V166I, p.V179G, and p.W257X). These four coding variants were observed in 6 of 398 (1.51%) patients with autism and none in 437 controls (Chi-Square test, Continuity Correction p = 0.032, two-sided). Functional prediction of impact of amino acid showed that p.R115W might affect protein function. These results indicate that ASMT might be a susceptibility gene for autism. Further studies in larger samples are needed to better understand the degree of variation in this gene as well as to understand the biochemical and clinical impacts of ASMT/melatonin deficiency.

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

PubMed

Carss, Keren J; Arno, Gavin; Erwood, Marie; Stephens, Jonathan; Sanchis-Juan, Alba; Hull, Sarah; Megy, Karyn; Grozeva, Detelina; Dewhurst, Eleanor; Malka, Samantha; Plagnol, Vincent; Penkett, Christopher; Stirrups, Kathleen; Rizzo, Roberta; Wright, Genevieve; Josifova, Dragana; Bitner-Glindzicz, Maria; Scott, Richard H; Clement, Emma; Allen, Louise; Armstrong, Ruth; Brady, Angela F; Carmichael, Jenny; Chitre, Manali; Henderson, Robert H H; Hurst, Jane; MacLaren, Robert E; Murphy, Elaine; Paterson, Joan; Rosser, Elisabeth; Thompson, Dorothy A; Wakeling, Emma; Ouwehand, Willem H; Michaelides, Michel; Moore, Anthony T; Webster, Andrew R; Raymond, F Lucy

2017-01-05

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease. Copyright © 2017. Published by Elsevier Inc.

Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.

PubMed

Bruse, Shannon; Moreau, Michael; Bromberg, Yana; Jang, Jun-Ho; Wang, Nan; Ha, Hongseok; Picchi, Maria; Lin, Yong; Langley, Raymond J; Qualls, Clifford; Klensney-Tait, Julia; Zabner, Joseph; Leng, Shuguang; Mao, Jenny; Belinsky, Steven A; Xing, Jinchuan; Nyunoya, Toru

2016-01-07

Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15-20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes. We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro. Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2 and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility.

Identifying and Caring for Rare Books in the Community or Junior College with No Special Collections Department.

ERIC Educational Resources Information Center

Visser, Michelle

2003-01-01

Discusses issues of identifying, storing, handling, and providing access to rare books and materials in institutions without special collections departments. Suggests that although many community colleges do not collect rare materials, they may nonetheless be in possession of books that are rare and that should receive special care. (ontains four…

Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing

PubMed Central

Lal, Dennis; Neubauer, Bernd A.; Toliat, Mohammad R.; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Kamrath, Clemens; Schänzer, Anne; Sander, Thomas; Hahn, Andreas; Nothnagel, Michael

2016-01-01

Massively parallel sequencing of whole genomes and exomes has facilitated a direct assessment of causative genetic variation, now enabling the identification of genetic factors involved in rare diseases (RD) with Mendelian inheritance patterns on an almost routine basis. Here, we describe the illustrative case of a single consanguineous family where this strategy suffered from the difficulty to distinguish between two etiologically distinct disorders, namely the co-occurrence of hereditary hypophosphatemic rickets (HRR) and congenital myopathies (CM), by their phenotypic manifestation alone. We used parametric linkage analysis, homozygosity mapping and whole exome-sequencing to identify mutations underlying HRR and CM. We also present an approximate approach for assessing the probability of co-occurrence of two unlinked recessive RD in a single family as a function of the degree of consanguinity and the frequency of the disease-causing alleles. Linkage analysis and homozygosity mapping yielded elusive results when assuming a single RD, but whole-exome sequencing helped to identify two mutations in two genes, namely SLC34A3 and SEPN1, that segregated independently in this family and that have previously been linked to two etiologically different diseases. We assess the increase in chance co-occurrence of rare diseases due to consanguinity, i.e. under circumstances that generally favor linkage mapping of recessive disease, and show that this probability can increase by several orders of magnitudes. We conclude that such potential co-occurrence represents an underestimated risk when analyzing rare or undefined diseases in consanguineous families and should be given more consideration in the clinical and genetic evaluation. PMID:26789268

[Difficulties of genetic counselling in rare, mainly neurogenetic disorders].

PubMed

Horváth, Emese; Nagy, Nikoletta; Széll, Márta

2014-08-03

In recent decades methods used for the investigation of the genetic background of rare diseases showed a great improvement. The aim of the authors was to demonstrate difficulties of genetic counselling and investigations in case of five rare, mainly neurogenetic diseases. During pre-test genetic counselling, the disease suspected from the clinical symptoms and the available genetic tests were considered. During post-test genetic counselling, the results of the genetic tests were discussed. In three of the five cases genetic tests identified the disease-causing genetic abnormalities, while in two cases the causative abnormalities were not identified. Despite a great improvement of the available genetic methods, the causative genetic abnormalities cannot be identified in some cases. The genetic counsellor has a key role in the assessment and interpretation of the results and in helping the family planning.

Using extreme phenotype sampling to identify the rare causal variants of quantitative traits in association studies.

PubMed

Li, Dalin; Lewinger, Juan Pablo; Gauderman, William J; Murcray, Cassandra Elizabeth; Conti, David

2011-12-01

Variants identified in recent genome-wide association studies based on the common-disease common-variant hypothesis are far from fully explaining the hereditability of complex traits. Rare variants may, in part, explain some of the missing hereditability. Here, we explored the advantage of the extreme phenotype sampling in rare-variant analysis and refined this design framework for future large-scale association studies on quantitative traits. We first proposed a power calculation approach for a likelihood-based analysis method. We then used this approach to demonstrate the potential advantages of extreme phenotype sampling for rare variants. Next, we discussed how this design can influence future sequencing-based association studies from a cost-efficiency (with the phenotyping cost included) perspective. Moreover, we discussed the potential of a two-stage design with the extreme sample as the first stage and the remaining nonextreme subjects as the second stage. We demonstrated that this two-stage design is a cost-efficient alternative to the one-stage cross-sectional design or traditional two-stage design. We then discussed the analysis strategies for this extreme two-stage design and proposed a corresponding design optimization procedure. To address many practical concerns, for example measurement error or phenotypic heterogeneity at the very extremes, we examined an approach in which individuals with very extreme phenotypes are discarded. We demonstrated that even with a substantial proportion of these extreme individuals discarded, an extreme-based sampling can still be more efficient. Finally, we expanded the current analysis and design framework to accommodate the CMC approach where multiple rare-variants in the same gene region are analyzed jointly. © 2011 Wiley Periodicals, Inc.

Using Extreme Phenotype Sampling to Identify the Rare Causal Variants of Quantitative Traits in Association Studies

PubMed Central

Li, Dalin; Lewinger, Juan Pablo; Gauderman, William J.; Murcray, Cassandra Elizabeth; Conti, David

2014-01-01

Variants identified in recent genome-wide association studies based on the common-disease common-variant hypothesis are far from fully explaining the hereditability of complex traits. Rare variants may, in part, explain some of the missing hereditability. Here, we explored the advantage of the extreme phenotype sampling in rare-variant analysis and refined this design framework for future large-scale association studies on quantitative traits. We first proposed a power calculation approach for a likelihood-based analysis method. We then used this approach to demonstrate the potential advantages of extreme phenotype sampling for rare variants. Next, we discussed how this design can influence future sequencing-based association studies from a cost-efficiency (with the phenotyping cost included) perspective. Moreover, we discussed the potential of a two-stage design with the extreme sample as the first stage and the remaining nonextreme subjects as the second stage. We demonstrated that this two-stage design is a cost-efficient alternative to the one-stage cross-sectional design or traditional two-stage design. We then discussed the analysis strategies for this extreme two-stage design and proposed a corresponding design optimization procedure. To address many practical concerns, for example measurement error or phenotypic heterogeneity at the very extremes, we examined an approach in which individuals with very extreme phenotypes are discarded. We demonstrated that even with a substantial proportion of these extreme individuals discarded, an extreme-based sampling can still be more efficient. Finally, we expanded the current analysis and design framework to accommodate the CMC approach where multiple rare-variants in the same gene region are analyzed jointly. PMID:21922541

[The use of Facebook in Spanish associations of rare diseases: how and what is it used for?].

