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niemann-pick type c

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https://www.readbyqxmd.com/read/29659804/high-content-screen-for-modifiers-of-niemann-pick-type-c-disease-in-patient-cells
#1
Emily K Pugach, McKenna Feltes, Randal J Kaufman, Daniel S Ory, Anne G Bang
Niemann-Pick type C disease (NPC) is a rare lysosomal storage disease caused primarily by mutations in NPC1. NPC1 encodes the lysosomal cholesterol transport protein NPC1. The most common NPC1 mutation is a missense mutation (NPC1I1061T) that causes misfolding and rapid degradation of mutant protein in the endoplasmic reticulum. Cholesterol accumulates in enlarged lysosomes as a result of decreased levels of lysosomal NPC1I1061T protein in patient cells. There is currently no cure or FDA-approved treatment for patients...
April 12, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29626102/identification-of-unusual-oxysterols-and-bile-acids-with-7-oxo-or-3%C3%AE-5%C3%AE-6%C3%AE-trihydroxy-functions-in-human-plasma-by-charge-tagging-mass-spectrometry-with-multistage-fragmentation
#2
William J Griffiths, Ian Gilmore, Eylan Yutuc, Jonas Abdel-Khalik, Peter J Crick, Thomas Hearn, Alison Dickson, Brian W Bigger, Teresa Hoi-Yee Wu, Anu Goenka, Arunabha Ghosh, Simon A Jones, Yuqin Wang
7-Oxocholesterol (7-OC), 5,6-epoxycholesterol (5,6-EC) and its hydrolysis product cholestane-3β,5α,6β-triol (3β,5α,6β-triol) are normally minor oxysterols in human samples, however, in disease their levels may be greatly elevated. This is the case in plasma from patients suffering from some lysosomal storage disorders e.g. Niemann Pick disease type C, or the inborn errors of sterol metabolism e.g. Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis. A complication in the analysis of 7-OC and 5,6-EC is that they can also be formed ex vivo from cholesterol during sample handling in air causing confusion with molecules formed in vivo...
April 6, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29625568/consensus-clinical-management-guidelines-for-niemann-pick-disease-type-c
#3
REVIEW
Tarekegn Geberhiwot, Alessandro Moro, Andrea Dardis, Uma Ramaswami, Sandra Sirrs, Mercedes Pineda Marfa, Marie T Vanier, Mark Walterfang, Shaun Bolton, Charlotte Dawson, Bénédicte Héron, Miriam Stampfer, Jackie Imrie, Christian Hendriksz, Paul Gissen, Ellen Crushell, Maria J Coll, Yann Nadjar, Hans Klünemann, Eugen Mengel, Martin Hrebicek, Simon A Jones, Daniel Ory, Bruno Bembi, Marc Patterson
Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy...
April 6, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29580834/niemann-pick-c2-protein-regulates-sterol-transport-between-plasma-membrane-and-late-endosomes-in-human-fibroblasts
#4
Zane Berzina, Lukasz M Solanko, Ahmed S Mehadi, Maria Louise V Jensen, Frederik W Lund, Maciej Modzel, Maria Szomek, Katarzyna A Solanko, Alice Dupont, Gitte Krogh Nielsen, Christian W Heegaard, Christer S Ejsing, Daniel Wüstner
Niemann-Pick disease type C2 is a lipid storage disorder in which mutations in the NPC2 protein cause accumulation of lipoprotein-derived cholesterol in late endosomes and lysosomes (LE/LYSs). Whether cholesterol delivered by other means to NPC2 deficient cells also accumulates in LE/LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous diffusion in disease cells (D ∼ 4...
March 23, 2018: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/29560273/large-scale-computational-drug-repositioning-to-find-treatments-for-rare-diseases
#5
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine, Michal Brylinski
Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning...
2018: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/29556840/contribution-of-tandem-mass-spectrometry-to-the-diagnosis-of-lysosomal-storage-disorders
#6
Monique Piraud, Magali Pettazzoni, Pamela Lavoie, Séverine Ruet, Cécile Pagan, David Cheillan, Philippe Latour, Christine Vianey-Saban, Christiane Auray-Blais, Roseline Froissart
Tandem mass spectrometry (MS/MS) is a highly sensitive and specific technique. Thanks to the development of triple quadrupole analyzers, it is becoming more widely used in laboratories working in the field of inborn errors of metabolism. We review here the state of the art of this technique applied to the diagnosis of lysosomal storage disorders (LSDs) and how MS/MS has changed the diagnostic rationale in recent years. This fine technology brings more sensitive, specific, and reliable methods than the previous biochemical ones for the analysis of urinary glycosaminoglycans, oligosaccharides, and sialic acid...
