Large-scale data-driven integrative framework for extracting essential targets and processes from disease-associated gene data sets.

Brief Bioinform. 2017 May 18;:

Authors: Mazandu GK, Chimusa ER, Rutherford K, Zekeng EG, Gebremariam ZZ, Onifade MY, Mulder NJ

Abstract
Populations worldwide currently face several public health challenges, including growing prevalence of infections and the emergence of new pathogenic organisms. The cost and risk associated with drug development make the development of new drugs for several diseases, especially orphan or rare diseases, unappealing to the pharmaceutical industry. Proof of drug safety and efficacy is required before market approval, and rigorous testing makes the drug development process slow, expensive and frequently result in failure. This failure is often because of the use of irrelevant targets identified in the early steps of the drug discovery process, suggesting that target identification and validation are cornerstones for the success of drug discovery and development. Here, we present a large-scale data-driven integrative computational framework to extract essential targets and processes from an existing disease-associated data set and enhance target selection by leveraging drug-target-disease association at the systems level. We applied this framework to tuberculosis and Ebola virus diseases combining heterogeneous data from multiple sources, including protein-protein functional interaction, functional annotation and pharmaceutical data sets. Results obtained demonstrate the effectiveness of the pipeline, leading to the extraction of essential drug targets and to the rational use of existing approved drugs. This provides an opportunity to move toward optimal target-based strategies for screening available drugs and for drug discovery. There is potential for this model to bridge the gap in the production of orphan disease therapies, offering a systematic approach to predict new uses for existing drugs, thereby harnessing their full therapeutic potential.

PMID: 28520909 [PubMed - as supplied by publisher]

Social/economic costs and health-related quality of life in patients with rare diseases in Europe.

Eur J Health Econ. 2016 Apr;17 Suppl 1:1-5

Authors: López-Bastida J, Oliva-Moreno J, Linertová R, Serrano-Aguilar P

PMID: 27023708 [PubMed - indexed for MEDLINE]

Uveal melanoma: From diagnosis to treatment and the science in between.

Cancer. 2016 Aug 01;122(15):2299-312

Authors: Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD, Esmaeli B, Grimm EA, Wargo JA, Woodman SE, Patel SP

Abstract
Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.

PMID: 26991400 [PubMed - indexed for MEDLINE]

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 2017/05/18

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 2017/05/18

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.

Fibrodysplasia ossificans progressiva. A case report and focus on the BMP signaling pathway.

Morphologie. 2016 Dec;100(331):250-255

Authors: Bouvard B, Masson C, Legrand E, Audran M

Abstract
Fibrodysplasia ossificans progressiva is a very rare heritable disease characterized by a progressive heterotopic endochondal ossification, occurring in the first decade of life, and leading thereafter to a severe ankylosis of the spine, limbs and jaw, with a progressive and severe functional disability. To date the cause of the disease remains unknown and no medical treatment has been proved efficient. It has recently been shown that a recurrent mutation in activation domain of the activin-receptor IA (ACVR1), a BMP receptor, could lead to an abnormal signalling pathway of BMP-4 and contribute to the occurrence of the devastating lesions characteristic of the disease.

PMID: 26948676 [PubMed - indexed for MEDLINE]

Treatment of rare factor deficiencies in 2016.

Hematology Am Soc Hematol Educ Program. 2016 Dec 02;2016(1):663-669

Authors: Peyvandi F, Menegatti M

Abstract
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti-tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.

PMID: 27913544 [PubMed - indexed for MEDLINE]

A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias.

Br J Haematol. 2016 Oct;175(2):318-330

Authors: Roy NB, Wilson EA, Henderson S, Wray K, Babbs C, Okoli S, Atoyebi W, Mixon A, Cahill MR, Carey P, Cullis J, Curtin J, Dreau H, Ferguson DJ, Gibson B, Hall G, Mason J, Morgan M, Proven M, Qureshi A, Sanchez Garcia J, Sirachainan N, Teo J, Tedgård U, Higgs D, Roberts D, Roberts I, Schuh A

Abstract
Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the 'discoverability' of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.

PMID: 27432187 [PubMed - indexed for MEDLINE]

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 2017/05/13

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.

Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.

Hum Mutat. 2017 May 11;:

Authors: Nakayama T, Wu J, Galvin-Parton P, Weiss J, Andriola MR, Hill RS, Vaughan D, El-Quessny M, Barry BJ, Partlow JN, Barkovich AJ, Ling J, Mochida GH

Abstract
Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth (CMT) disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy and spasticity. Whole exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity. This article is protected by copyright. All rights reserved.

PMID: 28493438 [PubMed - as supplied by publisher]

Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy.

Eur J Med Genet. 2017 May;60(5):245-249

Authors: Lakhani S, Doan R, Almureikhi M, Partlow JN, Al Saffar M, Elsaid MF, Alaaraj N, James Barkovich A, Walsh CA, Ben-Omran T

Abstract
Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

PMID: 28254648 [PubMed - indexed for MEDLINE]

[Renovascular disease in children - a rare diagnosis with few symptoms].