PubMed

Armayones, Manuel; Requena, Samantha; Gómez-Zúñiga, Beni; Pousada, Modesta; Bañón, Antonio M

2015-01-01

To study whether the use of Facebook is widespread in the field of patient associations for rare diseases and, if so, the purpose for which the site is being used. A descriptive study was conducted to determine whether associations within the Spanish Federation for Rare Diseases use Facebook and, if so, the type of use and its objectives. The analysis was performed based on a categorization system that has been used in the field of chronic diseases and has been adapted to the specific characteristics of rare diseases. Associations use Facebook to raise awareness of rare diseases in general and particularly to share content related to psychological, medical and social support, the promotion and dissemination of research, and fundraising. The alignment between the interests of associations through their presence on Facebook and policy areas of the national strategy for rare diseases is a reason for optimism about the feasibility of using Facebook as a tool for encounters and collaborative work. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

Comparison of different approaches applied in Analytic Hierarchy Process - an example of information needs of patients with rare diseases.

PubMed

Pauer, Frédéric; Schmidt, Katharina; Babac, Ana; Damm, Kathrin; Frank, Martin; von der Schulenburg, J-Matthias Graf

2016-09-09

The Analytic Hierarchy Process (AHP) is increasingly used to measure patient priorities. Studies have shown that there are several different approaches to data acquisition and data aggregation. The aim of this study was to measure the information needs of patients having a rare disease and to analyze the effects of these different AHP approaches. The ranking of information needs is then used to display information categories on a web-based information portal about rare diseases according to the patient's priorities. The information needs of patients suffering from rare diseases were identified by an Internet research study and a preliminary qualitative study. Hence, we designed a three-level hierarchy containing 13 criteria. For data acquisition, the differences in outcomes were investigated using individual versus group judgements separately. Furthermore, we analyzed the different effects when using the median and arithmetic and geometric means for data aggregation. A consistency ratio ≤0.2 was determined to represent an acceptable consistency level. Forty individual and three group judgements were collected from patients suffering from a rare disease and their close relatives. The consistency ratio of 31 individual and three group judgements was acceptable and thus these judgements were included in the study. To a large extent, the local ranks for individual and group judgements were similar. Interestingly, group judgements were in a significantly smaller range than individual judgements. According to our data, the ranks of the criteria differed slightly according to the data aggregation method used. It is important to explain and justify the choice of an appropriate method for data acquisition because response behaviors differ according to the method. We conclude that researchers should select a suitable method based on the thematic perspective or investigated topics in the study. Because the arithmetic mean is very vulnerable to outliers, the geometric mean

Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil.

PubMed

Gibbon, Sahra; Aureliano, Waleska

2018-04-01

Within the context of a globalising agenda for genetic research where 'global health' is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases 'rarenesss' has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the 'judicialisation' of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities.

Repurposing of Proton Pump Inhibitors as first identified small molecule inhibitors of endo-β-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease.

PubMed

Bi, Yiling; Might, Matthew; Vankayalapati, Hariprasad; Kuberan, Balagurunathan

2017-07-01

N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears. Unfortunately, there has not been any therapeutic option available for this rare disease so far. Recently, a proposed molecular mechanism for NGLY1 deficiency suggested that endo-β-N-acetylglucosaminidase (ENGase) inhibitors may be promising therapeutics for NGLY1 patients. Herein, we performed structure-based virtual screening utilizing FDA-approved drug database on this ENGase target to enable repurposing of existing drugs. Several Proton Pump Inhibitors (PPIs), a series of substituted 1H-benzo [d] imidazole, and 1H-imidazo [4,5-b] pyridines, among other scaffolds, have been identified as potent ENGase inhibitors. An electrophoretic mobility shift assay was employed to assess the inhibition of ENGase activity by these PPIs. Our efforts led to the discovery of Rabeprazole Sodium as the most promising hit with an IC 50 of 4.47±0.44μM. This is the first report that describes the discovery of small molecule ENGase inhibitors, which can potentially be used for the treatment of human NGLY1 deficiency. Copyright © 2017 Elsevier Ltd. All rights reserved.

Disease transmission by cannibalism: rare event or common occurrence?

PubMed

Rudolf, Volker H W; Antonovics, Janis

2007-05-07

Cannibalism has been documented as a possible disease transmission route in several species, including humans. However, the dynamics resulting from this type of disease transmission are not well understood. Using a theoretical model, we explore how cannibalism (i.e. killing and consumption of dead conspecifics) and intraspecific necrophagy (i.e. consumption of dead conspecifics) affect host-pathogen dynamics. We show that group cannibalism, i.e. shared consumption of victims, is a necessary condition for disease spread by cannibalism in the absence of alternative transmission modes. Thus, endemic diseases transmitted predominantly by cannibalism are likely to be rare, except in social organisms that share conspecific prey. These results are consistent with a review of the literature showing that diseases transmitted by cannibalism are infrequent in animals, even though both cannibalism and trophic transmission are very common.

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. © 2014 Wiley Periodicals, Inc.

Identifying Future Disease Hot Spots: Infectious Disease Vulnerability Index.

PubMed

Moore, Melinda; Gelfeld, Bill; Okunogbe, Adeyemi; Paul, Christopher

2017-06-01

Recent high-profile outbreaks, such as Ebola and Zika, have illustrated the transnational nature of infectious diseases. Countries that are most vulnerable to such outbreaks might be higher priorities for technical support. RAND created the Infectious Disease Vulnerability Index to help U.S. government and international agencies identify these countries and thereby inform programming to preemptively help mitigate the spread and effects of potential transnational outbreaks. The authors employed a rigorous methodology to identify the countries most vulnerable to disease outbreaks. They conducted a comprehensive review of relevant literature to identify factors influencing infectious disease vulnerability. Using widely available data, the authors created an index for identifying potentially vulnerable countries and then ranked countries by overall vulnerability score. Policymakers should focus on the 25 most-vulnerable countries with an eye toward a potential "disease belt" in the Sahel region of Africa. The infectious disease vulnerability scores for several countries were better than what would have been predicted on the basis of economic status alone. This suggests that low-income countries can overcome economic challenges and become more resilient to public health challenges, such as infectious disease outbreaks.

Pylephlebitis and Crohn's disease: A rare case of septic shock.