March 19, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29536386/long-term-therapy-with-miglustat-and-cognitive-decline-in-the-adult-form-of-niemann-pick-disease-type-c-a-case-report
#7
Stefano Tozza, Raffaele Dubbioso, Rosa Iodice, Antonietta Topa, Marcello Esposito, Lucia Ruggiero, Emanuele Spina, Anna De Rosa, Francesco Saccà, Lucio Santoro, Fiore Manganelli
Niemann-Pick disease type C (NPC) is a recessive lysosomal lipid storage disorder characterized by central nervous system involvement. Miglustat treatment might improve or stabilize neurological manifestations but there is still limited data on the long-term efficacy. The aim of our study was to report a four-year clinical, neuropsychological and electrophysiological follow-up of two sisters under treatment with miglustat. We report data at basal (T0) and after 4 years (T4) of treatment with miglustat from two sisters (P1 and P2) affected by NPC disease...
March 13, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29534570/predicting-the-binding-mode-of-2-hydroxypropyl-%C3%AE-cyclodextrin-hp%C3%AE-cd-to-cholesterol-by-means-of-the-md-simulation-and-the-3d-rism-kh-theory
#8
Yuji Hayashino, Masatake Sugita, Hidetoshi Arima, Tetsumi Irie, Takeshi Kikuchi, Fumio Hirata
It has been found that a cyclodextrin derivative, 2-hydroxypropyl-β-cyclodextrin (HPβCD), has reasonable therapeutic effect on Niemann-Pick disease type C which is caused by abnormal accumulation of unesterified cholesterol and glycolipids in the lysosomes and shortage of esterified cholesterol in other cellular compartments. We study the binding affinity and mode of HPβCD with cholesterol in order to elucidate the possible mechanism of HPβCD for removing cholesterol from the lysosomes. The dominant binding mode of HPβCD with cholesterol is found based on the Molecular Dynamics (MD) simulation and a statistical mechanics theory of liquids, or the 3D reference interaction site model theory with Kovalenko-Hirata closure relation (3D-RISM-KH)...
March 13, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29522754/the-formation-of-giant-plasma-membrane-vesicles-enable-new-insights-into-the-regulation-of-cholesterol-efflux
#9
Alanna Sedgwick, M Olivia Balmert, Crislyn D'Souza-Schorey
Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4 . Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation...
March 6, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29511534/recent-neuroimaging-neurophysiological-and-neuropathological-advances-for-the-understanding-of-npc
#10
REVIEW
Alberto Benussi, Maria Sofia Cotelli, Alessandro Padovani, Barbara Borroni
Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer's disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults...
2018: F1000Research
https://www.readbyqxmd.com/read/29497113/tolerance-of-chronic-hdaci-treatment-for-neurological-visceral-and-lung-niemann-pick-type-c-disease-in-mice
#11
Md Suhail Alam, Bruce Cooper, Joseph D Farris, Kasturi Haldar
Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann-Pick Type C (NPC) disease...
March 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29476731/metabolic-causes-of-nonimmune-hydrops-fetalis-a-next-generation-sequencing-panel-as-a-first-line-investigation
#12
Bénédicte Sudrié-Arnaud, Florent Marguet, Sophie Patrier, Jelena Martinovic, Ferielle Louillet, Françoise Broux, Françoise Charbonnier, Hélène Dranguet, Sophie Coutant, Myriam Vezain, Raphaël Lanos, Abdellah Tebani, Maria Fuller, Foudil Lamari, Pascal Chambon, Anne-Claire Brehin, Laetitia Trestard, Isabelle Tournier, Stéphane Marret, Eric Verspyck, Annie Laquerrière, Soumeya Bekri
PURPOSES: Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming...
February 21, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29457916/systematic-review-of-psychiatric-signs-in-niemann-pick-disease-type-c
#13
Olivier Bonnot, Hans-Hermann Klünemann, Christian Velten, Juan Vicente Torres Martin, Mark Walterfang
OBJECTIVES: We conducted the first systematic literature review and analysis of psychiatric manifestations in Niemann-Pick disease type C (NPC) to describe: 1) time of occurrence of psychiatric manifestations relative to other disease manifestations; 2) frequent combinations of psychiatric, neurological and visceral disease manifestations. METHODS: A systematic EMBase literature search was conducted to identify, collate and analyze published data from patients with NPC associated with psychiatric symptoms, published between January 1967 and November 2015...
February 19, 2018: World Journal of Biological Psychiatry
https://www.readbyqxmd.com/read/29453517/probable-diagnosis-of-a-patient-with-niemann-pick-disease-type-c-managing-pitfalls-of-exome-sequencing
#14
William A Zeiger, Nasheed I Jamal, Maren T Scheuner, Patricia Pittman, Kimiyo M Raymond, Massimo Morra, Shri K Mishra
Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several years failed to yield a diagnosis. Initial whole exome sequencing through a commercial laboratory identified several variants of uncertain significance; however, follow-up clinical examination and testing ruled each of these out. Eventually, repeat whole exome sequencing identified a known pathogenic intronic variant in the NPC1 gene (NM_000271...