Tidsskr Nor Laegeforen. 2017 Feb;137(4):279-282

Authors: Thorsteinsdottir H, Dorenberg E, Line PD, Bjerre A

Abstract
BACKGROUND To estimate the prevalence, symptoms, causes and treatment of renovascular disease in children, and also to assess the degree of secondary organ damage to the heart, kidneys and eyes (end organ damage).MATERIAL AND METHOD Retrospective review of data for all children (0 - 16 years) who were examined for resistant hypertension in the period 1998 - 2013 at Oslo University Hospital Rikshospitalet.RESULTS A total of 21 children/adolescents (median age 8.5 years, 11 girls) were assessed and treated for resistant hypertension in the study period. Altogether had 38 % no symptoms at the time of diagnosis and 19 % had classical symptoms of hypertension. Fifteen patients received invasive treatment in the form of percutaneous transluminal renal angioplasty (PTRA) (n = 5), nephrectomy (n = 6), coiling (n = 1), autotransplantation (n = 1) or a combination of these (n = 2). Blood pressure improved following treatment in 10 of 14 patients for whom outcomes were recorded in the medical records. End organ damage to the heart and retina was observed in 60 % and 50 % of patients, respectively.INTERPRETATION Children with severely elevated blood pressure as a result of renovascular disease often have unspecific or no symptoms. Blood pressure improved following invasive treatment in 10 of 14 children and few complications were recorded. Invasive treatment may be considered in children and adolescents when standard treatment for hypertension is insufficient.

PMID: 28225234 [PubMed - indexed for MEDLINE]

Congenital lobar emphysema: diagnostic and therapeutic challenges.

BMJ Case Rep. 2016 Jun 22;2016:

Authors: Mulvany JJ, Weatherall A, Charlton A, Selvadurai H

Abstract
Congenital lobar emphysema (CLE), a rare condition that usually presents in the neonatal period, can be a diagnostic and therapeutic challenge for the treating clinician. If unrecognised, it is a significant risk at the time of anaesthetic induction. We describe a case of CLE in a 3-month-old boy who was initially treated for suspected aspiration pneumonia at the referring hospital. We highlight the importance of careful consideration of common childhood respiratory illness as well as pneumothorax in the differential diagnosis, and the significance of appropriate preoperative anaesthetic management. We also emphasise the importance of acknowledging a mother's concerns when taking a paediatric history.

PMID: 27335360 [PubMed - indexed for MEDLINE]

Biology and management of clear cell sarcoma: state of the art and future perspectives.

Expert Rev Anticancer Ther. 2016 Aug;16(8):839-45

Authors: Cornillie J, van Cann T, Wozniak A, Hompes D, Schöffski P

Abstract
INTRODUCTION: Clear cell sarcoma (CCS) is an aggressive tumor, typically developing in tendons or aponeuroses. The outcome of this orphan disease is poor, with 5-year and 10-year survival rates of localized CCS around 60-70% and 40-50%. Once the disease has metastasized, it is usually fatal due to its chemotherapy-resistant nature. Systemic treatment options are poorly standardized and the use of chemotherapy is based on weak scientific evidence.
AREAS COVERED: In this review, we systematically discuss the current scientific evidence for the systemic treatment of CCS, including tyrosine kinase inhibitors, immunotherapy and MET inhibitors. Expert commentary: Recent insights in the biology of CCS have identified new potential therapeutic targets, which should be tested in prospective clinical trials. Whenever possible, patients with metastatic CCS should be included in clinical trials with good biological rationale. Innovative trial methodology and new regulatory mechanisms are required to provide patients with uncommon cancers with active drugs.

PMID: 27253849 [PubMed - indexed for MEDLINE]

Three Cases of Erdheim-Chester Disease With Intraocular Manifestations: Imaging and Histopathology Findings of a Rare Entity.

Am J Ophthalmol. 2017 Apr;176:141-147

Authors: Tan AC, Yzer S, Atebara N, Marr BP, Verdijk RM, Dalm VA, Freund KB, Yannuzzi L, Missotten T

Abstract
PURPOSE: To report intraocular manifestations of Erdheim-Chester Disease (ECD) with multimodal imaging.
DESIGN: A retrospective observational case series.
METHODS: This was a multicenter case series of 3 patients with confirmed tissue diagnosis of ECD that showed intraocular manifestations and were imaged at baseline and follow-up visits.
RESULTS: Intraocular manifestations are rarely observed in association with ECD. Intraocular manifestations of ECD seen on multimodal imaging include histiocytic choroidal infiltration causing choroidal lesions, complicated by recurrent serous retinal detachment (SRD). Short-term resolution of SRD was observed with ocular therapies including intravitreal injections of anti-vascular endothelial growth factor or verteporfin photodynamic therapy in combination with systemic chemotherapy therapies and oral corticosteroids; however, recurrences were common. Chorioretinal biopsy confirmed the diagnosis of ECD in 1 case, with the presence of histiocytic infiltration, fibrosis, and characteristic immunohistologic staining. In another case, with a novel ARAF positive mutation, treatment with sorafenib showed regression of the choroidal lesions and resolution of the SRD on multimodal imaging. These lesions were previously resistant to other forms of therapy.
CONCLUSIONS: Rare intraocular manifestations of ECD confirmed on histopathology can be imaged with multimodal imaging. We report 3 cases, including 1 case diagnosed through histology from chorioretinal biopsy and another case associated with a novel ARAF mutation responsive to targeted therapy with sorafenib. The identification of novel somatic mutation associated with ECD enabled treatment with a new-targeted systemic agent. Multimodal imaging in these cases can also be used to monitor response to therapy.

