Familial hypercholesterolemia with extensive coronary artery disease and tuberous and tendinous xanthomas: A case report and mutation analysis.

J Clin Lipidol. 2018 Apr 26;:

Authors: Agirbasli D, Hyatt T, Agirbasli M

Abstract
This is a case report of a 38-year-old Syrian refugee male with early-onset extensive atherosclerosis. The physical and laboratory examination were remarkable with severe xanthomas in the upper and lower extremities and with low-density lipoprotein cholesterol (LDL-C) 417 mg/dL, total cholesterol 495 mg/dL, high-density lipoprotein cholesterol 30 mg/dL, and triglycerides 242 mg/dL. LDL-C level responded poorly to the high-dose statin treatment. The genetic analysis indicated that the patient had a large homozygous deletion in LDL receptor gene including the exons 7-14. A 12-kb deletion had occurred between the 2 Alu repetitive sequences that were oriented in opposite directions, one in intron 6 and the other in intron 14. This deletion eliminated exons 7-14, which exactly corresponded to the entire exon sequence coding the epidermal growth factor precursor homology domain. This deletion in LDL receptor was previously reported. This rare case of homozygous familial hypercholesterolemia presenting with multiple large and widely distributed xanthomas implicates the need for novel treatment options in familial hypercholesterolemia patients. The case is a Syrian refugee and emphasizes the urgent need to address orphan disease in refugee populations throughout the world.

PMID: 29784571 [PubMed - as supplied by publisher]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies.

ESMO Open. 2018;3(Suppl 1):e000357

Authors: Park JH, Ahn JH, Kim SB

Abstract
Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the 'BRCAness' highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP-ribose) polymerase inhibitors. However, regardless of enriched chemosensitivity and immunogenicity, majority of patients with TNBC still suffer from dismal clinical outcomes including early relapse and metastatic spread. Therefore, efforts into more precise and personalised treatment are critical at this point. Accordingly, the advance of multiomics has revealed novel actionable targets including PI3K-Akt-mTOR and epidermal growth factor receptor signalling pathways, which might actively participate in modulating the chemosensitivity and immune system. Also, TNBC has long been considered a potential protagonist of immunotherapy in breast cancer, supported by abundant tumour-infiltrating lymphocytes and heterogeneous tumour microenvironment. Despite that, earlier studies showed somewhat unsatisfactory results of monotherapy with immune-checkpoint inhibitors, consistently durable responses in responders were noteworthy. Based on these results, further combinatorial trials either with other chemotherapy or targeted agents are underway. Incorporating immune-molecular targets into combination as well as refining the standard chemotherapy might be the key to unlock the future of TNBC. In this review, we share the current and upcoming treatment options of TNBC in the framework of scientific and clinical data, especially focusing on early stage of TNBC.

PMID: 29765774 [PubMed]

RDFIO: extending Semantic MediaWiki for interoperable biomedical data management.

J Biomed Semantics. 2017 Sep 04;8(1):35

Authors: Lampa S, Willighagen E, Kohonen P, King A, Vrandečić D, Grafström R, Spjuth O

Abstract
BACKGROUND: Biological sciences are characterised not only by an increasing amount but also the extreme complexity of its data. This stresses the need for efficient ways of integrating these data in a coherent description of biological systems. In many cases, biological data needs organization before integration. This is not seldom a collaborative effort, and it is thus important that tools for data integration support a collaborative way of working. Wiki systems with support for structured semantic data authoring, such as Semantic MediaWiki, provide a powerful solution for collaborative editing of data combined with machine-readability, so that data can be handled in an automated fashion in any downstream analyses. Semantic MediaWiki lacks a built-in data import function though, which hinders efficient round-tripping of data between interoperable Semantic Web formats such as RDF and the internal wiki format.
RESULTS: To solve this deficiency, the RDFIO suite of tools is presented, which supports importing of RDF data into Semantic MediaWiki, with metadata needed to export it again in the same RDF format, or ontology. Additionally, the new functionality enables mash-ups of automated data imports combined with manually created data presentations. The application of the suite of tools is demonstrated by importing drug discovery related data about rare diseases from Orphanet and acid dissociation constants from Wikidata. The RDFIO suite of tools is freely available for download via pharmb.io/project/rdfio .
CONCLUSIONS: Through a set of biomedical demonstrators, it is demonstrated how the new functionality enables a number of usage scenarios where the interoperability of SMW and the wider Semantic Web is leveraged for biomedical data sets, to create an easy to use and flexible platform for exploring and working with biomedical data.

