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Sample records for identify rare disease

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

    PubMed Central

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-01-01

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

  2. Gene-based rare allele analysis identified a risk gene of Alzheimer's disease.

    PubMed

    Kim, Jong Hun; Song, Pamela; Lim, Hyunsun; Lee, Jae-Hyung; Lee, Jun Hong; Park, Sun Ah

    2014-01-01

    Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P<1.8×10(-6) (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.

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

    PubMed

    Walter, Klaudia; Min, Josine L; Huang, Jie; Crooks, Lucy; Memari, Yasin; McCarthy, Shane; Perry, John R B; Xu, ChangJiang; Futema, Marta; Lawson, Daniel; Iotchkova, Valentina; Schiffels, Stephan; Hendricks, Audrey E; Danecek, Petr; Li, Rui; Floyd, James; Wain, Louise V; Barroso, Inês; Humphries, Steve E; Hurles, Matthew E; Zeggini, Eleftheria; Barrett, Jeffrey C; Plagnol, Vincent; Richards, J Brent; Greenwood, Celia M T; Timpson, Nicholas J; Durbin, Richard; Soranzo, Nicole

    2015-10-01

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

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

    PubMed Central

    2015-01-01

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

  5. DoEstRare: A statistical test to identify local enrichments in rare genomic variants associated with disease

    PubMed Central

    Karakachoff, Matilde; Le Scouarnec, Solena; Le Clézio, Camille; Campion, Dominique; Schott, Jean-Jacques

    2017-01-01

    Next-generation sequencing technologies made it possible to assay the effect of rare variants on complex diseases. As an extension of the “common disease-common variant” paradigm, rare variant studies are necessary to get a more complete insight into the genetic architecture of human traits. Association studies of these rare variations show new challenges in terms of statistical analysis. Due to their low frequency, rare variants must be tested by groups. This approach is then hindered by the fact that an unknown proportion of the variants could be neutral. The risk level of a rare variation may be determined by its impact but also by its position in the protein sequence. More generally, the molecular mechanisms underlying the disease architecture may involve specific protein domains or inter-genic regulatory regions. While a large variety of methods are optimizing functionality weights for each single marker, few evaluate variant position differences between cases and controls. Here, we propose a test called DoEstRare, which aims to simultaneously detect clusters of disease risk variants and global allele frequency differences in genomic regions. This test estimates, for cases and controls, variant position densities in the genetic region by a kernel method, weighted by a function of allele frequencies. We compared DoEstRare with previously published strategies through simulation studies as well as re-analysis of real datasets. Based on simulation under various scenarios, DoEstRare was the sole to consistently show highest performance, in terms of type I error and power both when variants were clustered or not. DoEstRare was also applied to Brugada syndrome and early-onset Alzheimer’s disease data and provided complementary results to other existing tests. DoEstRare, by integrating variant position information, gives new opportunities to explain disease susceptibility. DoEstRare is implemented in a user-friendly R package. PMID:28742119

  6. DoEstRare: A statistical test to identify local enrichments in rare genomic variants associated with disease.

    PubMed

    Persyn, Elodie; Karakachoff, Matilde; Le Scouarnec, Solena; Le Clézio, Camille; Campion, Dominique; Consortium, French Exome; Schott, Jean-Jacques; Redon, Richard; Bellanger, Lise; Dina, Christian

    2017-01-01

    Next-generation sequencing technologies made it possible to assay the effect of rare variants on complex diseases. As an extension of the "common disease-common variant" paradigm, rare variant studies are necessary to get a more complete insight into the genetic architecture of human traits. Association studies of these rare variations show new challenges in terms of statistical analysis. Due to their low frequency, rare variants must be tested by groups. This approach is then hindered by the fact that an unknown proportion of the variants could be neutral. The risk level of a rare variation may be determined by its impact but also by its position in the protein sequence. More generally, the molecular mechanisms underlying the disease architecture may involve specific protein domains or inter-genic regulatory regions. While a large variety of methods are optimizing functionality weights for each single marker, few evaluate variant position differences between cases and controls. Here, we propose a test called DoEstRare, which aims to simultaneously detect clusters of disease risk variants and global allele frequency differences in genomic regions. This test estimates, for cases and controls, variant position densities in the genetic region by a kernel method, weighted by a function of allele frequencies. We compared DoEstRare with previously published strategies through simulation studies as well as re-analysis of real datasets. Based on simulation under various scenarios, DoEstRare was the sole to consistently show highest performance, in terms of type I error and power both when variants were clustered or not. DoEstRare was also applied to Brugada syndrome and early-onset Alzheimer's disease data and provided complementary results to other existing tests. DoEstRare, by integrating variant position information, gives new opportunities to explain disease susceptibility. DoEstRare is implemented in a user-friendly R package.

  7. Leveraging network analytics to infer patient syndrome and identify causal genes in rare disease cases.

    PubMed

    Krämer, Andreas; Shah, Sohela; Rebres, Robert Anthony; Tang, Susan; Richards, Daniel Rene

    2017-08-11

    Next-generation sequencing is widely used to identify disease-causing variants in patients with rare genetic disorders. Identifying those variants from whole-genome or exome data can be both scientifically challenging and time consuming. A significant amount of time is spent on variant annotation, and interpretation. Fully or partly automated solutions are therefore needed to streamline and scale this process. We describe Phenotype Driven Ranking (PDR), an algorithm integrated into Ingenuity Variant Analysis, that uses observed patient phenotypes to prioritize diseases and genes in order to expedite causal-variant discovery. Our method is based on a network of phenotype-disease-gene relationships derived from the QIAGEN Knowledge Base, which allows for efficient computational association of phenotypes to implicated diseases, and also enables scoring and ranking. We have demonstrated the utility and performance of PDR by applying it to a number of clinical rare-disease cases, where the true causal gene was known beforehand. It is also shown that PDR compares favorably to a representative alternative tool.

  8. Genes that affect brain structure and function identified by rare variant analyses of Mendelian neurologic disease

    PubMed Central

    Karaca, Ender; Harel, Tamar; Pehlivan, Davut; Jhangiani, Shalini N.; Gambin, Tomasz; Akdemir, Zeynep Coban; Gonzaga-Jauregui, Claudia; Erdin, Serkan; Bayram, Yavuz; Campbell, Ian M.; Hunter, Jill V.; Atik, Mehmed M.; Van Esch, Hilde; Yuan, Bo; Wiszniewski, Wojciech; Isikay, Sedat; Yesil, Gozde; Yuregir, Ozge O.; Bozdogan, Sevcan Tug; Aslan, Huseyin; Aydin, Hatip; Tos, Tulay; Aksoy, Ayse; De Vivo, Darryl C.; Jain, Preti; Geckinli, B. Bilge; Sezer, Ozlem; Gul, Davut; Durmaz, Burak; Cogulu, Ozgur; Ozkinay, Ferda; Topcu, Vehap; Candan, Sukru; Cebi, Alper Han; Ikbal, Mevlit; Gulec, Elif Yilmaz; Gezdirici, Alper; Koparir, Erkan; Ekici, Fatma; Coskun, Salih; Cicek, Salih; Karaer, Kadri; Koparir, Asuman; Duz, Mehmet Bugrahan; Kirat, Emre; Fenercioglu, Elif; Ulucan, Hakan; Seven, Mehmet; Guran, Tulay; Elcioglu, Nursel; Yildirim, Mahmut Selman; Aktas, Dilek; Alikaşifoğlu, Mehmet; Ture, Mehmet; Yakut, Tahsin; Overton, John D.; Yuksel, Adnan; Ozen, Mustafa; Muzny, Donna M.; Adams, David R.; Boerwinkle, Eric; Chung, Wendy K.; Gibbs, Richard A.; Lupski, James R

    2015-01-01

    Development of the human nervous system involves complex interactions between fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families, and homozygous loss of function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations. PMID:26539891

  9. The risk of re-identification versus the need to identify individuals in rare disease research

    PubMed Central

    Hansson, Mats G; Lochmüller, Hanns; Riess, Olaf; Schaefer, Franz; Orth, Michael; Rubinstein, Yaffa; Molster, Caron; Dawkins, Hugh; Taruscio, Domenica; Posada, Manuel; Woods, Simon

    2016-01-01

    There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers. PMID:27222291

  10. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease.

    PubMed

    Mefford, Heather C; Cooper, Gregory M; Zerr, Troy; Smith, Joshua D; Baker, Carl; Shafer, Neil; Thorland, Erik C; Skinner, Cindy; Schwartz, Charles E; Nickerson, Deborah A; Eichler, Evan E

    2009-09-01

    Copy-number variants (CNVs) are substantial contributors to human disease. A central challenge in CNV-disease association studies is to characterize the pathogenicity of rare and possibly incompletely penetrant events, which requires the accurate detection of rare CNVs in large numbers of individuals. Cost and throughput issues limit our ability to perform these studies. We have adapted the Illumina BeadXpress SNP genotyping assay and developed an algorithm, SNP-Conditional OUTlier detection (SCOUT), to rapidly and accurately detect both rare and common CNVs in large cohorts. This approach is customizable, cost effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in 1105 children with unexplained intellectual disability, identifying pathogenic variants in 3.1% of these individuals and potentially pathogenic variants in an additional 2.3%. We identified seven individuals (0.7%) with a deletion of 16p11.2, which has been previously associated with autism. Our results widen the phenotypic spectrum of these deletions to include intellectual disability without autism. We also detected 1.65-3.4 Mbp duplications at 16p13.11 in 1.1% of affected individuals and 350 kbp deletions at 15q11.2, near the Prader-Willi/Angelman syndrome critical region, in 0.8% of affected individuals. Compared to published CNVs in controls they are significantly (P = 4.7 x 10(-5) and 0.003, respectively) enriched in these children, supporting previously published hypotheses that they are neurocognitive disease risk factors. More generally, this approach offers a previously unavailable balance between customization, cost, and throughput for analysis of CNVs and should prove valuable for targeted CNV detection in both research and diagnostic settings.

  11. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

    PubMed Central

    Trynka, Gosia; Hunt, Karen A; Bockett, Nicholas A; Romanos, Jihane; Mistry, Vanisha; Szperl, Agata; Bakker, Sjoerd F; Bardella, Maria Teresa; Bhaw-Rosun, Leena; Castillejo, Gemma; de la Concha, Emilio G.; de Almeida, Rodrigo Coutinho; Dias, Kerith-Rae M; van Diemen, Cleo C.; Dubois, Patrick CA; Duerr, Richard H.; Edkins, Sarah; Franke, Lude; Fransen, Karin; Gutierrez, Javier; Heap, Graham AR; Hrdlickova, Barbara; Hunt, Sarah; Izurieta, Leticia Plaza; Izzo, Valentina; Joosten, Leo AB; Langford, Cordelia; Mazzilli, Maria Cristina; Mein, Charles A; Midah, Vandana; Mitrovic, Mitja; Mora, Barbara; Morelli, Marinita; Nutland, Sarah; Núñez, Concepción; Onengut-Gumuscu, Suna; Pearce, Kerra; Platteel, Mathieu; Polanco, Isabel; Potter, Simon; Ribes-Koninckx, Carmen; Ricaño-Ponce, Isis; Rich, Stephen S.; Rybak, Anna; Santiago, José Luis; Senapati, Sabyasachi; Sood, Ajit; Szajewska, Hania; Troncone, Riccardo; Varadé, Jezabel; Wallace, Chris; Wolters, Victorien M; Zhernakova, Alexandra; Thelma, B.K.; Cukrowska, Bozena; Urcelay, Elena; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Barrett, Jeffrey C; Plagnol, Vincent; Deloukas, Panos; Wijmenga, Cisca; van Heel, David A

    2011-01-01

    We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non-HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms. PMID:22057235

  12. Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

    PubMed Central

    Vardarajan, Badri N.; Ghani, Mahdi; Kahn, Amanda; Sheikh, Stephanie; Sato, Christine; Barral, Sandra; Lee, Joseph H.; Cheng, Rong; Reitz, Christiane; Lantigua, Rafael; Reyes‐Dumeyer, Dolly; Medrano, Martin; Jimenez‐Velazquez, Ivonne Z.; Rogaeva, Ekaterina; St George‐Hyslop, Peter

    2015-01-01

    Objective To detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD). Methods We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies. Results Overall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered. Interpretation Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498 PMID:26101835

  13. 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…

  14. 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…

  15. Identifying causal rare variants of disease through family-based analysis of Genetics Analysis Workshop 17 data set

    PubMed Central

    2011-01-01

    Linkage- and association-based methods have been proposed for mapping disease-causing rare variants. Based on the family information provided in the Genetic Analysis Workshop 17 data set, we formulate a two-pronged approach that combines both methods. Using the identity-by-descent information provided for eight extended pedigrees (n = 697) and the simulated quantitative trait Q1, we explore various traditional nonparametric linkage analysis methods; the best result is obtained by assuming between-family heterogeneity and applying the Haseman-Elston regression to each pedigree separately. We discover strong signals from two genes in two different families and weaker signals for a third gene from two other families. As an exploratory approach, we apply an association test based on a modified family-based association test statistic to all rare variants (frequency < 1% or < 3%) designated as causal for Q1. Family-based association tests correctly identified causal single-nucleotide polymorphisms for four genes (KDR, VEGFA, VEGFC, and FLT1). Our results suggest that both linkage and association tests with families show promise for identifying rare variants. PMID:22373204

  16. Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS

    PubMed Central

    Kallio, Suvi P.; Jakkula, Eveliina; Purcell, Shaun; Suvela, Minna; Koivisto, Keijo; Tienari, Pentti J.; Elovaara, Irina; Pirttilä, Tuula; Reunanen, Mauri; Bronnikov, Denis; Viander, Markku; Meri, Seppo; Hillert, Jan; Lundmark, Frida; Harbo, Hanne F.; Lorentzen, Åslaug R.; De Jager, Philip L.; Daly, Mark J.; Hafler, David A.; Palotie, Aarno; Peltonen, Leena; Saarela, Janna

    2009-01-01

    Large case–control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles. PMID:19221116

  17. Rare Parotid Gland Diseases.

    PubMed

    Sanan, Akshay; Cognetti, David M

    2016-04-01

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

  18. 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…

  19. 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…

  20. A Rare Duplication on Chromosome 16p11.2 Is Identified in Patients with Psychosis in Alzheimer's Disease

    PubMed Central

    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. PMID:25379732

  1. Rare Diseases Research

    PubMed Central

    2013-01-01

    Extensive public-private partnerships, including the National Institutes of Health (NIH) and the rare diseases community, which is seeing a renewed industry interest in smaller niche markets, have resulted in an increase of interventions for rare diseases. Significant collaborative efforts are required among the pharmaceutical industry, foundations, patient-advocacy groups, academic and government investigators and funding programs, regulatory scientists, and reimbursement agencies to meet the unmet diagnostic and treatment needs for approximately 25 million people in the United States with 7,000 rare diseases. The expanding role and outreach activities of patient-advocacy groups have increased public awareness. In the United States, a rare disease is defined as a disorder or condition with a prevalence of < 200,000 people. In 2011, the NIH provided > $3.5 billion for rare diseases research, including $750 million for orphan product development activities, nearly 11.4% of the NIH research budget. Several research institutes and centers of the NIH, including the National Center for Advancing Translational Sciences, have initiated varied translational research efforts to address the absence of preclinical and clinical data required for regulatory review purposes. Clinicians can expect to see significant increases in requests from patients and their families to participate in patient registries and natural history or observational studies to gather specific information from a larger pool of patients on the progression of the disease or response to treatments. An expanding emphasis on rare diseases provides hope for the millions of patients with rare diseases. PMID:23880676

  2. Camurati-Engelmann disease-a rare cause of tetany identified on bone scintigraphy: A case report.

    PubMed

    Xie, Peng; Huang, Jian-Min; Li, Huan-Li; Huang, Xiao-Jie; Wei, Ling-Ge

    2017-07-01

    Camurati-Engelmann disease (i.e., progressive diaphyseal dysplasia) is an extremely rare autosomal dominant bone disorder. The most common clinical manifestations were chronic skeletal pain, waddling gait, muscular weakness. We described that a 27-year-old male with a 1-year history of intermittent tetany was referred for bone scintigraphy. The whole body bone scan images showed abnormal increased uptake of the tracer in the long bones of the upper and lower extremities as well as in the skull. Combined the family history, the findings of the images and the genetic study, the diagnosis of Camurati-Engelmann disease was confirmed. The patient responded well to the treatment of calcium gluconate. Bone scintigraphy would be helpful in the diagnosis and assessing the severity of Camurati-Engelmann disease.

  3. [Adult-onset rare diseases].

    PubMed

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

    2014-03-02

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

  4. Exome sequencing deciphers rare diseases.

    PubMed

    Maxmen, Amy

    2011-03-04

    Two years ago, NIH's Undiagnosed Diseases Program began delivering genomics to the clinic on an unprecedented scale. Now, with 128 exomes sequenced and 39 rare diseases diagnosed, the program's success is paving the way for widespread personal genomics while pioneering new techniques for reigning in the "tsunami" of genomics data.

  5. Lipedema, a rare disease.

    PubMed

    Shin, Bae Wook; Sim, Young-Joo; Jeong, Ho Joong; Kim, Ghi Chan

    2011-12-01

    Lipedema is a chronic disease of lipid metabolism that results in the symmetrical impairment of fatty tissue distribution and storage combined with the hyperplasia of individual fat cells. Lipedema occurs almost exclusively in women and is usually associated with a family history and characteristic features. It can be diagnosed based on clinical history and physical examination. Lipedema is usually symmetrical, but spares the feet, is often painful to palpation, and is negative for Stemmer's sign. Additionally, lipedema patients can present with microangiopathies and lipomas. The well-known therapies for lipedema include complex decongestive therapy, pneumatic compression, and diet modifications. However, whether these treatments help reduce swelling is debatable. We encountered a case of lipedema that was initially misdiagnosed as lymphedema. The patient's clinical features and history were different from those typical of lymphedema, prompting a diagnosis of lipedema and she was treated with a complex decongestive therapy program.

  6. Lipedema, a Rare Disease

    PubMed Central

    Shin, Bae Wook; Jeong, Ho Joong; Kim, Ghi Chan

    2011-01-01

    Lipedema is a chronic disease of lipid metabolism that results in the symmetrical impairment of fatty tissue distribution and storage combined with the hyperplasia of individual fat cells. Lipedema occurs almost exclusively in women and is usually associated with a family history and characteristic features. It can be diagnosed based on clinical history and physical examination. Lipedema is usually symmetrical, but spares the feet, is often painful to palpation, and is negative for Stemmer's sign. Additionally, lipedema patients can present with microangiopathies and lipomas. The well-known therapies for lipedema include complex decongestive therapy, pneumatic compression, and diet modifications. However, whether these treatments help reduce swelling is debatable. We encountered a case of lipedema that was initially misdiagnosed as lymphedema. The patient's clinical features and history were different from those typical of lymphedema, prompting a diagnosis of lipedema and she was treated with a complex decongestive therapy program. PMID:22506222

  7. Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

    PubMed

    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

    2015-02-01

    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.

  8. [Care for patients with rare diseases].

    PubMed

    Smetsers, Stephanie E; Takkenberg, J J M Hanneke; Bierings, Marc B

    2014-01-01

    A rare disease usually concerns only a handful of patients, but all patients with a rare disease combined represent a significant health burden. Due to limited knowledge and the absence of treatment guidelines, patients with rare diseases usually experience delayed diagnosis and suboptimal treatment. Historically, rare diseases have never been considered a major health problem. However, rare diseases have recently been receiving increased attention. In the Netherlands, a national plan for rare diseases was published in late 2013, with recommendations on how to improve the organisation of healthcare for people with rare diseases. Using the example of the rare disease Fanconi anemia, this paper describes the challenges and opportunities in organising healthcare for rare diseases. Two critical steps in optimising healthcare for rare diseases are developing multidisciplinary healthcare teams and stimulating patient empowerment. Optimal cooperation between patients, patient organisations, multidisciplinary healthcare teams and scientists is of great importance. In this respect, transition to adult healthcare requires special attention.

  9. Sustainable public health systems for rare diseases.

    PubMed

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

    2017-01-01

    In the framework of the Joint Action for Rare Diseases (RD-ACTION), a specific task was defined to identify mechanisms influencing sustainability, equity and resilience of health systems for rare diseases (RDs). Literature narrative review on health systems sustainability and resilience for RDs. Years: 2000-2015. Databases: PubMed, Scopus, EBSCOHost, EMBAL, PASCAL, EMBASE, STN International and GoogleScholar. interpretive synthesis concept and thematic analysis (Dixon-Wood, et al.). 97 papers and 4 grey literature publications were identified. Two main topics stand out: economic evaluation and networks. The first topic did not identify widely accepted criterion to assign more weight to individuals with greater health needs. Healthcare network are identified as increasingly important for sustainability and resilience, in all of their aspects: professional "expertise", "experience" networks of users and carers; policy, learning, and interest networks. Possible mechanisms for ensuring sustainability can be identified in networking, patients' empowerment and reorienting healthcare towards integrated community and home care.

  10. A Network Approach to Rare Disease Modeling

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

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

  11. Lessons from rare diseases of cartilage and bone.

    PubMed

    Gallagher, James A; Ranganath, Lakshminarayan R; Boyde, Alan

    2015-06-01

    Studying severe phenotypes of rare syndromes can elucidate disease mechanisms of more common disorders and identify potential therapeutic targets. Lessons from rare bone diseases contributed to the development of the most successful class of bone active agents, the bisphosphonates. More recent research on rare bone diseases has helped elucidate key pathways and identify new targets in bone resorption and bone formation including cathepsin K and sclerostin, for which drugs are now in clinical trials. By contrast, there has been much less focus on rare cartilage diseases and osteoarthritis (OA) remains a common disease with no effective therapy. Investigation of rare cartilage syndromes is identifying new potential targets in OA including GDF5 and lubricin. Research on the arthropathy of the ultra-rare disease alkaptonuria has identified several new features of the OA phenotype, including high density mineralized protrusions (HDMPs) which constitute a newly identified mechanism of joint destruction.

  12. 75 FR 47458 - TRICARE; Rare Diseases Definition

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-06

    ... Office of the Secretary 32 CFR Part 199 RIN 0720-AB26 TRICARE; Rare Diseases Definition AGENCY: Office of... diseases to adopt the definition of a rare disease as promulgated by the National Institutes of Health, Office of Rare Diseases. The rule modification will result in the definition used by the TRICARE...

  13. Erythromelalgia: a rare microvascular disease.

    PubMed

    Latessa, Victoria

    2010-06-01

    Erythromelalgia (EM) is a rare condition of unknown etiology that results in intense, burning pain and redness primarily of the feet, and, even more rarely, in the hands. Most cases are idiopathic (primary EM); others occur secondary to medical conditions, such as autoimmune diseases, and neurological or hematological disorders. Symptoms are episodic and can result in severe disability. Triggers, such as exposure to warmth, pressure or exercise, become apparent to those afflicted with this condition; however, triggers may be unavoidable during the course of daily living. There are no diagnostic tests for EM. Diagnosis is based on history, physical examination during symptomatic episode and the exclusion of other probable causes for the syndrome. Early recognition of the signs and symptoms as well as early treatment offer patients the best hope of remissions and improved quality of life. (c) 2010 Society for Vascular Nursing, Inc. Published by Mosby, Inc. All rights reserved.

  14. 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.

  15. CEMARA an information system for rare diseases.

    PubMed

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

    2010-01-01

    Rare diseases cover a group of conditions characterized by a low prevalence, affecting less than 1 in 2,000 people; 5000 to 7000 rare diseases have been currently identified in Europe. Most diseases do not have any curative treatment. They represent thus an important public health concern. CEMARA is based on a n-tier architecture. Its main objective is to collect continuous and complete records of patients with rare diseases, and their follow-up through a web-based Information System, and to analyse the epidemiological patterns. In France, 41 out of 131 labelled Reference Centres (RC) are sharing CEMARA. Presently 56,593 cases have been registered by more than 850 health care professionals belonging to 171 clinical sites. The national demand of care was explored in relation with the offer of care in order to reach an improved match. Within 2 years, CEMARA stimulated sharing a common platform, a common ontology with Orphanet and initiating new cohorts of rare diseases for improving patient care and research.

  16. Rare diseases in ICD11: making rare diseases visible in health information systems through appropriate coding.

    PubMed

    Aymé, Ségolène; Bellet, Bertrand; Rath, Ana

    2015-03-26

    Because of their individual rarity, genetic diseases and other types of rare diseases are under-represented in healthcare coding systems; this contributes to a lack of ascertainment and recognition of their importance for healthcare planning and resource allocation, and prevents clinical research from being performed. Orphanet was given the task to develop an inventory of rare diseases and a classification system which could serve as a template to update International terminologies. When the World Health Organization (WHO) launched the revision process of the International Classification of Diseases (ICD), a Topic Advisory Group for rare diseases was established, managed by Orphanet and funded by the European Commission. So far 5,400 rare diseases listed in the Orphanet database have an endorsed representation in the foundation layer of ICD-11, and are thus provided with a unique identifier in the Beta version of ICD-11, which is 10 times more than in ICD10. A rare disease linearization is also planned. The current beta version is open for public consultation and comments, and to be used for field testing. The adoption by the World Health Assembly is planned for 2017. The overall revision process was carried out with very limited means considering its scope, ambition and strategic significance, and experienced significant hurdles and setbacks. The lack of funding impacted the level of professionalism that could be attained. The contrast between the initially declared goals and the currently foreseen final product is disappointing. In the context of uncertainty around the outcome of the field testing and the potential willingness of countries to adopt this new version, the European Commission Expert Group on Rare Diseases adopted in November 2014 a recommendation for health care coding systems to consider using ORPHA codes in addition to ICD10 codes for rare diseases having no specific ICD10 codes. The Orphanet terminology, classifications and mappings with other

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Senn, A; Filzmaier, K

    2015-12-01

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

  20. [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.

  1. [Global strategy for rare and intractable diseases].

    PubMed

    Kawashima Kodama, Tomoko

    2013-01-01

    The progress has been made in research on rare and intractable diseases, for which new drug development has long been limited due to rarity, by establishing a global network in recent years. In Japan, the countermeasure of rare and intractable diseases has been implemented under national policy outline as an integrated strategy since 1972, including surveys and research, construction of medical facilities, reducing burden of medical expenses for patients, and enhancement of welfare and improving QOL of patients. Along with legislation or regulation of orphan drugs development, treatment and care for rare diseases have been emphasized in each national healthcare system globally. In the US, the Office of Rare Diseases was established under NIH in 1989 and European countries also started collaboration for rare disease projects with their own national plans in 1999. As a platform of rare diseases patients, healthcare professionals, researchers, pharmaceutical industry, and policy makers, Orphanet has a well-designed website which networks them. In Japan, there are urgent needs for global standard patient registration system and strengthening global collaboration for developing treatment and care for the patients of rare and intractable diseases, which needs more cooperative relations with patient organizations and pharmaceutical industry within country.

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

    PubMed

    Aymé, Ségolène; Rodwell, Charlotte

    2014-02-28

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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. Tale of two rare diseases

    PubMed Central

    Shukla, Ravindra; Basu, Asish Kumar; Mandal, Biplab; Mukhopadhyay, Pradip; Maity, Animesh; Sinha, Anirban

    2013-01-01

    Idiopathic Hypogonadotropic hypogonadism (IHH) phenotype is variable &various genes have been decribed in association with IHH. We describe association of IHH with mosaic trisomy 13. A 20 year old male presented with lack of development of secondary sexual characters, normal height, micropenis, small testes, gynaecomastia, absence of axillary and pubic hairs, hyposmia, synkinesis, bilateral horizontal nystagmus and high arched palate. Investigations showed low gonadotropin, low total testosterone, LH after stimulation with 100 mcg tryptorelin sc was 11.42 mU/mL at 40 min. MRI of hypothalamo-pituitary region showed normal olfactory bulb and tract but shallow olfactory sulcus. Karyotype showed homologous Robertsonian translocation of chromosome 13. This case fits classical IHH except for LH rise on stimulation. Features of Patau syndrome which is associated with trisomy 13 are absent in our case. Mosaic trisomy 13, which can otherwise be rare incidental finding, has not been described in association with IHH. Causal association of novel mutation on chromosome 13 leading to aforementioned phenotype cannot be rule out. PMID:24251138

  8. Rare thyroid non-neoplastic diseases.

    PubMed

    Lacka, Katarzyna; Maciejewski, Adam

    2015-01-01

    Rare diseases are usually defined as entities affecting less than 1 person per 2,000. About 7,000 different rare entities are distinguished and, among them, rare diseases of the thyroid gland. Although not frequent, they can be found in the everyday practice of endocrinologists and should be considered in differential diagnosis. Rare non-neoplastic thyroid diseases will be discussed. Congenital hypothyroidism's frequency is relatively high and its early treatment is of vital importance for neonatal psychomotor development; CH is caused primarily by thyroid dysgenesis (85%) or dyshormonogenesis (10-15%), although secondary defects - hypothalamic and pituitary - can also be found; up to 40% of cases diagnosed on neonatal screening are transient. Inherited abnormalities of thyroid hormone binding proteins (TBG, TBP and albumin) include alterations in their concentration or affinity for iodothyronines, this leads to laboratory test abnormalities, although usually with normal free hormones and clinical euthyroidism. Thyroid hormone resistance is most commonly found in THRB gene mutations and more rarely in THRA mutations; in some cases both genes are unchanged (non-TR RTH). Recently the term 'reduced sensitivity to thyroid hormones' was introduced, which encompass not only iodothyronine receptor defects but also their defective transmembrane transport or metabolism. Rare causes of hyperthyroidism are: activating mutations in TSHR or GNAS genes, pituitary adenomas, differentiated thyroid cancer or gestational trophoblastic disease; congenital hyperthyroidism cases are also seen, although less frequently than CH. Like other organs and tissues, the thyroid can be affected by different inflammatory and infectious processes, including tuberculosis and sarcoidosis. In most of the rare thyroid diseases genetic factors play a key role, many of them can be classified as monogenic disorders. Although there are still some limitations, progress has been made in our understanding of

  9. Organization for rare diseases India (ORDI) - addressing the challenges and opportunities for the Indian rare diseases' community.

    PubMed

    Rajasimha, Harsha Karur; Shirol, Prasannakumar Basayya; Ramamoorthy, Preveen; Hegde, Madhuri; Barde, Sangeeta; Chandru, Vijay; Ravinandan, M E; Ramchandran, Ramani; Haldar, Kasturi; Lin, Jimmy C; Babar, Imran A; Girisha, Katta M; Srinivasan, Sudha; Navaneetham, Duraiswamy; Battu, Rajani; Devarakonda, Rajashree; Kini, Usha; Vijayachandra, Kinnimulki; Verma, Ishwar C

    2014-08-13

    In order to address the unmet needs and create opportunities that benefit patients with rare disease in India, a group of volunteers created a not-for-profit organization named Organization for Rare Diseases India (ORDI; www.ordindia.org). ORDI plans to represent the collective voice and advocate the needs of patients with rare diseases and other stakeholders in India. The ORDI team members come from diverse backgrounds such as genetics, molecular diagnostics, drug development, bioinformatics, communications, information technology, patient advocacy and public service. ORDI builds on the lessons learned from numerous similar organizations in the USA, European Union and disease-specific rare disease foundations in India. In this review, we provide a background on the landscape of rare diseases and the organizations that are active in this area globally and in India. We discuss the unique challenges in tackling rare diseases in India, and highlight the unmet needs of the key stakeholders of rare diseases. Finally, we define the vision, mission, goals and objectives of ORDI, identify the key developments in the health care context in India and welcome community feedback and comments on our approach.

  10. 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

  11. 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.