PMID: 28153505 [PubMed - indexed for MEDLINE]

Perforation With Submucosal Cleft Palate in a Previously Undiagnosed Adult Patient.

J Craniofac Surg. 2016 Oct;27(7):e659-e661

Authors: Evin ŞG, Karamese M, Akdag O, Selimoglu MN, Tosun Z

Abstract
Perforation with a submucosal cleft palate (SMCP) is a rare condition with a limited number of cases reported in the literature. However, most described cases include neonates and infants, but not cases due to trauma or infection. Here, we present a case of an adult patient with SMCP with a perforation of the palate who was undiagnosed. In light of this case, diagnosis and treatment of perforation in SMCP are presented. A new diagram that can be used in the management of these patients with velopharyngeal insufficiency is proposed.

PMID: 27526237 [PubMed - indexed for MEDLINE]

Pharmacotherapy of inborn errors of metabolism illustrating challenges in orphan diseases.

J Pharmacol Toxicol Methods. 2016 Sep-Oct;81:9-14

Authors: Das AM

Abstract
Orphan diseases (OD) have special challenges based on the rarity of the conditions. Mostly multicentre studies are required, controlled studies are difficult to perform. Based on the often chronic course of OD with slow progress the effect of therapeutic interventions is difficult to assess. Development and production of pharmaceutical substances for OD is difficult, time-consuming and sophisticated. Special incentives by the regulatory bodies like protocol assistance, long marketing exclusivity and reduced licencing fees encourage the development of orphan drugs. Inborn errors of metabolism (IEMs) due to enzyme or transporter deficiencies are taken as an example for OD. Accumulation of substrates proximal to the deficient enzyme during catabolic episodes leads to autointoxication with acute onset of symptoms. IEMs due to transporter deficiency usually have a more stable, chronic course. Therapeutic options are substrate reduction by diet or drugs, vitamin/cofactor supplementation, enzyme replacement, enzyme augmentation and transplantation of organs or cells. Phenylketonuria (PKU) is the prototype of an IEM which can be successfully treated by diet. The outcome of hepatorenal tyrosinaemia type 1 was revolutionarized by substrate reduction using nitisinone (NTBC) which was discovered by chance. Lysosomal storage diseases are examples where enzyme replacement therapy is successful. Enzyme augmentation can be achieved in some IEM-patients with a mild phenotype (residual enzyme activity) by chaperones which stabilize the enzyme. Organ transplantation is an option in those patients who cannot be managed by drugs and/or diet. Bone marrow transplantation is successful in some patients where CNS-involvement occurs. The CNS cannot be reached by enzyme replacement therapy (blood-brain barrier). While safety and efficacy of drugs for OD have been demonstrated pre-marketing, post-marketing surveys are often necessary to include more patients.

PMID: 26921514 [PubMed - indexed for MEDLINE]

Metachronous gallbladder metastasis from renal cell carcinoma-a rare clinical manifestation.

Wien Klin Wochenschr. 2016 Sep;128(17-18):669-71

Authors: Mrak K, Lackner C, Mischinger HJ, Kornprat P

Abstract
Renal cell carcinoma (RCC) represents a rare tumor entity accounting for approximately 3 % of all malignancies in the adult population. Approximately 30 % of all patients suffering from RCC develop metastases after nephrectomy and another 30 % of patients suffer from synchronous metastases at the date of diagnosis. Gallbladder metastases represent an extremely rare clinical condition and up to date there are only 35 published cases of gallbladder metastasis from RCC. Surgical resection should be the treatment of choice in any case based on the reported data in literature. In spite of the small series of cases, survival can be improved even in patients suffering from additional sites of metastases.

PMID: 27624324 [PubMed - indexed for MEDLINE]

First report of otitis externa caused by Schizophyllum commune and review of the literature.

Wien Klin Wochenschr. 2016 May;128(9-10):387-90

Authors: Matos T, Tomazin R, Battelino S

Abstract
Basidiomycete Schizophyllum commune is a widely distributed cellulolytic fungus that is a well-known pathogen. It can cause a wide range of different infections, and here we describe the first case of otitis externa and a molecularly based identification process.

PMID: 26802032 [PubMed - indexed for MEDLINE]

The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease.

Am J Hum Genet. 2017 Feb 02;100(2):185-192

Authors: Ramoni RB, Mulvihill JJ, Adams DR, Allard P, Ashley EA, Bernstein JA, Gahl WA, Hamid R, Loscalzo J, McCray AT, Shashi V, Tifft CJ, Undiagnosed Diseases Network, Wise AL

Abstract
Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

PMID: 28157539 [PubMed - indexed for MEDLINE]