PMID: 28870259 [PubMed - indexed for MEDLINE]

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

Ann Am Thorac Soc. 2017 Aug;14(8):1239-1247

Authors: Kristof AS, Petrof BJ, Hamid Q, Kolb M, Landry JS, MacKenzie A, McCormack FX, Murawski IJ, Moss J, Rauch F, Rosas IO, Shapiro AJ, Smith BM, Thomas DY, Trapnell BC, Young LR, Zariwala MA, ATS Assembly on Respiratory Cell and Molecular Biology

Abstract
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.

PMID: 28763267 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Economic Modeling Considerations for Rare Diseases.

Value Health. 2018 May;21(5):515-524

Authors: Pearson I, Rothwell B, Olaye A, Knight C

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

PMID: 29753347 [PubMed - in process]

Carpal tunnel syndrome in mucopolysaccharidosis: the value of rare disease registries.

Dev Med Child Neurol. 2017 12;59(12):1213-1214

Authors: White KK

PMID: 28940237 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2018/05/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

High-content drug screening for rare diseases.

J Inherit Metab Dis. 2017 Jul;40(4):601-607

Authors: Bellomo F, Medina DL, De Leo E, Panarella A, Emma F

Abstract
Per definition, rare diseases affect only a small number of subjects within a given population. Taken together however, they represent a considerable medical burden, which remains poorly addressed in terms of treatment. Compared to other diseases, obstacles to the development of therapies for rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Recently, advances in high-throughput and high-content screening (HTS and HCS) have been fostered by the development of specific routines that use robot- and computer-assisted technologies to automatize tasks, allowing screening of a large number of compounds in a short period of time, using experimental model of diseases. These approaches are particularly relevant for drug repositioning in rare disease, which restricts the search to compounds that have already been tested in humans, thereby reducing the need for extensive preclinical tests. In the future, these same tools, combined with computational modeling and artificial neural network analyses, may also be used to predict individual clinical responses to drugs in a personalized medicine approach.

PMID: 28593466 [PubMed - indexed for MEDLINE]

Development of a database to record orofacial manifestations in patients with rare diseases: a status report from the ROMSE (recording of orofacial manifestations in people with rare diseases) database.

Br J Oral Maxillofac Surg. 2017 Jun;55(5):500-503

Authors: Hanisch M, Hanisch L, Benz K, Kleinheinz J, Jackowski J

Abstract
The aim of this working group was to establish a ROMSE (recording of orofacial manifestations in people with rare diseases) database to provide clinicians, patients, and their families with better information about these diseases. In 2011, we began to search the databases Orphanet, OMIM® (Online Mendelian Inheritance in Man®), and PubMed, for rare diseases with orofacial symptoms, and since 2013, the collected information has been incorporated into a web-based, freely accessible database. To date, 471 rare diseases with orofacial signs have been listed on ROMSE, and 10 main categories with 99 subcategories of signs such as different types of dental anomalies, changes in the oral mucosa, dysgnathia, and orofacial clefts, have been defined. The database provides a platform for general clinicians, orthodontists, and oral and maxillofacial surgeons to work on the best treatments.

PMID: 28238524 [PubMed - indexed for MEDLINE]

De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.

PLoS Genet. 2018 May 08;14(5):e1007281

Authors: Heinzen EL, O'Neill AC, Zhu X, Allen AS, Bahlo M, Chelly J, Dobyns WB, Freytag S, Guerrini R, Leventer RJ, Poduri A, Robertson SP, Walsh CA, Zhang M, Epi4K Consortium, Epilepsy Phenome/Genome Project

Abstract
Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

PMID: 29738522 [PubMed - as supplied by publisher]

Development of minimum standards of care for juvenile localized scleroderma.