  12. Applying Complement Therapeutics to Rare Diseases

    PubMed Central

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

    2015-01-01

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

  13. Applying complement therapeutics to rare diseases.

    PubMed

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

    2015-12-01

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

  14. Imaging in the diagnosis of rare diseases.

    PubMed

    Bekiesińska-Figatowska, Monika

    2015-01-01

    A disease is considered rare if it affects no more than 5 in 10,000 people. More than six thousand rare diseases have been detected so far and they affect 6-8% of the population which equals 2.3-3 million people in Poland. Some of the rare diseases are already diagnosed in utero, e.g. skeletal dysplasias on ultrasonography or central nervous system diseases on magnetic resonance imaging (MRI). Many cases are finally diagnosed after radiologist's suggestion in a radiological report. Although diagnostic imaging cannot be considered as a basis for diagnosis of most of rare diseases, these studies represent an important element in the diagnostic chain. The complicated and long process of diagnosis may be significantly shortened by suggestions of the radiologist, based on the observation of these elements of radiological appearance of the lesions that are characteristic for a particular group of diseases, or even for a particular disease entity. However, the absolute condition for success is the close clinical-radiological cooperation, with clinicians providing the radiologists with their knowledge of patient's history, clinical manifestations, and the results of other investigations.

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

    PubMed Central

    McCormack, Francis X.

    2010-01-01

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

  16. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group.

    PubMed

    Richter, Trevor; Nestler-Parr, Sandra; Babela, Robert; Khan, Zeba M; Tesoro, Theresa; Molsen, Elizabeth; Hughes, Dyfrig A

    2015-09-01

    At present, there is no universal definition of rare disease. To provide an overview of rare disease definitions currently used globally. We systematically searched for definitions related to rare disease from organizations in 32 international jurisdictions. Descriptive statistics of definitions were generated and prevalence thresholds were calculated. We identified 296 definitions from 1109 organizations. The terms "rare disease(s)" and "orphan drug(s)" were used most frequently (38% and 27% of the definitions, respectively). Qualitative descriptors such as "life-threatening" were used infrequently. A prevalence threshold was specified in at least one definition in 88% of the jurisdictions. The average prevalence threshold across organizations within individual jurisdictions ranged from 5 to 76 cases/100,000 people. Most jurisdictions (66%) had an average prevalence threshold between 40 and 50 cases/100,000 people, with a global average of 40 cases/100,000 people. Prevalence thresholds used by different organizations within individual jurisdictions varied substantially. Across jurisdictions, umbrella patient organizations had the highest (most liberal) average prevalence threshold (47 cases/100,000 people), whereas private payers had the lowest threshold (18 cases/100,000 people). Despite variation in the terminology and prevalence thresholds used to define rare diseases among different jurisdictions and organizations, the terms "rare disease" and "orphan drug" are used most widely and the average prevalence threshold is between 40 and 50 cases/100,000 people. These findings highlight the existing diversity among definitions of rare diseases, but suggest that any attempts to harmonize rare disease definitions should focus on standardizing objective criteria such as prevalence thresholds and avoid qualitative descriptors. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  17. 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 IC50 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.

  18. 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…

  19. 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…

  20. New therapeutic targets in rare genetic skeletal diseases

    PubMed Central

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

    2015-01-01

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

  1. New therapeutic targets in rare genetic skeletal diseases.

    PubMed

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

    2015-10-03

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

  2. [Computer-assisted diagnosis of rare diseases].

    PubMed

    Müller, T; Jerrentrup, A; Schäfer, J R

    2017-03-31

    To establish a comprehensive diagnosis is by far the most challenging task in a physician's daily routine. Especially rare diseases place high demands on differential diagnosis, caused by the high number of around 8000 diseases and their clinical variability. No clinician can be aware of all the different entities and memorizing them all is impossible and inefficient. Specific diagnostic decision-supported systems provide better results than standard search engines in this context. The systems FindZebra, Phenomizer, Orphanet, and Isabel are presented here concisely with their advantages and limitations. An outlook is given to social media usage and big data technologies. Due to the high number of initial misdiagnoses and long periods of time until a confirmatory diagnosis is reached, these tools might be promising in practice to improve the diagnosis of rare diseases.

  3. 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.

  4. 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

  5. [Rare Diseases: chronic diseases that need a new approach].

    PubMed

    Avellaneda, A; Izquierdo, M; Torrent-Farnell, J; Ramón, J R

    2007-01-01

    The concept of Rare Diseases is relatively new. They are those processes "...that can be mortal or to cause a chronic weakening of the patient and who, due to its little prevalence, require combined efforts to treat them. For indicative purposes, a little prevalence is considered when is lesser than 5 cases per 10,000 people in the Community". The existence of these diseases is closely tied with orphan drugs, meaning all drugs, prosthesis, biological agents or dietetic preparations destined to the treatment of a Rare Disease. Besides, it is necessary to add two factors more: 1. The Primary Attention physicians do not feel very motivated in their knowledge and 2. These diseases need a complex sociosanitary attention, habitually more expensive than chronic diseases. By all exposed the Rare Diseases appear like a universe that requires a new sociosanitary approach from the health system.

  6. 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 ...

  7. 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

  8. Marble Bone Disease: A Rare Bone Disorder

    PubMed Central

    Harinathbabu, Maheswari; Thillaigovindan, Ranjani; Prabhu, Geetha

    2015-01-01

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

  9. Next generation sequencing: Coping with rare genetic diseases in China

    PubMed Central

    Cram, David S; Zhou, Daixing

    2016-01-01

    Summary With a population of 1.4 billion, China shares the largest burden of rare genetic diseases worldwide. Current estimates suggest that there are over ten million individuals afflicted with chromosome disease syndromes and well over one million individuals with monogenic disease. Care of patients with rare genetic diseases remains a largely unmet need due to the paucity of available and affordable treatments. Over recent years, there is increasing recognition of the need for affirmative action by government, health providers, clinicians and patients. The advent of new next generation sequencing (NGS) technologies such as whole genome/exome sequencing, offers an unprecedented opportunity to provide large-scale population screening of the Chinese population to identify the molecular causes of rare genetic diseases. As a surrogate for lack of effective treatments, recent development and implementation of noninvasive prenatal testing (NIPT) in China has the greatest potential, as a single technology, for reducing the number of children born with rare genetic diseases. PMID:27672536

  10. Social Media Methods for Studying Rare Diseases

    PubMed Central

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

    2014-01-01

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

  11. Creating a global rare disease patient registry linked to a rare diseases biorepository database: Rare Disease-HUB (RD-HUB).

    PubMed

    Rubinstein, Yaffa R; Groft, Stephen C; Bartek, Ronald; Brown, Kyle; Christensen, Ronald A; Collier, Elaine; Farber, Amy; Farmer, Jennifer; Ferguson, John H; Forrest, Christopher B; Lockhart, Nicole C; McCurdy, Kate R; Moore, Helen; Pollen, Geraldine B; Richesson, Rachel; Miller, Vanessa Rangel; Hull, Sara; Vaught, Jim

    2010-09-01

    A movement to create a global patient registry for as many as 7,000 rare diseases was launched at a workshop, "Advancing Rare Disease Research: The Intersection of Patient Registries, Biospecimen Repositories, and Clinical Data." http://rarediseases.info.nih.gov/PATIENT_REGISTRIES_WORKSHOP/. The workshop was sponsored by the Office of Rare Diseases Research (ORDR). The focus was the building of an infrastructure for an internet-based global registry linking to biorepositories. Such a registry would serve the patients, investigators, and drug companies. To aid researchers the participants suggested the creation of a centralized database of biorepositories for rare biospecimens (RD-HUB)http://biospecimens.ordr.info.nih.gov/ that could be linked to the registry. Over two days of presentations and breakout sessions, several hundred attendees discussed government rules and regulations concerning privacy and patients' rights and the nature and scope of data to be entered into a central registry as well as concerns about how to validate patient and clinician-entered data to ensure data accuracy. Mechanisms for aggregating data from existing registries were also discussed. The attendees identified registry best practices, model coding systems, international systems for recruiting patients into clinical trials and novel ways of using the internet directly to invite participation in research. They also speculated about who would bear ultimate responsibility for the informatics in the registry and who would have access to the information. Hurdles associated with biospecimen collection and how to overcome them were detailed. The development of the recommendations was, in itself, an indication of the commitment of the rare disease community as never before. Published by Elsevier Inc.

  12. 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

  13. Melorheostosis - Case Report of Rare Disease.

    PubMed

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

    2014-01-01

    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. 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. 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.

  14. 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...

  15. 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..

  16. Identifying Pilots with Parkinson's Disease.

    PubMed

    Clem, Peter A; Navathe, Pooshan D; Drane, Michael A

    2016-06-01

    In 2012 the Australian Institute of Health and Welfare produced a report titled 'Dementia in Australia.'(2) The report noted that the number of people with dementia in Australia would reach almost 400,000 by 2020. Australia is a jurisdiction which does not impose a mandatory retirement age for pilots. With an aging population it was hypothesized that conditions such as Parkinson's disease (PD) were likely to be seen more commonly by the Civil Aviation Safety Authority (CASA). It was decided that this was an appropriate time to retrospectively study the data held by CASA. An interrogation of CASA databases was undertaken. Data was produced comparing percentage of Class 1 certificate holders over 60 yr of age against time. A cohort of pilots and controllers with PD was identified. The history of the cases was reviewed. The study confirms that the pilot population is aging in line with population trends. Over a period from 1992 to 2012, 22 cases of pilots and controllers with PD were identified. The study confirmed that PD will be of increased relevance over the next decade. Gaps between policy and practice managing past cases were identified. Updated guidelines have been published aiming to address the deficiencies identified in the study. Historically pilots and controllers have been able to maintain certification for an average of 3.75 yr. This information should be of benefit to clinicians, pilots, and controllers when considering occupation and treatment options.

  17. Challenges and Hurdles to Business as Usual in Drug Development for Treatment of Rare Diseases.

    PubMed

    Swinney, D C

    2016-10-01

    Only 10-15 first-in-class new medicines are approved each year by the global pharmaceutical industry for all diseases, of which less than a third is for rare (orphan) diseases. The drug discovery processes to identify rare and common diseases are similar, suggesting it will be impossible to discover new drugs for even a small fraction of the rare diseases using the current paradigm. Different approaches are required to address this large unmet medical need.

  18. Drugs Against Rare Diseases: Are The Regulatory Standards Higher?

    PubMed Central

    Pastoor, D

    2016-01-01

    The US Food and Drug Administration (FDA) recently issued a draft Guidance for Industry for Rare Diseases: Common Issues in Drug Development (referred to as “Rare Diseases Guidance”). In our opinion, the FDA should consider: (a) explicitly acknowledging the standards are higher for rare diseases for the reasons presented in this article; and (b) illustrating innovative development pathways that may be acceptable for rare diseases, including case studies. PMID:27326701

  19. Rare disease research: Breaking the privacy barrier.

    PubMed

    Mascalzoni, Deborah; Paradiso, Angelo; Hansson, Matts

    2014-06-01

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

  20. Innovative research methods for studying treatments for rare diseases: methodological review.

    PubMed

    Gagne, Joshua J; Thompson, Lauren; O'Keefe, Kelly; Kesselheim, Aaron S

    2014-11-24

    To examine methods for generating evidence on health outcomes in patients with rare diseases. Methodological review of existing literature. PubMed, Embase, and Academic Search Premier searched for articles describing innovative approaches to randomized trial design and analysis methods and methods for conducting observational research in patients with rare diseases. We assessed information related to the proposed methods, the specific rare disease being studied, and outcomes from the application of the methods. We summarize methods with respect to their advantages in studying health outcomes in rare diseases and provide examples of their application. We identified 46 articles that proposed or described methods for studying patient health outcomes in rare diseases. Articles covered a wide range of rare diseases and most (72%) were published in 2008 or later. We identified 16 research strategies for studying rare disease. Innovative clinical trial methods minimize sample size requirements (n=4) and maximize the proportion of patients who receive active treatment (n=2), strategies crucial to studying small populations of patients with limited treatment choices. No studies describing unique methods for conducting observational studies in patients with rare diseases were identified. Though numerous studies apply unique clinical trial designs and considerations to assess patient health outcomes in rare diseases, less attention has been paid to innovative methods for studying rare diseases using observational data. © Gagne et al 2014.

  1. How the EUCERD Joint Action supported initiatives on Rare Diseases.

    PubMed

    Lynn, Stephen; Hedley, Victoria; Atalaia, Antonio; Evangelista, Teresinha; Bushby, Kate

    2017-03-01

    Joint Actions are successful initiatives from the European Commission (EC) that have helped to raise awareness and to bring significant benefit to those suffering from a rare disease (RD). In this paper, we will focus on the activities developed by the EUCERD Joint Action (EJA) and by the Orphanet Joint Action ("Orphanet Europe"). EUCERD Joint Action was co-funded by the EC and the Member States between 2012 and 2015 to help to define the activities and policies in the field of RD and foster exchange of experiences amongst Member States. This project is the continuation of previous efforts to turn RD a priority in the EC Health Programmes. "Orphanet Europe" was a Joint Action co-funded by INSERM, the French Directorate General for Health and the EC to address the need for a common portal that would gather the most update information regarding RD. This need was identified in the European Commission report "Rare Diseases: Europe's challenge" and in the Recommendation of the Council for a European RD portal. These joint actions have supported the policy development work of the European Commission, through the support of their committees for rare diseases. In this paper, the authors aim to raise awareness of the work done by the EUCERD Joint Action on behalf of the rare disease community and the policies established.

  2. Developing methodology for the creation of clinical practice guidelines for rare diseases: A report from RARE-Bestpractices

    PubMed Central

    Pai, Menaka; Iorio, Alfonso; Meerpohl, Joerg; Taruscio, Domenica; Laricchiuta, Paola; Mincarone, Pierpaolo; Morciano, Cristina; Leo, Carlo Giacomo; Sabina, Saverio; Akl, Elie; Treweek, Shaun; Djulbegovic, Benjamin; Schunemann, Holger

    2015-01-01

    Rare diseases are a global public health priority; they can cause significant morbidity and mortality, can gravely affect quality of life, and can confer a social and economic burden on families and communities. These conditions are, by their nature, encountered very infrequently by clinicians. Thus, clinical practice guidelines are potentially very helpful in supporting clinical decisions, health policy and resource allocation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system is a structured and transparent approach to developing and presenting summaries of evidence, grading its quality, and then transparently interpreting the available evidence to make recommendations in health care. GRADE has been adopted widely. However, its use in creating guidelines for rare diseases – which are often plagued by a paucity of high quality evidence – has not yet been explored. RARE-Bestpractices is a project to create and populate a platform for sharing best practices for management of rare diseases. A major aim of this project is to ensure that European Union countries have the capacity to produce high quality clinical practice guidelines for rare diseases. On February 12, 2013 at the Istituto Superiore di Sanità, in Rome, Italy, the RARE-Bestpractices group held the first of a series of 2 workshops to discuss methodology for creating clinical practice guidelines, and explore issues specific to rare diseases. This paper summarizes key results of the first workshop, and explores how the current GRADE approach might (or might not) work for rare diseases. Avenues for future research are also identified.

  3. Identifying future zoonotic disease threats

    PubMed Central

    Cooper, Natalie; Nunn, Charles L.

    2013-01-01

    Background and objectives: Emerging infectious diseases often originate in wildlife, making it important to identify infectious agents in wild populations. It is widely acknowledged that wild animals are incompletely sampled for infectious agents, especially in developing countries, but it is unclear how much more sampling is needed, and where that effort should focus in terms of host species and geographic locations. Here, we identify these gaps in primate parasites, many of which have already emerged as threats to human health. Methodology: We obtained primate host–parasite records and other variables from existing databases. We then investigated sampling effort within primates relative to their geographic range size, and within countries relative to their primate species richness. We used generalized linear models, controlling for phylogenetic or spatial autocorrelation, to model variation in sampling effort across primates and countries. Finally, we used species richness estimators to extrapolate parasite species richness. Results: We found uneven sampling effort within all primate groups and continents. Sampling effort among primates was influenced by their geographic range size and substrate use, with terrestrial species receiving more sampling. Our parasite species richness estimates suggested that, among the best sampled primates and countries, almost half of primate parasites remain to be sampled; for most primate hosts, the situation is much worse. Conclusions and implications: Sampling effort for primate parasites is uneven and low. The sobering message is that we know little about even the best studied primates, and even less regarding the spatial and temporal distribution of parasitism within species. PMID:24481184

  4. Clinical Practice Guidelines for Rare Diseases: The Orphanet Database

    PubMed Central

    Pavan, Sonia; Rommel, Kathrin; Mateo Marquina, María Elena; Höhn, Sophie; Lanneau, Valérie; Rath, Ana

    2017-01-01

    Clinical practice guidelines (CPGs) for rare diseases (RDs) are scarce, may be difficult to identify through Internet searches and may vary in quality depending on the source and methodology used. In order to contribute to the improvement of the diagnosis, treatment and care of patients, Orphanet (www.orpha.net) has set up a procedure for the selection, quality evaluation and dissemination of CPGs, with the aim to provide easy access to relevant, accurate and specific recommendations for the management of RDs. This article provides an analysis of selected CPGs by medical domain coverage, prevalence of diseases, languages and type of producer, and addresses the variability in CPG quality and availability. CPGs are identified via bibliographic databases, websites of research networks, expert centres or medical societies. They are assessed according to quality criteria derived from the Appraisal of Guidelines, REsearch and Evaluation (AGREE II) Instrument. Only open access CPGs and documents for which permission from the copyright holders has been obtained are disseminated on the Orphanet website. From January 2012 to July 2015, 277 CPGs were disseminated, representing coverage of 1,122 groups of diseases, diseases or subtypes in the Orphanet database. No language restriction is applied, and so far 10 languages are represented, with a predominance of CPGs in English, French and German (92% of all CPGs). A large proportion of diseases with identified CPGs belong to rare oncologic, neurologic, hematologic diseases or developmental anomalies. The Orphanet project on CPG collection, evaluation and dissemination is a continuous process, with regular addition of new guidelines, and updates. CPGs meeting the quality criteria are integrated to the Orphanet database of rare diseases, together with other types of textual information and the appropriate services for patients, researchers and healthcare professionals in 40 countries. PMID:28099516

  5. Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

    PubMed Central

    Smith, Bradley N.; Ticozzi, Nicola; Fallini, Claudia; Gkazi, Athina Soragia; Topp, Simon; Kenna, Kevin P.; Scotter, Emma L.; Kost, Jason; Keagle, Pamela; Miller, Jack W.; Calini, Daniela; Vance, Caroline; Danielson, Eric W.; Troakes, Claire; Tiloca, Cinzia; Al-Sarraj, Safa; Lewis, Elizabeth A.; King, Andrew; Colombrita, Claudia; Pensato, Viviana; Castellotti, Barbara; de Belleroche, Jacqueline; Baas, Frank; ten Asbroek, Anneloor LMA; Sapp, Peter C.; McKenna-Yasek, Diane; McLaughlin, Russell L.; Polak, Meraida; Asress, Seneshaw; Esteban-Pérez, Jesús; oz-Blanco, José Luis Muñ; Simpson, Michael; Consortium, SLAGEN; van Rheenen, Wouter; Diekstra, Frank P.; Lauria, Giuseppe; Duga, Stefano; Corti, Stefania; Cereda, Cristina; Corrado, Lucia; Sorarù, Gianni; Morrison, Karen E.; Williams, Kelly L.; Nicholson, Garth A.; Blair, Ian P.; Dion, Patrick A.; Leblond, Claire S.; Rouleau, Guy A.; Hardiman, Orla; Veldink, Jan H.; van den Berg, Leonard H.; Al-Chalabi, Ammar; Pall, Hardev; Shaw, Pamela J.; Turner, Martin R.; Talbot, Kevin; Taroni, Franco; García-Redondo, Alberto; Wu, Zheyang; Glass, Jonathan D.; Gellera, Cinzia; Ratti, Antonia; Brown, Robert H.; Silani, Vincenzo; Shaw, Christopher E.; Landers, John E.

    2015-01-01

    SUMMARY Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis. PMID:25374358

  6. [Pycnodysostosis: a rare disease with frequent fractures].

    PubMed

    Sánchez Lázaro, J A; Linares Álvarez, L

    2014-04-01

    Pycnodysostosis is a rare disease caused by a dysfunction of the osteoclasts due to a mutation in the cathepsin K gene. We present a case of a young adult patient with the above mentioned syndrome, who suffered an atypical fracture of the tibia after a low energy fall. Some bone changes that could have predisposed the fracture were observed when examined in the Emergency Department. Not long afterwards he suffered the same type of fracture in another tibia. Due to the conditions typical of the pycnodysostosis, the above mentioned fracture required an unconventional approach for this mid-shaft tibial fracture (osteosynthesis plate), combined with a longer consolidation time. The case was finally resolved satisfactorily. Copyright © 2013 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  7. Rare lung diseases II: Pulmonary alveolar proteinosis

    PubMed Central

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

    2008-01-01

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

  8. Lymphocytic hypophysitis: a rare or underestimated disease?

    PubMed

    Bellastella, Antonio; Bizzarro, Antonio; Coronella, Concetta; Bellastella, Giuseppe; Sinisi, Antonio Agostino; De Bellis, Annamaria

    2003-11-01

    Lymphocytic hypophysitis (LYH) is an uncommon autoimmune disease in which the pituitary gland is infiltrated by lymphocytes, plasma cells and macrophages and its function is usually impaired. It has to be suspected in pregnant women and in women with recent delivery presenting with hyperprolactinemia, headache, visual field alterations and changes of one or more pituitary hormone secretions with secondary impairment of related peripheral target glands, especially when associated with other autoimmune endocrine or non-endocrine disorders. It can also occur less frequently in prepubertal or post-menopausal women and in men. Headache, visual field impairment and more rarely diplopia are due to extrasellar pituitary enlargement with optic chiasma compression and/or to invasion of cavernous sinuses. Among the 'isolated' pituitary hormone deficiencies, ACTH deficit is usually the earliest and most frequent hormonal impairment and in rare cases can induce an acute secondary hyposurrenalism as the first sign of the disease, with high mortality in affected patients. Histopathological findings from pituitary biopsy show lymphoplasmacytic infiltrate with lymphoid aggregates surrounding atropic acini of pituitary cells; immunohistochemical analysis shows numerous mast cells randomly distributed and also localized in the vicinity of capillaries, suggesting a possible influence on capillary permeability and angiogenesis, thus favoring the inflammatory and immunological aggression against pituitary cells. Nuclear magnetic resonance imaging shows uniform sellar floor depression and an extrasellar symmetrical pituitary enlargement, usually displacing the optic chiasma, which shows a rapid homogeneous enhancement after gadolinium also involving the adjacent dura (dural tail). Antipituitary antibodies have been detected in several patients with LYH but their role needs to be clarified. Since a possible spontaneous remission can occur, a careful follow-up is required in subclinical

  9. Gene-based segregation method for identifying rare variants in family-based sequencing studies.

    PubMed

    Qiao, Dandi; Lange, Christoph; Laird, Nan M; Won, Sungho; Hersh, Craig P; Morrow, Jarrett; Hobbs, Brian D; Lutz, Sharon M; Ruczinski, Ingo; Beaty, Terri H; Silverman, Edwin K; Cho, Michael H

    2017-02-13

    Whole-exome sequencing using family data has identified rare coding variants in Mendelian diseases or complex diseases with Mendelian subtypes, using filters based on variant novelty, functionality, and segregation with the phenotype within families. However, formal statistical approaches are limited. We propose a gene-based segregation test (GESE) that quantifies the uncertainty of the filtering approach. It is constructed using the probability of segregation events under the null hypothesis of Mendelian transmission. This test takes into account different degrees of relatedness in families, the number of functional rare variants in the gene, and their minor allele frequencies in the corresponding population. In addition, a weighted version of this test allows incorporating additional subject phenotypes to improve statistical power. We show via simulations that the GESE and weighted GESE tests maintain appropriate type I error rate, and have greater power than several commonly used region-based methods. We apply our method to whole-exome sequencing data from 49 extended pedigrees with severe, early-onset chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD study (BEOCOPD) and identify several promising candidate genes. Our proposed methods show great potential for identifying rare coding variants of large effect and high penetrance for family-based sequencing data. The proposed tests are implemented in an R package that is available on CRAN (https://cran.r-project.org/web/packages/GESE/).

  10. Bardet-Biedl syndrome: A rare genetic disease.

    PubMed

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

    2013-06-01

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

  11. 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

  12. 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.

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

    PubMed

    Chen, Kai; Yao, Lan; Liu, Zhiyong

    2015-04-01

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

  14. Hirayama Disease: A Rare Disease with Unusual Features

    PubMed Central

    Fanai, Vanlalmalsawmdawngliana

    2016-01-01

    Hirayama disease, also known as monomelic amyotrophy (MMA), is a rare cervical myelopathy that manifests itself as a self-limited, asymmetrical, slowly progressive atrophic weakness of the forearms and hands predominantly in young males. The forward displacement of the posterior dura of the lower cervical dural canal during neck flexion has been postulated to lead to lower cervical cord atrophy with asymmetric flattening. We report a case of Hirayama disease in a 25-year-old Indian man presenting with gradually progressive asymmetrical weakness and wasting of both hands and forearms along with unusual features of autonomic dysfunction and upper motor neuron lesion. PMID:28097028

  15. Hirayama Disease: A Rare Disease with Unusual Features.

    PubMed

    Anuradha, S; Fanai, Vanlalmalsawmdawngliana

    2016-01-01

    Hirayama disease, also known as monomelic amyotrophy (MMA), is a rare cervical myelopathy that manifests itself as a self-limited, asymmetrical, slowly progressive atrophic weakness of the forearms and hands predominantly in young males. The forward displacement of the posterior dura of the lower cervical dural canal during neck flexion has been postulated to lead to lower cervical cord atrophy with asymmetric flattening. We report a case of Hirayama disease in a 25-year-old Indian man presenting with gradually progressive asymmetrical weakness and wasting of both hands and forearms along with unusual features of autonomic dysfunction and upper motor neuron lesion.

  16. [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.

  17. 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

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  20. 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

  1. Focusing on rare diseases in China: are we there yet?

    PubMed

    Yang, Li; Su, Chang; Lee, Ashley M; Bai, Harrison X

    2015-11-02

    The Chinese researchers have made significant progress in studying rare diseases in the recent years. From 2000 to 2014, 269 out of 1892 clinically relevant original research papers published on high impact journals by Chinese institutions, and 2678 out of 6040 clinical trials conducted by Chinese institutions and registered at ClinicalTrial.gov are focused on rare diseases. The number of research papers and of clinical trials has shown a steady trend of increase. Creating public databases for rare disease will escalate progress in rare disease and enable multicenter studies.

  2. The NIH Undiagnosed Diseases Program: Insights into Rare Diseases

    PubMed Central

    Gahl, William A.; Markello, Thomas C.; Toro, Camilo; Fajardo, Karin Fuentes; Sincan, Murat; Gill, Fred; Carlson-Donohoe, Hannah; Gropman, Andrea; Pierson, Tyler Mark; Golas, Gretchen; Wolfe, Lynne; Groden, Catherine; Godfrey, Rena; Nehrebecky, Michele; Wahl, Colleen; Landis, Dennis M. D.; Yang, Sandra; Madeo, Anne; Mullikin, James C; Boerkoel, Cornelius F.; Tifft, Cynthia J.; Adams, David

    2014-01-01

    Purpose This report describes the NIH Undiagnosed Diseases Program (UDP), details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate over its first two years. Methods Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density SNP arrays and whole exome or genome analysis. Results Of 1191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the NIH Clinical Center on the UDP service. Of those, 47% were children, 55% were females, and 53% had neurological disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathological, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based upon SNP array analysis and three others using WES and filtering of variants. Two new disorders were discovered. Analysis of the SNP-array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. Conclusions The NIH UDP addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies, and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup. PMID:22237431

  3. Brexit and rare diseases: big risk, bigger opportunity?

    PubMed

    Hyry, Hanna I; Cox, Timothy M; Roos, Jonathan C P

    2017-04-01

    The UK's planned exit from the EU will leave its national health sector in a very dangerous position. It will also have profound consequences for domestic UK law. The impact may be particularly drastic for patients for whom EU law protects the right to treatment. At a particular risk are patients with rare, 'orphan', diseases whose treatments are uniquely enabled at the EU level. We examine the potential effects of Brexit on the orphan sector and identify an opportunity to solve long-standing and intensifying difficulties, especially the pricing of orphan drugs.

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

    PubMed

    Rodwell, Charlotte; Aymé, Ségolène

    2015-10-01

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

  5. Drug Might Help Some Babies with Rare, Fatal Disease

    MedlinePlus

    ... Might Help Some Babies With Rare, Fatal Disease Spinal muscular atrophy is typically lethal within 2 years, but new ... promise, researchers report. There is no treatment for spinal muscular atrophy type 1 (SMA-1), a degenerative neuromuscular disease ...

  6. Elephantiasis Nostras Verrucosa: a rare thyroid dermopathy in Graves' disease.

    PubMed

    Kakati, S; Doley, B; Pal, S; Deka, U J

    2005-06-01

    Elephantiasis Nostras Verrucosa (ENV) is a rare form of pretibial myxedema, which is nearly always associated with Graves' disease. A case is presented here of Graves' disease who had elephantiasis variety of pre-tibial myxedema (PTM).

  7. 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.

  8. 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…

  9. 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…

  10. 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.

  11. 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

  12. Computer-assisted initial diagnosis of rare diseases.

    PubMed

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

    2016-01-01

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

  13. Creating an effective clinical registry for rare diseases

    PubMed Central

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

    2015-01-01

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

  14. Rare diseases research: expanding collaborative translational research opportunities.

    PubMed

    Groft, Stephen C

    2013-07-01

    Extensive public-private partnerships, including the National Institutes of Health (NIH) and the rare diseases community, which is seeing a renewed industry interest in smaller niche markets, have resulted in an increase of interventions for rare diseases. Significant collaborative efforts are required among the pharmaceutical industry, foundations, patient-advocacy groups, academic and government investigators and funding programs, regulatory scientists, and reimbursement agencies to meet the unmet diagnostic and treatment needs for approximately 25 million people in the United States with 7,000 rare diseases. The expanding role and outreach activities of patient-advocacy groups have increased public awareness. In the United States, a rare disease is defined as a disorder or condition with a prevalence of <200,000 people. In 2011, the NIH provided >$3.5 billion for rare diseases research, including $750 million for orphan product development activities, nearly 11.4% of the NIH research budget. Several research institutes and centers of the NIH, including the National Center for Advancing Translational Sciences, have initiated varied translational research efforts to address the absence of preclinical and clinical data required for regulatory review purposes. Clinicians can expect to see significant increases in requests from patients and their families to participate in patient registries and natural history or observational studies to gather specific information from a larger pool of patients on the progression of the disease or response to treatments. An expanding emphasis on rare diseases provides hope for the millions of patients with rare diseases.

  15. Health technologies for rare diseases: does conventional HTA still apply?

    PubMed

    Simoens, Steven

    2014-06-01

    As part of a health technology assessment, economic evaluation of health technologies for rare diseases poses specific challenges given that such technologies are rarely cost-effective. Therefore, conventional economic evaluation techniques appear to be less relevant to health technologies for rare diseases. However, the definition of health technology assessment points to multi-criteria decision analysis by stating that a health technology needs to be assessed against multiple criteria in order to pronounce a judgement about the value of the health technology. Thus, this editorial argues that a full health technology assessment which uses a multi-criteria decision analysis framework to evaluate the value of a technology can be applied to health technologies for rare diseases. Past experiences demonstrate that the specific characteristics of health technologies for rare diseases can fit in the conventional health technology assessment paradigm by means of multi-criteria decision analysis.

  16. Rare disease relations through common genes and protein interactions.

    PubMed

    Fernandez-Novo, Sara; Pazos, Florencio; Chagoyen, Monica

    2016-06-01

    ODCs (Orphan Disease Connections), available at http://csbg.cnb.csic.es/odcs, is a novel resource to explore potential molecular relations between rare diseases. These molecular relations have been established through the integration of disease susceptibility genes and human protein-protein interactions. The database currently contains 54,941 relations between 3032 diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. 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

  18. 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.

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

    PubMed Central

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

    2010-01-01

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

  20. Colloid milium: a rare cutaneous deposition disease.

    PubMed

    Rahman, Simeen Ber; Arfan Ul Bari; Mumtaz, Nadeem

    2008-04-01

    Colloid milium is a rare degenerative skin disorder known by the development of small translucent, yellowish brown pappular nodules or plaques, generally located in sun exposed areas. Clinically they are of two types, adult and juvenile type. We present a case of adult type Colloid milium in a 60 years old female patient with clinical and histological findings unmistakable of the condition. She was treated with IPL. (Intense Pulsed Light) laser following unsatisfactory response with dermabrasion.