PubMed

Scaringi, Stefano; Giudici, Francesco; Gabbani, Giacomo; Zambonin, Daniela; Morelli, Marco; Carrà, Rossella; Bechi, Paolo

2017-01-01

Troncular pylephlebitis, defined as septic thrombophlebitis of the portal vein, is usually secondary to suppurative infection from the regions drained by the portal system. Therefore, pylephlebitis can occur from the portal vein main tributaries. The occurrence of mesenteric pylephlebitis in Crohn's disease is extremely rare. We describe a case of septic shock due to mesenteric pylephlebitis in a 47 years old male affected with Crohn's disease. The patient was admitted to the emergency department after he had been complained from 3h of a peri-umbilical abdominal pain associated to fever and shivering quickly followed by a severe hypotension. His medical history included histologically confirmed ileal Crohn's disease diagnosed 4 years before and treated with mesalamine only. Computed tomography scan confirmed the mesenteric pylephlebitis diagnosis. After medical therapy with antibiotics and systemic nutrition, the patient was successfully operated to treat his ileal Crohn's disease. In our case, the quick onset of a septic shock was not due to a peritonitis complicating a Crohn's disease, but to a rare condition not needing an urgent surgical resolution. This report shows that, even in Crohn's disease, once diagnosis is performed, antibiotic therapy associated to enteral and parenteral nutrition can lead to a complete clinical remission of mesenteric pylephlebitis, mandatory to perform an elective surgery. This case highlights the importance of promptly considerate and treat mesenteric pylephlebitis in presence of a septic shock in a Crohn's disease patient who is not showing clinical signs of peritonitis. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Rare endocrine cancers have novel genetic alterations

Cancer.gov

A molecular characterization of adrenocortical carcinoma, a rare cancer of the adrenal cortex, analyzed 91 cases for alterations in the tumor genomes and identified several novel genetic mutations as likely mechanisms driving the disease as well as whole genome doubling as a probable driver of the disease.

Inclusion and exclusion in the globalisation of genomics; the case of rare genetic disease in Brazil

PubMed Central

Gibbon, Sahra

2018-01-01

ABSTRACT Within the context of a globalising agenda for genetic research where ‘global health’ is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care. It examines how in these different cases ‘rarenesss’ has been diversely situated and differently politicised and how clinicians, patients and their families grapple with the slippery boundaries between research, rights to health and the limits of care, therapy or prevention. It illustrates how attention to rare genetic disease in Brazil emerges at the intersection of a particular history of genetic research and public health infrastructure, densely complicated feedback loops between clinical care and research, patient mobilisation around the ‘judicialisation’ of health and recent state legislation regarding rare disease in Brazil. It highlights the relevance of local configurations in the way rare genetic disease is being made relevant for and by different communities. PMID:29533091

Researchers identify potential therapeutic targets for a rare childhood cancer | Center for Cancer Research

Cancer.gov

CCR researchers have identified the mechanism behind a rare but extremely aggressive childhood cancer called alveolar rhabdomyosarcoma (ARMS) and have pinpointed a potential drug target for its treatment. Learn more...

Identifying Candidate Chemical-Disease Linkages ...

EPA Pesticide Factsheets

Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment. Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment.

Disease transmission by cannibalism: rare event or common occurrence?

PubMed Central

Rudolf, Volker H.W; Antonovics, Janis

2007-01-01

Cannibalism has been documented as a possible disease transmission route in several species, including humans. However, the dynamics resulting from this type of disease transmission are not well understood. Using a theoretical model, we explore how cannibalism (i.e. killing and consumption of dead conspecifics) and intraspecific necrophagy (i.e. consumption of dead conspecifics) affect host–pathogen dynamics. We show that group cannibalism, i.e. shared consumption of victims, is a necessary condition for disease spread by cannibalism in the absence of alternative transmission modes. Thus, endemic diseases transmitted predominantly by cannibalism are likely to be rare, except in social organisms that share conspecific prey. These results are consistent with a review of the literature showing that diseases transmitted by cannibalism are infrequent in animals, even though both cannibalism and trophic transmission are very common. PMID:17327205

Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases.

PubMed

Stein, Susan; Bogard, Elizabeth; Boice, Nicole; Fernandez, Vivian; Field, Tessa; Gilstrap, Alan; Kahn, Susan R; Larkindale, Jane; Mathieson, Toni

2018-01-22

Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Patient advocacy organizations may play a major role by positively influencing research and development, clinical trials, and regulations. Thus, collaboration among patient advocacy organizations and industry is essential to bring new therapeutics to patients. We identified an unmet need for guidelines on day-to-day decision-making by rare disease patient advocacy organizations when working with biopharmaceutical partners. We convened an Independent Expert Panel experienced in collaborations between patient advocacy organizations and biopharmaceutical companies (April 2017) to develop consensus guidelines for these relationships. The guidelines were based on an original version by the International Fibrodysplasia Ossificans Progressiva Association (IFOPA). The Expert Panel reviewed and broadened these to be applicable to all patient advocacy organizations. Comments on the draft Guidelines were provided first by Panel participants and subsequently by six independent experts from patient advocacy organizations and industry. The Panel comprised four experts from the rare disease community who lead patient advocacy organizations; three leaders who perform advocacy functions within biopharmaceutical companies; and two facilitators, both having leadership experience in rare diseases and industry. The finalized Guidelines consist of four main sections: Identification and Engagement With Companies, Patient Engagement and Patient Privacy, Financial Contributions, and Clinical Trial Communication and Support. The Guidelines address the daily considerations, choices, and consequences of patient advocacy organizations as they engage with biopharmaceutical

78 FR 58311 - Complex Issues in Developing Drug and Biological Products for Rare Diseases; Public Workshop...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-23

...] Complex Issues in Developing Drug and Biological Products for Rare Diseases; Public Workshop; Request for... Issues in Developing Drug and Biological Products for Rare Diseases.'' The purpose of the public workshop is twofold: To discuss complex issues in clinical trials for developing drug and biological products...

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. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Marking 15 years of the Genetic and Rare Diseases Information Center

PubMed Central

Lewis, Janine; Snyder, Michelle; Hyatt-Knorr, Henrietta

2017-01-01

BACKGROUND: The Genetic and Rare Diseases Information Center (GARD), a program of the National Center for Advancing Translational Sciences, was established in 2002 to assist the public in finding reliable, timely, and easy-to-understand information about genetic and/or rare diseases in English or Spanish. OBJECTIVE: A review of longitudinal data on GARD inquiries from 2002 to 2016 and assessment of the results of two user satisfaction surveys were conducted to understand the demographics and needs of GARD customers over time. METHODS: Since 2002, GARD has collected anonymized data while responding to questions received via e-mail, website, telephone, fax, letter, or TTY. Between 2002 and 2016 GARD received a total of 60,106 inquiries. User satisfaction surveys were conducted in 2006 and 2014, in which users self-selected to participate. RESULTS: The annual number of inquiries has risen steadily since 2002. Inquiries are overwhelmingly from educated female patients, family, and friends seeking disease-specific information, treatment options, referrals, and research studies. Most users report satisfaction with the experience. CONCLUSIONS: Rare disease patients and their families face challenges in finding information about their symptoms or diagnosis, prognosis, treatment options, significance for family members, and research opportunities. Lack of available clinical expertise can leave patients, their family, and friends with little choice but to become knowledgeable on their own. GARD fills a critical need by providing the public with vetted, evidence-based information that empowers people to engage in their own health care and seek research studies of relevance. PMID:29152459

Application of a policy framework for the public funding of drugs for rare diseases.

PubMed

Winquist, Eric; Coyle, Doug; Clarke, Joe T R; Evans, Gerald A; Seager, Christine; Chan, Winnie; Martin, Janet

2014-08-01

In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs. To report the initial experience of applying a novel evaluation framework to funding applications for drugs for rare diseases. Retrospective observational cohort study. Clinical effectiveness, costs, funding recommendations, funding approval. Between March 2008 and February 2013, eight drugs were evaluated using the DRDWG framework. The estimated average annual drug cost per patient ranged from 28,000 to 1,200,000 Canadian dollars (CAD). For five drugs, full evaluations were completed, specific funding recommendations were made by the DRDWG, and funding was approved after risk-sharing agreements with the manufacturers were negotiated. For two drugs, the disease indications were determined to be ineligible for consideration. For one drug, there was insufficient natural history data for the disease to provide a basis for recommendation. For the five drugs fully evaluated, 32 patients met the predefined eligibility criteria for funding, and five were denied based on predefined exclusion criteria. The framework improved transparency and consistency for evaluation and public funding of drugs for rare diseases in Ontario. The evaluation process will continue to be iteratively refined as feedback on actual versus expected clinical and economic outcomes is incorporated.

Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease

PubMed Central

Soemedi, Rachel; Wilson, Ian J.; Bentham, Jamie; Darlay, Rebecca; Töpf, Ana; Zelenika, Diana; Cosgrove, Catherine; Setchfield, Kerry; Thornborough, Chris; Granados-Riveron, Javier; Blue, Gillian M.; Breckpot, Jeroen; Hellens, Stephen; Zwolinkski, Simon; Glen, Elise; Mamasoula, Chrysovalanto; Rahman, Thahira J.; Hall, Darroch; Rauch, Anita; Devriendt, Koenraad; Gewillig, Marc; O’ Sullivan, John; Winlaw, David S.; Bu’Lock, Frances; Brook, J. David; Bhattacharya, Shoumo; Lathrop, Mark; Santibanez-Koref, Mauro; Cordell, Heather J.; Goodship, Judith A.; Keavney, Bernard D.

2012-01-01

Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 × 10−5). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ∼5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., HAND2 and GJA5). Rare genic deletions contribute ∼4% of the population-attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias. PMID:22939634

The Supportive Care Needs of Parents With a Child With a Rare Disease: A Qualitative Descriptive Study.

PubMed

Pelentsov, Lemuel J; Fielder, Andrea L; Esterman, Adrian J

2016-01-01

There are few studies that exist which focus specifically on parents with a child with a rare disease. The purpose of this study was to better understand the lived experiences and supportive care needs (SCN) of parents caring for a child across a spectrum of rare diseases. A qualitative descriptive approach was used to guide the research, and four semi-structured focus group interviews were conducted with 23 parents (17 mothers and 6 fathers). Participants described 'feeling boxed-in outside the box' due to a number of limitations unique to their child's disease, daily practical challenges in providing care and the various relational impacts of caring for a child with a rare disease were discussed. The results from this study help to give clearer direction for health professionals on where to focus future efforts in better meeting the supportive care needs of parents and their child with a rare disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Programmed Sports Therapy (PST) in People with Haemophilia (PwH) "Sports Therapy Model for Rare Diseases".

PubMed

Hilberg, Thomas

2018-03-05

Sports and exercise therapy becomes more and more integrated in the treatment plan of different diseases. Although the benefits of this therapy are of high quality evidence, e.g. in cardiovascular diseases, no concepts of sports therapy are available as a treatment option for rare diseases.During the last eighteen years, we analyzed the situation as well as necessity, and developed a model, contents and the concept of the "Programmed Sports Therapy (PST)" for the treatment of PwH (people with haemophilia) as our model of rare disease. Many studies have shown that motoric skills are depressed in PwH, and that this gap to healthy people increases during age. The only way to reduce this progression is an appropriate therapy, adapted to the necessities of PwH. In haemophilia, in particular, physio- and sports therapy treatments should go hand in hand, the first in the acute phase after bleeding, the second later, after the acute phase has finished. One model, which considers all the different challenges, can be the cogwheel model presented here. Since haemophilia is a rare disease, new training concepts are necessary because classical group therapies are often impossible. PST based on the combination of sports therapy camps together with a supervised autonomous home training helps to directly bring the training to the trainee, in order to enhance key competences and improve the individual situation in PwH, and perhaps in patients with other rare diseases.The experience and scientific data substantiate the success of "Programmed Sports Therapy (PST)" and even this can be a model for other rare diseases.

Rare-Variant Association Analysis: Study Designs and Statistical Tests

PubMed Central

Lee, Seunggeung; Abecasis, Gonçalo R.; Boehnke, Michael; Lin, Xihong

2014-01-01

Despite the extensive discovery of trait- and disease-associated common variants, much of the genetic contribution to complex traits remains unexplained. Rare variants can explain additional disease risk or trait variability. An increasing number of studies are underway to identify trait- and disease-associated rare variants. In this review, we provide an overview of statistical issues in rare-variant association studies with a focus on study designs and statistical tests. We present the design and analysis pipeline of rare-variant studies and review cost-effective sequencing designs and genotyping platforms. We compare various gene- or region-based association tests, including burden tests, variance-component tests, and combined omnibus tests, in terms of their assumptions and performance. Also discussed are the related topics of meta-analysis, population-stratification adjustment, genotype imputation, follow-up studies, and heritability due to rare variants. We provide guidelines for analysis and discuss some of the challenges inherent in these studies and future research directions. PMID:24995866

Using whole-exome sequencing to identify variants inherited from mosaic parents

PubMed Central

Rios, Jonathan J; Delgado, Mauricio R

2015-01-01

Whole-exome sequencing (WES) has allowed the discovery of genes and variants causing rare human disease. This is often achieved by comparing nonsynonymous variants between unrelated patients, and particularly for sporadic or recessive disease, often identifies a single or few candidate genes for further consideration. However, despite the potential for this approach to elucidate the genetic cause of rare human disease, a majority of patients fail to realize a genetic diagnosis using standard exome analysis methods. Although genetic heterogeneity contributes to the difficulty of exome sequence analysis between patients, it remains plausible that rare human disease is not caused by de novo or recessive variants. Multiple human disorders have been described for which the variant was inherited from a phenotypically normal mosaic parent. Here we highlight the potential for exome sequencing to identify a reasonable number of candidate genes when dominant disease variants are inherited from a mosaic parent. We show the power of WES to identify a limited number of candidate genes using this disease model and how sequence coverage affects identification of mosaic variants by WES. We propose this analysis as an alternative to discover genetic causes of rare human disorders for which typical WES approaches fail to identify likely pathogenic variants. PMID:24986828

The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases

PubMed Central

2011-01-01

Background Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases. Methods To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments. Results We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment. Conclusion Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases. PMID:21733145

The art and science of choosing efficacy endpoints for rare disease clinical trials.

PubMed

Cox, Gerald F

2018-04-01

An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients. © 2018 Wiley Periodicals, Inc.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.

PubMed

Lambertus, Stanley; Bax, Nathalie M; Fakin, Ana; Groenewoud, Joannes M M; Klevering, B Jeroen; Moore, Anthony T; Michaelides, Michel; Webster, Andrew R; van der Wilt, Gert Jan; Hoyng, Carel B

2017-01-01

Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in

Personalized Medicine: What's in it for Rare Diseases?

PubMed

Schee Genannt Halfmann, Sebastian; Mählmann, Laura; Leyens, Lada; Reumann, Matthias; Brand, Angela

2017-01-01

Personalised Medicine has become a reality over the last years. The emergence of 'omics' and big data has started revolutionizing healthcare. New 'omics' technologies lead to a better molecular characterization of diseases and a new understanding of the complexity of diseases. The approach of PM is already successfully applied in different healthcare areas such as oncology, cardiology, nutrition and for rare diseases. However, health systems across the EU are often still promoting the 'one-size fits all' approach, even if it is known that patients do greatly vary in their molecular characteristics and response to drugs and other interventions. To make use of the full potentials of PM in the next years ahead several challenges need to be addressed such as the integration of big data, patient empowerment, translation of basic to clinical research, bringing the innovation to the market and shaping sustainable healthcare systems.