Eur J Pediatr. 2018 May 04;:

Authors: Constantin T, Foeldvari I, Pain CE, Pálinkás A, Höger P, Moll M, Nemkova D, Weibel L, Laczkovszki M, Clements P, Torok KS

Abstract
Juvenile localized scleroderma (jLS), also known as morphea, is an orphan disease. Pediatric guidelines regarding diagnosis, assessment, and management are lacking.Our objective was to develop minimum standards of care for diagnosis, assessment, and management of jLS. A systematic review was undertaken to establish the pediatric evidence for assessment and monitoring of jLS. An expert panel, including members of the Pediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and, where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. Recommendations for diagnosis, assessment, and management were developed. Due to a lack of pediatric evidence, these were primarily consensus driven. Careful assessment for extra-cutaneous manifestations including synovitis, brain involvement, and uveitis were key features together with joint assessments between Dermatology and Rheumatology to improve and standardize care.
CONCLUSION: Management of jLS is varied. These recommendations should help provide standardization of assessment and care for those with this rare and potentially debilitating condition. What is Known: • Children with juvenile localized scleroderma (jLS) are managed by a number of specialties including pediatric rheumatologists and dermatologists, sometimes in shared clinics. Studies have shown that management varies considerably and that there are notable differences between specialties [1]. • There is very little published guidance on management of jLS. What is new: • These recommendations aim to standardize diagnosis, assessment, and management through review of pediatric evidence and consensus agreement. • Joint review of patients by both pediatric rheumatologists and dermatologists is recommended.

PMID: 29728839 [PubMed - as supplied by publisher]

Melorheostosis: a Rare Sclerosing Bone Dysplasia.

Curr Osteoporos Rep. 2017 Aug;15(4):335-342

Authors: Kotwal A, Clarke BL

Abstract
PURPOSE OF REVIEW: Melorheostosis is a rare sclerosing bone dysplasia that affects both cortical bone and adjacent soft tissue structures in a sclerotomal distribution. In this review, we describe the natural history, radiological features, proposed pathogenesis, and management options for this debilitating condition.
RECENT FINDINGS: Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series. Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton and usually presents with lower limb deformity. Diagnosis is based on a combination of clinical and radiological features that help differentiate this condition from other sclerosing bone dysplasias. LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis. The exact etiology of classic sporadically occurring melorheostosis remains unknown, with possible causes being somatic LEMD3 mutations, somatic mutations in the bone morphogenetic protein/transforming growth factor-beta pathway, mutations in multiple genes, or other non-genetic causes. Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy. Melorheostosis may present as mixed or atypical osseous involvement in addition to the classically described "dripping candle wax" appearance of hyperostosis. Some patients may have overlap with osteopoikilosis or Buschke-Ollendorff syndrome. In the future, better characterization of genetic and developmental factors predisposing to melorheostosis may lead to the development of targeted therapy for this condition, as well as for more commonly encountered skeletal abnormalities.

PMID: 28676968 [PubMed - indexed for MEDLINE]

[Liver Transplantation as Treatment for Rare Diseases in Adults].

Zentralbl Chir. 2017 Apr;142(2):169-179

Authors: Bauschke A, Malessa C, Rauchfuss F, Zanow J, Settmacher U

Abstract
In addition to the main indications pertaining to 95 % of all patients receiving liver transplantation in Germany, there are numerous other diseases that may become clinically evident in the adult age and may lead to the decision for liver transplantation. These may be metabolic diseases with their main defect located in the liver, malformations of liver cells, hepatic vascular diseases and rare tumours of the liver. Standard exceptions for the listing are in place only for a limited number of diseases. Exact diagnostics and the point in time for transplantation are crucial for the prognosis.

PMID: 24241952 [PubMed - indexed for MEDLINE]

H Syndrome: A Rare Genodermatosis Imaged With 18F-FDG PET/CT.

Clin Nucl Med. 2018 Jan;43(1):36-37

Authors: Turpin S, Patey N, Beaudin M, Mitchell G, Lambert R

Abstract
H syndrome (OMIM 612391) is an extremely rare autosomal recessive genodermatosis, characterized by extensive skin infiltration. We report a case imaged with F-FDG PET/CT.

PMID: 29189375 [PubMed - indexed for MEDLINE]

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

J Health Econ. 2017 Jul;54:56-65

Authors: Iizuka T, Uchida G

Abstract
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.

PMID: 28448950 [PubMed - indexed for MEDLINE]