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

    PubMed

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

    2014-05-24

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

  2. 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

  3. [Extrinsic allergic alveolitis--rarely diagnosed disease].

    PubMed

    Lauková, D; Marget, I; Plutinský, J

    2009-05-01

    Extrinsic allergic alveolitis (EAA), known as hypersensitive pneumonitis, causes interstitial lung involvement by inhaled antigen. The clinical presentation of the disease has been defined as acute, subacute and chronic. The most often symptoms of the acute form of the disease are flu-like symptoms, dyspnoe and cough. The progressive dyspnoe in particullary is characterized for the chronic form of EAA. Dyspnoe is worsed, if the disease is combinied with usual respiratory infection or reexposition of inhaled antigen. It seems the diagnostic definition of EAA should be easy and prevalence of EAA relative high. The disease belongs to the group of interstitial lung diseases and it is underestimated as a matter of fact. The clinic, radiographic, laboratory and histologic abnormalities are results of inhaled antigen contact and support the diagnosis of EAA. Specific IgG antibodies against the offending antigen along with them are consedered to be detected (established) of EAA.

  4. Rare disease patients in China anticipate the sunlight of legislation.

    PubMed

    Gao, J J; Song, P P; Tang, W

    2013-06-01

    It is estimated that there are over ten million rare disease patients in China currently. Due to a lack of effective drugs and reimbursement regulations for medical expenses the diseases bring most patients enormous physical suffering and psychological despair. Past experience in other countries such as the United States, Japan, and the European Union have shown that legislation is the critical step to improve the miserable situation of rare disease patients. Laws and regulations for rare diseases in these countries prescribe a series of incentives for research and development of orphan drugs which turn out to obviously allow these drugs to flourish. Legislation has also established a drug reimbursement system to reduce the medical burden of the patients. These measures effectively protect the rights and interests of patients with rare diseases. In China, legislation for rare diseases has begun to attract the attention of authorities. It is anticipated that relevant laws and regulations will be established as early as possible to provide safeguards for rare disease patients in China.

  5. Database for Parkinson Disease Mutations and Rare Variants

    DTIC Science & Technology

    2016-09-01

    for Parkinson Disease Mutations and Rare Variants 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jeffery M...Vance, J.M.: “Parkinson Disease Variant Database”. MDS 19th International Congress of Parkinson’s Disease and Movement Disorders, San Diego, CA, June 14

  6. 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.

  7. 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 ...

  8. 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.

  9. 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.

  10. Menkes kinky hair syndrome: a rare neurodegenerative disease.

    PubMed

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

    2012-01-01

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

  11. 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.

  12. 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 (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 (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 (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

  13. 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

  14. Taming molecular flexibility to tackle rare diseases

    PubMed Central

    Cubellis, Maria Vittoria; Baaden, Marc; Andreotti, Giuseppina

    2015-01-01

    Many mutations responsible of Fabry disease destabilize lysosomal alpha-galactosidase, but retain the enzymatic activity. These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis. We demonstrate the effectiveness of molecular dynamics simulations to correlate the genotype to the severity of the disease. We studied the relation between protein flexibility and residual enzymatic activity of pathological missense mutants in the cell. We found that mutations occurring at flexible sites are likely to retain activity in vivo. The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases. PMID:25841341

  15. Taming molecular flexibility to tackle rare diseases.

    PubMed

    Cubellis, Maria Vittoria; Baaden, Marc; Andreotti, Giuseppina

    2015-06-01

    Many mutations responsible of Fabry disease destabilize lysosomal alpha-galactosidase, but retain the enzymatic activity. These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis. We demonstrate the effectiveness of molecular dynamics simulations to correlate the genotype to the severity of the disease. We studied the relation between protein flexibility and residual enzymatic activity of pathological missense mutants in the cell. We found that mutations occurring at flexible sites are likely to retain activity in vivo. The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases.

  16. A rare presentation of Legionnaires' disease.

    PubMed

    Delicata, Mark; Banerjee, Amit

    2015-07-01

    We present an interesting case of Legionnaires' disease masquerading as acute pyelonephritis, with complete absence of respiratory symptoms on admission. A 45-year-old man was diagnosed with Legionnaires' disease 2 days after presenting to hospital with dysuria and right loin pain. He became critically unwell during the hospital admission, with headache, uncontrolled fever, breathlessness, decreasing oxygen saturations and increasing oxygen requirements. A CT pulmonary angiography demonstrated right upper lobar consolidation and Legionella urinary antigen was positive. He was treated with ciprofloxacin and rifampicin and made a full recovery.

  17. 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.

  18. 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.

  19. 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

  20. [Biological treatment of rare inflammatory rheumatic diseases].

    PubMed

    Baslund, Bo

    2008-06-09

    The current status of the use of biological medicine in the treatment of adult onset morbus still, Wegeners granulomatosis and systemic lupus erythematosus (SLE) is reviewed. The need for controlled trials is emphasized. Anti-CD20 treatment for SLE patients with kidney involvement and patients with Wegeners granulomatosis seems promising. Anti-TNF and IL1 receptor antagonist can control disease activity in most patients with adult morbus still.

  1. Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model.

    PubMed

    Alves, Maria M; Sribudiani, Yunia; Brouwer, Rutger W W; Amiel, Jeanne; Antiñolo, Guillermo; Borrego, Salud; Ceccherini, Isabella; Chakravarti, Aravinda; Fernández, Raquel M; Garcia-Barcelo, Maria-Mercè; Griseri, Paola; Lyonnet, Stanislas; Tam, Paul K; van Ijcken, Wilfred F J; Eggen, Bart J L; te Meerman, Gerard J; Hofstra, Robert M W

    2013-10-01

    Finding genes for complex diseases has been the goal of many genetic studies. Most of these studies have been successful by searching for genes and mutations in rare familial cases, by screening candidate genes and by performing genome wide association studies. However, only a small fraction of the total genetic risk for these complex genetic diseases can be explained by the identified mutations and associated genetic loci. In this review we focus on Hirschsprung disease (HSCR) as an example of a complex genetic disorder. We describe the genes identified in this congenital malformation and postulate that both common 'low penetrant' variants in combination with rare or private 'high penetrant' variants determine the risk on HSCR, and likely, on other complex diseases. We also discuss how new technological advances can be used to gain further insights in the genetic background of complex diseases. Finally, we outline a few steps to develop functional assays in order to determine the involvement of these variants in disease development.

  2. 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

  3. 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.

  4. Pregnancy Outcomes in Women With Rare Autoimmune Diseases.

    PubMed

    Chen, Jian S; Roberts, Christine L; Simpson, Judy M; March, Lyn M

    2015-12-01

    To examine pregnancy outcomes and pregnancy-related health service utilization among women with rare autoimmune diseases. This population-based cohort study of an Australian obstetric population (2001-2011) used birth records linked to hospital records for identification of rare autoimmune diseases including systemic vasculitis, vasculitis limited to the skin, Sjögren's syndrome, systemic sclerosis, Behçet's disease, polymyositis/dermatomyositis, and other systemic involvement of connective tissue. We excluded births in women with systemic lupus erythematosus or rheumatoid arthritis as well as births occurring ≥6 months before the diagnosis of the rare autoimmune disease. Modified Poisson regression was used to compare study outcomes between women with autoimmune diseases and the general obstetric population. There were 991,701 births, including 409 births (0.04%) in 293 women with rare autoimmune diseases. Of the 409 births, 202 (49%) were delivered by cesarean section and 72 (18%) were preterm; these rates were significantly higher than those in the general obstetric population (28% and 7%, respectively). Compared to the general population, women with autoimmune diseases had higher rates of hypertensive disorders, antepartum hemorrhage, and severe maternal morbidity and required longer hospitalization at delivery, more hospital admissions, and tertiary obstetric care. Compared to other infants, those whose mothers had a rare autoimmune disease were at increased risk of admission to a neonatal intensive care unit, severe neonatal morbidity, and perinatal death. While the majority of women with rare autoimmune diseases delivered healthy infants, they were at increased risk of having both maternal complications and adverse neonatal outcomes, suggesting that their pregnancies should be closely monitored. © 2015, American College of Rheumatology.

  5. Hirayama Disease with Periscapular Involvement: A Rare Association

    PubMed Central

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

    2016-01-01

    Hirayama disease (HD) is a rare disease commonly seen in India and Japan typically presenting in adolescent age group with male predominance and asymmetrical distal pure motor, lower-motor neuron-type weakness. We report a patient of HD who had significant involvement of proximal periscapular muscles along with typical distal involvement. The patient also had scapular winging, which is rare in HD. He was treated conservatively with physiotherapy and hard cervical collar and is presently under follow-up during the static phase of disease. PMID:27536023

  6. 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...

  7. 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.

  8. A rare case of bilateral orbital Castleman disease.

    PubMed

    Mukherjee, Bipasha; Alam, Mohammad Shahid; Krishnakumar, S

    2014-08-01

    Castleman disease is a non-neoplastic cause of lymphadenopathy, first described in 1956 by Dr. Benjamin Castleman. Orbital involvement in Castleman disease is extremely rare. We report a case of bilateral orbital Castleman disease in a 48-year-old Asian male who presented with bilateral inferior dystopia. MRI revealed bilateral extraconal superior orbital mass. Histopathology and immunohistochemistry of the mass revealed features of Castleman disease of hyaline vascular type. Castleman disease should be a differential in suspected idiopathic orbital inflammatory disease and lymphoproliferative disorders.

  9. 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.

  10. [Orphan drugs : New opportunities for the treatment of rare diseases].

    PubMed

    Beck, M

    2016-11-01

    Not only in Europe and USA, but also in many other countries rare disorders-so-called orphan diseases-have attracted more and more attention. The formation of specialized centers for rare disorders has enabled the diagnosis of diseases that have been widely unknown before. In addition, pharmaceutical companies have recognized orphan diseases as a profitable source of revenue. The development and marketing of new drugs for rare diseases-so-called orphan diseases-means a great challenge for all who participate in the health care system: Because the number of patients who are available for a clinical study is mostly very small, it is often very difficult or even impossible to show statistically firm evidence of efficacy. The standard placebo-controlled, double-blind clinical trial is often inappropriate for the approval procedure of an orphan drug; thus other study designs or other parameters (e.g. biomarkers) have to be used to prove clinical efficacy of the study drug. Only relatively small amounts of drugs can be sold to the generally few patients affected by an orphan disease and clinical trials require an high amount of financial investment; therefore orphan drugs have in general extremely high prices. How long these high expenses can be borne by the health care system in view of the great number of rare diseases remains questionable.

  11. 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

  12. Common vs. Rare Allele Hypotheses for Complex Diseases

    PubMed Central

    Schork, Nicholas J.; Murray, Sarah S.; Frazer, Kelly A.; Topol, Eric J.

    2010-01-01

    There has been growing debate over the nature of the genetic contribution to individual susceptibility to common complex diseases such as diabetes, osteoporosis, and cancer. The ‘Common Disease, Common Variant (CDCV)’ hypothesis argues that genetic variations with appreciable frequency in the population at large, but relatively low ‘penetrance’ (or the probability that a carrier of the relevant variants will express the disease), are the major contributors to genetic susceptibility to common diseases. The ‘Common Disease, Rare Variant (CDRV)’ hypothesis, on the other hand, argues that multiple rare DNA sequence variations, each with relatively high penetrance, are the major contributors to genetic susceptibility to common diseases. Both hypotheses have their place in current research efforts. PMID:19481926

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

    ClinicalTrials.gov

    2016-09-01

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

  14. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.

    PubMed

    Surendran, Praveen; Drenos, Fotios; Young, Robin; Warren, Helen; Cook, James P; Manning, Alisa K; Grarup, Niels; Sim, Xueling; Barnes, Daniel R; Witkowska, Kate; Staley, James R; Tragante, Vinicius; Tukiainen, Taru; Yaghootkar, Hanieh; Masca, Nicholas; Freitag, Daniel F; Ferreira, Teresa; Giannakopoulou, Olga; Tinker, Andrew; Harakalova, Magdalena; Mihailov, Evelin; Liu, Chunyu; Kraja, Aldi T; Nielsen, Sune Fallgaard; Rasheed, Asif; Samuel, Maria; Zhao, Wei; Bonnycastle, Lori L; Jackson, Anne U; Narisu, Narisu; Swift, Amy J; Southam, Lorraine; Marten, Jonathan; Huyghe, Jeroen R; Stančáková, Alena; Fava, Cristiano; Ohlsson, Therese; Matchan, Angela; Stirrups, Kathleen E; Bork-Jensen, Jette; Gjesing, Anette P; Kontto, Jukka; Perola, Markus; Shaw-Hawkins, Susan; Havulinna, Aki S; Zhang, He; Donnelly, Louise A; Groves, Christopher J; Rayner, N William; Neville, Matt J; Robertson, Neil R; Yiorkas, Andrianos M; Herzig, Karl-Heinz; Kajantie, Eero; Zhang, Weihua; Willems, Sara M; Lannfelt, Lars; Malerba, Giovanni; Soranzo, Nicole; Trabetti, Elisabetta; Verweij, Niek; Evangelou, Evangelos; Moayyeri, Alireza; Vergnaud, Anne-Claire; Nelson, Christopher P; Poveda, Alaitz; Varga, Tibor V; Caslake, Muriel; de Craen, Anton J M; Trompet, Stella; Luan, Jian'an; Scott, Robert A; Harris, Sarah E; Liewald, David C M; Marioni, Riccardo; Menni, Cristina; Farmaki, Aliki-Eleni; Hallmans, Göran; Renström, Frida; Huffman, Jennifer E; Hassinen, Maija; Burgess, Stephen; Vasan, Ramachandran S; Felix, Janine F; Uria-Nickelsen, Maria; Malarstig, Anders; Reilly, Dermot F; Hoek, Maarten; Vogt, Thomas F; Lin, Honghuang; Lieb, Wolfgang; Traylor, Matthew; Markus, Hugh S; Highland, Heather M; Justice, Anne E; Marouli, Eirini; Lindström, Jaana; Uusitupa, Matti; Komulainen, Pirjo; Lakka, Timo A; Rauramaa, Rainer; Polasek, Ozren; Rudan, Igor; Rolandsson, Olov; Franks, Paul W; Dedoussis, George; Spector, Timothy D; Jousilahti, Pekka; Männistö, Satu; Deary, Ian J; Starr, John M; Langenberg, Claudia; Wareham, Nick J; Brown, Morris J; Dominiczak, Anna F; Connell, John M; Jukema, J Wouter; Sattar, Naveed; Ford, Ian; Packard, Chris J; Esko, Tõnu; Mägi, Reedik; Metspalu, Andres; de Boer, Rudolf A; van der Meer, Peter; van der Harst, Pim; Gambaro, Giovanni; Ingelsson, Erik; Lind, Lars; de Bakker, Paul I W; Numans, Mattijs E; Brandslund, Ivan; Christensen, Cramer; Petersen, Eva R B; Korpi-Hyövälti, Eeva; Oksa, Heikki; Chambers, John C; Kooner, Jaspal S; Blakemore, Alexandra I F; Franks, Steve; Jarvelin, Marjo-Riitta; Husemoen, Lise L; Linneberg, Allan; Skaaby, Tea; Thuesen, Betina; Karpe, Fredrik; Tuomilehto, Jaakko; Doney, Alex S F; Morris, Andrew D; Palmer, Colin N A; Holmen, Oddgeir Lingaas; Hveem, Kristian; Willer, Cristen J; Tuomi, Tiinamaija; Groop, Leif; Käräjämäki, AnneMari; Palotie, Aarno; Ripatti, Samuli; Salomaa, Veikko; Alam, Dewan S; Majumder, Abdulla Al Shafi; Di Angelantonio, Emanuele; Chowdhury, Rajiv; McCarthy, Mark I; Poulter, Neil; Stanton, Alice V; Sever, Peter; Amouyel, Philippe; Arveiler, Dominique; Blankenberg, Stefan; Ferrières, Jean; Kee, Frank; Kuulasmaa, Kari; Müller-Nurasyid, Martina; Veronesi, Giovanni; Virtamo, Jarmo; Deloukas, Panos; Elliott, Paul; Zeggini, Eleftheria; Kathiresan, Sekar; Melander, Olle; Kuusisto, Johanna; Laakso, Markku; Padmanabhan, Sandosh; Porteous, David J; Hayward, Caroline; Scotland, Generation; Collins, Francis S; Mohlke, Karen L; Hansen, Torben; Pedersen, Oluf; Boehnke, Michael; Stringham, Heather M; Frossard, Philippe; Newton-Cheh, Christopher; Tobin, Martin D; Nordestgaard, Børge Grønne; Caulfield, Mark J; Mahajan, Anubha; Morris, Andrew P; Tomaszewski, Maciej; Samani, Nilesh J; Saleheen, Danish; Asselbergs, Folkert W; Lindgren, Cecilia M; Danesh, John; Wain, Louise V; Butterworth, Adam S; Howson, Joanna M M; Munroe, Patricia B

    2016-10-01

    High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

  15. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

    PubMed Central

    Barnes, Daniel R; Witkowska, Kate; Staley, James R; Tragante, Vinicius; Tukiainen, Taru; Yaghootkar, Hanieh; Masca, Nicholas; Freitag, Daniel F; Ferreira, Teresa; Giannakopoulou, Olga; Tinker, Andrew; Harakalova, Magdalena; Mihailov, Evelin; Liu, Chunyu; Kraja, Aldi T; Fallgaard Nielsen, Sune; Rasheed, Asif; Samuel, Maria; Zhao, Wei; Bonnycastle, Lori L; Jackson, Anne U; Narisu, Narisu; Swift, Amy J; Southam, Lorraine; Marten, Jonathan; Huyghe, Jeroen R; Stančáková, Alena; Fava, Cristiano; Ohlsson, Therese; Matchan, Angela; Stirrups, Kathleen E; Bork-Jensen, Jette; Gjesing, Anette P; Kontto, Jukka; Perola, Markus; Shaw-Hawkins, Susan; Havulinna, Aki S; Zhang, He; Donnelly, Louise A; Groves, Christopher J; Rayner, N William; Neville, Matt J; Robertson, Neil R; Yiorkas, Andrianos M; Herzig, Karl-Heinz; Kajantie, Eero; Zhang, Weihua; Willems, Sara M; Lannfelt, Lars; Malerba, Giovanni; Soranzo, Nicole; Trabetti, Elisabetta; Verweij, Niek; Evangelou, Evangelos; Moayyeri, Alireza; Vergnaud, Anne-Claire; Nelson, Christopher P; Poveda, Alaitz; Varga, Tibor V; Caslake, Muriel; de Craen, Anton JM; Trompet, Stella; Luan, Jian’an; Scott, Robert A; Harris, Sarah E; Liewald, David CM; Marioni, Riccardo; Menni, Cristina; Farmaki, Aliki-Eleni; Hallmans, Göran; Renström, Frida; Huffman, Jennifer E; Hassinen, Maija; Burgess, Stephen; Vasan, Ramachandran S; Felix, Janine F; Uria-Nickelsen, Maria; Malarstig, Anders; Reily, Dermot F; Hoek, Maarten; Vogt, Thomas; Lin, Honghuang; Lieb, Wolfgang; Traylor, Matthew; Markus, Hugh F; Highland, Heather M; Justice, Anne E; Marouli, Eirini; Lindström, Jaana; Uusitupa, Matti; Komulainen, Pirjo; Lakka, Timo A; Rauramaa, Rainer; Polasek, Ozren; Rudan, Igor; Rolandsson, Olov; Franks, Paul W; Dedoussis, George; Spector, Timothy D; Jousilahti, Pekka; Männistö, Satu; Deary, Ian J; Starr, John M; Langenberg, Claudia; Wareham, Nick J; Brown, Morris J; Dominiczak, Anna F; Connell, John M; Jukema, J Wouter; Sattar, Naveed; Ford, Ian; Packard, Chris J; Esko, Tõnu; Mägi, Reedik; Metspalu, Andres; de Boer, Rudolf A; van der Meer, Peter; van der Harst, Pim; Gambaro, Giovanni; Ingelsson, Erik; Lind, Lars; de Bakker, Paul IW; Numans, Mattijs E; Brandslund, Ivan; Christensen, Cramer; Petersen, Eva RB; Korpi-Hyövälti, Eeva; Oksa, Heikki; Chambers, John C; Kooner, Jaspal S; Blakemore, Alexandra IF; Franks, Steve; Jarvelin, Marjo-Riitta; Husemoen, Lise L; Linneberg, Allan; Skaaby, Tea; Thuesen, Betina; Karpe, Fredrik; Tuomilehto, Jaakko; Doney, Alex SF; Morris, Andrew D; Palmer, Colin NA; Holmen, Oddgeir Lingaas; Hveem, Kristian; Willer, Cristen J; Tuomi, Tiinamaija; Groop, Leif; Käräjämäki, AnneMari; Palotie, Aarno; Ripatti, Samuli; Salomaa, Veikko; Alam, Dewan S; Shafi Majumder, Abdulla al; Di Angelantonio, Emanuele; Chowdhury, Rajiv; McCarthy, Mark I; Poulter, Neil; Stanton, Alice V; Sever, Peter; Amouyel, Philippe; Arveiler, Dominique; Blankenberg, Stefan; Ferrières, Jean; Kee, Frank; Kuulasmaa, Kari; Müller-Nurasyid, Martina; Veronesi, Giovanni; Virtamo, Jarmo; Deloukas, Panos; Elliott, Paul; Zeggini, Eleftheria; Kathiresan, Sekar; Melander, Olle; Kuusisto, Johanna; Laakso, Markku; Padmanabhan, Sandosh; Porteous, David; Hayward, Caroline; Scotland, Generation; Collins, Francis S; Mohlke, Karen L; Hansen, Torben; Pedersen, Oluf; Boehnke, Michael; Stringham, Heather M; Frossard, Philippe; Newton-Cheh, Christopher; Tobin, Martin D; Nordestgaard, Børge Grønne; Caulfield, Mark J; Mahajan, Anubha; Morris, Andrew P; Tomaszewski, Maciej; Samani, Nilesh J

    2016-01-01

    High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention. PMID:27618447

  16. [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.

  17. [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.

  18. 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

  19. 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.

  20. Rare hereditary diseases with defects in DNA-repair.

    PubMed

    Knoch, Jennifer; Kamenisch, York; Kubisch, Christian; Berneburg, Mark

    2012-01-01

    The human genome is constantly exposed to various sources of DNA damage. Ineffective protection from this damage leads to genetic instability which can ultimately give rise to somatic disease, causing mutations. Therefore our organism commands a number of highly conserved and effective mechanisms responsible for DNA repair. If these repair mechanisms are defective due to germline mutations in relevant genes, rare diseases with DNA repair deficiencies can arise. Today, a limited number of rare hereditary diseases characterized by genetic defects of DNA repair mechanisms is known, comprising ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy. Although heterogeneous in respect to selected symptoms, these rare disorders share many clinical features such as growth retardation, neurological disorders, premature ageing, skin alterations including abnormal pigmentation, telangiectasia, xerosis cutis, pathological wound healing as well as an increased risk of developing different types of cancer. Based on the clinical similarities of symptoms as well as the predominant diagnostic technology available, many of these rare disorders were formerly classified as genodermatoses with cancer predisposition or chromosomal breakage symptoms. These pathological conditions not only severely impair patients with these rare genetic diseases but also represent symptoms affecting large parts of the general population.

  1. 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

  2. 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

  3. The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

    SciTech Connect

    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.

    2015-09-17

    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 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. 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.

  4. [Ethical aspects of clinical trials in rare diseases].

    PubMed

    Hasford, Joerg; Koch, Armin

    2017-03-08

    It is estimated that there are about four million people suffering from rare diseases in Germany. For roughly the last 20 years, there has been an increasing interest in therapeutic research for rare diseases. Drug research is highly regulated via numerous laws, regulations and ethical conventions that do not offer any waivers for clinical trials in rare diseases. Thus the ethical assessment of the clinical trial application for a rare disease is basically the same as for a common disease. As the ethical standards of clinical research, for example regarding informed consent, are derived from constitutional rights and have been codified in the German drug law, it is no surprise that they cannot depend on the frequency of a disease. A very important aspect of the ethical assessment is the biometric quality with regard to study design, sample size estimation and statistical analysis, as methodologically poor research with humans is per se unethical. Problems with sample size estimations and pilot studies will be addressed in more detail. Pilot studies should be avoided and sample size estimations should not assume overoptimistic effect sizes and should not increase the error probability beyond 5% two-sided.

  5. [Perception of rare diseases by the primary care physicians].

    PubMed

    Avellaneda Fernández, A; Pérez Martín, A; Pombo Allés, G; Gutiérrez Delgado, E; Izquierdo Martínez, M

    2012-10-01

    Identify the elements that lead to the perception that primary health care physicians (PHCP) have as regards rare diseases (RD) as a whole, and to analyse the characteristics of these patients with rare diseases. Descriptive cross-sectional study. Surveys completed by PHCP during the years 2008-2010 were used to explore socio-demographic data, health care facilities, manpower, and services, knowledge level, expectations, means of obtaining available information, and training-support preferences of RD. A total of 260 questionnaires were analysed. The average level of knowledge was 3.68 (SD 1.93), of interest 7.34 (SD 2.02), and of importance 7.51 (SD 1.69). Less than one quarter (20.4%) of responders had done some training activity. Care at home (6.38, SD 2.07) is the most valued long term care option, emphasising the need of primary prevention (7.63 SD 1.5). Over one-third (35%) applied for some aid, mainly economic (37.4%). Internet is their main source of information (71.2%), and an average of 7.85 (SD 2.38) perceived the need for specific continuing training. By registered lists, each professional attends a mean of 2.45 (SD 3.69) patients with RD, 1.604% having temporary work disability, 1.479% having some disability and 1.62% with a dependence situation. The follow up of RD patients was: at Hospital level 55.72%, by special reference units 44.34%, by specialists 39.75%, and exclusively at PHCP level 14.46%. PHCP have a low level of knowledge of RD, although a high interest, with emphasis on primary prevention, the importance of the family environment, genetic counselling and health education. They rarely request medical resources for RD. Internet is their main source of information, and prefer specific continuing education courses. Copyright © 2011 Elsevier España, S.L. y SEMERGEN. All rights reserved.

  6. Coverage of Rare Disease Names in Standard Terminologies and Implications for Patients, Providers, and Research

    PubMed Central

    Fung, Kin Wah; Richesson, Rachel; Bodenreider, Olivier

    2014-01-01

    Small numbers of patients are a special challenge for rare diseases research. Electronic health record (EHR) data can facilitate research if patients with rare diseases can be reliably identified. We estimate the coverage of the names of a set of 6,519 rare diseases. Using the UMLS, 697 (11%) diseases were matched to ICD-9-CM, 1,386 (21%) to ICD-10-CM and 2,848 (44%) to SNOMED CT. Using published mappings from SNOMED CT to ICD, we further estimate additional broader matches of 2,569 (39%) rare diseases to ICD-9-CM and 1,635 (25%) to ICD-10-CM. The number of codes that match one and only one disease are 1,081 (62%) for ICD-9-CM, 1,403 (73%) for ICD-10-CM, and 3,311 (85%) for SNOMED CT. Our findings confirm that SNOMED CT has the greatest coverage and specificity needed to identify patients with a rare disease from EHR-data, and can facilitate research and evidence-based care. PMID:25954361

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

    PubMed Central

    Rao, Aliz R; Yourshaw, Michael; Christensen, Bryce; Nelson, Stanley F; Kerner, Berit

    2016-01-01

    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 5 090 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 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. PMID:27725659

  8. Hiccup: An Extremely Rare Presentation of Thyrotoxicosis of Graves’ Disease

    PubMed Central

    Ahmed, Feroze; Ganie, Mohammed Ashraf; Shamas, Nasir; Wani, Mohammad; Parray, Irshad

    2011-01-01

    Persistent hiccup is a rare but potentially severe condition that can be symptomatic of a variety of diseases or idiopathic. Most episodes last only a few minutes and are self-limited, but hiccup can get persistent and become a real problem for physician and patient alike. The center of hiccup may be activated by a great variety of stimuli travelling along different nerve pathways and bring different effecter responses. We report a case of persistent hiccup as a presentation of impending thyroid storm of Graves’ disease. Though the condition is rare, clinicians should remain alert to the possibility of this diagnosis. PMID:22043400

  9. Hiccup: an extremely rare presentation of thyrotoxicosis of graves' disease.

    PubMed

    Ahmed, Feroze; Ganie, Mohammed Ashraf; Shamas, Nasir; Wani, Mohammad; Parray, Irshad

    2011-03-01

    Persistent hiccup is a rare but potentially severe condition that can be symptomatic of a variety of diseases or idiopathic. Most episodes last only a few minutes and are self-limited, but hiccup can get persistent and become a real problem for physician and patient alike. The center of hiccup may be activated by a great variety of stimuli travelling along different nerve pathways and bring different effecter responses. We report a case of persistent hiccup as a presentation of impending thyroid storm of Graves' disease. Though the condition is rare, clinicians should remain alert to the possibility of this diagnosis.

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

    PubMed Central

    Lee, Sangmoon

    2016-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  12. 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.

  13. Physicians and Physician Trainees Rarely Identify or Address Overweight/Obesity in Hospitalized Children.

    PubMed

    King, Marta A; Nkoy, Flory L; Maloney, Christopher G; Mihalopoulos, Nicole L

    2015-10-01

    To determine how frequently physicians identify and address overweight/obesity in hospitalized children and to compare physician documentation across training level (medical student, intern, resident, attending). We conducted a retrospective chart review. Using an administrative database, Centers for Disease Control and Prevention body mass index calculator, and random sampling technique, we identified a study population of 300 children aged 2-18 years with overweight/obesity hospitalized on the general medical service of a tertiary care pediatric hospital. We reviewed admission, progress, and discharge notes to determine how frequently physicians and physician trainees identified (documented in history, physical exam, or assessment) and addressed (documented in hospital or discharge plan) overweight/obesity. Physicians and physician trainees identified overweight/obesity in 8.3% (n = 25) and addressed it in 4% (n = 12) of 300 hospitalized children with overweight/obesity. Interns were most likely to document overweight/obesity in history (8.3% of the 266 patients they followed). Attendings were most likely to document overweight/obesity in physical examination (8.3%), assessment (4%), and plan (4%) of the 300 patients they followed. Medical students were least likely to document overweight/obesity including it in the assessment (0.4%) and plan (0.4%) of the 244 hospitalized children with overweight/obesity they followed. Physicians and physician trainees rarely identify or address overweight/obesity in hospitalized children. This represents a missed opportunity for both patient care and physician trainee education. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-10-01

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

  16. 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

  17. The long tail and rare disease research: the impact of next-generation sequencing for rare Mendelian disorders.

    PubMed

    Shen, Tony; Lee, Ariel; Shen, Carol; Lin, C Jimmy

    2015-09-14

    There are an estimated 6000-8000 rare Mendelian diseases that collectively affect 30 million individuals in the United States. The low incidence and prevalence of these diseases present significant challenges to improving diagnostics and treatments. Next-generation sequencing (NGS) technologies have revolutionized research of rare diseases. This article will first comment on the effectiveness of NGS through the lens of long-tailed economics. We then provide an overview of recent developments and challenges of NGS-based research on rare diseases. As the quality of NGS studies improve and the cost of sequencing decreases, NGS will continue to make a significant impact on the study of rare diseases moving forward.

  18. 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

    2017-07-19

    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.

  19. 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.

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

    PubMed Central

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

    2015-01-01

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

  1. 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

  2. Unintended effects of orphan product designation for rare neurological diseases.

    PubMed

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

    2012-10-01

    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 for drugs that 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 disease, adrenocorticotropic hormone for infantile spasms, and enzyme replacement therapy with alglucosidase alpha for Pompe disease, we highlight these paradoxical effects.

  3. 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

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

    PubMed Central

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

    2017-01-01

    Background 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. Objective 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. Methods 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. Results 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

  5. 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.

  6. 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…

  7. Pulmonary necrobiotic nodules: a rare extraintestinal manifestation of Crohn's disease.

    PubMed

    Warwick, G; Leecy, T; Silverstone, E; Rainer, S; Feller, R; Yates, D H

    2009-03-01

    The present article reports the case of a 22-yr-old female with new onset Crohn's colitis, anterior uveitis and multiple pulmonary nodules which, on histological examination, were necrobiotic nodules. This is a rare but recognised pulmonary extraintestinal manifestation of Crohn's disease and only the fourth reported case. The present case report is followed by a brief review of the relevant literature.