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…

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

LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems.

PubMed

Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

Characterizing a rare disease diagnosis for a given patient is often made through expert's networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine.

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

PubMed

Lubbe, S J; Escott-Price, V; Brice, A; Gasser, T; Pittman, A M; Bras, J; Hardy, J; Heutink, P; Wood, N M; Singleton, A B; Grosset, D G; Carroll, C B; Law, M H; Demenais, F; Iles, M M; Bishop, D T; Newton-Bishop, J; Williams, N M; Morris, H R

2016-12-01

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

26 CFR 1.28-0 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions; table of...

Code of Federal Regulations, 2011 CFR

2011-04-01

... drugs for rare diseases or conditions; table of contents. 1.28-0 Section 1.28-0 Internal Revenue... Taxable Year § 1.28-0 Credit for clinical testing expenses for certain drugs for rare diseases or... 505(i). (d) Definition and special rules. (1) Definition of “rare disease or condition”. (i) In...

26 CFR 1.28-0 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions; table of...

Code of Federal Regulations, 2010 CFR

2010-04-01

... drugs for rare diseases or conditions; table of contents. 1.28-0 Section 1.28-0 Internal Revenue... Taxable Year § 1.28-0 Credit for clinical testing expenses for certain drugs for rare diseases or... 505(i). (d) Definition and special rules. (1) Definition of “rare disease or condition”. (i) In...

26 CFR 1.28-0 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions; table of...

Code of Federal Regulations, 2013 CFR

2013-04-01

... drugs for rare diseases or conditions; table of contents. 1.28-0 Section 1.28-0 Internal Revenue... Taxable Year § 1.28-0 Credit for clinical testing expenses for certain drugs for rare diseases or... 505(i). (d) Definition and special rules. (1) Definition of “rare disease or condition”. (i) In...

26 CFR 1.28-0 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions; table of...

Code of Federal Regulations, 2012 CFR

2012-04-01

... drugs for rare diseases or conditions; table of contents. 1.28-0 Section 1.28-0 Internal Revenue... Taxable Year § 1.28-0 Credit for clinical testing expenses for certain drugs for rare diseases or... 505(i). (d) Definition and special rules. (1) Definition of “rare disease or condition”. (i) In...

26 CFR 1.28-0 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions; table of...

Code of Federal Regulations, 2014 CFR

2014-04-01

... drugs for rare diseases or conditions; table of contents. 1.28-0 Section 1.28-0 Internal Revenue... Taxable Year § 1.28-0 Credit for clinical testing expenses for certain drugs for rare diseases or... 505(i). (d) Definition and special rules. (1) Definition of “rare disease or condition”. (i) In...

A rare case of an ACTH/CRH co-secreting midgut neuroendocrine tumor mimicking Cushing's disease.

PubMed

Streuli, Regina; Krull, Ina; Brändle, Michael; Kolb, Walter; Stalla, Günter; Theodoropoulou, Marily; Enzler-Tschudy, Annette; Bilz, Stefan

2017-01-01

Ectopic ACTH/CRH co-secreting tumors are a very rare cause of Cushing's syndrome and only a few cases have been reported in the literature. Differentiating between Cushing's disease and ectopic Cushing's syndrome may be particularly difficult if predominant ectopic CRH secretion leads to pituitary corticotroph hyperplasia that may mimic Cushing's disease during dynamic testing with both dexamethasone and CRH as well as bilateral inferior petrosal sinus sampling (BIPSS). We present the case of a 24-year-old man diagnosed with ACTH-dependent Cushing's syndrome caused by an ACTH/CRH co-secreting midgut NET. Both high-dose dexamethasone testing and BIPSS suggested Cushing's disease. However, the clinical presentation with a rather rapid onset of cushingoid features, hyperpigmentation and hypokalemia led to the consideration of ectopic ACTH/CRH-secretion and prompted a further workup. Computed tomography (CT) of the abdomen revealed a cecal mass which was identified as a predominantly CRH-secreting neuroendocrine tumor. To the best of our knowledge, this is the first reported case of an ACTH/CRH co-secreting tumor of the cecum presenting with biochemical features suggestive of Cushing's disease. The discrimination between a Cushing's disease and ectopic Cushing's syndrome is challenging and has many caveats.Ectopic ACTH/CRH co-secreting tumors are very rare.Dynamic tests as well as BIPSS may be compatible with Cushing's disease in ectopic CRH-secretion.High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH.Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing's syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing's syndrome and lead to further investigations.

A rare case of an ACTH/CRH co-secreting midgut neuroendocrine tumor mimicking Cushing's disease

PubMed Central

Streuli, Regina; Krull, Ina; Brändle, Michael; Kolb, Walter; Stalla, Günter; Theodoropoulou, Marily; Enzler-Tschudy, Annette

2017-01-01

Ectopic ACTH/CRH co-secreting tumors are a very rare cause of Cushing’s syndrome and only a few cases have been reported in the literature. Differentiating between Cushing’s disease and ectopic Cushing’s syndrome may be particularly difficult if predominant ectopic CRH secretion leads to pituitary corticotroph hyperplasia that may mimic Cushing’s disease during dynamic testing with both dexamethasone and CRH as well as bilateral inferior petrosal sinus sampling (BIPSS). We present the case of a 24-year-old man diagnosed with ACTH-dependent Cushing’s syndrome caused by an ACTH/CRH co-secreting midgut NET. Both high-dose dexamethasone testing and BIPSS suggested Cushing’s disease. However, the clinical presentation with a rather rapid onset of cushingoid features, hyperpigmentation and hypokalemia led to the consideration of ectopic ACTH/CRH-secretion and prompted a further workup. Computed tomography (CT) of the abdomen revealed a cecal mass which was identified as a predominantly CRH-secreting neuroendocrine tumor. To the best of our knowledge, this is the first reported case of an ACTH/CRH co-secreting tumor of the cecum presenting with biochemical features suggestive of Cushing’s disease. Learning points: The discrimination between a Cushing’s disease and ectopic Cushing’s syndrome is challenging and has many caveats. Ectopic ACTH/CRH co-secreting tumors are very rare. Dynamic tests as well as BIPSS may be compatible with Cushing’s disease in ectopic CRH-secretion. High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH. Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing’s syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing’s syndrome and lead to further investigations

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

Celiac Crisis: A Rare Or Rarely Recognized Disease.

PubMed

Waheed, Nadia; Cheema, Huma Arshad; Suleman, Hassan; Fayyaz, Zafar; Mushtaq, Iqra; Muhammad; Hashmi, Almas

2016-01-01

Celiac crisis is a serious life threatening complication of celiac disease characterized by profuse diarrhoea, severe dehydration and metabolic disturbances leading to neuromuscular weakness, cardiac arrhythmias and sudden death. It has been described as rare condition and not well documented in the literature. To improve awareness and facilitate diagnosis of this condition, we studied risk factors, pattern of presentation and management plans of celiac crisis. It was a descriptive cross sectional study. Patients presenting in emergency room(ER) with profuse diarrhoea leading to severe dehydration, neuromuscular weakness, and metabolic acidosis and electrolyte abnormalities enrolled in the studies after positive serology and small bowel biopsy suggestive of celiac disease. Total 126 patients out of 350 fulfilled the criteria including 54 (42.8%) male and 71 (56.3%) female. The mean age at presentation was 5.25±1.18 years. Risk factors were poor social status (97.60%), consanguinity (96.77%), early weaning with gluten contained diet (93.54%), and Presenting complaints were loose motion (100%), loss of neck holding (96.77%), dehydration (96.77%), polyuria (95.96%), inability to walk (67.74%), abdominal distension (85.86%). Electrolytes imbalances were hypokalaemia (2.4±0.55), hypocalcaemia (7.29±0.66), hypomagnesaemia (1.89±0.50), hypophosphatemia (2.8±0.68), hypoalbuminemia (3.05±0.48) and metabolic acidosis (96%). One hundred & twenty patients were stabilized with GFD and correction of dehydration, acidosis and electrolyte imbalance. Six patients needed parenteral steroids ant total parenteral nutrition (TPN). Recovery time from crisis was mean 5.4±2.73 days (range 3-20 days). Celiac crisis is a common but under recognized problem in developing countries. Commonest presenting feature is neuromuscular paralysis and biochemical abnormality is hypokalaemia.