February 17, 2018: JIMD Reports
https://www.readbyqxmd.com/read/29447902/the-erythrocyte-osmotic-resistance-test-as-screening-tool-for-cholesterol-related-lysosomal-storage-diseases
#15
Laura López de Frutos, Jorge J Cebolla, Pilar Irún, Ralf Köhler, Pilar Giraldo
BACKGROUND: Erythrocyte volume regulation and membrane elasticity are essential for adaptation to osmotic and mechanical stress, and life span. Here, we evaluated whether defective cholesterol trafficking caused by the rare lysosomal storages diseases (LSDs), Niemann-Pick type C (NPC) and Lysosomal acid lipase (LAL) deficiency (LALD) impairs these properties. Moreover, we tested whether measurements of cholesterol membrane content and osmotic resistance serve as a screening test for these LSDs...
February 12, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29431164/recommendations-for-the-detection-and-diagnosis-of-niemann-pick-disease-type-c-an-update
#16
REVIEW
Marc C Patterson, Peter Clayton, Paul Gissen, Mathieu Anheim, Peter Bauer, Olivier Bonnot, Andrea Dardis, Carlo Dionisi-Vici, Hans-Hermann Klünemann, Philippe Latour, Charles M Lourenço, Daniel S Ory, Alasdair Parker, Miguel Pocoví, Michael Strupp, Marie T Vanier, Mark Walterfang, Thorsten Marquardt
Purpose of review: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. Recent findings: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C...
December 2017: Neurology. Clinical Practice
https://www.readbyqxmd.com/read/29431050/tdp-43-post-translational-modifications-in-health-and-disease
#17
Emanuele Buratti
Nuclear factor TDP-43 is a ubiquitously expressed RNA binding protein that plays a key causative role in several neurodegenerative diseases, especially in the ALS/FTD spectrum. In addition, its aberrant aggregation and expression has been recently observed in other type of diseases, such as myopathies and Niemann-Pick C, a lysosomal storage disease. Areas Covered. This review aims to specifically cover the post-translational modifications (PTMs) that can affect TDP-43 function and cellular status both in health and disease...
February 10, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29429782/long-term-treatment-of-niemann-pick-type-c1-disease-with-intrathecal-2-hydroxypropyl-%C3%AE-cyclodextrin
#18
Elizabeth Berry-Kravis, Jamie Chin, Anne Hoffmann, Amy Winston, Robin Stoner, Lisa LaGorio, Katherine Friedmann, Mariana Hernandez, Daniel S Ory, Forbes D Porter, Joan A O'Keefe
BACKGROUND: Intrathecal 2-hydoxypropyl-β-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol. OBJECTIVE: In this study, the long-term effects of intrathecal 2-hydoxypropyl-β-cyclodextrin treatment for 2...
January 8, 2018: Pediatric Neurology
https://www.readbyqxmd.com/read/29406968/lovastatin-promotes-myelin-formation-in-npc1-mutant-oligodendrocytes
#19
Fan Yang, Xiao Feng, Arndt Rolfs, Jiankai Luo
Niemann-Pick Type C (NPC) disease is a rare neurovisceral disorder caused by mutations of either NPC1 or NPC2 gene and characterized by defective intracellular transport of cholesterol and glycosphingolipids, leading to neuron loss and myelin aberration in the central nervous system. In this study, by comparing protein expression in the cortical white matter tracts from mice at different postnatal days, we identified that in the NPC1 mutant (NPC1-/-) mice, the onset of myelination is delayed and the amount of the major myelin protein MBP and PLP, and oligodendrocyte regulatory factor Olig1 and Olig2, but not NG2 and Sox10, decreased significantly, suggesting a disruption of oligodendrocyte differentiation...
March 15, 2018: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/29397865/the-role-of-purkinje-cell-derived-vegf-in-cerebellar-astrogliosis-in-niemann-pick-type-c-mice
#20
Min Hee Park, Ju Youn Lee, Min Seock Jeong, Hyung Sup Jang, Shogo Endo, Jae-Sung Bae, Hee Kyung Jin
Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative disorder caused by a deficiency of NPC1 gene function, which leads to severe neuroinflammation such as astrogliosis. While reports demonstrating neuroinflammation are prevalent in NP-C, information about the onset and progression of cerebellar astrogliosis in this disorder is lacking. Using gene targeting, we generated vascular endothelial growth factor (VEGF) conditional null mutant mice. Deletion of VEGF in cerebellar Purkinje neurons (PNs) led to a significant increase of astrogliosis in the brain of NP-C mice in addition to the loss of PNs, suggesting PN-derived VEGF as an important factor in NP-C pathology...
February 5, 2018: BMB Reports
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