  8. The Dr Pheo Blog and virtual counselling for rare diseases.

    PubMed

    Yu, Run

    2015-01-01

    Patients with suspected or diagnosed rare diseases face challenges. Their own physicians usually do not have a large experience in a particular rare disease, specialists may not be easily accessible, and medical knowledge on rare diseases is either not readily available or too general to be applied to the patients' individual situations. As a specialist with experience in pheochromocytoma, I therefore started a blog to disseminate knowledge about the tumour and to discuss readers' questions about it (http://drpheo.blogspot.com/). Between 2009 and 2014, the blog was viewed 81,223 times and received 1286 comments during the 5-year period. About half of the comments contained mostly questions (questioning comments), including 429 directly on pheochromocytoma (7.5/month). The majority of the questioning comments were about the diagnosis (62%) and natural history (21%) of pheochromocytoma, with the remainder on management (14%) and follow-up or prognosis (4%). Many readers' comments started with encouraging words about the blog and remarked how difficult it was to find useful information on pheochromocytoma elsewhere. Experience with the Dr Pheo Blog suggests that physician specialist-written blogs are potentially an effective and convenient way of providing pertinent knowledge on rare diseases to the public. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  9. 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.

  10. 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…

  11. The changing face of a rare disease: lymphangioleiomyomatosis.

    PubMed

    Harari, Sergio; Torre, Olga; Cassandro, Roberto; Moss, Joel

    2015-11-01

    Lymphangioleiomyomatosis is a rare disease characterised by cystic destruction of the lung, lymphatic abnormalities and abdominal tumours. It affects almost exclusively females and can occur sporadically or in patients with tuberous sclerosis complex. In the past decade remarkable progress has been made in understanding of the pathogenesis of this disease leading to a new therapeutic approach. This review summarises recent advances regarding pathogenic mechanisms and clinical manifestations, and highlights the current and the most promising future therapeutic strategies. Copyright ©ERS 2015.

  12. 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.

  13. 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

  14. A CRISPR/Cas9 Functional Screen Identifies Rare Tumor Suppressors

    PubMed Central

    Katigbak, Alexandra; Cencic, Regina; Robert, Francis; Sénécha, Patrick; Scuoppo, Claudio; Pelletier, Jerry

    2016-01-01

    An enormous amount of tumor sequencing data has been generated through large scale sequencing efforts. The functional consequences of the majority of mutations identified by such projects remain an open, unexplored question. This problem is particularly complicated in the case of rare mutations where frequency of occurrence alone or prediction of functional consequences are insufficient to distinguish driver from passenger or bystander mutations. We combine genome editing technology with a powerful mouse cancer model to uncover previously unsuspected rare oncogenic mutations in Burkitt’s lymphoma. We identify two candidate tumor suppressors whose loss cooperate with MYC over-expression to accelerate lymphomagenesis. Our results highlight the utility of in vivo CRISPR/Cas9 screens combined with powerful mouse models to identify and validate rare oncogenic modifier events from tumor mutational data. PMID:27982060

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

    PubMed

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

    2015-10-01

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

  16. Diagnostic needs for rare diseases and shared prediagnostic phenomena: Results of a German-wide expert Delphi survey

    PubMed Central

    Blöß, Susanne; Klemann, Christian; Rother, Ann-Katrin; Mehmecke, Sandra; Schumacher, Ulrike; Mücke, Urs; Mücke, Martin; Stieber, Christiane; Klawonn, Frank; Kortum, Xiaowei; Lechner, Werner; Grigull, Lorenz

    2017-01-01

    Background Worldwide approximately 7,000 rare diseases have been identified. Accordingly, 4 million individuals live with a rare disease in Germany. The mean time to diagnosis is about 6 years and patients receive several incorrect diagnoses during this time. A multiplicity of factors renders diagnosing a rare disease extremely difficult. Detection of shared phenomena among individuals with different rare diseases could assist the diagnostic process. In order to explore the demand for diagnostic support and to obtain the commonalities among patients, a nationwide Delphi survey of centers for rare diseases and patient groups was conducted. Methods A two-step Delphi survey was conducted using web-based technologies in all centers for rare diseases in Germany. Moreover, the leading patient support group, the German foundation for rare diseases (ACHSE), was contacted to involve patients as experts in their disease. In the survey the experts were invited to name rare diseases with special need for diagnostic improvement. Secondly, communal experiences of affected individuals were collected. Results 166 of 474 contacted experts (35%) participated in the first round of the Delphi process and 95 of 166 (57%) participated in the second round. Metabolic (n = 74) and autoimmune diseases (n = 39) were ranked the highest for need for diagnostic support. For three diseases (i.e. scleroderma, Pompe’s disease, and pulmonary arterial hypertension), a crucial need for diagnostic support was explicitly stated. A typical experience of individuals with a rare disease was stigmatization of having psychological or psychosomatic problems. In addition, most experts endured an ‘odyssey’ of seeing many different medical specialists before a correct diagnosis (n = 38) was confirmed. Conclusion There is need for improving the diagnostic process in individuals with rare diseases. Shared experiences in individuals with a rare disease were observed, which could possibly be utilized for

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

    PubMed Central

    Li, Xin; Montgomery, Stephen B.

    2013-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  19. Rare diseases, orphan drugs and their regulation: questions and misconceptions.

    PubMed

    Tambuyzer, Erik

    2010-12-01

    Sustained advocacy efforts driven by patients' organizations to make rare diseases a health priority have led to regulatory and economic incentives for industry to develop drugs for these diseases, known as orphan drugs. These incentives, enacted in regulations first introduced in the United States in 1983 and later in Japan, Europe and elsewhere, have resulted in substantial improvements in the treatment for patients with a range of rare diseases. However, the advent of orphan drug development has also triggered several questions, from the definition of rarity to the pricing of orphan drugs and their impact on health-care systems. This article provides an industry perspective on some of the common questions and misconceptions related to orphan drug development and its regulation, with the aim of facilitating future progress in the field.

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

    PubMed

    Gallagher, Patrick G

    2015-01-01

    Rare, congenital nonimmune hemolytic disorders of the erythrocyte, although uncommon, are important causes of anemia in the child and adult. These are a heterogeneous group of diseases that disrupt normal erythrocyte structure and function in varying ways. Predominant are abnormalities of hemoglobin stability, defects of erythrocyte metabolism, and disorders of erythrocyte hydration. Unstable hemoglobinopathies may lead to chronic or episodic hemolysis. Perturbation of critical enzymes of the Embden-Meyerhof pathway lead to altered erythrocyte metabolism and chronic hemolysis. Disorders of erythrocyte hydration are an under-recognized cause of hemolytic anemia. Beyond pathophysiologic mechanisms of disease, clinical, laboratory, and genetic heterogeneity characterize this group of disorders. Often, they are underdiagnosed or misdiagnosed. This review discusses pathophysiology, inheritance, clinical findings, laboratory manifestations, and management considerations in several rare nonimmune hemolytic diseases including the unstable hemoglobins, disorders of erythrocyte metabolism, and abnormalities of erythrocyte hydration. © 2015 by The American Society of Hematology. All rights reserved.

  1. Rare and low-frequency variants in human common diseases and other complex traits.

    PubMed

    Lettre, Guillaume

    2014-11-01

    In humans, most of the genetic variation is rare and often population-specific. Whereas the role of rare genetic variants in familial monogenic diseases is firmly established, we are only now starting to explore the contribution of this class of genetic variation to human common diseases and other complex traits. Such large-scale experiments are possible due to the development of next-generation DNA sequencing. Early findings suggested that rare and low-frequency coding variation might have a large effect on human phenotypes (eg, PCSK9 missense variants on low-density lipoprotein-cholesterol and coronary heart diseases). This observation sparked excitement in prognostic and diagnostic medicine, as well as in genetics-driven strategies to develop new drugs. In this review, I describe results and present initial conclusions regarding some of the recent rare and low-frequency variant discoveries. We can already assume that most phenotype-associated rare and low-frequency variants have modest-to-weak phenotypical effect. Thus, we will need large cohorts to identify them, as for common variants in genome-wide association studies. As we expand the list of associated rare and low-frequency variants, we can also better recognise the current limitations: we need to develop better statistical methods to optimally test association with rare variants, including non-coding variation, and to account for potential confounders such as population stratification.

  2. Advances in Identifying Beryllium Sensitization and Disease

    PubMed Central

    Middleton, Dan; Kowalski, Peter

    2010-01-01

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

  3. Advances in identifying beryllium sensitization and disease.

    PubMed

    Middleton, Dan; Kowalski, Peter

    2010-01-01

    Beryllium is a lightweight metal with unique qualities related to stiffness, corrosion resistance, and conductivity. While there are many useful applications, researchers in the 1930s and 1940s linked beryllium exposure to a progressive occupational lung disease. Acute beryllium disease is a pulmonary irritant response to high exposure levels, whereas chronic beryllium disease (CBD) typically results from a hypersensitivity response to lower exposure levels. A blood test, the beryllium lymphocyte proliferation test (BeLPT), was an important advance in identifying individuals who are sensitized to beryllium (BeS) and thus at risk for developing CBD. While there is no true "gold standard" for BeS, basic epidemiologic concepts have been used to advance our understanding of the different screening algorithms.

  4. [Refsum disease--rare, but world-famous].

    PubMed

    Stokke, O

    2001-01-30

    Sigvald Bernhard Refsum (1907-91) was an outstanding Norwegian neurologist, highly respected and recognised both nationally and internationally. His main scientific achievement was that he by clinical means singled out a previously unknown disease entity in the multitude of different neurodegenerative features. In his monograph from 1946 he named the disease "heredopathia atactica polyneuritiformis"; however, it was rapidly known as Refsum's disease. Twenty years later, two German scientists, Klenk and Kahlke, detected large amounts of a peculiar branched-chain fatty acid, phytanic acid, in a Refsum patient. This started an amazing revelation of the biochemical background of the disease, and also led to a logical and effective treatment. Although Refsum's disease is extremely rare, it has become well-known due to this elucidation of both the normal metabolism of phytanic acid and the pathophysiology of the disease.

  5. 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

  6. 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

  7. 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.

  8. Network Analysis Identifies Disease-Specific Pathways for Parkinson's Disease.

    PubMed

    Monti, Chiara; Colugnat, Ilaria; Lopiano, Leonardo; Chiò, Adriano; Alberio, Tiziana

    2016-12-21

    Neurodegenerative diseases are characterized by the progressive loss of specific neurons in selected regions of the central nervous system. The main clinical manifestation (movement disorders, cognitive impairment, and/or psychiatric disturbances) depends on the neuron population being primarily affected. Parkinson's disease is a common movement disorder, whose etiology remains mostly unknown. Progressive loss of dopaminergic neurons in the substantia nigra causes an impairment of the motor control. Some of the pathogenetic mechanisms causing the progressive deterioration of these neurons are not specific for Parkinson's disease but are shared by other neurodegenerative diseases, like Alzheimer's disease and amyotrophic lateral sclerosis. Here, we performed a meta-analysis of the literature of all the quantitative proteomic investigations of neuronal alterations in different models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis to distinguish between general and Parkinson's disease-specific pattern of neurodegeneration. Then, we merged proteomics data with genetics information from the DisGeNET database. The comparison of gene and protein information allowed us to identify 25 proteins involved uniquely in Parkinson's disease and we verified the alteration of one of them, i.e., transaldolase 1 (TALDO1), in the substantia nigra of 5 patients. By using open-source bioinformatics tools, we identified the biological processes specifically affected in Parkinson's disease, i.e., proteolysis, mitochondrion organization, and mitophagy. Eventually, we highlighted four cellular component complexes mostly involved in the pathogenesis: the proteasome complex, the protein phosphatase 2A, the chaperonins CCT complex, and the complex III of the respiratory chain.

  9. It's Not All on the Net: Identifying, Preserving and Protecting Rare and Unique Federal Documents.

    ERIC Educational Resources Information Center

    Sleeman, William

    2002-01-01

    Discusses the fact that paper and microfiche materials remain a substantial part of most federal document collections and suggests ways to identify rare and unique documents that need to be preserved. Describes preservation activities and options and considers whether digitization is a good alternative. (LRW)

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

    PubMed

    De Souza, Lorraine H; Frank, Andrew O

    2016-08-01

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

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

    PubMed Central

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

    2016-01-01

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

  12. 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.

  13. 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

  14. 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

    ... considerations for pediatric rare diseases; (3) pediatric rare cancers; and (4) development of gene therapies for... to encourage and accelerate the development of new therapies for pediatric rare diseases. FDA is... strategic plan to encourage and accelerate the development of new therapies for rare diseases. Date and Time...

  15. Generalized eruptive histiocytoma: a rare disease in an elderly patient*

    PubMed Central

    Cardoso, Fernanda; Serafini, Natália Battisti; Reis, Brisa Dondoni; Nuñez, Mónica Daniela Gauto; Nery, José Augusto da Costa; Lupi, Omar

    2013-01-01

    Generalized eruptive histiocytoma is considered an extremely rare subtype of non-Langerhans cells histiocytosis. In the literature, there are few reports of this disease that mainly affects adults. In this report, we present a case of generalized eruptive histiocytoma in an elderly patient who had presented symptoms for over two months. Multiple erythematous papules, asymptomatic and symmetrically distributed were observed on the trunk and limbs. Histological examination showed a dense mononuclear cell dermal infiltrate. In the immunohistochemical analysis, the cells were CD68 positive, but CD1a, S100 and CD34 negative. A diagnosis of generalized eruptive histiocytoma was established. The aim of our paper is to report a case of a very rare disease, whose subtype and affected age group are even more unusual. PMID:23539013

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

    PubMed

    Angelis, Aris; Tordrup, David; Kanavos, Panos

    2015-07-01

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

  17. Renal replacement therapy for rare diseases affecting the kidney: an analysis of the ERA-EDTA Registry.

    PubMed

    Wühl, Elke; van Stralen, Karlijn J; Wanner, Christoph; Ariceta, Gema; Heaf, James Goya; Bjerre, Anna K; Palsson, Runolfur; Duneau, Gabrielle; Hoitsma, Andries J; Ravani, Pietro; Schaefer, Franz; Jager, Kitty J

    2014-09-01

    In recent years, increased efforts have been undertaken to address the needs of patients with rare diseases by international initiatives and consortia devoted to rare disease research and management. However, information on the overall prevalence of rare diseases within the end-stage renal disease (ESRD) population is limited. The aims of this study were (i) to identify those rare diseases within the ERA-EDTA Registry for which renal replacement therapy (RRT) is being provided and (ii) to determine the prevalence and incidence of RRT for ESRD due to rare diseases, both overall and separately for children and adults. The Orphanet classification of rare disease was searched for rare diseases potentially causing ESRD, and these diagnosis codes were mapped to the corresponding ERA-EDTA primary renal disease codes. Thirty-one diagnoses were defined as rare diseases causing ESRD. From 1 January 2007 to 31 December 2011, 7194 patients started RRT for a rare disease (10.6% children). While some diseases were exclusively found in adults (e.g. Fabry disease), primary oxalosis, cystinosis, congenital anomalies of the kidney and urinary tract (CAKUT) and medullary cystic kidney disease affected young patients in up to 46%. On 31 December 2011, 20 595 patients (12.4% of the total RRT population) were on RRT for ESRD caused by a rare disease. The point prevalence was 32.5 per million age-related population in children and 152.0 in adults. Only 5.8% of these patients were younger than 20 years; however, 57.7% of all children on RRT had a rare disease, compared with only 11.9% in adults. CAKUT and focal segmental glomerulosclerosis were the most prevalent rare disease entities among patients on RRT. More than half of all children and one of nine adults on RRT in the ERA-EDTA Registry suffer from kidney failure due to a rare disease, potentially with a large number of additional undiagnosed or miscoded cases. Comprehensive diagnostic assessment and the application of accurate

  18. 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.

  19. Database for Parkinson Disease Mutations and Rare Variants

    DTIC Science & Technology

    2015-07-01

    due to time or knowledge restrained to sift through scattered information. Current databases do not address actual contribution of variant to PD...variant discovery , the Parkinson Disease project focuses on identification of rare variants and their differential accumulation within a gene region...During her three year fellowship in Miami, she has extended her knowledge and acquired vast experience working with next generation sequencing

  20. Giant cell arteritis: a systemic disease with rare cutaneous manifestations.

    PubMed

    Baum, E W; Sams, W M; Payne, R R

    1982-06-01

    Giant cell arteritis is a systemic disease usually occurring in patients in the fifth decade or older, more often in women. Dermatologic manifestations are rare but, when found, are usually expressed as scalp ulcerations or blanching associated with gangrene of the tongue. The dermatologist should be familiar with the entity because it is often more severe when associated with scalp necrosis, and prompt intervention with corticosteroids can prevent catastrophic sequelae.

  1. [Crohn's disease associated with Berger's disease. A rare complication].

    PubMed

    López Barbarín, J M; Lafuente Martínez, P; García Campos, F; Ibarra Peña, B; Díaz de Otazu, R

    1990-10-01

    We report the case of a male patient with Crohn's disease associated with IgA nephropathy. He was treated surgically for the intestinal disorder and then with corticoids and sulfasalazine. Six years after treatment the patient was asymptomatic. As the intestinal situation improved there was concomitant normalization of urinary sediment, maintaining renal function. The fact that the digestive mucosa is one of the body's major sources of secretory IgA may account for the existence of a common for Crohn's disease and certain forms of IgA nephropathy.

  2. 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.

  3. Characterization of a rare Unverricht–Lundborg disease mutation

    PubMed Central

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

    2015-01-01

    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. PMID:26937413

  4. 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.

  5. Dendritic Cell Trafficking and Function in Rare Lung Diseases.

    PubMed

    Liu, Huan; Jakubzick, Claudia; Osterburg, Andrew R; Nelson, Rebecca L; Gupta, Nishant; McCormack, Francis X; Borchers, Michael T

    2017-10-01

    Dendritic cells (DCs) are highly specialized immune cells that capture antigens and then migrate to lymphoid tissue and present antigen to T cells. This critical function of DCs is well defined, and recent studies further demonstrate that DCs are also key regulators of several innate immune responses. Studies focused on the roles of DCs in the pathogenesis of common lung diseases, such as asthma, infection, and cancer, have traditionally driven our mechanistic understanding of pulmonary DC biology. The emerging development of novel DC reagents, techniques, and genetically modified animal models has provided abundant data revealing distinct populations of DCs in the lung, and allow us to examine mechanisms of DC development, migration, and function in pulmonary disease with unprecedented detail. This enhanced understanding of DCs permits the examination of the potential role of DCs in diseases with known or suspected immunological underpinnings. Recent advances in the study of rare lung diseases, including pulmonary Langerhans cell histiocytosis, sarcoidosis, hypersensitivity pneumonitis, and pulmonary fibrosis, reveal expanding potential pathogenic roles for DCs. Here, we provide a review of DC development, trafficking, and effector functions in the lung, and discuss how alterations in these DC pathways contribute to the pathogenesis of rare lung diseases.

  6. Risks and prevention of nosocomial transmission of rare zoonotic diseases.

    PubMed

    Weber, D J; Rutala, W A

    2001-02-01

    Americans are increasingly exposed to exotic zoonotic diseases through travel, contact with exotic pets, occupational exposure, and leisure pursuits. Appropriate isolation precautions are required to prevent nosocomial transmission of rare zoonotic diseases for which person-to-person transmission has been documented. This minireview provides guidelines for the isolation of patients and management of staff exposed to the following infectious diseases with documented person-to-person transmission: Andes hantavirus disease, anthrax, B virus infection, hemorrhagic fevers (due to Ebola, Marburg, Lassa, Crimean-Congo hemorrhagic fever, Argentine hemorrhagic fever, and Bolivian hemorrhagic fever viruses), monkeypox, plague, Q fever, and rabies. Several of these infections may also be encountered as bioterrorism hazards (i.e., anthrax, hemorrhagic fever viruses, plague, and Q fever). Adherence to recommended isolation precautions will allow for proper patient care while protecting the health care workers who provide care to patients with known or suspected zoonotic infections capable of nosocomial transmission.

  7. Drugs for rare diseases: mixed assessment in Europe.

    PubMed

    2007-02-01

    (1) Worldwide, there are an estimated 6000 to 7000 rare diseases. Patients face special difficulties in obtaining an accurate diagnosis, adequate information about the disease, and access to qualified specialists. (2) Drug companies do not spontaneously conduct research on drugs for rare diseases, mainly because of the limited market for each indication. Only a few dozen of these drugs were available in France before 2000. (3) In 2000 the European Union adopted a Regulation, based on experience in the United States, aimed at promoting the development of drugs for patients suffering from rare diseases, i.e. 'orphan drugs'. (4) In Europe, orphan drug status can be granted when the prevalence of the disease does not exceed 5 cases per 10 000 inhabitants (or when it is more frequent but profitability is likely to be inadequate). (5) Companies that market an orphan drug receive a variety of financial assistance as well as a 10-year marketing monopoly. (6) Between April 2000 and April 2005, 268 medicinal products received European orphan drug status and 22 were granted European marketing authorization. (7) Access to these drugs varies greatly from one European Union Member State to another, mainly because of the high annual treatment costs (up to 300 000 euros per patient). Worldwide sales of the orphan drug imatinib reached more than two thousand million dollars in 2005. (8) Our systematic analyses (see the New Products column of our French edition la revue Prescrire) show that only 5 drugs which received European orphan drug status before May 2005 were for diseases for which there had previously been no treatment. (9) Clinical evaluation of orphan drugs is hindered by the small number of patients available for clinical trials. Some orphan drugs are adequately tested before being brought to market. Others are not compared to existing treatments. In many cases, surrogate criteria are used instead of clinical endpoints. These methodological flaws are in no way limited to

  8. 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 Central

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

    2017-01-01

    Summary 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. PMID:28357175

  9. [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.

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

    PubMed

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

    2016-01-01

    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

  11. The expanding spectrum of rare monogenic autoinflammatory diseases

    PubMed Central

    2013-01-01

    Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle diseases, but we wanted to focus on the most recent rare syndromes. A comprehensive review is thus provided, including taxonomic, genetic, and epidemiological data, along with characteristics defining positive and differential diagnoses and treatment. We believe that this update will assist physicians in correctly naming their patient’s illness. This is an essential step for the effective and targeted management of an orphan disease. PMID:24131530

  12. A rare case of febrile abdominal pain revealing Horton's disease.

    PubMed

    Chaudet, Arnaud; Goujon, Jean-Michel; Ghazali, Aiham Daniel

    2017-07-08

    Horton's disease is a systemic inflammatory vasculitis, usually found in persons over 50years old. It affects medium and large-sized arteries stemming from the external carotid, especially the superficial temporal arteries. It can affect extracranial large vessels but only rarely the aorta. Diagnosis of aortitis is difficult and its incidence is probably underestimated. A 68-year-old Caucasian woman consulted in an emergency department for febrile abdominal pain with inflammatory syndrome. Abdomen was soft with right-side flank sensitivity. A contrast-enhanced CT scan showed aortitis from the descending aorta to the iliac arteries without complication. Because of age, clinical presentation and aortitis, Horton disease was suspected. The temporal artery biopsy showed a histological aspect of degenerative endarteritis with intimal thickening and luminal stenosis. High-dose corticosteroid therapy was introduced which improved clinical conditions and resulted in the amendment of the pain. In the present case, this patient had Horton's disease, based on 3 criteria of The American College of Rheumatology (age, temporal artery abnormalities and inflammatory syndrome) associated with aortitis. However, aortitis is a rare complication of Horton disease and is a major cause of mortality inasmuch as it can be complicated by aneurysm and dissection. It is unusual to diagnose Horton's disease from aortitis symptoms without complications. The aorta represents the most severe localization of Horton's disease. It should not be ignored in etiological hypotheses regarding febrile abdominal pain in the elderly. Corticosteroids should be started rapidly at high doses and temporal artery biopsy should be planned. Copyright © 2017. Published by Elsevier Inc.

  13. 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

  14. New insights into Whipple's disease - a rare intestinal inflammatory disorder.

    PubMed

    Marth, Thomas

    2009-01-01

    Whipple's disease (WD) is a rare systemic infectious disorder caused by the actinomycete Tropheryma whipplei. This chronic disease, first described by Whipple as 'intestinal lipodystrophy', affects preferentially middle-aged white men who may present with weight loss, diarrhea, abdominal pain and arthralgia. Thus, it represents an important differential diagnosis of chronic diarrhea. A variety of other clinical patterns, such as involvement of the heart, lung, or central nervous system (CNS), are frequent. In addition, individuals with isolated heart valve involvement or asymptomatic carriers may be observed. The diagnosis often is established by small bowel biopsy, which is characterized by periodic acid-Schiff-positive inclusions representing the causative bacteria. T. whipplei can be detected by specific polymerase chain reaction, immunohistochemistry or electron microscopy and was cultured a few years ago. Several studies show that subtle defects of the cell-mediated immunity exist in active and inactive WD which may predispose individuals with a certain HLA type to a clinical manifestation of T. whipplei infection. As confirmed in a recent controlled trial, most patients respond well to a prolonged antibiotic treatment, but some patients with relapsing disease or CNS manifestation may have a poor prognosis. In the presentation, the relevance of WD in the differential diagnosis of chronic diarrhea and the new findings of this enigmatic rare disorder will be discussed.

  15. 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…

  16. 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…

  17. 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

  18. 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

  19. [Rare pulmonary occupational diseases--importance of microanalytical examination].

    PubMed

    Brasch, Fank; Müller, Klaus-Michael

    2004-01-01

    In legal proceedings on the subject of occupational diseases concerning comparatively rare pneumoconioses, additional analyses such as energy dispersive x-ray microanalysis (EDX) and electron energy loss spectroscopy (EELS) offer decisive information for the pathologist in establishing causal connections between occupational exposure to hazardous substances, foreign particle deposits in lung tissue and pulmonary reaction patterns. Using the example of silver finisher's lung, dental technician's lung and talcosis, the connections between foreign particle deposits in lung tissue and granulomatous and fibrosing pulmonary changes are shown.

  20. Ofuji disease: a rare dermatosis and its challenging therapeutic approach*

    PubMed Central

    de Brito, Fernanda Freitas; Martelli, Antonio Carlos Ceribelli; Cavalcante, Maria Lopes Lamenha Lins; Pinto, Ana Cecília Versiani Duarte; Itimura, Gabriela; Soares, Cleverson Teixeira

    2016-01-01

    Eosinophilic pustular folliculitis (EPF) or Ofuji disease is a rare dermatosis, prone to recurrence and chronicity. The peak incidence occurs in the third decade of life and its exact etiology remains unknown. Evidence suggests that the expression of adhesion molecules and the production of cytokines activate the follicular unit, but the stimulus that triggers these changes remains unclear. The three clinical variants reported in the literature include classic EPF, immunosuppression-associated EPF, and infancy-associated EPF. We report a case of eosinophilic pustular folliculitis with peculiar epidemiological characteristics, which represents a challenging therapeutic scenario. PMID:27828641

  1. Rare structural genetic variation in human prion diseases.

    PubMed

    Lukic, Ana; Uphill, James; Brown, Craig A; Beck, John; Poulter, Mark; Campbell, Tracy; Adamson, Gary; Hummerich, Holger; Whitfield, Jerome; Ponto, Claudia; Zerr, Inga; Lloyd, Sarah E; Collinge, John; Mead, Simon

    2015-05-01

    Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

  2. Shared genomic segment analysis: the power to find rare disease variants.

    PubMed

    Knight, Stacey; Abo, Ryan P; Abel, Haley J; Neklason, Deborah W; Tuohy, Therese M; Burt, Randall W; Thomas, Alun; Camp, Nicola J

    2012-11-01

    Shared genomic segment (SGS) analysis uses dense single nucleotide polymorphism genotyping in high-risk (HR) pedigrees to identify regions of sharing between cases. Here, we illustrate the power of SGS to identify dominant rare risk variants. Using simulated pedigrees, we consider 12 disease models based on disease prevalence, minor allele frequency and penetrance to represent disease loci that explain 0.2-99.8% of total disease risk. Pedigrees were required to contain ≥ 15 meioses between all cases and to be HR based on significant excess of disease (P < 0.001 or P < 0.00001). Across these scenarios, the power for a single pedigree ranged widely. Nonetheless, fewer than 10 pedigrees were sufficient for excellent power in the majority of models. Power increased with the risk attributable to the disease locus, penetrance and the excess of disease in the pedigree. Sharing allowing for one sporadic case was uniformly more powerful than sharing using all cases. Furthermore, an SGS analysis using a large attenuated familial adenomatous polyposis pedigree identified a 1.96 Mb region containing the known causal APC gene with genome-wide significance. SGS is a powerful method for detecting rare variants and a valuable complement to genome-wide association studies and linkage analysis.

  3. 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; Megevand, Gordana Sunaric; 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; Cueto, Luis Fernández-Vega; 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.

  4. Statistical methods for the geographical analysis of rare diseases.

    PubMed

    Gómez-Rubio, Virgilio; López-Quílez, Antonio

    2010-01-01

    In this chapter we provide a summary of different methods for the detection of disease clusters. First of all, we give a summary of methods for computing estimates of the relative risk. These estimates provide smoothed values of the relative risks that can account for its spatial variation. Some methods for assessing spatial autocorrelation and general clustering are also discussed to test for significant spatial variation of the risk. In order to find the actual location of the clusters, scan methods are introduced. The spatial scan statistic is discussed as well as its extension by means of Generalised Linear Models that allows for the inclusion of covariates and cluster effects. In this context, zero-inflated models are introduced to account for the high number of zeros that appear when studying rare diseases. Finally, two applications of these methods are shown using data of Systemic Lupus Erythematosus in Spain and brain cancer in Navarre (Spain).

  5. [The subacute angiohypertrophic myelomalacia Foix-Alajouanine--a rare disease?].

    PubMed

    Cegan, M; Ceganová, L; Stĕrba, J; Dvorácková, J; Ehrmann, J; Kod'ousek, R

    2006-04-01

    The subacute angiohypertrophic myelomalacia Foix-Alajouanine was first described by French authors in 1926 and belongs to the wider category of CNS vascular malformations. Both individual casuistics and larger sets of patients with this disease can be found in literature scarcely. We are presenting three necroptic cases of subacute angiohypertrophic myelomalacia (Foix-Alajouanine) that were mistakenly diagnosed clinically, once as metastatic lesion of spinal canal, once as amyotrophic lateral sclerosis, and once as inflammatory lesion of spinal cord. The histologic finding is dominated by myelomalacia of varying extent with varicosely dilated, constricted or even occluded arterialized both extra- and intramedullary veins, sporadically coupled with secondary thrombi. Clinical diagnostics is difficult and requires spinal angiography. According to literature data, it is presumable that this disease is not as rare as it may seem at first sign.

  6. A Rare Disease of the Digestive Tract: Esophageal Melanosis

    PubMed Central

    Destek, Sebahattin; Gul, Vahit Onur; Ahioglu, Serkan; Erbil, Yesim

    2016-01-01

    Esophageal melanosis which is characterized by melanocytic proliferation in the squamous epithelium of the esophagus and melanin accumulatin of esophageal mucosa (EM) is a rare disease of the digestive system. Although esophageal melanosis is considered to be a benign disease, its etiology is not cleared and has been reported to be the precursor lesion of esophageal primary melanomas. In this report, we aimed to note esophageal melanosis in a 55-year-old female case who applied to our clinic with difficulty in swallowing, burning behind the breastbone in the stomach, heartburn, indigestion, and pain in the upper abdomen after endoscopic and pathologic evaluation. Complaints dropped with anti-acid therapy and case was followed by intermittent endoscopic procedures because of precursor melanocytic lesions. PMID:27785326

  7. Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis.

    PubMed

    Baschal, Erin E; Wethey, Cambria I; Swindle, Kandice; Baschal, Robin M; Gowan, Katherine; Tang, Nelson L S; Alvarado, David M; Haller, Gabe E; Dobbs, Matthew B; Taylor, Matthew R G; Gurnett, Christina A; Jones, Kenneth L; Miller, Nancy H

    2014-12-12

    Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype. Copyright © 2015 Baschal et al.