Anterior hypopituitarism is rare and autoimmune disease is common in adults with idiopathic central diabetes insipidus.

PubMed

Hannon, M J; Orr, C; Moran, C; Behan, L A; Agha, A; Ball, S G; Thompson, C J

2012-05-01

Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood-onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function. One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty-three percent had at least one autoimmune disease in addition to central diabetes insipidus. Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology. © 2012 Blackwell Publishing Ltd.

LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems

PubMed Central

Choquet, Remy; Maaroufi, Meriem; Fonjallaz, Yannick; de Carrara, Albane; Vandenbussche, Pierre-Yves; Dhombres, Ferdinand; Landais, Paul

2015-01-01

Characterizing a rare disease diagnosis for a given patient is often made through expert’s networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine. PMID:26958175

Towards data integration automation for the French rare disease registry.

PubMed

Maaroufi, Meriem; Choquet, Rémy; Landais, Paul; Jaulent, Marie-Christine

2015-01-01

Building a medical registry upon an existing infrastructure and rooted practices is not an easy task. It is the case for the BNDMR project, the French rare disease registry, that aims to collect administrative and medical data of rare disease patients seen in different hospitals. To avoid duplicating data entry for health professionals, the project plans to deploy connectors with the existing systems to automatically retrieve data. Given the data heterogeneity and the large number of source systems, the automation of connectors creation is required. In this context, we propose a methodology that optimizes the use of existing alignment approaches in the data integration processes. The generated mappings are formalized in exploitable mapping expressions. Following this methodology, a process has been experimented on specific data types of a source system: Boolean and predefined lists. As a result, effectiveness of the used alignment approach has been enhanced and more good mappings have been detected. Nonetheless, further improvements could be done to deal with the semantic issue and process other data types.

Towards data integration automation for the French rare disease registry

PubMed Central

Maaroufi, Meriem; Choquet, Rémy; Landais, Paul; Jaulent, Marie-Christine

2015-01-01

Building a medical registry upon an existing infrastructure and rooted practices is not an easy task. It is the case for the BNDMR project, the French rare disease registry, that aims to collect administrative and medical data of rare disease patients seen in different hospitals. To avoid duplicating data entry for health professionals, the project plans to deploy connectors with the existing systems to automatically retrieve data. Given the data heterogeneity and the large number of source systems, the automation of connectors creation is required. In this context, we propose a methodology that optimizes the use of existing alignment approaches in the data integration processes. The generated mappings are formalized in exploitable mapping expressions. Following this methodology, a process has been experimented on specific data types of a source system: Boolean and predefined lists. As a result, effectiveness of the used alignment approach has been enhanced and more good mappings have been detected. Nonetheless, further improvements could be done to deal with the semantic issue and process other data types. PMID:26958224

Applying World Wide Web technology to the study of patients with rare diseases.

PubMed

de Groen, P C; Barry, J A; Schaller, W J

1998-07-15

Randomized, controlled trials of sporadic diseases are rarely conducted. Recent developments in communication technology, particularly the World Wide Web, allow efficient dissemination and exchange of information. However, software for the identification of patients with a rare disease and subsequent data entry and analysis in a secure Web database are currently not available. To study cholangiocarcinoma, a rare cancer of the bile ducts, we developed a computerized disease tracing system coupled with a database accessible on the Web. The tracing system scans computerized information systems on a daily basis and forwards demographic information on patients with bile duct abnormalities to an electronic mailbox. If informed consent is given, the patient's demographic and preexisting medical information available in medical database servers are electronically forwarded to a UNIX research database. Information from further patient-physician interactions and procedures is also entered into this database. The database is equipped with a Web user interface that allows data entry from various platforms (PC-compatible, Macintosh, and UNIX workstations) anywhere inside or outside our institution. To ensure patient confidentiality and data security, the database includes all security measures required for electronic medical records. The combination of a Web-based disease tracing system and a database has broad applications, particularly for the integration of clinical research within clinical practice and for the coordination of multicenter trials.

A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic

PubMed Central

Madsen, Bo Eskerod; Browning, Sharon R.

2009-01-01

Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used. PMID:19214210

Rare Compound Heterozygous Frameshift Mutations in ALMS1 Gene Identified Through Exome Sequencing in a Taiwanese Patient With Alström Syndrome.

PubMed

Tsai, Meng-Che; Yu, Hui-Wen; Liu, Tsunglin; Chou, Yen-Yin; Chiou, Yuan-Yow; Chen, Peng-Chieh

2018-01-01

Alström syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c.10290_10291delTA, p.Lys3431Serfs * 10) and a rare mutation in 16 (c.10823_10824delAG, p.Arg3609Alafs * 6) of ALMS1 gene. The compound heterozygous mutations were predicted to render truncated proteins. This report highlighted the clinical utility of exome sequencing and extended the knowledge of mutation spectrum in AS patients.

Determinants and Equity Evaluation for Health Expenditure Among Patients with Rare Diseases in China.

PubMed

Xin, Xiao-Xiong; Zhao, Liang; Guan, Xiao-Dong; Shi, Lu-Wen

2016-06-20

China has not established social security system for rare diseases. Rare diseases could easily impoverish patients and their families. Little research has studied the equity and accessibility of health services for patients with rare diseases in China. This study aimed to explore the factors that influence health expenditure of rare diseases and evaluate its equity. Questionnaire survey about living conditions and cost burden of patients with rare diseases was conducted. Individual and family information, health expenditure and reimbursement in 2014 of 982 patients were collected. The impact of medical insurance, individual sociodemographic characteristics, family characteristics, and healthcare need on total and out-of-pocket (OOP) health expenditures was analyzed through the generalized linear model. Equity of health expenditure was evaluated by both concentration index and Lorenz curve. Of all the surveyed patients, 11.41% had no medical insurance and 92.10% spent money to seek medical treatment in 2014. It was suggested female (P = 0.048), over 50 years of age (P = 0.062), high-income group (P = 0.021), hospitalization (P = 0.000), and reimbursement ratio (RR) (P = 0.000) were positively correlated with total health expenditure. Diseases not needing long-term treatment (P = 0.000) was negatively correlated with total health expenditure. Over 50 years of age (P = 0.065), high-income group (P = 0.018), hospitalization (P = 0.000) and having Urban Employee Basic Medical Insurance (UEBMI) (P = 0.022) were positively correlated with OOP health expenditure. Patient or the head of the household having received higher education (P = 0.044 and P = 0.081) and reimbursement ratio (P = 0.078) were negatively correlated with OOP health expenditure. The equity evaluation found concentration indexes of health expenditure before and after reimbursement were 0.0550 and 0.0539, respectively. OOP health expenditure of patients with UEBMI was significantly more than that of

Australian children living with rare diseases: experiences of diagnosis and perceived consequences of diagnostic delays.