  8. Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis

    PubMed Central

    Baschal, Erin E.; Wethey, Cambria I.; Swindle, Kandice; Baschal, Robin M.; Gowan, Katherine; Tang, Nelson L.S.; Alvarado, David M.; Haller, Gabe E.; Dobbs, Matthew B.; Taylor, Matthew R.G.; Gurnett, Christina A.; Jones, Kenneth L.; Miller, Nancy H.

    2014-01-01

    Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype. PMID:25504735

  9. 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

  10. 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.

  11. 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

  12. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites.

    PubMed

    Long, Tao; Hicks, Michael; Yu, Hung-Chun; Biggs, William H; Kirkness, Ewen F; Menni, Cristina; Zierer, Jonas; Small, Kerrin S; Mangino, Massimo; Messier, Helen; Brewerton, Suzanne; Turpaz, Yaron; Perkins, Brad A; Evans, Anne M; Miller, Luke A D; Guo, Lining; Caskey, C Thomas; Schork, Nicholas J; Garner, Chad; Spector, Tim D; Venter, J Craig; Telenti, Amalio

    2017-04-01

    Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10(-11)). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.

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

    PubMed

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

    2015-02-05

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

  14. Crohn’s disease and schistosomiasis: a rare association

    PubMed Central

    Limaiem, Faten; Sassi, Asma; Mzabi, Sabeh

    2016-01-01

    Schistosomiasis is a chronic enteropathogenic disease caused by blood flukes of the genus Schistosoma. Coexistence of schistosomiasis with Crohn's disease is very rare. To the best of our knowledge, this association has been described in literature only once. A 20-year-old male patient with a past medical history of appendectomy and ileocecal Crohn's disease, presented with abdominal pain and vomiting. Ileocolonoscopy showed an ulcerated and congested appearance of the upper rectum and sigmoid. Computed tomography scan revealed a circumferential thickening of the terminal ileum with luminal stenosis. Histopathological examination of the biopsy specimens revealed a focally ulcerated colonic epithelium. The lamina propria was fibrous harbouring a polymorphic inflammatory infiltrate including lymphocytes and plasma cells organized in lymphoid follicles admixed with eosinophils and neutrophils. In the submucosa, there were two well-preserved schistosoma eggs surrounded by a thick shell with a barely visible terminal spine. The final pathological diagnosis was colonic schistosomiasis associated with Crohn's disease. The patient underwent an ileocecal resection for stenosis of the terminal ileum complicated with enterocutaneous fistula. The postoperative course was uneventful. A stool examination and serology tests were planned for this patient who was lost to follow-up. PMID:28292086

  15. Graves' Orbitopathy: Imperfect Treatments for a Rare Disease

    PubMed Central

    Bartalena, Luigi

    2013-01-01

    Graves' orbitopathy (GO) is the most frequent and invalidating extrathyroidal expression of Graves' disease. Its incidence and prevalence are, however, low. About three quarters of Graves' patients have no GO at diagnosis, and moderate-to-severe and severe forms represent no more that 5-6% of cases. Progression to severe forms occurs rarely, but it may be caused by risk factors, the most important being smoking and poor control of thyroid dysfunction. Lot of progress has been recently achieved in the understanding of GO pathogenesis, while the disease remains a therapeutic challenge and dilemma. Common treatments for moderate-to-severe and active forms of GO (glucocorticoids and orbital radiotherapy) frequently provide incomplete responses and may be followed by relapse or progression of GO. After the disease has been inactivated by medical treatment, many patients need rehabilitative surgery for residual manifestations (orbital decompression for exophthalmos, squint surgery for extraocular muscle dysfunction, eyelid surgery for eyelid malposition). Novel pharmacological treatments are on the horizon and might target pathogenetic mechanisms of the disease better than glucocorticoids. Clinical evidence concerning their efficacy and safety is presently lacking. PMID:24783057

  16. Diplopia and Sjogren's disease: A rare case report.

    PubMed

    Tripathi, Kaushalendra; Tripathi, Richa; Seraji-Bozorgzad, Navid

    2017-01-15

    Sjogren's syndrome is a chronic autoimmune disorder which affects the exocrine glands with lymphocytic infiltration, and occasionally involves central nervous system. It is usually rare and manifests as a lesion in the trigeminal nerve. Our case discusses the involvement of the oculomotor and abducens nerves along with the prevalence of such cases as seen on literature review. We describe a case of a middle aged woman who presented with ophthalmoplegic symptoms. The symptoms resolved in response to steroid therapy and serum analysis was positive for anti SSA antibodies. Increasing use of imaging modalities has enabled identifying cranial nerve enhancements easily. Correlating this to serum analysis, as in our case; has helped identify more cases of third and sixth cranial nerve involvement than was previously known to occur with primary Sjogren's syndrome.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-01-01

    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. 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. 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. 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. © The Author 2014. Published by Oxford University Press on behalf of the American

  19. 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

  20. 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.

  1. Surgical treatment for scoliosis associated with rare disease.

    PubMed

    Greggi, T; Lolli, F; Maredi, E; Di Silvestre, M; Martikos, K; Vommaro, F; Giacomini, S; Baioni, A; Cioni, A

    2012-01-01

    This is a retrospective study of 11 patients, 7 females and 4 males, treated at Our Department for an early onset scoliosis (EOS) associated with rare syndromes with growing spinal implants (Growing Rod or VEPTR-like) from 2006 to 2011. Mean follow-up was 24 months (range, 12 to 36). The mean age at surgery was 7. Patients were affected by Escobar's syndrome (1), scoliosis associated to congenital heart disease (1), Arnold Chiari type 1 (1), syringomyelia (1), NF 1 (2), Prader-Willi syndrome (1), trisomy 8 (1), arthrogryposis (2) and spondylo-rib dysplasia (1). Each patient was studied from the genetic point of view, and were performed: brain-spine MRI, pulmonary function tests, Cardio-US and abdominal US, neuropsychiatric and neurological evaluation, C0-C2 CT scan. After first implant and lengthening procedures (11), the correction of the thoracic curve averaged 50%. Unfortunately, a little loss of correction of the lumbar curve occurred during the follow up. There were 8 post-operative complications, that required revision surgery in 2 cases. Our results confirmed the effectiveness and safety of growing spinal implants in the treatment of early-onset scoliosis in rare syndromes.

  2. Innovation by patients with rare diseases and chronic needs.

    PubMed

    Oliveira, Pedro; Zejnilovic, Leid; Canhão, Helena; von Hippel, Eric

    2015-04-09

    We provide the first empirical exploration of disease-related innovation by patients and their caregivers. Our aims were to explore to what degree do patients develop innovative solutions; how many of these are unique developments; and do these solutions have positive perceived impact on the patients' overall quality of life? In addition, we explored the factors associated with patient innovation development, and sharing of the solutions that the patients developed. We administered a questionnaire via telephone interviewing to a sample of 500 rare disease patients and caregivers. The solutions reported were pre-screened by the authors for their fit with the self-developed innovation aim of the study. All the reported solutions were then validated for their novelty by two medical professionals. Logistic regression models were used to test the relationships between our key variables, patient innovation and solution sharing. 263 (53%) of our survey respondents reported developing and using a solution to improve management of their diseases. An initial screening removed 81 (16%) solutions for being an obvious misfit to the self-developed innovation aim of the study. This lowered the sample of potentially innovative solutions to 182 (36%). Assessment of novelty and usefulness of the solutions, conducted by two medical evaluators, confirmed that 40 solutions (8%) were indeed novel, while the remaining 142 (28%) were already known to medicine. The likelihood of patient innovation increased as the education level increased (OR 2, p < 0.05), and as their perception of limitations imposed by their disease increased (OR 1.3, p < 0.05). 55 individuals diffused their solutions to some degree, with 50 of these sharing via direct diffusion to other patients. There is a positive relationship between the impact of a solution on the respondents' overall quality of life and likelihood of solution sharing. Given that hundreds of millions of people worldwide are afflicted by rare

  3. 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.

  4. Recombinant adeno-associated virus vectors in the treatment of rare diseases

    PubMed Central

    Hastie, Eric; Samulski, R. Jude

    2016-01-01

    Introduction An estimated 25 million Americans are living with rare diseases. Adeno-associated virus (AAV)-mediated gene therapy is an emerging therapeutic option for the more than 7,000 identified rare diseases. This paper highlights the benefits of AAV therapy compared to conventional small molecules, discusses current pre-clinical and clinical applications of AAV-mediated gene therapy, and offers insights into cutting edge research that will shape the future of AAV for broad therapeutic use. Areas covered In this review the biology of AAV and our ability to generate disease-specific variants is summarized. Limitations of current therapy are reviewed, with an emphasis on immune detection of virus, viral tropism and tissue targeting, and limitations of gene expression. Information for this review was found using PubMed and clinicaltrials.gov. Expert opinion Currently the scope of clinical trials of AAV gene therapy is concentrated in an array of phase I/II safety trials with less than two dozen rare diseases featured. Pre-clinical, translational studies are expanding in number as developments within the last decade have made generation of improved AAV vectors available to more researchers. Further, one bottleneck that is being overcome is the availability of disease models, which will allow for improved preclinical testing and advancement of AAV to more clinical applications. PMID:27668135

  5. Cat Scratch Disease: the Rare Role of Afipia felis

    PubMed Central

    Giladi, Michael; Avidor, Boaz; Kletter, Yehudith; Abulafia, Suzy; Slater, Leonard N.; Welch, David F.; Brenner, Don J.; Steigerwalt, Arnold G.; Whitney, Anne M.; Ephros, Moshe

    1998-01-01

    Since its isolation in 1988, Afipia felis has been associated with cat scratch disease (CSD) in only one report and its role in CSD has been questioned. We have cultured A. felis from a lymph node of a patient with CSD. 16S rRNA gene sequencing, DNA relatedness studies, fatty acid analysis, and PCR of the A. felis ferredoxin gene showed that the isolate is identical to the previously reported A. felis isolate. To determine the role of A. felis in CSD, PCR of the 16S rRNA gene followed by hybridizations with specific probes were performed with lymph node specimens from CSD patients. All 32 specimens tested positive for Bartonella henselae and negative for A. felis. We conclude that A. felis is a rare cause of CSD. Diagnostic tests not conducive to the identification of A. felis might cause the diagnosis of CSD due to A. felis to be missed. PMID:9705382

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

    PubMed

    Patra, Kailash Chandra; Shirolkar, Mukund Sudhir

    2015-01-01

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

  7. A rare association of celiac disease and rectal neuroendocrine tumor.

    PubMed

    Çetin, Deniz; Tanrıverdi, Özgür; Solak Özşeker, Havva; Özşeker, Burak

    2017-07-28

    Celiac disease (CD) is a chronic immune-mediated enteropathy which is triggered by dietary gluten in genetically predisposed individuals. Increased risk of all gastrointestinal cancers was found during the first year after diagnosis of CD. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous tumor group originating from the diffuse neuroendocrine system. Today, the incidences of both GEP-NETs and CD have increased due to the increased availability of diagnostic tools and awareness. Association of GEP-NETs with CD is rarely seen. Here we aimed to present a case in which we diagnosed CD with concurrent rectal NET. Association of CD and rectal NET has not been reported in the literature, and we believe that our case report can contribute to the epidemiological data.

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

    PubMed Central

    Patra, Kailash Chandra; Shirolkar, Mukund Sudhir

    2015-01-01

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

  9. [Deregulation of pre-messenger RNA splicing and rare diseases].

    PubMed

    de la Grange, Pierre

    2016-12-01

    Most of protein-coding human genes are subjected to alternative pre-mRNA splicing. This mechanism is highly regulated to precisely modulate detection of specific splice sites. This regulation is under control of the spliceosome and several splicing factors are also required to modulate the alternative usage of splice sites. Splicing factors and spliceosome components recognize splicing signals and regulatory sequences of the pre-mRNAs. These splicing sequences make splicing susceptible to polymorphisms and mutations. Examples of associations between human rare diseases and defects in pre-messenger RNA splicing are accumulating. Although many alterations are caused by mutations in splicing sequence (i.e., cis acting mutations), recent studies described the disruptive impact of mutations within spliceosome components or splicing factors (i.e., trans acting mutations). Following growing of knowledge regarding splicing regulation, several approaches have been developed to compensate for the effect of deleterious mutations and to restore sufficient amounts of functional protein.

  10. Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy*

    PubMed Central

    Pinto, Jose Renato; Siegfried, Jill D.; Parvatiyar, Michelle S.; Li, Duanxiang; Norton, Nadine; Jones, Michelle A.; Liang, Jingsheng; Potter, James D.; Hershberger, Ray E.

    2011-01-01

    TNNC1, which encodes cardiac troponin C (cTnC), remains elusive as a dilated cardiomyopathy (DCM) gene. Here, we report the clinical, genetic, and functional characterization of four TNNC1 rare variants (Y5H, M103I, D145E, and I148V), all previously reported by us in association with DCM (Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., and Gonzalez-Quintana, J. (2010) Circ. Cardiovasc. Genet. 3, 155–161); in the previous study, two variants (Y5H and D145E) were identified in subjects who also carried MYH7 and MYBPC3 rare variants, respectively. Functional studies using the recombinant human mutant cTnC proteins reconstituted into porcine papillary skinned fibers showed decreased Ca2+ sensitivity of force development (Y5H and M103I). Furthermore, the cTnC mutants diminished (Y5H and I148V) or abolished (M103I) the effects of PKA phosphorylation on Ca2+ sensitivity. Only M103I decreased the troponin activation properties of the actomyosin ATPase when Ca2+ was present. CD spectroscopic studies of apo (absence of divalent cations)-, Mg2+-, and Ca2+/Mg2+-bound states indicated that all of the cTnC mutants (except I148V in the Ca2+/Mg2+ condition) decreased the α-helical content. These results suggest that each mutation alters the function/ability of the myofilament to bind Ca2+ as a result of modifications in cTnC structure. One variant (D145E) that was previously reported in association with hypertrophic cardiomyopathy and that produced results in vivo in this study consistent with prior hypertrophic cardiomyopathy functional studies was found associated with the MYBPC3 P910T rare variant, likely contributing to the observed DCM phenotype. We conclude that these rare variants alter the regulation of contraction in some way, and the combined clinical, molecular, genetic, and functional data reinforce the importance of TNNC1 rare variants in the pathogenesis of DCM. PMID:21832052

  11. 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.

  12. Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level

    PubMed Central

    2010-01-01

    Background Targeted re-sequencing of candidate genes in individuals at the extremes of a quantitative phenotype distribution is a method of choice to gain information on the contribution of rare variants to disease susceptibility. The endocannabinoid system mediates signaling in the brain and peripheral tissues involved in the regulation of energy balance, is highly active in obese patients, and represents a strong candidate pathway to examine for genetic association with body mass index (BMI). Results We sequenced two intervals (covering 188 kb) encoding the endocannabinoid metabolic enzymes fatty-acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal controls and 142 extremely obese cases. After applying quality filters, we called 1,393 high quality single nucleotide variants, 55% of which are rare, and 143 indels. Using single marker tests and collapsed marker tests, we identified four intervals associated with BMI: the FAAH promoter, the MGLL promoter, MGLL intron 2, and MGLL intron 3. Two of these intervals are composed of rare variants and the majority of the associated variants are located in promoter sequences or in predicted transcriptional enhancers, suggesting a regulatory role. The set of rare variants in the FAAH promoter associated with BMI is also associated with increased level of FAAH substrate anandamide, further implicating a functional role in obesity. Conclusions Our study, which is one of the first reports of a sequence-based association study using next-generation sequencing of candidate genes, provides insights into study design and analysis approaches and demonstrates the importance of examining regulatory elements rather than exclusively focusing on exon sequences. PMID:21118518

  13. 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.

  14. Mycobacterium abscessus hand-and-foot disease in children: rare or emerging disease?

    PubMed

    Sinagra, Jo Linda M; Kanitz, Elisabeth E; Cerocchi, Carlo; Cota, Carlo; Fantetti, Ottavia; Prignano, Grazia; Donati, Pietro; Tortoli, Enrico M; D'Ancona, Francesco P; Capitanio, Bruno

    2014-01-01

    Mycobacterium abscessus is emerging as an important cause of cutaneous infections in sporadic cases and outbreak settings. Although immunosuppressed or elderly patients are most commonly affected, in 2006 an outbreak of clinically distinct cutaneous lesions on the hands and feet caused by M. abscessus in a population of healthy children using a public swimming pool was reported. This article describes an outbreak of skin infection in a population of healthy Italian children attending the same school and using the same swimming pool. In January 2010 we identified three children with multiple, painful nodules on the palms and soles. M. abscessus was isolated from one child's lesions. A public health investigation was conducted and a team of dermatologists and public health officers visited all of the children; 514 children were screened and 29 cases were identified overall. All of the affected children had used the school's swimming pool. These children were treated with oral clarithromycin for 4 to 8 weeks. Because of the long period of time between the presentation and diagnosis of the first cases, the possibility that the number of cases may have been underestimated cannot be excluded. To our knowledge, this is the second largest reported cluster of M. abscessus skin infection suspected to be related to swimming pool exposure in a population of otherwise healthy children. It is unclear whether this disease is rare or should be considered as an emerging clinical entity. © 2014 Wiley Periodicals, Inc.

  15. Construction and implications of structural equation modeling network for pediatric cataract: a data mining research of rare diseases.

    PubMed

    Long, Erping; Xu, Shuangjuan; Liu, Zhenzhen; Wu, Xiaohang; Zhang, Xiayin; Wang, Jinghui; Li, Wangting; Liu, Runzhong; Chen, Zicong; Chen, Kexin; Yu, Tongyong; Wu, Dongxuan; Zhao, Xutu; Chen, Jingjing; Lin, Zhuoling; Cao, Qianzhong; Lin, Duoru; Li, Xiaoyan; Cai, Jingheng; Lin, Haotian

    2017-05-19

    The majority of rare diseases are complex diseases caused by a combination of multiple morbigenous factors. However, uncovering the complex etiology and pathogenesis of rare diseases is difficult due to limited clinical resources and conventional statistical methods. This study aims to investigate the interrelationship and the effectiveness of potential factors of pediatric cataract, for the exploration of data mining strategy in the scenarios of rare diseases. We established a pilot rare disease specialized care center to systematically record all information and the entire treatment process of pediatric cataract patients. These clinical records contain the medical history, multiple structural indices, and comprehensive functional metrics. A two-layer structural equation model network was applied, and eight potential factors were filtered and included in the final modeling. Four risk factors (area, density, location, and abnormal pregnancy experience) and four beneficial factors (axis length, uncorrected visual acuity, intraocular pressure, and age at diagnosis) were identified. Quantifiable results suggested that abnormal pregnancy history may be the principle risk factor among medical history for pediatric cataracts. Moreover, axis length, density, uncorrected visual acuity and age at diagnosis served as the dominant factors and should be emphasized in regular clinical practice. This study proposes a generalized evidence-based pattern for rare and complex disease data mining, provides new insights and clinical implications on pediatric cataract, and promotes rare-disease research and prevention to benefit patients.

  16. Fatality in Kikuchi-Fujimoto disease: A rare phenomenon

    PubMed Central

    Barbat, Bianca; Jhaj, Ruby; Khurram, Daniyeh

    2017-01-01

    Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is an uncommon condition, typically characterized by lymphadenopathy and fevers. It usually has a benign course; however, it may progress to fatality in extremely rare occasions. The diagnosis is made via lymph node biopsy and histopathology. Our patient was a young female who presented with shortness of breath, fever, and malaise. Physical examination revealed significant cervical and axillary lymphadenopathy. Chest X-ray displayed multilobar pneumonia. She required intubation and mechanical ventilation for progressive respiratory distress. Histopathology of lymph nodes demonstrated variable involvement of patchy areas of necrosis within the paracortex composed of karyorrhectic debris with abundant histiocytes consistent with KFD. After initial stabilization, the patient’s condition quickly deteriorated with acute anemia, thrombocytopenia and elevated prothrombin time, partial prothrombin time, and D-dimer levels. Disseminated intravascular coagulopathy (DIC) ensued resulting in the patient’s fatality. DIC in KFD is not well understood, but it is an important cause of mortality in patients with aggressive disease. PMID:28255545

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

    MedlinePlus

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

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

    NASA Astrophysics Data System (ADS)

    Artyomov, Maxim; Meissner, Alex; Chakraborty, Arup

    2010-03-01

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

  19. Patients with rare diseases using pharmacists for medication information.

    PubMed

    Carpenter, Delesha M; Blalock, Susan J; DeVellis, Robert F

    2012-01-01

    To determine whether patients with a rare illness (1) use pharmacists for medication information more or less frequently than physicians and the Internet, (2) perceive pharmacists as a more or less credible medical information resource than physicians and the Internet, and (3) obtain different types of medication information from pharmacists, physicians, and the Internet. Cross-sectional survey. Online data collected between 2008 and 2009. Adult, English-proficient vasculitis patients (n = 232) who were taking at least one medication to treat their vasculitis. Administration of online survey. Patient use of pharmacists, physicians, and the Internet for medication information; perceived credibility of pharmacists, physicians, and the Internet as sources of medication information; and types of medication information obtained from pharmacists, physicians, and the Internet. Participants consulted physicians and the Internet more than pharmacists for medication information; only 96 participants (41.4%) ever used pharmacists for vasculitis medication information. Females and participants who used community pharmacies were significantly more likely to consult pharmacists for medication information as compared with males and patients who did not use community pharmacies. Participants perceived pharmacists were a less credible source of medication information than physicians and the Internet. Participants used physicians and/or the Internet more than pharmacists for five of eight types of medication information, including adverse effects and drug effectiveness. Vasculitis patients consulted sources other than pharmacists for medication information. Several factors, including perceived pharmacist credibility and a noncommunity-based pharmacy, may contribute to infrequent patient use of pharmacists as a medication information source. Future qualitative research should document how patients with rare disease perceive and interact with pharmacists to understand why many view

  20. Chronic granulomatous disease: lessons from a rare disorder.

    PubMed

    Segal, Brahm H; Veys, Paul; Malech, Harry; Cowan, Morton J

    2011-01-01

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

  1. 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

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

    PubMed

    Mazzucato, Monica; Visonà Dalla Pozza, Laura; Manea, Silvia; Minichiello, Cinzia; Facchin, Paola

    2014-03-19

    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. 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. 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. 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 is important for public health planning

  3. Empirical power of very rare variants for common traits and disease: results from sanger sequencing 1998 individuals

    PubMed Central

    Ladouceur, Martin; Zheng, Hou-Feng; Greenwood, Celia M T; Richards, J Brent

    2013-01-01

    The optimal study design for identifying rare variants associated with common disease is not yet clear and researchers have to decide whether to prioritize lower sequencing coverage on larger sample sizes, or higher coverage on smaller sample sizes. High-coverage sequencing affords several advantages, such as genotype accuracy and improved identification of very rare variants, but this comes at increased cost. However, the magnitude of the contribution of very rare variants to the statistical power of gene-based association tests is unknown. By using Sanger sequence data on seven genes from 1998 subjects with simulated phenotypes, we provide evidence that excluding very rare variants, in general, reduces the statistical power of rare variant association tests only modestly. However, if the probability of being causal and the effect size of the causal variants are inversely related to the minor allele frequency, then very rare variants do contribute to some power, however the absolute power remains low. As very rare variants constitute the majority of variants identified in sequencing studies, these findings suggest that careful attention need to be placed on the plausible relationship that exist between very rare variants and common disease. PMID:23321613

  4. A case report on a rare disease: dyskeratosis congenita.

    PubMed

    Shiferaw, Bethel; Mukka, Satish; Ha, Lawrence; Bekele, Ebisa; Ramos De Oleo, Radhames

    2015-05-01

    Dyskeratosis congenita (DC) is a rare hereditary disorder characterized by bone marrow failure, cancer predisposition (11-fold increase compared to general population), ectodermal dysplasia (nail dystrophy, oral leukoplakia, and abnormal skin pigmentation) and other additional somatic abnormalities. A 22-year-old man presented with fever, chills, and a painful throat. Leukoplakia was noted on his tongue and some of his fingers and toe nails were markedly dystrophic. His skin seemed spotted with pigmentation on the anterior chest and neck. Patient reported family history of "blood disease" and leukemia. He was admitted for the management of neutropenic fever (102.9 °F, WBC: 940, ANC: 404, platelets: 21,000 and Hb: 9.2), and was put on broad spectrum antibiotics. A bone marrow biopsy revealed normocellular marrow with erythroid predominance and mild dyserythropoiesis. Chromosomal analysis indicated no numerical or structural chromosomal abnormalities. The fluorescence in situ hybridization report did not reveal any assay specific abnormalities. Viral marker for hepatitis and studies of autoimmune antibodies showed negative results. CT scan had shown splenomegaly. Patient was discharged after he has been fever and symptoms free, with a follow-up at hematology clinic. Individuals with DC most commonly present with skin pigmentation, dystrophic nails and leukoplakia, as presented in this case. Genetic abnormality was not confirmed in our patient, but it is suggested that X-linked recessive pattern would be significant because of greater prevalence in men than in women (10:1). The distribution of blood counts and bone marrow biopsy categorizes our patient in the moderate aplastic anemia class which is the most prevalent pattern. When fever in young patients with a failing bone marrow is diagnosed, it is important that physicians rule out the possible underlying causes. DC is a rare disease, but can be diagnosed by simple inspection of the mucocutaneous abnormalities. DC

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

    PubMed Central

    Miller, Jeri L.; Grady, Patricia A.

    2016-01-01

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

  6. The overweight: a rare presentation of celiac disease.

    PubMed

    Capriati, T; Francavilla, R; Ferretti, F; Castellaneta, S; Ancinelli, M; Diamanti, A

    2016-02-01

    We describe the nutritional status of a cohort of celiac disease (CD) children at presentation and during follow-up on gluten-free diet (GFD). Two Italian centers (Rome and Bari) prospectively enrolled 445 biopsy-confirmed CD children, diagnosed between 2009 and 2013. Body Mass Index was used as a measure of nutritional status according to Italian growth charts of Cacciari. The overweight/obese subject was 7.8% at onset and did not significantly increase during follow-up (9.8% at final assessment). The prevalence of overweight/obesity was significantly higher among males than females. Furthermore, overweight/obesity children as compared with those with normal weight were significantly older and had significantly lower levels of tTG antibodies. This study shows that some CD children are obese/overweight at diagnosis; therefore, overweight/obesity can be considered a rare but a possible mode of CD presentation. Thus, CD diagnosis must be considered even in overweight/obese children where this diagnosis can be easily missed.

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

    PubMed Central

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

    2015-01-01

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

  8. Chronic Granulomatous Disease: Lessons from a Rare Disorder

    PubMed Central

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

    2010-01-01

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

  9. 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

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

    PubMed

    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

    2014-07-01

    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. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

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

    PubMed

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

    2015-11-01

    Genetic α-1 antitrypsin (AAT) deficiency is characterized by low serum AAT levels and the identification of causal mutations or an abnormal protein. It needs to be distinguished from deficiency because of nongenetic causes, and diagnostic delay may contribute to worse patient outcome. Current routine clinical testing assesses for only the most common mutations. We wanted to determine the proportion of unexplained cases of AAT deficiency that harbor causal mutations not identified through current standard allele-specific genotyping and isoelectric focusing (IEF). All prospective cases from December 1, 2013, to October 1, 2014, with a low serum AAT level not explained by allele-specific genotyping and IEF were assessed through full-gene sequencing with a direct sequencing method for pathogenic mutations. We reviewed the results using American Council of Medical Genetics criteria. Of 3523 cases, 42 (1.2%) met study inclusion criteria. Pathogenic or likely pathogenic mutations not identified through clinical testing were detected through full-gene sequencing in 16 (38%) of the 42 cases. Rare mutations not detected with current allele-specific testing and IEF underlie a substantial proportion of genetic AAT deficiency. Full-gene sequencing, therefore, has the ability to improve accuracy in the diagnosis of AAT deficiency. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

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

    PubMed

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

    2016-03-29

    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

  13. 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

  14. Extranodal right-optic nerve Rosai–Dorfman disease: A rare localization case report

    PubMed Central

    Nemir, Jakob; Trninic, Ines; Duric, Kresimir S.; Jakovcevic, Antonia; Mrak, Goran; Paladino, Josip

    2016-01-01

    Background: Rosai–Dorfman is a rare disease that usually occurs in young adults. It is characterized with massive painless cervical lymphadenopathy and histiocyte proliferation. Isolated intracranial involvement is extremely rare. Our aim is to present a new rare case of extranodal Rosai–Dorfman disease that involved the right optic nerve in a 4-year-old boy. Case Description: A 4-year-old boy with right-sided convergent strabismus and amblyopia lasting for 1 year was treated at the Department of pediatric ophthalmology. Initial optical fundus examination was normal. Examination repeated after 1 year noted the atrophy of the optic nerve papilla. Visual evoked potentials of the right eye showed normal findings of prechiasmatic visual pathway with severe dysfunction of the right optic nerve. Magnetic resonance imaging (MRI) of the brain and orbits showed expansive changed and elongated right optic nerve with contrast enhancement, and smaller lesion in the right temporal operculum region visible in T2 and fluid-attenuated inversion recovery sequence. Through small eyebrow “keyhole” osteoplastic frontoorbital craniotomy the fusiform enlarged (to 2 cm) right optic nerve was identified, resected between the eyeball and optic chiasm, and transferred for pathohistological analysis. Early postoperative course had no complications. Histological, immunohistochemical, and ultrastructural analyses revealed extranodal Rosai–Dorfman disease. Right periorbital edema was verified on the 7th postoperative day and regressed to supportive therapy. Control multi slice computed tomography (MSCT) and MRI of endocranium and orbits showed total tumor removal with no signs of complications. Conclusion: Although rare, extranodular intracranial Rosai–Dorfman disease should be taken into account in the differential diagnosis of intracranial and intraorbital lesions, especially in the pediatric age group. PMID:28194305

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

    PubMed Central

    Gong, Shiwei; Jin, Si

    2012-01-01

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

  16. Progress in rare diseases research 2010-2016: an IRDiRC perspective.

    PubMed

    Dawkins, Hugh Js; Draghia-Akli, Ruxandra; Lasko, Paul; Lau, Lilian Pl; Jonker, Anneliene H; Cutillo, Christine M; Rath, Ana; Boycott, Kym M; Baynam, Gareth; Lochmüller, Hanns; Kaufmann, Petra; Cam, Yann Le; Hivert, Virginie; Austin, Christopher P

    2017-08-10

    In 2011, the International Rare Diseases Research Consortium (IRDiRC) was formed to unite public and private sector funders of research, patient advocacy groups, and scientific researchers to advance rare diseases research worldwide. Six years after its official launch, IRDiRC is now reflecting on its progress and achievements toward its ambitious goals for the rare diseases research collective - to develop 200 new therapies and the means to diagnose most rare genetic diseases by the year 2020. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  17. Future of Rare Diseases Research 2017-2027: an IRDiRC Perspective.