PubMed

Zurynski, Yvonne; Deverell, Marie; Dalkeith, Troy; Johnson, Sandra; Christodoulou, John; Leonard, Helen; Elliott, Elizabeth J

2017-04-11

Children and families living with rare disease often experience significant health, psychosocial, economic burdens and diagnostic delays. Experiences appear to be constant, regardless of the specific rare disease diagnosis. Systematically collected Australian data to support policy response on rare diseases are scarce. We address this gap by providing survey results about 462 children aged <19 years living with approximately 200 different rare diseases. Of 462 children, 96% were born in Australia, 55% were male, median age was 8.9 years (0-18.2). Four-hundred-and-twenty-eight (93%) had received a definitive diagnosis but 29 (7%) remained undiagnosed. Before receiving the correct diagnosis 38% consulted ≥ 6 different doctors. Among those with a diagnosis, 37% believed the diagnosis was delayed and 27% initially received a wrong diagnosis. Consequences of delayed diagnosis include anxiety, loss of reproductive confidence because of an ill-defined genetic risk, frustration and stress (54%), disease progression (37%), delays in treatment (25%) and inappropriate treatments (10%). Perceived reasons for diagnostic delays included lack of knowledge about the disease among health professionals (69.2%), lack of symptom awareness by the family (21.2%) and difficulties accessing tests (17.9%). Children with inborn errors of metabolism were less likely to have a delayed diagnosis compared with other disease groups (Chi-Sq = 17.1; P < 0.0001), most likely due to well-established and accessible biochemical screening processes. Diagnosis was given in person in 74% of cases, telephone in 18.5% and via a letter in 3.5%. Some families (16%) were dissatisfied with the way the diagnosis was delivered, citing lack of empathy and lack of information from health professionals. Psychological support at diagnosis was provided to 47.5%, but 86.2% believed that it should always be provided. Although 74.9% of parents believed that the diagnosis could have an impact on future

The Rare Diseases Clinical Research Network's organization and approach to observational research and health outcomes research.

PubMed

Krischer, Jeffrey P; Gopal-Srivastava, Rashmi; Groft, Stephen C; Eckstein, David J

2014-08-01

Established in 2003 by the Office of Rare Diseases Research (ORDR), in collaboration with several National Institutes of Health (NIH) Institutes/Centers, the Rare Diseases Clinical Research Network (RDCRN) consists of multiple clinical consortia conducting research in more than 200 rare diseases. The RDCRN supports longitudinal or natural history, pilot, Phase I, II, and III, case-control, cross-sectional, chart review, physician survey, bio-repository, and RDCRN Contact Registry (CR) studies. To date, there have been 24,684 participants enrolled on 120 studies from 446 sites worldwide. An additional 11,533 individuals participate in the CR. Through a central data management and coordinating center (DMCC), the RDCRN's platform for the conduct of observational research encompasses electronic case report forms, federated databases, and an online CR for epidemiological and survey research. An ORDR-governed data repository (through dbGaP, a database for genotype and phenotype information from the National Library of Medicine) has been created. DMCC coordinates with ORDR to register and upload study data to dbGaP for data sharing with the scientific community. The platform provided by the RDCRN DMCC has supported 128 studies, six of which were successfully conducted through the online CR, with 2,352 individuals accrued and a median enrollment time of just 2 months. The RDCRN has built a powerful suite of web-based tools that provide for integration of federated and online database support that can accommodate a large number of rare diseases on a global scale. RDCRN studies have made important advances in the diagnosis and treatment of rare diseases.

A rare variant of α 1 antitrypsin mutations detected in Vietnamese children with liver disease.

PubMed

Hoàng, Thu Hà; Phạm, Thiên Ngọc; Nguyễn, Gia Khánh; Lê, Quang Huấn

2013-07-01

Alpha 1 antitrypsin (A1AT) is the major plasma serine protease inhibitor that is produced in liver cells. A1AT deficiency is recognized globally as a common genetic cause of liver disease in children, which results from mutations in the SERine Protease INhibitor A1 (SERPINA1) gene. The importance of A1AT deficiency in Viet Nam is unclear. The aim of this study was to determine the A1AT variants present in paediatric patients with liver diseases in order to clarify whether A1AT deficiency is present in Viet Nam. A1AT studies were carried out in 130 children with liver disease of indeterminate aetiology. A1AT levels were determined by immunoturbidimetry. Phenotype analysis of A1AT was performed by isoelectric focusing (IEF) in all patients. Genotype analyses to determine A1AT mutations were performed by direct sequencing. We identified a rare variant of A1AT named Zbristol. The Zbristol appeared to be deficient in the plasma to about the same degree as the PI S protein resulting in low concentration of A1AT in one of these two Vietnamese patients. No other deficient A1AT allele was detected, although 11 patients (8.5%) showed a reduced serum concentration of A1AT. These are the first two cases of a rare A1AT deficiency allele to be found in Viet Nam clearly inferring that A1AT deficiency is not just a disease of Caucasians. As such, the laboratory diagnosis of A1AT deficiency including A1AT concentration determination and phenotype and genotype testing should form part of the routine differential diagnosis of paediatric liver disease of indeterminate aetiology in Vietnamese patients.

Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

PubMed

Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

2015-02-10

For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into

Rare esophageal ulcers related to Behçet disease: A case report.

PubMed

Jia, Ning; Tang, Yanping; Liu, Huayi; Li, Yang; Liu, Simiao; Liu, Lei

2017-11-01

The fundamental pathogenesis of Behçet disease (BD) is still unclear and controversial. Many cases of oral aphthous ulcers and genital ulcers related to BD are reported; nevertheless, idiopathic giant esophageal ulcers related to BD are rare. A rare case for esophageal ulcers related to BD is presented. In China, BD is represented with esophageal involvement which is called esophageal BD (EBD). A 56-year-old man diagnosed to the Gastroenterology Department of Integrated Traditional Chinese and Western Medicine Hospital, for multiple discrete, elliptical esophageal ulcers related to BD. The esophageal ulcers were treated with corticosteroid treatment for 12 weeks. The esophageal ulcers were cured. Our report might give further strength to avoiding the erroneous diagnosis or missed diagnosis for EBD, which is different from esophageal carcinoma, esophageal tuberculosis and esophageal Crohns disease.

Illness Perception and Information Behaviour of Patients with Rare Chronic Diseases

ERIC Educational Resources Information Center

Katavic, Snježana Stanarevic; Tanackovic, Sanjica Faletar; Badurina, Boris

2016-01-01

Introduction: This study examined possible correlations between health information behaviour and illness perception among patients with rare chronic diseases. Illness perception is related to coping strategies used by patients, and some health information behaviour practices may be associated with better coping and more positive perception of…

Does the low prevalence affect the sample size of interventional clinical trials of rare diseases? An analysis of data from the aggregate analysis of clinicaltrials.gov.

PubMed

Hee, Siew Wan; Willis, Adrian; Tudur Smith, Catrin; Day, Simon; Miller, Frank; Madan, Jason; Posch, Martin; Zohar, Sarah; Stallard, Nigel

2017-03-02

Clinical trials are typically designed using the classical frequentist framework to constrain type I and II error rates. Sample sizes required in such designs typically range from hundreds to thousands of patients which can be challenging for rare diseases. It has been shown that rare disease trials have smaller sample sizes than non-rare disease trials. Indeed some orphan drugs were approved by the European Medicines Agency based on studies with as few as 12 patients. However, some studies supporting marketing authorisation included several hundred patients. In this work, we explore the relationship between disease prevalence and other factors and the size of interventional phase 2 and 3 rare disease trials conducted in the US and/or EU. We downloaded all clinical trials from Aggregate Analysis of ClinialTrials.gov (AACT) and identified rare disease trials by cross-referencing MeSH terms in AACT with the list from Orphadata. We examined the effects of prevalence and phase of study in a multiple linear regression model adjusting for other statistically significant trial characteristics. Of 186941 ClinicalTrials.gov trials only 1567 (0.8%) studied a single rare condition with prevalence information from Orphadata. There were 19 (1.2%) trials studying disease with prevalence <1/1,000,000, 126 (8.0%) trials with 1-9/1,000,000, 791 (50.5%) trials with 1-9/100,000 and 631 (40.3%) trials with 1-5/10,000. Of the 1567 trials, 1160 (74%) were phase 2 trials. The fitted mean sample size for the rarest disease (prevalence <1/1,000,000) in phase 2 trials was the lowest (mean, 15.7; 95% CI, 8.7-28.1) but were similar across all the other prevalence classes; mean, 26.2 (16.1-42.6), 33.8 (22.1-51.7) and 35.6 (23.3-54.3) for prevalence 1-9/1,000,000, 1-9/100,000 and 1-5/10,000, respectively. Fitted mean size of phase 3 trials of rarer diseases, <1/1,000,000 (19.2, 6.9-53.2) and 1-9/1,000,000 (33.1, 18.6-58.9), were similar to those in phase 2 but were statistically significant

Using online health communication to manage chronic sorrow: mothers of children with rare diseases speak.

PubMed

Glenn, Adriana D

2015-01-01

Families affected by rare disease experience psychosocial reactions similar to families with prevalent chronic diseases. The ability to respond and manage the condition depends on psychosocial factors. This phenomenological study of 16 mothers of children with Alagille syndrome explored their lived experience in using online health communications to manage their chronic sorrow. Data consisted of semi-structured interviews analyzed using techniques described by van Manen. Analysis yielded four essential themes: connectedness, online triggers, empowerment, and seasons of online use contributed to online communication essential to a rare disease community. Findings suggest mothers need emotional support and help accessing appropriate online resources. Copyright © 2015 Elsevier Inc. All rights reserved.

Reported Numbers of Patients with Rare Diseases Based on Ten-Year Longitudinal National Disability Registries in Taiwan

ERIC Educational Resources Information Center

Lin, Jin-Ding; Lin, Lan-Ping; Hung, Wen-Jiu

2013-01-01

This paper aims to describe a general demographic picture of patients with rare diseases in Taiwan and particularly focuses on the prevalence of rare diseases over time, age and gender distributions. We analyzed data mainly from the national disability registry from 2002 to 2011 in Taiwan, Republic of China. The results showed that the number of…

Integrated Transitions of Care for Patients With Rare Pulmonary Diseases.

PubMed

Moreo, Kathleen; Lattimer, Cheri; Lett, James E; Heggen-Peay, Cherilyn L; Simone, Laura

Many continuing education (CE) resources are available to support case management professionals in developing competencies in transitions of care (TOC) that apply generally across disease areas. However, CE programs and tools are lacking for advanced TOC competencies in specific disease areas. This article describes 2 projects in which leading TOC, case management, and CE organizations collaborated to develop CE-accredited interdisciplinary pathways for promoting safe and effective TOC for patients with rare pulmonary diseases, including pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). The interdisciplinary pathways apply to PAH and IPF case management practice and TOC across settings that include community-based primary care and specialty care, PAH or IPF centers of expertise, acute care and post-acute settings, long-term care, rehabilitation and skilled nursing facilities, and patients' homes. Both PAH and IPF are chronic, progressive respiratory diseases that are associated with severe morbidity and mortality, along with high health care costs. Because they are relatively rare diseases with nonspecific symptoms and many comorbidities, PAH and IPF are difficult to diagnose. Early diagnosis, referral to centers of expertise, and aggressive treatment initiation are essential for slowing disease progression and maintaining quality of life and function. Both the rarity and complexity of PAH and IPF pose unique challenges to ensuring effective and safe TOC. Expert consensus and evidence-based approaches to meeting these challenges, and thereby improving PAH and IPF patient outcomes, are presented in the 2 interdisciplinary TOC pathways that are described in this article. In coordinating care for patients with complex pulmonary diseases such as PAH and IPF, case managers across practice settings can play key roles in improving workflow processes and communication, transition planning, coordinating TOC with centers of expertise

The impact of rare variation on gene expression across tissues.

PubMed

Li, Xin; Kim, Yungil; Tsang, Emily K; Davis, Joe R; Damani, Farhan N; Chiang, Colby; Hess, Gaelen T; Zappala, Zachary; Strober, Benjamin J; Scott, Alexandra J; Li, Amy; Ganna, Andrea; Bassik, Michael C; Merker, Jason D; Hall, Ira M; Battle, Alexis; Montgomery, Stephen B

2017-10-11

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

4th Rare Disease South Eastern Europe (See) Meeting Skopje, Macedonia (November 14th, 2015).

PubMed

Gucev, Zoran; Tasic, Velibor; Polenakovic, Momir

2015-01-01

The 4th meeting on rare diseases in South Eastern Europe (SEE) was held in Skopje, at the Macedonian Academy of Sciences and Arts (MASA) on the 14(th) of November 2015. The focuses were metabolic, rare brain diseases as well as the rare dysmorphic syndrome. The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. The talk on an iminosugar-based pharmacological chaperone compound as a drug candidate for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B) was enlightening. To date, there is no treatment available to be offered to patients, but chaperones lead mutated proteins to adopt a native-like conformation and to successfully traffic to their normal cellular destination. DORPHAN is developing an iminosugar-based pharmacological chaperone compound for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB. A talk on recent developments in the laboratory diagnosis of mucopolysaccharidoses (MPS) was particularly interesting, covering the laboratory diagnosis of the MPS diseases by a strategy of clinical examination, biochemical analysis of urine samples, enzyme tests and genetic characterization of underlying mutations. New techniques were developed, including analysis of urinary glycosaminoglycans with tandem mass spectrometry, miniaturized enzyme tests or novel synthetic substrates for enzyme assays using mass spectrometry detection of products using dried blood spots. Feasibility and cost-effectiveness of these methods in newborn screening programs have been demonstrated. Neuromuscular RDs, and especially familial amyloid polyneuropathy (FAP) were a topic of the Bulgarian colleagues. Diagnosis, screening and the role of microglia were also topics of particular interest. In summary, this year RD meeting was exciting and productive on a wide range of diseases and on a novel insights on

An event-related potential paradigm for identifying (rare negative) attitude stimuli that people intentionally misreport.

PubMed

Crites, Stephen L; Mojica, Andrew J; Corral, Guadalupe; Taylor, Jennifer H

2010-09-01

This experiment explored whether a late positive potential (LPP) of the event-related brain potential is useful for examining attitudes that people attempt to conceal. Participants identified a set of liked, neutral, and disliked people and viewed sequences consisting of either names or pictures of these people. Disliked people appeared rarely among liked people, and participants either: (1) always accurately reported their negative attitudes toward the people; (2) misreported negative attitudes as positive when they saw a picture of a disliked person; or (3) misreported negative attitudes as positive when they saw a name of a disliked person. Rare negative stimuli evoked a larger-amplitude LPP than frequent positive stimuli. Misreporting attitudes significantly reduced the amplitude difference between rare negative and frequent positive stimuli, though it remained significant.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

PubMed Central

Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

2017-01-01

Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a