    PubMed

    Austin, Christopher P; Cutillo, Christine M; Lau, Lilian Pl; Jonker, Anneliene H; Rath, Ana; Julkowska, Daria; Thomson, David; Terry, Sharon; de Montleau, Beatrice; Ardigò, Diego; Hivert, Virginie; Boycott, Kym M; Baynam, Gareth; Kaufmann, Petra; Taruscio, Domenica; Lochmüller, Hanns; Suematsu, Makoto; Incerti, Carlo; Draghia-Akli, Ruxandra; Norstedt, Irene; Wang, Lu; Dawkins, Hugh Js

    2017-08-10

    Due to the remarkable global surge in activity in rare diseases research over the last six years, including contributions by the International Rare Diseases Research Consortium (IRDiRC), the Consortium's 2020 goals have been largely achieved by 2017. Though these developments are gratifying, enormous challenges remain. With this paradox in mind, IRDiRC set new global rare disease goals for the coming decade with the ultimate aim of improved health for people living with rare diseases worldwide. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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

    PubMed

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

    2016-01-01

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

  19. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-10-27

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

  2. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

    PubMed Central

    Liu, Chunyu; Kraja, Aldi T.; Smith, Jennifer A.; Brody, Jennifer A.; Franceschini, Nora; Bis, Joshua C.; Rice, Kenneth; Morrison, Alanna C.; Lu, Yingchang; Weiss, Stefan; Guo, Xiuqing; Palmas, Walter; Martin, Lisa W.; Chen, Yii-Der Ida; Surendran, Praveen; Drenos, Fotios; Cook, James P.; Auer, Paul L.; Chu, Audrey Y.; Giri, Ayush; Zhao, Wei; Jakobsdottir, Johanna; Lin, Li-An; Stafford, Jeanette M.; Amin, Najaf; Mei, Hao; Yao, Jie; Voorman, Arend; Larson, Martin G.; Grove, Megan L.; Smith, Albert V.; Hwang, Shih-Jen; Chen, Han; Huan, Tianxiao; Kosova, Gulum; Stitziel, Nathan O.; Kathiresan, Sekar; Samani, Nilesh; Schunkert, Heribert; Deloukas, Panos; Li, Man; Fuchsberger, Christian; Pattaro, Cristian; Gorski, Mathias; Kooperberg, Charles; Papanicolaou, George J.; Rossouw, Jacques E.; Faul, Jessica D.; Kardia, Sharon L.R.; Bouchard, Claude; Raffel, Leslie J.; Uitterlinden, André G.; Franco, Oscar H.; Vasan, Ramachandran S.; O'Donnell, Christopher J.; Taylor, Kent D.; Liu, Kiang; Bottinger, Erwin P.; Gottesman, Omri; Daw, E. Warwick; Giulianini, Franco; Ganesh, Santhi; Salfati, Elias; Harris, Tamara B.; Launer, Lenore J.; Dörr, Marcus; Felix, Stephan B.; Rettig, Rainer; Völzke, Henry; Kim, Eric; Lee, Wen-Jane; Lee, I-Te; Sheu, Wayne H-H; Tsosie, Krystal S.; Velez Edwards, Digna R.; Liu, Yongmei; Correa, Adolfo; Weir, David R.; Völker, Uwe; Ridker, Paul M; Boerwinkle, Eric; Gudnason, Vilmundur; Reiner, Alexander P.; van Duijn, Cornelia M.; Borecki, Ingrid B.; Edwards, Todd L.; Chakravarti, Aravinda; Rotter, Jerome I.; Psaty, Bruce M.; Loos, Ruth J.F.; Fornage, Myriam; Ehret, Georg; Newton-Cheh, Christopher; Levy, Daniel; Chasman, Daniel I.

    2017-01-01

    Meta-analyses of association results for blood pressure using exome-centric single-variants and gene-based tests identified 31 novel loci in discovery among 146,562 individuals with follow-up and meta-analysis in 180,726 additional individuals (Ntotal=327,288). These blood pressure loci are enriched for known cardiometabolic trait variants. Associations were also observed for the aggregation of rare/low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure loci suggests new therapeutic strategies for hypertension emphasizing a link with cardiometabolic risk. PMID:27618448

  3. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.

    PubMed

    Liu, Chunyu; Kraja, Aldi T; Smith, Jennifer A; Brody, Jennifer A; Franceschini, Nora; Bis, Joshua C; Rice, Kenneth; Morrison, Alanna C; Lu, Yingchang; Weiss, Stefan; Guo, Xiuqing; Palmas, Walter; Martin, Lisa W; Chen, Yii-Der Ida; Surendran, Praveen; Drenos, Fotios; Cook, James P; Auer, Paul L; Chu, Audrey Y; Giri, Ayush; Zhao, Wei; Jakobsdottir, Johanna; Lin, Li-An; Stafford, Jeanette M; Amin, Najaf; Mei, Hao; Yao, Jie; Voorman, Arend; Larson, Martin G; Grove, Megan L; Smith, Albert V; Hwang, Shih-Jen; Chen, Han; Huan, Tianxiao; Kosova, Gulum; Stitziel, Nathan O; Kathiresan, Sekar; Samani, Nilesh; Schunkert, Heribert; Deloukas, Panos; Li, Man; Fuchsberger, Christian; Pattaro, Cristian; Gorski, Mathias; Kooperberg, Charles; Papanicolaou, George J; Rossouw, Jacques E; Faul, Jessica D; Kardia, Sharon L R; Bouchard, Claude; Raffel, Leslie J; Uitterlinden, André G; Franco, Oscar H; Vasan, Ramachandran S; O'Donnell, Christopher J; Taylor, Kent D; Liu, Kiang; Bottinger, Erwin P; Gottesman, Omri; Daw, E Warwick; Giulianini, Franco; Ganesh, Santhi; Salfati, Elias; Harris, Tamara B; Launer, Lenore J; Dörr, Marcus; Felix, Stephan B; Rettig, Rainer; Völzke, Henry; Kim, Eric; Lee, Wen-Jane; Lee, I-Te; Sheu, Wayne H-H; Tsosie, Krystal S; Edwards, Digna R Velez; Liu, Yongmei; Correa, Adolfo; Weir, David R; Völker, Uwe; Ridker, Paul M; Boerwinkle, Eric; Gudnason, Vilmundur; Reiner, Alexander P; van Duijn, Cornelia M; Borecki, Ingrid B; Edwards, Todd L; Chakravarti, Aravinda; Rotter, Jerome I; Psaty, Bruce M; Loos, Ruth J F; Fornage, Myriam; Ehret, Georg B; Newton-Cheh, Christopher; Levy, Daniel; Chasman, Daniel I

    2016-10-01

    Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

  4. 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.

  5. A Bayesian adaptive design for clinical trials in rare diseases.

    PubMed

    Williamson, S Faye; Jacko, Peter; Villar, Sofía S; Jaki, Thomas

    2017-09-01

    Development of treatments for rare diseases is challenging due to the limited number of patients available for participation. Learning about treatment effectiveness with a view to treat patients in the larger outside population, as in the traditional fixed randomised design, may not be a plausible goal. An alternative goal is to treat the patients within the trial as effectively as possible. Using the framework of finite-horizon Markov decision processes and dynamic programming (DP), a novel randomised response-adaptive design is proposed which maximises the total number of patient successes in the trial and penalises if a minimum number of patients are not recruited to each treatment arm. Several performance measures of the proposed design are evaluated and compared to alternative designs through extensive simulation studies using a recently published trial as motivation. For simplicity, a two-armed trial with binary endpoints and immediate responses is considered. Simulation results for the proposed design show that: (i) the percentage of patients allocated to the superior arm is much higher than in the traditional fixed randomised design; (ii) relative to the optimal DP design, the power is largely improved upon and (iii) it exhibits only a very small bias and mean squared error of the treatment effect estimator. Furthermore, this design is fully randomised which is an advantage from a practical point of view because it protects the trial against various sources of bias. As such, the proposed design addresses some of the key issues that have been suggested as preventing so-called bandit models from being implemented in clinical practice.

  6. Prioritizing treatment of rare diseases: a survey of preferences of Norwegian doctors.

    PubMed

    Desser, Arna S

    2013-10-01

    Understanding doctors' preferences for prioritizing treatment of rare diseases can provide an important context for policy makers who must decide whether to exempt rare disease treatments, which are often quite expensive, from standard cost-effectiveness criteria. We surveyed a random sample of 551 Norwegian doctors in November 2011 and compared results to a similar survey of the Norwegian population. Respondents chose whether to prioritize treatment of patients with rare versus common diseases and then decided how to allocate funds between the two groups for each of two scenarios: (1) equal costs per person and (2) higher costs for the rare disease. Respondents were randomized to treatment costs for the rare disease in the second scenario that were either 8 or 25 times higher than treating the common disease. Except for different prevalence, the diseases were described identically. Doctors displayed no general preference for prioritizing treatment of rare diseases, but a large number favored the principle of reserving a small share of funds for rare disease patients. Doctors' responses differed significantly from those of the general population when the rare disease was more costly to treat. A larger share of doctors prioritized the common disease group for treatment while a smaller share expressed indifference. When dividing funds between the two patient groups, doctors allocated a smaller share of funds to the rare disease. Doctors were much less likely than the general population to divide funds equally between the groups. This study indicates that there is little support among Norwegian doctors for prioritizing the treatment of rare diseases.

  7. 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

  8. "It's not all in my head!" - The complex relationship between rare diseases and mental health problems.

    PubMed

    Nunn, Rebecca

    2017-02-27

    The incidence of mental health disorders is significantly higher in individuals with a rare disease, compared to the general population. This letter considers the possible reasons for this in terms of the many ways in which a rare disease impacts on an individual's life, and how these impacts can be strongly related to factors which predispose to mental health difficulties.Furthermore, issues surrounding mental health can also play a significant role in the process of diagnosing a rare disease. The unusual nature of such diseases intrinsically predisposes an individual to obtain an inaccurate diagnosis of a psychosomatic disorder, a diagnosis which can often be further complicated by the presence of genuine psychiatric symptoms.This letter argues that these common experiences of rare disease patients have impacts upon the way in which their psychiatric care should be offered and managed, and that sensitivity and understanding surrounding these issues should be considered a necessary part of effective care for rare disease patients.

  9. Rare autosomal copy number variations in early-onset familial Alzheimer's disease.

    PubMed

    Hooli, B V; Kovacs-Vajna, Z M; Mullin, K; Blumenthal, M A; Mattheisen, M; Zhang, C; Lange, C; Mohapatra, G; Bertram, L; Tanzi, R E

    2014-06-01

    Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.

  10. 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

  11. 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.

  12. 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.

  13. Whole Exome Sequence Analysis Implicates Rare Il17REL Variants In Familial And Sporadic Inflammatory Bowel Disease

    PubMed Central

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

    2015-01-01

    Background 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. Methods To discover candidate rare variants associated with IBD, we performed whole exome sequencing (WES) on six members of a pediatric-onset IBD family with multiple affected individuals. To determine whether the variants discovered in this family are also associated with non-familial IBD, we investigated their influence on disease in two large case-control (CC) series. Results We identified two rare variants, rs142430606 and rs200958270, both in the established IBD-susceptibility gene IL17REL, carried by all four affected family members and their obligate-carrier parents. We then demonstrated that both variants are associated with sporadic ulcerative colitis (UC) in two independent datasets. For UC in CC 1: rs142430606 (OR=2.99, Padj=0.028; MAFcases=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). Conclusions We discover in a family and replicate in two CC datasets two rare susceptibility variants for IBD, both in IL17REL. Our results illustrate that WES 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. PMID:26480299

  14. A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis.

    PubMed

    Maiwald, Stephanie; Motazacker, Mahdi M; van Capelleveen, Julian C; Sivapalaratnam, Suthesh; van der Wal, Allard C; van der Loos, Chris; Kastelein, John J P; Ouwehand, Willem H; Hovingh, G Kees; Trip, Mieke D; van Buul, Jaap D; Dallinga-Thie, Geesje M

    2016-01-01

    Cardiovascular disease (CVD) is a major cause of death in Western societies. CVD risk is largely genetically determined. The molecular pathology is, however, not elucidated in a large number of families suffering from CVD. We applied exclusion linkage analysis and next-generation sequencing to elucidate the molecular defect underlying premature CVD in a small pedigree, comprising two generations of which six members suffered from premature CVD. A total of three variants showed co-segregation with the disease status in the family. Two of these variants were excluded from further analysis based on the prevalence in replication cohorts, whereas a non-synonymous variant in MCF.2 Cell Line Derived Transforming Sequence-like protein (MCF2L, c.2066A>G; p.(Asp689Gly); NM_001112732.1), located in the DH domain, was only present in the studied family. MCF2L is a guanine exchange factor that potentially links pathways that signal through Rac1 and RhoA. Indeed, in HeLa cells, MCF2L689Gly failed to activate Rac1 as well as RhoA, resulting in impaired stress fiber formation. Moreover, MCF2L protein was found in human atherosclerotic lesions but not in healthy tissue segments. In conclusion, a rare functional variant in MCF2L, leading to impaired DH function, was identified in a small pedigree with premature CVD. The presence of MCF2L in human atherosclerotic plaque specimen lends further support to its potential role in atherosclerosis.

  15. 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.

  16. 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.

  17. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.

    PubMed

    Gahl, William A; Markello, Thomas C; Toro, Camilo; Fajardo, Karin Fuentes; Sincan, Murat; Gill, Fred; Carlson-Donohoe, Hannah; Gropman, Andrea; Pierson, Tyler Mark; Golas, Gretchen; Wolfe, Lynne; Groden, Catherine; Godfrey, Rena; Nehrebecky, Michele; Wahl, Colleen; Landis, Dennis M D; Yang, Sandra; Madeo, Anne; Mullikin, James C; Boerkoel, Cornelius F; Tifft, Cynthia J; Adams, David

    2012-01-01

    This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.

  18. Involvement of Patient Organisations in Research and Development of Orphan Drugs for Rare Diseases in Europe

    PubMed Central

    Mavris, M.; Le Cam, Y.

    2012-01-01

    Patients’ representatives have an increasingly present voice in all aspects of drug development from fundamental research through regulatory processes to health technology assessment. Although major advances have been made in raising awareness and increasing funding for rare diseases, important challenges remain in terms of best use of resources, coordinating efforts and improving policy. This article describes actions taken by rare disease patients’ organisations as well as initiatives at the national and European levels to promote research into rare diseases. A survey conducted by EURORDIS (European Organisation for Rare Diseases) on the support (financial and non-financial) provided by patients’ organisations in rare disease research is described as well as the involvement of patients’ representatives in regulatory processes for medicinal products at the European Medicines Agency. The importance of including patients’ groups in fundamental and clinical research as equal partners has become a fact that clearly contributes to the success of an application and the research conducted. PMID:23293582

  19. An Official American Thoracic Society Workshop Report: Translational Research in Rare Respiratory Diseases.

    PubMed

    Kristof, Arnold S; Petrof, Basil J; Hamid, Qutayba; Kolb, Martin; Landry, Jennifer S; MacKenzie, Alex; McCormack, Francis X; Murawski, Inga J; Moss, Joel; Rauch, Frank; Rosas, Ivan O; Shapiro, Adam J; Smith, Benjamin M; Thomas, David Y; Trapnell, Bruce C; Young, Lisa R; Zariwala, Maimoona A

    2017-08-01

    Rare respiratory diseases (RRDs) are a heterogeneous group of disorders that collectively represent a significant health care burden. In recent years, strong advocacy and policy initiatives have led to advances in the implementation of research and clinical care for rare diseases. The development of specialized centers and research networks has facilitated support for affected individuals as well as emerging programs in basic, translational, and clinical research. In selected RRDs, subsequent gains in knowledge have informed the development of targeted therapies and effective diagnostic tests, but many gaps persist. There was therefore a desire to identify the elements contributing to an effective translational research program in RRDs. To this end, a workshop was convened in October 2015 with a focus on the implementation of effective transnational research networks and collaborations aimed at developing novel diagnostic and therapeutic tools. Key elements included an emphasis on molecular pathogenesis, the continuing engagement of patient advocacy groups and policy makers, the effective use of preclinical models in the translational research pipeline, and the detailed phenotyping of patient cohorts. During the course of the workshop, current logistical and knowledge gaps were identified, and new solutions or opportunities were highlighted.

  20. A vector space model approach to identify genetically related diseases

    PubMed Central

    2012-01-01

    Objective The relationship between diseases and their causative genes can be complex, especially in the case of polygenic diseases. Further exacerbating the challenges in their study is that many genes may be causally related to multiple diseases. This study explored the relationship between diseases through the adaptation of an approach pioneered in the context of information retrieval: vector space models. Materials and Methods A vector space model approach was developed that bridges gene disease knowledge inferred across three knowledge bases: Online Mendelian Inheritance in Man, GenBank, and Medline. The approach was then used to identify potentially related diseases for two target diseases: Alzheimer disease and Prader-Willi Syndrome. Results In the case of both Alzheimer Disease and Prader-Willi Syndrome, a set of plausible diseases were identified that may warrant further exploration. Discussion This study furthers seminal work by Swanson, et al. that demonstrated the potential for mining literature for putative correlations. Using a vector space modeling approach, information from both biomedical literature and genomic resources (like GenBank) can be combined towards identification of putative correlations of interest. To this end, the relevance of the predicted diseases of interest in this study using the vector space modeling approach were validated based on supporting literature. Conclusion The results of this study suggest that a vector space model approach may be a useful means to identify potential relationships between complex diseases, and thereby enable the coordination of gene-based findings across multiple complex diseases. PMID:22227640

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

    PubMed Central

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

    2016-01-01

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

  2. 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.

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

    PubMed

    Fierabracci, Alessandra

    2016-07-12

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

  4. Acropigmentation of Kitamura with immigration delay disease: A rare entity

    PubMed Central

    Kumar, Sumir; Mahajan, Bharat Bhushan; Kamra, Nidhi; Bhoyar, Pritish A.

    2015-01-01

    Reticulate acropigmentation of Kitamura (RAK) is a rare, autosomal dominant disorder first described in Japan characterised by a reticulate pattern of slightly atrophic, angulated, hyperpigmented macules affecting the acral areas of the body. We hereby report a case of RAK in a young Indian male with adermatoglyphia that has not been previously reported in the literature. PMID:26009721

  5. Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma.

    PubMed

    Darlington, T M; Pimentel, R; Smith, K; Bakian, A V; Jerominski, L; Cardon, J; Camp, N J; Callor, W B; Grey, T; Singleton, M; Yandell, M; Renshaw, P F; Yurgelun-Todd, D A; Gray, D; Coon, H

    2014-10-21

    Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12,000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to

  6. Simultaneous Occurrence of a Rare Pancreatic Lymphoepithelial Cyst and Duodenal Mesenteric Castleman's Disease: a Case Report.

    PubMed

    Mei, Yong; Peng, Ci-Jun; Shu, De-Jun; Zhu, Hong-Jiang; Li, Xiong-Xiong; Li, Wei-Nan

    2015-04-01

    Pancreatic lymphoepithelial cyst is a rare pancreatic lesion of undetermined pathogenesis, which is a true pancreatic cyst. Castleman's disease is a rare lymphoproliferative disorder, and a mesenteric location is unusual. The simultaneous occurrence of the two diseases are rarer than metachronous ones and has not been reported to date. We present a case report of a patient with simultaneous occurrence of pancreatic lymphoepithelial cyst and duodenal mesenteric Castleman's disease.

  7. Management options for rare diseases in children and adolescents in Georgia (experience of the country with transitional economy).

    PubMed

    Pagava, K; Abesadze, G; Uberi, N; Korinteli, I; Paghava, I; Kvezereli-Kopadze, M; Parulava, T; Korinteli, M; Kiseliova, T

    2011-04-01

    We present the results of our research and organizational work aimed at the management optimization for the rare diseases in Georgia (the Country with Transitional Economy). We compiled a list of the rare diseases actual for Georgia; elaborated algorythms and expert systems supporting the diagnosis making process for various clusters of the rare diseases; translated into Georgian and adapted textual materials regarding the management of various rare disorders; assessed the awareness level for the rare diseases of the pediatricians and general practioners in Georgia and attempted to raise it by organizing seminars and conferences, including international ones, in various regions of Georgia; elaborated a model of the expert system (based on the fuzzy logic principles) for unmasking the cases suspicious for the rare disease; laid the foundation for the national register of the rare diseases in children and adolescents; elaborated the module for post-graduate education regarding rare diseases; organized the center for the rare diseases.

  8. [Registries for rare diseases : OSSE - An open-source framework for technical implementation].

    PubMed

    Storf, Holger; Schaaf, Jannik; Kadioglu, Dennis; Göbel, Jens; Wagner, Thomas O F; Ückert, Frank

    2017-05-01

    Meager amounts of data stored locally, a small number of experts, and a broad spectrum of technological solutions incompatible with each other characterize the landscape of registries for rare diseases in Germany. Hence, the free software Open Source Registry for Rare Diseases (OSSE) was created to unify and streamline the process of establishing specific rare disease patient registries. The data to be collected is specified based on metadata descriptions within the registry framework's so-called metadata repository (MDR), which was developed according to the ISO/IEC 11179 standard. The use of a central MDR allows for sharing the same data elements across any number of registries, thus providing a technical prerequisite for making data comparable and mergeable between registries and promoting interoperability.With OSSE, the foundation is laid to operate linked patient registries while respecting strong data protection regulations. Using the federated search feature, data for clinical studies can be identified across registries. Data integrity, however, remains intact since no actual data leaves the premises without the owner's consent. Additionally, registry solutions other than OSSE can participate via the OSSE bridgehead, which acts as a translator between OSSE registry networks and non-OSSE registries. The pseudonymization service Mainzelliste adds further data protection.Currently, more than 10 installations are under construction in clinical environments (including university hospitals in Frankfurt, Hamburg, Freiburg and Münster). The feedback given by the users will influence further development of OSSE. As an example, the installation process of the registry for undiagnosed patients at University Hospital Frankfurt is described in more detail.

  9. 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

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

    PubMed

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

    2016-09-01

    Amyloid primarily affecting the lungs is a seldom seen clinical entity. This case discusses the work-up of a patient presenting with exercise-induced haemoptysis and diffuse cystic lung disease on radiographic imaging. The common clinical and radiographic findings of diffuse cystic lung diseases as well as a brief overview of pulmonary amyloid are presented. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  11. 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

  12. 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

  13. Premature Craniosynostosis in a Rare Genetic Disease- A Case Report

    PubMed Central

    DHARAMSHI, Hasnain abbas; RAZA, Tufail; MOHSIN ALI, Ali Abbas; LILANI, Zuhair; AHSAN, Syed Zohaib; FARAZ, Ahmad; NAQVI, Syeda Tahira

    2015-01-01

    Background: Crouzon syndrome is a rare genetic disorder inherited in autosomal dominant pattern with complete penetration and variable expressivity. Its most notable characteristic feature is premature synostosis of cranial sutures The case presented is of a 4 yr old boy with box like head with microcephaly, protuberant eyes, hydrocephalus, low visual acquity diagnosed as a case of crouzon syndrome after clinical and radiological assessment. PMID:25905085

  14. [Peripartum cardiomyopathy: a rare, unknown and potentially fatal disease].

    PubMed

    Massou, E; Lebon, A; Vardon, D; Dreyfus, M; Benoist, G

    2013-11-01

    Peripartum cardiomyopathy occurs in women with no prior history of cardiac dysfunction, and is presented by left heart failure. It occurs late in pregnancy or in the months after delivery. Rare in Europe, it is not well-known by obstetricians. The prognosis can be good with restitutio in integrum of the maternal cardiac function but the outcome can be dramatic and lead to death of the patient as the case in this report.

  15. Celiac crisis is a rare but serious complication of celiac disease in adults

    PubMed Central

    Jamma, Shailaja; Rubio-Tapia, Alberto; Kelly, Ciaran P.; Murray, Joseph; Sheth, Sunil; Schuppan, Detlef; Dennis, Melinda; Leffler, Daniel A.

    2010-01-01

    Background & Aims Celiac crisis is a life-threatening syndrome in which patients with celiac disease have profuse diarrhea and severe metabolic disturbances. Celiac crisis is rare among adults and not well documented. To improve awareness of this condition and to facilitate diagnosis, we reviewed cases of celiac crisis to identify presenting features, formulate diagnostic criteria, and develop treatment strategies. Methods Cases of biopsy-proven celiac disease were reviewed. Celiac crisis was defined as acute onset or rapid progression of gastrointestinal symptoms that could be attributed to celiac disease and required hospitalization and/or parenteral nutrition, along with signs or symptoms of dehydration or malnutrition. Results Twelve patients met preset criteria for celiac crisis; 11 developed celiac crisis before they were diagnosed with celiac disease. Eleven patients had increased titres of tTG and 1 had immunoglobulin A deficiency. Results of biopsy analyses of duodenum samples from all patients were consistent with a Marsh 3 score (33% with total villous atrophy). Patients presented with severe dehydration, renal dysfunction, and electrolyte disturbances. All patients required hospitalization and intravenous fluids, 6 required corticosteroids, and 5 required parenteral nutrition. All patients eventually had a full response to a gluten-free diet. Conclusion Celiac crisis has a high morbidity and, although rarely described, occurs in adults and often has a clear precipitating factor. Patients that present with severe unexplained diarrhea and malabsorption should be tested for celiac disease; treatment with systemic steroids or oral budesonide should be considered. Nutritional support is often required in the short term but most patients ultimately respond to gluten avoidance. PMID:20417725

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

    PubMed Central

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

    2013-01-01

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

  17. 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.

  18. International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

    PubMed

    Boycott, Kym M; Rath, Ana; Chong, Jessica X; Hartley, Taila; Alkuraya, Fowzan S; Baynam, Gareth; Brookes, Anthony J; Brudno, Michael; Carracedo, Angel; den Dunnen, Johan T; Dyke, Stephanie O M; Estivill, Xavier; Goldblatt, Jack; Gonthier, Catherine; Groft, Stephen C; Gut, Ivo; Hamosh, Ada; Hieter, Philip; Höhn, Sophie; Hurles, Matthew E; Kaufmann, Petra; Knoppers, Bartha M; Krischer, Jeffrey P; Macek, Milan; Matthijs, Gert; Olry, Annie; Parker, Samantha; Paschall, Justin; Philippakis, Anthony A; Rehm, Heidi L; Robinson, Peter N; Sham, Pak-Chung; Stefanov, Rumen; Taruscio, Domenica; Unni, Divya; Vanstone, Megan R; Zhang, Feng; Brunner, Han; Bamshad, Michael J; Lochmüller, Hanns

    2017-05-04

    Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  19. Statistical Guidance for Experimental Design and Data Analysis of Mutation Detection in Rare Monogenic Mendelian Diseases by Exome Sequencing

    PubMed Central

    Zhi, Degui; Chen, Rui

    2012-01-01

    Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying rare Mendelian disease genes, we propose that a viable approach is to combine, sequence, and analyze patients with the same disease together, leveraging the statistical framework presented in this work. PMID:22348076

  20. A rare variant in MCF2L identified using exclusion linkage in a pedigree with premature atherosclerosis

    PubMed Central

    Maiwald, Stephanie; Motazacker, Mahdi M; van Capelleveen, Julian C; Sivapalaratnam, Suthesh; van der Wal, Allard C; van der Loos, Chris; Kastelein, John J P; Ouwehand, Willem H; Hovingh, G Kees; Trip, Mieke D; van Buul, Jaap D; Dallinga-Thie, Geesje M

    2016-01-01

    Cardiovascular disease (CVD) is a major cause of death in Western societies. CVD risk is largely genetically determined. The molecular pathology is, however, not elucidated in a large number of families suffering from CVD. We applied exclusion linkage analysis and next-generation sequencing to elucidate the molecular defect underlying premature CVD in a small pedigree, comprising two generations of which six members suffered from premature CVD. A total of three variants showed co-segregation with the disease status in the family. Two of these variants were excluded from further analysis based on the prevalence in replication cohorts, whereas a non-synonymous variant in MCF.2 Cell Line Derived Transforming Sequence-like protein (MCF2L, c.2066A>G; p.(Asp689Gly); NM_001112732.1), located in the DH domain, was only present in the studied family. MCF2L is a guanine exchange factor that potentially links pathways that signal through Rac1 and RhoA. Indeed, in HeLa cells, MCF2L689Gly failed to activate Rac1 as well as RhoA, resulting in impaired stress fiber formation. Moreover, MCF2L protein was found in human atherosclerotic lesions but not in healthy tissue segments. In conclusion, a rare functional variant in MCF2L, leading to impaired DH function, was identified in a small pedigree with premature CVD. The presence of MCF2L in human atherosclerotic plaque specimen lends further support to its potential role in atherosclerosis. PMID:25898923

  1. Using Administrative Data to Ascertain True Cases of Muscular Dystrophy: Rare Disease Surveillance.

    PubMed

    Smith, Michael G; Royer, Julie; Mann, Joshua R; McDermott, Suzanne

    2017-01-12

    Administrative records from insurance and hospital discharge data sources are important public health tools to conduct passive surveillance of disease in populations. Identifying rare but catastrophic conditions is a challenge since approaches for maximizing valid case detection are not firmly established. The purpose of our study was to explore a number of algorithms in which International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and other administrative variables could be used to identify cases of muscular dystrophy (MD). We used active surveillance to identify possible cases of MD in medical practices in neurology, genetics, and orthopedics in 5 urban South Carolina counties and to identify the cases that had diagnostic support (ie, true cases). We then developed an algorithm to identify cases based on a combination of ICD-9-CM codes and administrative variables from a public (Medicaid) and private insurer claims-based system and a statewide hospital discharge dataset (passive surveillance). Cases of all types of MD and those with Duchenne or Becker MD (DBMD) that were common to both surveillance systems were examined to identify the most specific administrative variables for ascertainment of true cases. Passive statewide surveillance identified 3235 possible cases with MD in the state, and active surveillance identified 2057 possible cases in 5 actively surveilled counties that included 2 large metropolitan areas where many people seek medical care. There were 537 common cases found in both the active and passive systems, and 260 (48.4%) were confirmed by active surveillance to be true cases. Of the 260 confirmed cases, 70 (26.9%) were recorded as DBMD. Accuracy of finding a true case in a passive surveillance system was improved substantially when specific diagnosis codes, number of times a code was used, age of the patient, and specialty provider variables were used.

  2. Using Administrative Data to Ascertain True Cases of Muscular Dystrophy: Rare Disease Surveillance

    PubMed Central

    2017-01-01

    Background Administrative records from insurance and hospital discharge data sources are important public health tools to conduct passive surveillance of disease in populations. Identifying rare but catastrophic conditions is a challenge since approaches for maximizing valid case detection are not firmly established. Objective The purpose of our study was to explore a number of algorithms in which International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and other administrative variables could be used to identify cases of muscular dystrophy (MD). Methods We used active surveillance to identify possible cases of MD in medical practices in neurology, genetics, and orthopedics in 5 urban South Carolina counties and to identify the cases that had diagnostic support (ie, true cases). We then developed an algorithm to identify cases based on a combination of ICD-9-CM codes and administrative variables from a public (Medicaid) and private insurer claims-based system and a statewide hospital discharge dataset (passive surveillance). Cases of all types of MD and those with Duchenne or Becker MD (DBMD) that were common to both surveillance systems were examined to identify the most specific administrative variables for ascertainment of true cases. Results Passive statewide surveillance identified 3235 possible cases with MD in the state, and active surveillance identified 2057 possible cases in 5 actively surveilled counties that included 2 large metropolitan areas where many people seek medical care. There were 537 common cases found in both the active and passive systems, and 260 (48.4%) were confirmed by active surveillance to be true cases. Of the 260 confirmed cases, 70 (26.9%) were recorded as DBMD. Conclusions Accuracy of finding a true case in a passive surveillance system was improved substantially when specific diagnosis codes, number of times a code was used, age of the patient, and specialty provider variables were used

  3. Bone scintigraphy in Ollier's disease: A rare case report

    PubMed Central

    Khan, Shoukat H; Rather, Tanveer A; Koul, Parvaiz A; Makhdoomi, Rumana; Bhat, Abdul Rashid; Malik, Dharmender; Manohar, Ram

    2013-01-01

    Ollier's disease is characterized by multiple skeletal enchondroma. There are published data regarding Ollier's disease being associated with vascular malformations and non-skeletal neoplasms. We report a case of Ollier's disease in a young male associated with osteochondroma, low grade glioma in the insular cortex of brain and Gilbert's syndrome. Technetium-99m methylene diphosphonate whole body bone scan is a sensitive investigation to ascertain the complete extent of skeletal involvement particularly the asymptomatic sites. PMID:24379533

  4. 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.

  5. 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.

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

    PubMed Central

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

    2016-01-01

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

  7. Angiofollicular lymph node hyperplasia resembling a spinal nerve sheath tumor: a rare case of Castleman's disease.

    PubMed

    Stevens, E Andrew; Strowd, Roy E; Mott, Ryan T; Oaks, Timothy E; Wilson, John A

    2009-09-01

    Angiofollicular lymph node hyperplasia (Castleman's disease) is a lymphoproliferative disorder of unknown etiology. Although uncommon, the localized form of this disease can manifest in the central nervous system, typically as a meningeal-based intracranial lesion. Castleman's disease involving the spine is exceedingly rare. This represents only the second reported case of a patient with Castleman's disease whose presentation mimicked that of a spinal nerve sheath tumor. We report a rare case of angiofollicular lymph node hyperplasia that mimicked a spinal nerve sheath tumor and was treated with gross total resection. Case report. A 31-year-old female with angiofollicular lymph node hyperplasia presenting with a paraspinal mass. The patient's outcome was based on clinical history, physical and radiographic examinations. A 31-year-old woman with a mediastinal mass previously diagnosed as sarcoid via biopsy presented with the new onset of radicular pain and radiographic enlargement of her mass. Magnetic resonance imaging demonstrated a 4.3x5.7x6.0 cm homogenously enhancing soft-tissue lesion that emanated from and widened the T3/T4 neural foramen on the left. The differential diagnosis based on the location of the lesion and imaging characteristics included schwannoma, neurofibroma, paraganglioma, sarcoid, and lymphoma. Gross total resection was performed via thoracotomy. Histological examination identified angiofollicular lymph node hyperplasia (Castleman's disease) of the hyaline-vascular subtype. The patient did not receive adjuvant chemotherapy or radiation therapy. The patient had resolution of her symptoms without any clinical or radiographic evidence of recurrence at 1-year follow-up using magnetic resonance imaging with and without contrast. Castleman's disease is a rare pathologic entity that should be considered in the differential diagnosis of a patient with a paraspinal mass. Spine surgeons should be aware of this diagnosis as it has treatment and follow

  8. 76 FR 78931 - Food and Drug Administration Rare Disease Patient Advocacy Day; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-20

    ... Disorders, and the Genetic Alliance. FDA encourages all attendees to also plan on attending the NIH Rare... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Food and Drug Administration Rare Disease Patient...

  9. Rare manifestations in a case of Osler-Weber-Rendu disease

    PubMed Central

    Singh, Abhijai; Suri, Vikas; Jain, Sanjay; Varma, Subhash

    2015-01-01

    Osler-Weber-Rendu disease (OWRD) is a rare vascular dysplasia that presents most commonly with epistaxis. The most dreaded complication, however, is an intracranial haemorrhage. We present a patient with two rare manifestations of OWRD, subdural haematoma and portal venous hypertension, both seldom reported in the literature. The patient made a full recovery and continues to do well at this time. PMID:25564593

  10. Genotype analysis identifies the cause of the "royal disease".

    PubMed

    Rogaev, Evgeny I; Grigorenko, Anastasia P; Faskhutdinova, Gulnaz; Kittler, Ellen L W; Moliaka, Yuri K

    2009-11-06

    The "royal disease," a blood disorder transmitted from Queen Victoria to European royal families, is a striking example of X-linked recessive inheritance. Although the disease is widely recognized to be a form of the blood clotting disorder hemophilia, its molecular basis has never been identified, and the royal disease is now likely extinct. We identified the likely disease-causing mutation by applying genomic methodologies (multiplex target amplification and massively parallel sequencing) to historical specimens from the Romanov branch of the royal family. The mutation occurs in F9, a gene on the X chromosome that encodes blood coagulation factor IX, and is predicted to alter RNA splicing and to lead to production of a truncated form of factor IX. Thus, the royal disease is the severe form of hemophilia, also known as hemophilia B or Christmas disease.

  11. A Rare Haemoglobin Variant Identified as K Woolwich in a Pakistani Male.

    PubMed

    Ali, Sidra Asad; Ali, Natasha

    2015-10-01

    Haemoglobin (Hb) K Woolwich is a rare Hb variant which was first described in a family from West Indies and its occurrence was later reported mainly in Black families from many African countries. We report a case of a young male who came for evaluation of anemia. His complete blood count showed hypochromic, microcytic anemia and his serum ferritin was low. Hb electrophoresis done as part of initial workup showed an abnormal band which moved faster than HbA. For further evaluation, Hb analysis by high performance liquid chromatography was subsequently performed and revealed Hb K Woolwich. This is a rare Hb variant recognized in Pakistani population for the first time through careful interpretation of the chromatographic behavior of the Hb.

  12. Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis.

    PubMed

    Reynolds, Tim

    2013-11-01

    Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.

  13. Listeriosis: Is It a Rare Disease in Thailand?

    PubMed

    Lawtongkum, Weerasak; Thisyakorn, Usa

    2016-02-01

    The prevalence of Listeria monocytogenes infection has been characterized as rare in Thailand. Within one month, 3 cases of listeriosis were seen at Vachira Phuket Hospital in Phuket, Thailand. Two cases were neonates with septicemia, of which one made an uneventful recovery and the other expired. The third case was an eleven-year-old boy with meningitis who also succumbed to his illness. All isolated L. monocytogenes were sensitive to ampicillin. An outbreak investigation revealed no L. monocytogenes contamination in tested food sources in Phuket.

  14. Identifying Rare and Subtle Behaviors: A Weakly Supervised Joint Topic Model.

    PubMed

    Hospedales, Timothy M; Li, Jian; Gong, Shaogang; Xiang, Tao

    2011-12-01

    One of the most interesting and desired capabilities for automated video behavior analysis is the identification of rarely occurring and subtle behaviors. This is of practical value because dangerous or illegal activities often have few or possibly only one prior example to learn from and are often subtle. Rare and subtle behavior learning is challenging for two reasons: (1) Contemporary modeling approaches require more data and supervision than may be available and (2) the most interesting and potentially critical rare behaviors are often visually subtle-occurring among more obvious typical behaviors or being defined by only small spatio-temporal deviations from typical behaviors. In this paper, we introduce a novel weakly supervised joint topic model which addresses these issues. Specifically, we introduce a multiclass topic model with partially shared latent structure and associated learning and inference algorithms. These contributions will permit modeling of behaviors from as few as one example, even without localization by the user and when occurring in clutter, and subsequent classification and localization of such behaviors online and in real time. We extensively validate our approach on two standard public-space data sets, where it clearly outperforms a batch of contemporary alternatives.

  15. 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 Central

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

    2016-01-01

    Background 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. Objective To develop a scale for measuring the supportive care needs of parents of children with rare diseases. Method 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. Results 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. Conclusion 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

  16. Monogenic diabetes: implications for therapy of rare types of disease.

    PubMed

    Malecki, Maciej T; Mlynarski, Wojciech

    2008-08-01

    There are two major forms of diabetes: type 1 and type 2. However, monogenic diabetes, associated with severe beta-cell dysfunction or with severe resistance to insulin action, is diagnosed with increasing frequency by genetic testing. The list of such forms of diabetes includes MODY, mitochondrial diabetes, permanent neonatal diabetes (PNDM) and transient neonatal diabetes, familial lipodystrophies and some others. These rare forms constitute probably at least a few per cent of all diabetes cases seen in diabetic clinics. The identification of the molecular background of specific forms of diabetes gives new insight into the underlying aetiology. This knowledge helps to optimize treatment in specific clinical situations. The proper differential diagnosis also helps to predict the progress of diabetes in affected individuals and defines the prognosis in the family. For example, in patients with MODY2 because of glucokinase mutations who have very mild diabetes characterized by modest fasting, hyperglycaemia diet is frequently sufficient. Some other forms of monogenic diabetes associated with impaired function of the beta-cell, such as MODY3 and PNDM linked to mutations in Kir6.2 and SUR1 genes, can be successfully managed by sulphonylurea agents. Although the examples of pharmacogenetics seem to be less spectacular in rare syndromes of insulin resistance, those patients can also benefit from genetic testing. In this paper, the aetiology of some monogenic diabetes forms is reviewed together with the clinical aspects of management of the affected individuals.

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

    PubMed

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

    2015-01-01

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

  18. [Purposefulness of using fuzzy logic approaches in the rare disease clinical trials].

    PubMed

    Kiseleva, T S; Pagava, K I; Korinteli, I A; Korinteli, M G; Shonvadze, D N

    2011-04-01

    Different methods being used in the rare diseases clinical trials are examined. There is shown the purposefulness of using fuzzy approaches for such studies. Some advantages of Fuzzy logic methods in comparison with Baysian approach are substantiated.

  19. 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.

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

    PubMed Central

    Collins, Christy

    2016-01-01

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

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

    PubMed

    Lynch, Sally Ann; Borg, Isabella

    2016-04-01

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

  2. Comprehensive analysis of 225 Castleman's diseases in the oral maxillofacial and neck region: a rare disease revisited.

    PubMed

    He, Xiaotong; Wang, Qiong; Wu, Yaping; Hu, Jiaan; Wang, Dongmiao; Qi, Bin; Zhang, Wei; Wang, Yanling; Cheng, Jie

    2017-10-04

    The aim of the present study was to comprehensively summarize the epidemiological, clinicopathological characteristics, treatments as well as prognosis of Castleman's disease (CD) identified in the oral maxillofacial and neck region. Patients with CD in the oral maxillofacial and neck were retrieved from disease registry at our institution from Jan. 1990 to Dec. 2015. Systematic reviews from both English and Chinese literature were performed to collect the detailed information about the oral maxillofacial and neck CD. The epidemiological, clinicopathological data and treatment outcomes were further statistically analyzed. Four patients with the oral maxillofacial and neck CD were identified and histologically confirmed as hyaline-vascular type. They underwent surgical excision without recurrence during the follow-up. Systematic literature reviews identified 221 cases from 123 eligible articles which satisfied the inclusion criteria. In 225 patients, most patients were diagnosed as unicentric (207) or hyaline-vascular type (205) of CD and identified in the neck, and treated by surgical resection with good prognosis. In contrast, the minority of patients was multicentric or plasma-cell/mixed type and treated by chemotherapy with inferior outcomes. Kaplan-Meir analyses revealed that both clinical and pathological types were significantly associated with patients' overall survival. Although rare, most cases of the oral maxillofacial neck CD are found in adults and classified as unicentric and hyaline-vascular type of CD. Complete surgical excision is preferred with favorable prognosis for unicentric disease, whereas chemotherapy is usually exploited for multicentric disease with inferior outcomes. These data provide comprehensive information about the epidemiology, clinicopathological features, treatments, and outcomes of the oral maxillofacial and neck CD.

  3. Systems biology approaches to identify developmental bases for lung diseases.

    PubMed

    Bhattacharya, Soumyaroop; Mariani, Thomas J

    2013-04-01

    A greater understanding of the regulatory processes contributing to lung development could be helpful to identify strategies to ameliorate morbidity and mortality in premature infants and to identify individuals at risk for congenital and/or chronic lung diseases. Over the past decade, genomics technologies have enabled the production of rich gene expression databases providing information for all genes across developmental time or in diseased tissue. These data sets facilitate systems biology approaches for identifying underlying biological modules and programs contributing to the complex processes of normal development and those that may be associated with disease states. The next decade will undoubtedly see rapid and significant advances in redefining both lung development and disease at the systems level.

  4. Disseminated Abdominal Hydatidosis: A Rare Presentation of Common Infectious Disease

    PubMed Central

    Almalik, Abdulrahman; Alsharidi, Aynaa; Al-Sheef, Mohammed; Enani, Mushirah

    2014-01-01

    Hydatid disease is one of the most geographically widespread zoonoses with substantial disease burden. In this report we are discussing an unusual case of intra-abdominal HD that was ongoing for 22 years despite two surgical interventions. Significant symptomatic relief was achieved within the first two months of combination therapy with albendazole and praziquantel. HD is still of public health concern in the Middle East that needs optimized care. PMID:25114815

  5. 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

  6. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression.

    PubMed

    Knight, Helen M; Pickard, Benjamin S; Maclean, Alan; Malloy, Mary P; Soares, Dinesh C; McRae, Allan F; Condie, Alison; White, Angela; Hawkins, William; McGhee, Kevin; van Beck, Margaret; MacIntyre, Donald J; Starr, John M; Deary, Ian J; Visscher, Peter M; Porteous, David J; Cannon, Ronald E; St Clair, David; Muir, Walter J; Blackwood, Douglas H R

    2009-12-01

    Schizophrenia and bipolar disorder are leading causes of morbidity across all populations, with heritability estimates of approximately 80% indicating a substantial genetic component. Population genetics and genome-wide association studies suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders.

  7. 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.

  8. 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

  9. Bullosis Diabeticorum: Rare Presentation in a Common Disease

    PubMed Central

    Bajwa, Jaswinder

    2014-01-01

    A 27-year-old African American male presented with a sudden onset of blisters. He had a past medical history of uncontrolled diabetes mellitus type I, diabetic vasculopathy, and neuropathy. The physical examination revealed nonerythematous skin denudations on both elbows and lateral aspect of arm bilaterally. Investigations which included skin biopsies confirmed the diagnosis of bullosis diabeticorum. The bullae were treated with hydrotherapy and healed with no complications in 4 weeks. We present this case to illustrate the rare occurrence of diabetic bulla in a diabetic patient especially with poor glycemic control. The case is also a reminder of the importance of diabetes screening in nondiabetic patients who are diagnosed with diabetic bulla. PMID:25478251

  10. Dent–Wrong disease and other rare causes of the Fanconi syndrome

    PubMed Central

    Solano, Alejandro; Lew, Susie Q; Ing, Todd S.

    2014-01-01

    Dent–Wrong disease, an X-linked recessive disorder of the proximal tubules, presents with hypercalciuria, nephrocalcinosis, nephrolithiasis, renal insufficiency, low-molecular-weight proteinuria, rickets and/or osteomalacia. Dent and Friedman initially characterized the disorder in 1964 following studies of two patients with rickets who presented with hypercalciuria, hyperphosphaturia, proteinuria and aminoaciduria. Since then, extensive investigation identified two genetic mutations (CLCN5 and OCRL1) to be associated with Dent–Wrong disease. Clinical features supported by laboratory findings consistent with proximal tubule dysfunction help diagnose Dent–Wrong disease. Genetic analysis supports the diagnosis; however, these two genes can be normal in a small subset of patients. The differential diagnosis includes other forms of the Fanconi syndrome, which can be hereditary or acquired (e.g. those related to exposure to exogenous substances). Treatment is supportive with special attention to the prevention of nephrolithiasis and treatment of hypercalciuria. We review the rare forms of Fanconi syndrome with special attention to Dent–Wrong disease. PMID:25852908

  11. 26 CFR 1.28-1 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... drugs for rare diseases or conditions. 1.28-1 Section 1.28-1 Internal Revenue INTERNAL REVENUE SERVICE... clinical testing expenses for certain drugs for rare diseases or conditions. (a) General rule. Section 28... regulations relating thereto (21 CFR part 312) for the purpose of testing a drug for a rare disease...

  12. 26 CFR 1.28-1 - Credit for clinical testing expenses for certain drugs for rare diseases or conditions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... drugs for rare diseases or conditions. 1.28-1 Section 1.28-1 Internal Revenue INTERNAL REVENUE SERVICE... clinical testing expenses for certain drugs for rare diseases or conditions. (a) General rule. Section 28... regulations relating thereto (21 CFR part 312) for the purpose of testing a drug for a rare disease...

  13. 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

  14. 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.

  15. Rare coding variants and breast cancer risk: Evaluation of susceptibility loci identified in genome-wide association studies

    PubMed Central

    Zhang, Yanfeng; Long, Jirong; Lu, Wei; Shu, Xiao-Ou; Cai, Qiuyin; Zheng, Ying; Li, Chun; Li, Bingshan; Gao, Yu-Tang; Zheng, Wei

    2014-01-01

    Background To date, common genetic variants in ~70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk. Methods We investigated rare missense/nonsense variants with minor allele frequency (MAF) ≤ 5% located in flanking 500 kb of each of the index SNPs in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations. Results Single marker analyses identified 38 missense variants being association with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an odds ratio (OR) of 6.2 (95% CI: 1.4–27.6, P = 6.2×10−3). SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI: 2.2–124.5, P = 2.2×10−4). Gene-based analyses suggested eight genes associated with breast cancer risk at P < 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008). Conclusion Our results identified association of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biological mechanisms underlying the associations. Impact Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk. PMID:24470074

  16. Rare Submandibular Presentation of Pediatric Castleman Disease: Case Report.

    PubMed

    Hamilton, Jodi; Mandel, Louis

    2016-10-28

    Castleman disease (CD), a benign lymphoproliferative disorder that affects lymph nodes, is uncommon in children, with only approximately 100 cases published. Although 23% of pediatric CD cases are found in the neck, there is no substantial reported percentage found in the salivary glands, especially the submandibular salivary gland (SMSG). A pediatric case of CD involving the SMSG is reported because of its extreme rarity.

  17. A rare case of hidebound disease with dental implications

    PubMed Central

    Bali, Vikram; Dabra, Sarita; Behl, Ashima Bali; Bali, Rajiv

    2013-01-01

    Systemic sclerosis (also called as Scleroderma or hidebound disease) is a chronic sclerotic disease of unknown etiology which causes diffuse, increased deposition of extra cellular matrix in connective tissue with vascular abnormalities, resulting in tissue hypoxia. The disease is characterized by diffuse fibrosis; degenerative changes; and vascular abnormalities in the skin (scleroderma), articular structures, and internal organs. Aesthetic and facial dysfunctions are followed by important oral and facial manifestations. Most oral manifestations begin with tongue rigidity and facial skin changes. Bone resorption of mandibular angle and widening of periodontal ligament space on periapical radiographs are important radiological findings. Other systemic changes include the involvement of internal organs, which lead to serious complications as well as disorders in the cardiac muscle and Raynaud΄s phenomenon. This is a case report of 30-year-old female patient with the classical features of this disease. This case is reported for its rarity and variable expressivity. The main aim of this article is to describe thorough presentation of the case report, various forms of scleroderma, pathogenesis, oral, extraoral, periodontal manifestations of scleroderma, and its treatment options. A brief review of the literature, focusing on dental alterations is also presented. PMID:24130596

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    USGS Publications Warehouse

    Piper, David Z.; Bau, Michael

    2013-01-01

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

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

    PubMed

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

    2015-01-01

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

  2. Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features.

    PubMed

    Bombelli, Francesco; Stojkovic, Tanya; Dubourg, Odile; Echaniz-Laguna, Andoni; Tardieu, Sandrine; Larcher, Kathy; Amati-Bonneau, Patrizia; Latour, Philippe; Vignal, Odile; Cazeneuve, Cécile; Brice, Alexis; Leguern, Eric

    2014-08-01

    Axonal Charcot-Marie-Tooth disease (CMT) is genetically heterogeneous, with 11 genes identified. Axonal CMT has most frequently been associated with mutations in the MFN2 gene (CMT2A). To describe the clinical and molecular features of CMT2A, to delineate prognostic factors, to understand connections between a certain phenotype and more serious clinical consequences, and to identify interactions among the associated genes. We describe the clinical, molecular, electrophysiological, and additional features of 43 patients with CMT2A. The degree of physical disability was determined by the CMT neuropathy score and adapted to the CMT neuropathy score gradient to evaluate the clinical course. We evaluated all data within the context of the most recent and important publications concerning this issue. Twenty-five patients had early-onset CMT2A and severe functional disability, with 9 being wheelchair bound, and 18 had late-onset disease and a milder phenotype. Optic atrophy, vocal cord palsy, and auditory impairment were observed in 5, 6, and 2 patients, respectively. Among the 24 patients who underwent magnetic resonance imaging of the spinal cord, 6 had evidence of spinal atrophy with or without hydromyelia. In 1 patient, magnetic resonance imaging revealed hydrocephalus. Twenty different MFN2 mutations were identified, and 14 were considered new variants. Their transmission was predominantly autosomal dominant, with vertical transmission in 8 and de novo occurrence in 3. However, we also identified rare types of transmission, especially a germinal mosaicism and an autosomal recessive inheritance. One patient carried a rare variant in the GDAP1 gene and another in the OPA1 gene in association with MFN2 mutation. Charcot-Marie-Tooth disease type 2A associated with MFN2 mutations is clinically very heterogeneous. Ranging from a mild to a severe form, CMT2A exhibits various types of transmission. Optic atrophy and vocal cord palsy were observed in patients with severe

  3. Rare Lung Diseases: Interstitial Lung Diseases and Lung Manifestations of Rheumatological Diseases.

    PubMed

    Ramamurthy, Mahesh Babu; Goh, Daniel Y T; Lim, Michael Teik Chung

    2015-10-01

    The concept of Childhood Interstitial Lung Disease (ChILD) is relatively young. There has been tremendous progress in this field in the last decade. The key advance has been the recognition of interstitial lung diseases that are often distinct and occur mainly in infants. Diagnosis is challenging because the incidence is low and no single center in the world has enough cases to promote experience and clinical skills. This has led to formation of international groups of people interested in the field and the "Children's interstitial and diffuse lung disease research network" (ChILDRN) is one such group which contributed to the progress of this field. Clinically, these disorders overlap with those of other common respiratory disorders. Hence, clinical practice guidelines emphasize the additional role of chest imaging, genetic testing and lung biopsy in the diagnostic evaluation. Genetic testing, in particular, has shown tremendous progress in this field. Being noninvasive, it has the potential to help early recognition in a vast majority. Despite progress, definitive therapeutic modalities are still lacking and supportive care is still the backbone of management in the majority. Early recognition of the definitive diagnosis helps in the management, even if, in a significant number, it helps in avoiding unnecessary therapy. Also discussed in this article, is the pulmonary manifestation of rheumatic diseases in children. The incidence and spectrum of pulmonary involvement in rheumatic conditions vary and can be result of the primary disease or its management or due to an concurrent infection.

  4. Tuberculous epididymitis presenting with Addison's disease: a rare case.

    PubMed

    Guler, Zuhal Mujgan; Kanbay, Asiye; Kanbay, Mehmet; Ciftci, Bulent; Erdogan, Yurdanur

    2006-07-01

    This report describes a case of tuberculosis with an atypical presentation characterized by epididymitis and Addison's disease in the absence of lung involvement. A 54-year-old male who presented with acute right scrotal pain and a whitish discharge, had been diagnosed four months earlier with acute epididymitis and prescribed ciprofloxacin. The clinical diagnosis was epididymitis and Addison's disease. Hydrocortisone therapy was initiated, and bilateral epididymectomy was undertaken. Biopsy specimen showed the presence of acid-fast bacilli and antituberculous treatment was initiated. On follow-up, the patient was in good clinical condition and free of symptoms. We conclude that tuberculous epididymitis can cause serious complications and should be included in the differential diagnosis for chronic epididymitis of unknown cause that does not respond to routine treatment. A high index of suspicion is required for diagnosis.

  5. Kikuchi's Disease: A Rare Cause of Fever of Unknown Origin.

    PubMed

    Jalal-ud-din, Mir; Noor, Muhammad Munir; Ali, Shadab; Ali, Rashid

    2015-04-01

    Kikuchi Fujimoto Disease (KFD) or histiocytic necrotizing lymphadenitis can present with unexplained fever and lymphadenopathy. It is often mistaken for more serious conditions like malignant lymphoma or tuberculosis. First case was described by Kikuchi in Japan, very few cases have been reported in Pakistan. A middle aged female presented with fever and body aches for one month. She was investigated extensively for pyrexia of unknown origin, all of which came out to be normal except a raised ESR. Anti-tuberculous drugs were started on clinical suspicion, with no improvement after a month. Later, a detailed physical examination revealed cervical lymphadenopathy. One of the lymph nodes was excised and biopsied. The histopathology suggested Kikuchi's disease. Oral Prednisolone was started showing improvement. Her fever subsided and lymph nodes disappeared at the follow-up visit. No relapse was encountered in the subsequent visits.

  6. Castleman Disease: A Rare Condition with Endocrine Manifestations

    PubMed Central

    Correa, Ricardo

    2015-01-01

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

  7. Castleman Disease: A Rare Condition with Endocrine Manifestations.

    PubMed

    Cervantes, Carmen E; Correa, Ricardo

    2015-11-17

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

  8. Focal epithelial hyperplasia. A rare disease in our area.

    PubMed

    Segura-Saint-Gerons, Rafael; Toro-Rojas, Mariano; Ceballos-Salobreña, Alejandro; Aparicio-Soria, Jose Luis; Fuentes-Vaamonde, Helena

    2005-01-01

    Focal epithelial hyperplasia is a benign, asymptomatic disease, occurring with very low frequency within our population. It appears as papules, principally on the lower lip, although it can also be found on the retro-commissural mucosa and tongue, and less frequently on the upper lip, gingiva and palate. We present the clinical case of a 9-year-old Saharan girl with lesions that clinically and histologically corresponded to a focal epithelial hyperplasia.

  9. Postural & striatal deformities in Parkinson's disease: Are these rare?

    PubMed Central

    Pandey, Sanjay; Garg, Hitesh

    2016-01-01

    Parkinson's disease (PD) is the most common neurodegenerative disease and is characterized by tremor, rigidity and akinesia. Diagnosis is clinical in the majority of the patients. Patients with PD may have stooped posture but some of them develop different types of postural and striatal deformities. Usually these deformities are more common in atypical parkinsonian disorders such as progressive supranuclear palsy and multisystem atrophy. But in many studies it has been highlighted that these may also be present in approximately one third of PD patients leading to severe disability. These include antecollis or dropped head, camptocormia, Pisa syndrome, scoliosis, striatal hands and striatal toes. The pathogenesis of these deformities is a complex combination of central and peripheral influences such as rigidity, dystonia and degenerative skeletal changes. Duration of parkinsonism symptoms is an important risk factor and in majority of the patients these deformities are seen in advanced statge of the disease. The patients with such symptoms may initially respond to dopaminergic medications but if not intervened they may become fixed and difficult to treat. Pain and restriction of movement are most common clinical manifestations and these may mimick symptoms of musculoskeletal disorders like rheumatoid arthritis. Early diagnosis is important as the patients may respond to adjustment in dopaminergic medications. Recent advances such as deep brain stimulation (DBS) and ultrasound guided botulinum toxin injection are helpful in management of these deformities in patients with PD. PMID:26997007

  10. A linkage disequilibrium-based approach to selecting disease-associated rare variants.

    PubMed

    Talluri, Rajesh; Shete, Sanjay

    2013-01-01

    Rare variants have increasingly been cited as major contributors in the disease etiology of several complex disorders. Recently, several approaches have been proposed for analyzing the association of rare variants with disease. These approaches include collapsing rare variants, summing rare variant test statistics within a particular locus to improve power, and selecting a subset of rare variants for association testing, e.g., the step-up approach. We found that (a) if the variants being pooled are in linkage disequilibrium, the standard step-up method of selecting the best subset of variants results in loss of power compared to a model that pools all rare variants and (b) if the variants are in linkage equilibrium, performing a subset selection using step-based selection methods results in a gain of power of association compared to a model that pools all rare variants. Therefore, we propose an approach to selecting the best subset of variants to include in the model that is based on the linkage disequilibrium pattern among the rare variants. The proposed linkage disequilibrium-based variant selection model is flexible and borrows strength from the model that pools all rare variants when the rare variants are in linkage disequilibrium and from step-based selection methods when the variants are in linkage equilibrium. We performed simulations under three different realistic scenarios based on: (1) the HapMap3 dataset of the DRD2 gene, and CHRNA3/A5/B4 gene cluster (2) the block structure of linkage disequilibrium, and (3) linkage equilibrium. We proposed a permutation-based approach to control the type 1 error rate. The power comparisons after controlling the type 1 error show that the proposed linkage disequilibrium-based subset selection approach is an attractive alternative method for subset selection of rare variants.

  11. Ethical management in the constitution of a European database for leukodystrophies rare diseases.

    PubMed

    Duchange, Nathalie; Darquy, Sylviane; d'Audiffret, Diane; Callies, Ingrid; Lapointe, Anne-Sophie; Loeve, Boris; Boespflug-Tanguy, Odile; Moutel, Grégoire

    2014-09-01

    The EU LeukoTreat program aims to connect, enlarge and improve existing national databases for leukodystrophies (LDs) and other genetic diseases affecting the white matter of the brain. Ethical issues have been placed high on the agenda by pairing the participating LD expert research teams with experts in medical ethics and LD patient families and associations. The overarching goal is to apply core ethics principles to specific project needs and ensure patient rights and protection in research addressing the context of these rare diseases. This paper looks at how ethical issues were identified and handled at project management level when setting up an ethics committee. Through a work performed as a co-construction between health professionals, ethics experts, and patient representatives, we expose the major ethical issues identified. The committee acts as the forum for tackling specific issues tied to data sharing and patient participation: the thin line between care and research, the need for a charter establishing the commitments binding health professionals and the information items to be delivered. Ongoing feedback on the database, including delivering global results in a broad-audience format, emerged as a key recommendation. Information should be available to all patients in the partner countries developing the database and should be scaled to different patient profiles. This work led to a number of recommendations for ensuring transparency and optimizing the partnership between scientists and patients. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  12. 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.

  13. Clinical Trial Design for Alpha-1 Antitrypsin Deficiency: A Model for Rare Diseases

    PubMed Central

    Wanner, Adam; Groft, Stephen C.; Teagarden, J. Russell; Krischer, Jeffrey; Davis, Barry R.; Coffey, Christopher S.; Hickam, David H.; Teckman, Jeffrey; Nelson, David R.; McCaleb, Michael L.; Loomba, Rohit; Strange, Charlie; Sandhaus, Robert A.; Brantly, Mark; Edelman, Jonathan M.; Farrugia, Albert

    2015-01-01

    Clinical research in rare diseases, including alpha-1 antitrypsin deficiency (AATD), faces challenges not shared by common disease research. These challenges may include the limited number of patient volunteers available for research, lack of natural history studies on which to base many clinical trial interventions, an urgency for the development of drug therapies given the often poor prognosis of rare diseases and uncertainties about appropriate biomarkers and clinical outcomes critical to clinical trial design. To address these challenges and initiate formal discussions among key stakeholders—patients, researchers, industry, federal regulators—the Alpha-1 Foundation hosted the Clinical Trial Design for Alpha-1 Antitrypsin Deficiency: A Model for Rare Diseases conference February 3-4, 2014 in Bethesda, Maryland. Discussions at the conference led to the conclusions that 1) adaptive designs should be considered for rare disease clinical trials yet more dialogue and study is needed to make these designs feasible for smaller trials and to address current limitations; 2) natural history studies, including the identification of appropriate biomarkers are critically needed and precompetitive collaborations may offer a means of creating these costly studies; and 3) patient registries and databases within the rare disease community need to be more publicly available and integrated, particularly for AATD. This report summarizes the discussions leading to these conclusions. PMID:28848840

  14. [Patient-centred care in rare diseases. A patient organisations' perspective].

    PubMed

    Reimann, A; Bend, J; Dembski, B

    2007-12-01

    Patients living with rare diseases have special common needs. Although the 5,000-6,000 rare diseases are very different, many patients share the experience of a time-consuming and sometimes frustrating journey towards diagnosis, the lack of established standards of care and foremost the search for competent physicians. Because of their complexity, rare diseases mostly demand an interdisciplinary and cross-sectional medical care. The model of the "patient-centred health-care value chain" explains how primary (prevention, diagnosis, treatment) and secondary activities (exchange of information, quality management, identification of unmet needs, research and development) contribute to the patient benefit applying a holistic approach. This model thereby prevents an isolated view from the perspective of single health-care providers. A survey to which 21 German patient-organisations in the rare-disease field contributed, was performed to obtain insight into preferred medical care concepts and preferences in the way that care is provided. The results clearly suggest that the patient organisations have a clear view on how disease-specific care should be delivered; however, in reality those preferences seem to be met to a minor extent in Germany at present. According to patient organisations, rare-disease patient care should always be a patient- centred, interdisciplinary and holistic effort. The solidaric health-care system in Germany provides an excellent basis for this kind of medical care. However, a new patient- rather than system-oriented approach is needed to make it work in reality.

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

    USDA-ARS?s Scientific Manuscript database

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

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

    PubMed Central

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

    2015-01-01

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

  17. The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

    PubMed

    Hendriksz, Christian J; Anheim, Mathieu; Bauer, Peter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean-Christophe; de Koning, Tom J; Degtyareva, Anna; Dionisi-Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Klünemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovi, Miguel; Synofzik, Matthis; Terblanche, Alta; Then Bergh, Florian; Topçu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan A

    2017-05-01

    Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Several clinical niches have been identified that harbor patients at increased risk of NP-C.

  18. A rarely seen diffuse parenchymal lung disease: diffuse pulmonary meningotheliomatosis.

    PubMed

    Şen, Nazan; Canpolat, Emine Tuba; Koç, Zafer

    2015-01-01

    Pulmonary meningothelial-like nodules (MLNs) are usually detected incidentally during pathologic evaluation of resected pulmonary parenchymal specimens and autopsies. These nodules are generally asymptomatic and most often single. Diffuse pulmonary involvement by MLNs is less frequently described. MLNs are benign lesions and have been associated with neoplastic and non-neoplastic pulmonary conditions and occasionally with extrapulmonary diseases. We report a case of a female patient presenting with multiple and bilateral pulmonary nodules diagnosed with "diffuse pulmonary meningotheliomatosis" by video-assisted thoracoscopic surgery (VATS). Diffuse pulmonary meningotheliomatosis should be included in the differential diagnosis of diffuse bilateral lung nodules in the radiologic studies.

  19. Elastoma: clinical and histopathological aspects of a rare disease*

    PubMed Central

    Maciel, Marina Gagheggi; Enokihara, Milvia Maria Simões e Silva; Seize, Maria Bandeira de Melo Paiva; Marcassi, Aline Pantano; Piazza, Christiane Affonso De Donato; Cestari, Silmara da Costa Pereira

    2016-01-01

    Elastoma is a connective tissue nevus characterized by changes in elastic fibers. It can be congenital or acquired, and is usually diagnosed before puberty. Associated with osteopoikilosis, it is known as Buschke-Ollendorff syndrome. Histopathology with specific staining for elastic fibers is critical for a diagnostic conclusion. This report describes the case of a 7-year-old male patient with lesions diagnosed as elastoma, with absence of bone changes in the radiological imaging. This study aims to report the clinical presentation and histological examination of such unusual disease.

  20. Fahr's disease with oral manifestations: report of a rare case.

    PubMed

    Aditya, Amita; Lele, Shailesh; Aditya, Priyam

    2012-01-01

    The purpose of this article is to discuss the general and oral findings in a patient with Fahr's disease, an uncommon disorder. A patient presented with the complaint of partial anodontia, but further clinical and radiographic investigations showed a myriad of findings including stunted growth, osteoporosis and pathological calcifications. Oral findings included oligodontia and advanced periodontitis in relation to the present teeth. Full-mouth rehabilitation was eventually planned for the patient. This case shows the necessity for dentists to be aware of symptoms associated with Fahr's syndrome in order to make appropriate referrals and to enable diagnosis and treatment. Copyright © 2012 S. Karger AG, Basel.

  1. 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

  2. Adult-onset Still's disease and cardiac tamponade: a rare association.

    PubMed

    Carrilho-Ferreira, Pedro; Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-06-01

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

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

    PubMed Central

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

    2015-01-01

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

  4. 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.

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

    PubMed

    Azie, N; Vincent, J

    2012-08-01

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

  6. 77 FR 7167 - Global Rare Diseases Patient Registry and Data Repository (GRDR) Notice and Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-10

    ... to sustain itself as a public-private partnership. Because of the importance of biospecimens as... with each disease, the cumulative public health burden of rare diseases is significant, with great.... In recognition of both barriers and public health imperatives to advance knowledge regarding...

  7. 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.

  8. Identifying genetic interactions associated with late-onset Alzheimer's disease.

    PubMed

    Floudas, Charalampos S; Um, Nara; Kamboh, M Ilyas; Barmada, Michael M; Visweswaran, Shyam

    2014-01-01

    Identifying genetic interactions in data obtained from genome-wide association studies (GWASs) can help in understanding the genetic basis of complex diseases. The large number of single nucleotide polymorphisms (SNPs) in GWASs however makes the identification of genetic interactions computationally challenging. We developed the Bayesian Combinatorial Method (BCM) that can identify pairs of SNPs that in combination have high statistical association with disease. We applied BCM to two late-onset Alzheimer's disease (LOAD) GWAS datasets to identify SNPs that interact with known Alzheimer associated SNPs. We also compared BCM with logistic regression that is implemented in PLINK. Gene Ontology analysis of genes from the top 200 dataset SNPs for both GWAS datasets showed overrepresentation of LOAD-related terms. Four genes were common to both datasets: APOE and APOC1, which have well established associations with LOAD, and CAMK1D and FBXL13, not previously linked to LOAD but having evidence of involvement in LOAD. Supporting evidence was also found for additional genes from the top 30 dataset SNPs. BCM performed well in identifying several SNPs having evidence of involvement in the pathogenesis of LOAD that would not have been identified by univariate analysis due to small main effect. These results provide support for applying BCM to identify potential genetic variants such as SNPs from high dimensional GWAS datasets.

  9. 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

  10. Fibromuscular dysplasia: a rare disease that can mimic vasculitis.

    PubMed

    Capsoni, Franco; Poletto, Giorgio; Giorgetti, Pier Luigi

    2012-12-01

    Fibromuscular dysplasia (FMD) is an uncommon angiopathy that occurs mainly in young to middle-aged female individuals. It is an idiopathic, segmental, non-inflammatory and non-atherosclerotic vascular disease leading to stenosis of small- and medium-sized arteries. Clinical manifestations are determined by the artery involved, most commonly hypertension (renal artery) and stroke (carotid artery). When FMD affects multiple vascular beds, it may mimic a systemic vasculitis. Here, we present the case of a young female patient with FMD. The patient had a clinical history of bilateral internal carotid artery dissection that required surgical repair. Since a systemic vascular disease was suspected, abdominal angiography was done, showing evidence of a "string of beads" appearance involving the distal two-thirds of the right renal artery. This lesion is considered to be pathognomonic of the medial FMD that accounts for 70-95% of all cases of FMD. Two years later, a new magnetic resonance angiography confirmed the "string of beads" appearance of the middle to distal part of the right renal artery, with significant hemodynamic stenosis that was successfully dilated with percutaneous transluminal angioplasty.

  11. Rare diseases knowledge management: the contribution of proximity measurements in OntoOrpha and OMIM.

    PubMed

    Aimé, X; Charlet, J; Furst, F; Kuntz, P; Trichet, F; Dhombres, F

    2012-01-01

    In this paper, we introduce an application of Proxima and define a new measure of proximity between two concepts present in an ontology. The approach is based on the three dimensions of a conceptualization: intention with relations between concepts, expression with terms denoting concepts, and extension with instances of concepts. This preliminary work, in the field of rare diseases, involved the Orphanet Ontology of Rare Diseases (OntoOrpha) and corpus of texts extracted from Online Inheritance in Man (OMIM). The proximity measurements are consistent with an appropriate representation of groups of diseases in the ontology, which are derived from the Orphanet classifications of rare diseases. Other semantic relations are explored and new perspectives in medical knowledge curation are proposed.

  12. A rare cause of pleural effusion: adult onset Still’s disease

    PubMed Central

    Demirbas, Soner; Kutlu, Orkide; Kandemir, Bahar; Sakin, Abdullah

    2015-01-01

    Adult onset Still’s disease is a rare systemic inflammatory disorder. At the onset of the disease sore throat, pharyngitis; which does not respond to antibiotics, one or two times peaking febrile episodes, marked salmon-colored rash on the trunk and extremities, arthralgia, arthritis, myalgia, fatigue, loss of appetite with nausea and weight loss; hepatosplenomegaly and lymphadenopathy can be seen. Among laboratory examinations levels of ferritin and other acute phase reactants distinctly rise, and neutrophilic leukocytosis; ANA and RF negativity are detected. Pleural and pericardial effusions, transient pulmonary infiltration, and rarely myocarditis can be seen during the course of the disease. Here we report a patient who was examined for fever of unknown origin and diagnosed with adult onset Still’s disease which is a rare etiology of pleural effusion. PMID:28058358

  13. Unilateral renal cell carcinoma with coexistent renal disease: a rare cause of end-stage renal disease.

    PubMed

    Peces, R; Alvarez-Navascués, R

    2001-02-01

    Renal cell carcinoma (RCC) is a disorder encompassing a wide spectrum of pathological renal lesions. Coexistence of unilateral RCC and associated pathology in the contralateral kidney is an unusual and challenging therapeutic dilemma that can result in renal failure. So far, data on unilateral RCC with chronic renal failure necessitating renal replacement therapy have not been published. The aim of the present study was to evaluate the incidence of end-stage renal disease (ESRD) from unilateral RCC, and to assess the associated pathology and possible pathogenic factors. In 1999, a survey of the 350 patients treated by chronic dialysis in Asturias, Spain, was carried out to identify and collect clinical information on patients with primary unilateral RCC whilst on their renal replacement programme. Seven patients were identified as having ESRD and unilateral RCC, giving an incidence of 2% of patients treated by dialysis. There was a wide spectrum of associated disease and clinical presentation. All patients underwent radical or partial nephrectomy and were free of recurrence 6--64 months after surgery. Six patients were alive and free of malignancy recurrence for 6--30 months after the onset of haemodialysis. ESRD is rare in association with unilateral RCC, but does contribute to significant morbidity. However, the data presented here are encouraging and suggest that cancer-free survival with renal replacement therapy can be achieved in such patients.

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

    PubMed Central

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

    2016-01-01

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

  15. 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

    2017-01-27

    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.

  16. Mutations in DJ-1 are rare in familial Parkinson disease

    PubMed Central

    Pankratz, Nathan; Pauciulo, Michael W.; Elsaesser, Veronika E.; Marek, Diane K.; Halter, Cheryl A.; Wojcieszek, Joanne; Rudolph, Alice; Shults, Clifford W.; Foroud, Tatiana; Nichols Ph.D., William C.

    2006-01-01

    Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD. PMID:16997464

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

    PubMed Central

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

    2015-01-01

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

  18. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease.

    PubMed

    Palm, Noah W; de Zoete, Marcel R; Cullen, Thomas W; Barry, Natasha A; Stefanowski, Jonathan; Hao, Liming; Degnan, Patrick H; Hu, Jianzhong; Peter, Inga; Zhang, Wei; Ruggiero, Elizabeth; Cho, Judy H; Goodman, Andrew L; Flavell, Richard A

    2014-08-28

    Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow-cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) and show that high IgA coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA-SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with predefined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.

  19. An Optimal Weighted Aggregated Association Test for Identification of Rare Variants Involved in Common Diseases

    PubMed Central

    Sul, Jae Hoon; Han, Buhm; He, Dan; Eskin, Eleazar

    2011-01-01

    The advent of next generation sequencing technologies allows one to discover nearly all rare variants in a genomic region of interest. This technological development increases the need for an effective statistical method for testing the aggregated effect of rare variants in a gene on disease susceptibility. The idea behind this approach is that if a certain gene is involved in a disease, many rare variants within the gene will disrupt the function of the gene and are associated with the disease. In this article, we present the rare variant weighted aggregate statistic (RWAS), a method that groups rare variants and computes a weighted sum of differences between case and control mutation counts. We show that our method outperforms the groupwise association test of Madsen and Browning in the disease-risk model that assumes that each variant makes an equally small contribution to disease risk. In addition, we can incorporate prior information into our method of which variants are likely causal. By using simulated data and real mutation screening data of the susceptibility gene for ataxia telangiectasia, we demonstrate that prior information has a substantial influence on the statistical power of association studies. Our method is publicly available at http://genetics.cs.ucla.edu/rarevariants. PMID:21368279

  20. 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

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

    PubMed

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

    2016-08-01

    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.

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

    PubMed Central

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

    2016-01-01

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

  3. Identifying Causal Genes and Dysregulated Pathways in Complex Diseases

    PubMed Central

    Kim, Yoo-Ah; Wuchty, Stefan; Przytycka, Teresa M.

    2011-01-01

    In complex diseases, various combinations of genomic perturbations often lead to the same phenotype. On a molecular level, combinations of genomic perturbations are assumed to dys-regulate the same cellular pathways. Such a pathway-centric perspective is fundamental to understanding the mechanisms of complex diseases and the identification of potential drug targets. In order to provide an integrated perspective on complex disease mechanisms, we developed a novel computational method to simultaneously identify causal genes and dys-regulated pathways. First, we identified a representative set of genes that are differentially expressed in cancer compared to non-tumor control cases. Assuming that disease-associated gene expression changes are caused by genomic alterations, we determined potential paths from such genomic causes to target genes through a network of molecular interactions. Applying our method to sets of genomic alterations and gene expression profiles of 158 Glioblastoma multiforme (GBM) patients we uncovered candidate causal genes and causal paths that are potentially responsible for the altered expression of disease genes. We discovered a set of putative causal genes that potentially play a role in the disease. Combining an expression Quantitative Trait Loci (eQTL) analysis with pathway information, our approach allowed us not only to identify potential causal genes but also to find intermediate nodes and pathways mediating the information flow between causal and target genes. Our results indicate that different genomic perturbations indeed dys-regulate the same functional pathways, supporting a pathway-centric perspective of cancer. While copy number alterations and gene expression data of glioblastoma patients provided opportunities to test our approach, our method can be applied to any disease system where genetic variations play a fundamental causal role. PMID:21390271

  4. A novel approach for identifying causal models of complex diseases from family data.

    PubMed

    Park, Leeyoung; Kim, Ju H

    2015-04-01

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

  5. 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.

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

    PubMed

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

    2010-12-01

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

  7. The many faces of rare diseases (RD): meeting report on Rare Disease in South-Eastern Europe, 15-16 November 2013, Skopje, Republic of Macedonia.

    PubMed

    Gucev, Z; Tasic, V; Polenakovic, M

    2014-03-01

    The Second meeting on Rare Diseases in South Eastern Europe (SEE) was held in Skope, Macedonia on November 15-16, 2013. Objective and main data: Rare diseases (RD) are a major problem in developed and especially in countries without affluence. 6-8% of every population suffers from RD. The cumulative effect of RDs on the health system of a country is increasing. Diagnosis often remains a challenge and requires international collaboration. Treatment in diseases for which medication exist is often inaccessible to patients because of the high costs. All countries of SEE need screening programs that address more diseases. Patient organizations play a major role in increasing awareness and providing the needed pressure on society to treat treatable RDs. On the other hand, RDs are frequently a source of valuable new molecular insights not only on mechanisms of their etiology and pathology, but sometimes provide an insight on mechanisms of frequent diseases in man. Further efforts are needed in improving all the RD aspects mentioned.

  8. Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

    Cancer.gov

    Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

  9. Using hyperspectral imaging technology to identify diseased tomato leaves

    NASA Astrophysics Data System (ADS)

    Li, Cuiling; Wang, Xiu; Zhao, Xueguan; Meng, Zhijun; Zou, Wei

    2016-11-01

    In the process of tomato plants growth, due to the effect of plants genetic factors, poor environment factors, or disoperation of parasites, there will generate a series of unusual symptoms on tomato plants from physiology, organization structure and external form, as a result, they cannot grow normally, and further to influence the tomato yield and economic benefits. Hyperspectral image usually has high spectral resolution, not only contains spectral information, but also contains the image information, so this study adopted hyperspectral imaging technology to identify diseased tomato leaves, and developed a simple hyperspectral imaging system, including a halogen lamp light source unit, a hyperspectral image acquisition unit and a data processing unit. Spectrometer detection wavelength ranged from 400nm to 1000nm. After hyperspectral images of tomato leaves being captured, it was needed to calibrate hyperspectral images. This research used spectrum angle matching method and spectral red edge parameters discriminant method respectively to identify diseased tomato leaves. Using spectral red edge parameters discriminant method produced higher recognition accuracy, the accuracy was higher than 90%. Research results have shown that using hyperspectral imaging technology to identify diseased tomato leaves is feasible, and provides the discriminant basis for subsequent disease control of tomato plants.

  10. [High cost drugs for rare diseases in Brazil: the case of lysosomal storage disorders].

    PubMed

    de Souza, Mônica Vinhas; Krug, Bárbara Corrêa; Picon, Paulo Dornelles; Schwartz, Ida Vanessa Doederlein

    2010-11-01

    This paper approaches in a critical way aspects of Brazilian public policies for drugs, emphasizing those classified as high cost and for rare diseases. The lysosomal storage diseases was taken as an example because of their rarity and the international trend for the development of new drugs for their treatment, all at high costs. Three lysosomal storage diseases were approached: Gaucher disease, Fabry disease and mucopolysaccharidosis type I. Gaucher disease has its treatment drug licensed in Brazil and guidelines for its use are established through a clinical protocol by the Ministry of Health. The others have their drug treatments registered in Brazil; however, no treatment guidelines for them have been developed by the government. The objective of the paper was to foster the discussion on the role of health technology assessment for high-cost drugs for rare diseases in Brazil, emphasizing the need for establishing health policies with legitimacy towards these diseases. Despite the difficulties in establishing a health policy for each rare disease, it is possible to create rational models to deal with this growing challenge.

  11. A small n sequential multiple assignment randomized trial design for use in rare disease research.

    PubMed

    Tamura, Roy N; Krischer, Jeffrey P; Pagnoux, Christian; Micheletti, Robert; Grayson, Peter C; Chen, Yeh-Fong; Merkel, Peter A

    2016-01-01

    Clinical trials in rare diseases are difficult to conduct due to the limited number of patients available with each disorder. We developed a Phase 2 trial which is a small n sequential multiple assignment randomized trial (snSMART) design to test several treatments for a rare disease for which no standard therapy exists. This paper illustrates the design, sample size estimation and operating characteristics of an snSMART. We investigate the performance of a class of weighted Z statistics via computer simulations. We demonstrate the increase in power over traditional single stage designs, and indicate how the power changes as a function of the weight given to each stage. The snSMART design is promising in a rare disease setting where several alternative treatments are under consideration and small sample sizes are necessary. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Funding therapies for rare diseases: an ethical dilemma with a potential solution.

    PubMed

    Taylor, Colman; Jan, Stephen; Thompson, Kelly

    2016-02-16

    Funding rare disease therapies presents a challenge in Australia where there is a legislative requirement to consider cost-effectiveness. Currently the Life Saving Drugs Programme (LSDP) provides subsidised access to high-cost therapies for rare, life-threatening conditions. However the LSDP is currently under review by the Minsiter for Health and future access to rare disease therapies in uncertain. Internationally there is no gold standard model to evaluate and fund rare disease therapies, and considerable variation exists. However, common features of international systems include the opportunity for early stakeholder engagement, flexibility with evidence requirements, cost-effectiveness criteria and transparency in relation to the decision making framework and outcomes. Australians value equality and equal opportunity in relation to health care. To meet these expectations there is a clear need to maintain a separate fit-for-purpose framework to evaluate and fund rare disease therapies drawing on overseas best practice. This will provide certainty for industry to continue to invest in such treatments, as well as ensuring funding recommendations are reflective of Australian values balanced against the need for financial sustainability.

  13. The health and life path of rare disease patients: results of the 2015 French barometer

    PubMed Central

    Heuyer, Thomas; Pavan, Sonia; Vicard, Christine

    2017-01-01

    Purpose A barometer has been set up to provide better knowledge about the daily situation of French rare disease (RD) patients, their families and relatives, in order to contribute to the elaboration of improvement measures. This report focuses on the care and life path of RD patients. Patients and methods A preliminary survey was carried out with three patients, five parents and three RD experts to identify the main hurdles and disruptions in the life path of RD patients. It was used to design a larger survey comprising 60 questions as well as open fields allowing free expression. Respondents (448) comprised patients, parents of RD children and close relatives of patients. The Percentage of Maximum Deviation, Yates’ correction for continuity and Fisher’s test were employed to compare the responses between groups. Results Large disparities in the delays to obtain a diagnosis were identified (<1 year to >20 years), and longer delays were associated with negative perception of care conditions. While good interactions with education teams were reported (59% of respondents), the professional situation of both patients and parents was strongly and negatively impacted by the disease (51% did not work or stopped working). Three hundred respondents expressed various needs and psychological and personal issues were reported by 62% and 75% of respondents, respectively. Interestingly, the medical care path and daily life of RD patients were positively impacted by the follow-up in a specialized consultation, as reflected by changes in scores measured by our barometer (Fisher’s test, p<0.05). Conclusion Some of the main hurdles and sources of disruption in the life path of RD patients were identified, as well as some positive outcomes. These data could serve not only as a background for further studies, but also to better adapt the support to real needs and to improve the synergies between the many people involved in the life path of RD patients.

  14. The health and life path of rare disease patients: results of the 2015 French barometer.

    PubMed

    Heuyer, Thomas; Pavan, Sonia; Vicard, Christine

    2017-01-01

    A barometer has been set up to provide better knowledge about the daily situation of French rare disease (RD) patients, their families and relatives, in order to contribute to the elaboration of improvement measures. This report focuses on the care and life path of RD patients. A preliminary survey was carried out with three patients, five parents and three RD experts to identify the main hurdles and disruptions in the life path of RD patients. It was used to design a larger survey comprising 60 questions as well as open fields allowing free expression. Respondents (448) comprised patients, parents of RD children and close relatives of patients. The Percentage of Maximum Deviation, Yates' correction for continuity and Fisher's test were employed to compare the responses between groups. Large disparities in the delays to obtain a diagnosis were identified (<1 year to >20 years), and longer delays were associated with negative perception of care conditions. While good interactions with education teams were reported (59% of respondents), the professional situation of both patients and parents was strongly and negatively impacted by the disease (51% did not work or stopped working). Three hundred respondents expressed various needs and psychological and personal issues were reported by 62% and 75% of respondents, respectively. Interestingly, the medical care path and daily life of RD patients were positively impacted by the follow-up in a specialized consultation, as reflected by changes in scores measured by our barometer (Fisher's test, p<0.05). Some of the main hurdles and sources of disruption in the life path of RD patients were identified, as well as some positive outcomes. These data could serve not only as a background for further studies, but also to better adapt the support to real needs and to improve the synergies between the many people involved in the life path of RD patients.

  15. APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease

    PubMed Central

    Schellenberg, Gerard D.; Anderson, Leojean; O'dahl, Sheldon; Wisjman, Ellen M.; Sadovnick, Adele D.; Ball, Melvyn J.; Larson, Eric B.; Kukull, Walter A.; Martin, George M.; Roses, Allen D.; Bird, Thomas D.

    1991-01-01

    The amyloid precursor protein (APP) gene codes for the precursor to the β-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families, 127 “sporadic” AD subjects, 16 Down syndrome cases, and 256 normal controls for this mutation, and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis–Dutch type, for PRIP gene missense mutations at codons 102, 117, and 200, and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD. ImagesFigure 1 PMID:1679288

  16. Hashimoto's thyroiditis associated Evans syndrome: A rare case report on the clustered autoimmune disease triad.

    PubMed

    Koti, Kalyan; Thumma, Rayapa Reddy; Nagarajan, Swathanthra; Mathi, Atchyuta

    2013-07-01

    Evans syndrome is a rare combination of autoimmune hemolytic anemia and immune thrombocytopenia. Their association with autoimmune thyroid diseases has been reported by few authors; however, a sequential development of the Evans syndrome in cases of Hashimoto's thyroiditis is extremely rare. The clustering of these autoimmune diseases might share a common pathogenic pathway. We present the fourth such case in world literature, of a 34-year-old female diagnosed with Hashimoto's thyroiditis in 2006, who has been taking synthetic thyroid hormone since then. Her condition is now clinically complicated with the development of the Evans syndrome.

  17. Understanding rare and common diseases in the context of human evolution.

    PubMed

    Quintana-Murci, Lluis

    2016-11-07

    The wealth of available genetic information is allowing the reconstruction of human demographic and adaptive history. Demography and purifying selection affect the purge of rare, deleterious mutations from the human population, whereas positive and balancing selection can increase the frequency of advantageous variants, improving survival and reproduction in specific environmental conditions. In this review, I discuss how theoretical and empirical population genetics studies, using both modern and ancient DNA data, are a powerful tool for obtaining new insight into the genetic basis of severe disorders and complex disease phenotypes, rare and common, focusing particularly on infectious disease risk.

  18. Survey of healthcare experiences of Australian adults living with rare diseases.

    PubMed

    Molster, Caron; Urwin, Debra; Di Pietro, Louisa; Fookes, Megan; Petrie, Dianne; van der Laan, Sharon; Dawkins, Hugh

    2016-03-24

    Few studies have examined whether the healthcare needs of people living with rare diseases are being met. This study explores the experiences of Australian adults living with rare diseases in relation to diagnosis, information provision at the time of diagnosis, use of health and support services and involvement in research on their condition. The survey respondents are self-selected from the population of Australian residents aged 18 years and over who are living with a rare disease. An online survey was implemented between July-August 2014. Purposive snowballing sampling was used. The results are reported as percentages with significant differences between sub-groups assessed using chi-squared analyses. Eight hundred ten responses were obtained from adults living with a rare disease. 92.1% had a confirmed diagnosis, of which 30.0% waited five or more years for a diagnosis, 66.2% had seen three or more doctors to get a diagnosis and 45.9% had received at least one incorrect diagnosis. Almost three quarters (72.1%) received no or not enough information at the time of diagnosis. In the 12 months prior to the survey, over 80% of respondents had used the services of a general practitioner and a medical specialist while around a third had been inpatients at a hospital or had visited an emergency department. Only 15.4% of respondents had ever used paediatric services, 52.8% of these had experienced problems in the transition from paediatric to adult services. Only 20.3% knew of a patient registry for their condition and 24.8% were informed of clinical trials. These findings suggest that not all healthcare needs of people living with rare diseases are being met. Structural changes to Australian healthcare systems may be required to improve the integration and coordination of diagnosis and care. Health professionals may need greater awareness of rare diseases to improve the diagnostic process and support to meet the information requirements of people newly diagnosed with

  19. [Rare diseases--a problem of healthcare-related social security law].

    PubMed

    Rixen, Stephan

    2008-01-01

    In Germany orphan (or rare) diseases are not a major issue of healthcare-related social security law. Laws, regulations, courts and the legislature have so far not succeeded in shaping an adequate legal approach. The deficient legal framework seems to correlate to the lack of medical knowledge about orphan diseases. Consequently, equal access to treatment--one of the principles of the German healthcare system--for patients suffering from orphan diseases is not sufficiently assured. Therefore, German legislation is facing the urgent challenge to compensate for the lack of medical knowledge and healthcare resources in this field by defining new rules, by establishing specific health authorities and by reforming the allocation of research efforts. In a way, rare diseases are orphans that attract little public and scientific interest. Provision of an adequate legal framework for the treatment of and research into orphan diseases is likely to promote significant improvements for those affected.

  20. Identifying human microRNA-disease associations by a new diffusion-based method.

    PubMed

    Liao, Bo; Ding, Sumei; Chen, Haowen; Li, Zejun; Cai, Lijun

    2015-08-01

    Identifying the microRNA-disease relationship is vital for investigating the pathogenesis of various diseases. However, experimental verification of disease-related microRNAs remains considerable challenge to many researchers, particularly for the fact that numerous new microRNAs are discovered every year. As such, development of computational methods for disease-related microRNA prediction has recently gained eminent attention. In this paper, first, we construct a miRNA functional network and a disease similarity network by integrating different information sources. Then, we further introduce a new diffusion-based method (NDBM) to explore global network similarity for miRNA-disease association inference. Even though known miRNA-disease associations in the database are rare, NDBM still achieves an area under the ROC curve (AUC) of 85.62% in the leave-one-out cross-validation in improving the prediction accuracy of previous methods significantly. Moreover, our method is applicable to diseases with no known related miRNAs as well as new miRNAs with unknown target diseases. Some associations who strongly predicted by our method are confirmed by public databases. These superior performances suggest that NDBM could be an effective and important tool for biomedical research.

  1. [Patterns of rare congenital diseases in patients admitted to a regional hospital].

    PubMed

    Martínez Cirre, M C; Rodríguez Del Águila, M M; Fernández Valdivia, A; Peña Taveras, M; Martínez Tapias, J

    2013-09-06

    To describe the pattern of patients admitted due to rare diseases corresponding to congenital anomalies in a regional hospital. Retrospective transversal study. We considered hospital discharges for the years 2009-2012 with principal diagnosis between codes CIE 9R MC 740-759. The source of information was the Basic Minimum Data Set. Socio-demographic and clinical variables were analyzed. One point six percent (1.6%) of the population was admitted to hospital due to rare congenital diseases. Fifty-eight point five percent (58.5%) were male, with average age 21.4 ± 21.5 years. The major diagnostic categories were: diseases of the nervous system (86.9%), circulatory systems diseases (51.7%) and musculoskeletal system diseases (50.3%). Eighteen percent (18%) of hospital admissions corresponded to patient readmissions. The service with the greatest number of episodes was Pediatric Surgery, 29%, followed by Neurosurgery, 20%. The pattern of rare congenital disease in the "Virgen de Nieves" University Hospital corresponds to a young patient, with a disease belonging to the diseases of the nervous system group of the major diagnostic categories, treated surgically, and with a low percentage of readmissions.

  2. Simplified Microarray Technique for Identifying mRNA in Rare Samples

    NASA Technical Reports Server (NTRS)

    Almeida, Eduardo; Kadambi, Geeta

    2007-01-01

    Two simplified methods of identifying messenger ribonucleic acid (mRNA), and compact, low-power apparatuses to implement the methods, are at the proof-of-concept stage of development. These methods are related to traditional methods based on hybridization of nucleic acid, but whereas the traditional methods must be practiced in laboratory settings, these methods could be practiced in field settings. Hybridization of nucleic acid is a powerful technique for detection of specific complementary nucleic acid sequences, and is increasingly being used for detection of changes in gene expression in microarrays containing thousands of gene probes. A traditional microarray study entails at least the following six steps: 1. Purification of cellular RNA, 2. Amplification of complementary deoxyribonucleic acid [cDNA] by polymerase chain reaction (PCR), 3. Labeling of cDNA with fluorophores of Cy3 (a green cyanine dye) and Cy5 (a red cyanine dye), 4. Hybridization to a microarray chip, 5. Fluorescence scanning the array(s) with dual excitation wavelengths, and 6. Analysis of the resulting images. This six-step procedure must be performed in a laboratory because it requires bulky equipment.

  3. CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases.

    PubMed

    Apostolou, Paraskevi; Fostira, Florentia; Papamentzelopoulou, Myrto; Michelli, Maria; Panopoulos, Christos; Fountzilas, George; Konstantopoulou, Irene; Voutsinas, Gerassimos E; Yannoukakos, Drakoulis

    2015-04-01

    The CHEK2 gene encodes a protein kinase that plays a crucial role in maintenance of genomic integrity and the DNA repair mechanism. CHEK2 germline mutations are associated with increased risk of breast cancer and other malignancies. From a clinical perspective, the most significant mutation identified is the c.1100delC mutation, which is associated with an approximately 25% lifetime breast cancer risk. The distribution of this mutation shows wide geographical variation; it is more prevalent in the Northern European countries and less common, or even absent, in Southern Europe. In order to estimate the frequency of the CHEK2 c.1100delC mutation in Greek breast cancer patients, we genotyped 2,449 patients (2,408 females and 41 males), which was the largest series ever tested for c.1100delC. The mean age of female and male breast cancer diagnosis was 49 and 59 years, respectively. All patients had previously tested negative for the Greek BRCA1 founder and recurrent mutations. The CHEK2 c.1100delC mutation was detected in 0.16% (4 of 2,408) of females, all of whom were diagnosed with breast cancer before the age of 50 years. Only one c.1100delC carrier was reported with breast cancer family history. The present study indicates that the CHEK2 c.1100delC mutation does not contribute substantially to hereditary breast cancer in patients of Greek descent.

  4. Onchocerciasis, an undiagnosed disease in Mozambique: identifying research opportunities.

    PubMed

    Noormahomed, Emilia V; Akrami, Kevan; Mascaró-Lazcano, Carmen

    2016-03-31

    The objective of this paper is to summarise and critically review the available data about onchocerciasis in Mozambique, in order to report epidemiological and clinical aspects related to the disease and identify gaps in knowledge. The paper is intended to raise awareness of the existence and importance of this disease and to define research priorities. We examined the scarce epidemiological data at our disposal: two diagnostic studies in 1997 and 1998 (first reports on the existence of onchocerciasis in Mozambique), and two Rapid Epidemiological Mapping of Onchocerciasis (REMO) surveys in 2001 and 2007. We examined differences in study designs and methodologies as well as the differing geographical locations to explain the divergence in findings among the studies. Evidence indicates that onchocerciasis is hypoendemic in Mozambique (with national and imported cases), but still largely remains an undiagnosed illness. There is no awareness of the clinical aspects of the disease and nor of the differential diagnosis with lepromatous leprosy and dermatitis caused by Scabies spp. The use of skin biopsy and a symptom screening questionnaire, combined with nodule rate, in the first two studies may have captured even atypical or subacute presentations. Both REMO surveys relied solely on nodule detection and in the six years between the two studies, the prevalence of nodules detected more than doubled. The epidemiology and clinical as