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    Precision Medicine in Cats: Novel Niemann-Pick Type C1 Diagnosed by Whole-Genome Sequencing.
    J Vet Intern Med 2017 Feb 24. Epub 2017 Feb 24.
    Department of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Missouri - Columbia, Columbia, MO.
    State-of-the-art health care includes genome sequencing of the patient to identify genetic variants that contribute to either the cause of their malady or variants that can be targeted to improve treatment. The goal was to introduce state-of-the-art health care to cats using genomics and a precision medicine approach. To test the feasibility of a precision medicine approach in domestic cats, a single cat that presented to the University of Missouri, Veterinary Health Center with an undiagnosed neurologic disease was whole-genome sequenced. Read More

    Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD).
    Orphanet J Rare Dis 2017 Feb 23;12(1):41. Epub 2017 Feb 23.
    Department of Internal Medicine-Rheumatology, Hôpital de la Croix Saint Simon, Paris, France.
    Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically, ASMD has been classified as Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). NPD A is associated with a uniformly devastating disease course, with rapidly progressing psychomotor degeneration, leading to death typically by the age of 3 years, most often from respiratory failure. Read More

    Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.
    J Transl Med 2017 Feb 21;15(1):43. Epub 2017 Feb 21.
    Department of Biochemistry and Molecular and Cellular Biology, Faculty of Science, University of Zaragoza, C. Pedro Cerbuna 12, 50009, Saragossa, Spain.
    Background: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. Read More

    Measurement of Mitochondrial Cholesterol Import Using a Mitochondria-Targeted CYP11A1 Fusion Construct.
    Methods Mol Biol 2017 ;1583:163-184
    Department of Biochemistry and Molecular Biology, Dalhousie University, Sir Charles Tupper Medical Building 9G, 5850 College Street, Halifax, NS, Canada, B3H 4R2.
    All animal membranes require cholesterol as an essential regulator of biophysical properties and function, but the levels of cholesterol vary widely among different subcellular compartments. Mitochondria, and in particular the inner mitochondrial membrane, have the lowest levels of cholesterol in the cell. Nevertheless, mitochondria need cholesterol for membrane maintenance and biogenesis, as well as oxysterol, steroid, and hepatic bile acid production. Read More

    CRISPR/Cas9-Mediated Generation of Niemann-Pick C1 Knockout Cell Line.
    Methods Mol Biol 2017 ;1583:73-83
    School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia.
    Generating a cholesterol storage phenotype of Niemann-Pick Type C (NPC) disease is important for investigating the mechanisms of intracellular cholesterol trafficking, as well as screening drugs for potential treatment of NPC disease. The use of the CRISPR/Cas9 technology to knockout specific genes within the genome of mammals has become routine in the past few years. Here, we describe a protocol for producing a cellular NPC cholesterol storage phenotype in HeLa cells using the CRISPR-Cas9 system to disrupt the NPC1 gene. Read More

    Anesthetic Management in a Child With Niemann-Pick Disease.
    Iran J Pediatr 2016 Oct 31;26(5):e5479. Epub 2016 Jul 31.
    Anesthesiology and Critical Care, Tehran University of Medical Sciences, Tehran, IR Iran.
    Niemann-Pick is a lipid storage disease that results from a lysosomal enzyme deficiency (sphingomyelinase). It has different presentations, and it may affect various organs such as the central nervous system, kidney, liver, and spleen. Due to the complexity of the disease, careful perianesthetic management is necessary in order to reduce the risks and sequels. Read More

    Inhibition of Intermediate-Conductance Calcium-Activated K Channel (KCa3.1) and Fibroblast Mitogenesis by α-Linolenic Acid and Alterations of Channel Expression in the Lysosomal Storage Disorders, Fabry Disease, and Niemann Pick C.
    Front Physiol 2017 31;8:39. Epub 2017 Jan 31.
    Instituto de Investigación Sanitaria AragónZaragoza, Spain; Aragón Institute of Health SciencesZaragoza, Spain; Centro de Investigación Biomédica en Red de Enfermedades RarasZaragoza, Spain; Aragón Agency for Research and DevelopmentZaragoza, Spain.
    The calcium/calmodulin-gated KCa3.1 channel regulates normal and abnormal mitogenesis by controlling K(+)-efflux, cell volume, and membrane hyperpolarization-driven calcium-entry. Recent studies suggest modulation of KCa3. Read More

    Histone deacetylase inhibitors correct the cholesterol storage defect in most NPC1 mutant cells.
    J Lipid Res 2017 Feb 13. Epub 2017 Feb 13.
    Weill Cornell Medical College, United States;
    Niemann Pick C disease (NPC) is an autosomal recessive disorder that leads to excessive storage of cholesterol and other lipids in late endosomes and lysosomes. The large majority of NPC disease is caused by mutations in NPC1, a large polytopic membrane protein that functions in late endosomes. There are many disease-associated mutations in NPC1, and most patients are compound heterozygotes. Read More

    Effect of Inhibition of Intestinal Cholesterol Absorption on the Prevention of Cholesterol Gallstone Formation.
    Med Chem 2017 Feb 9. Epub 2017 Feb 9.
    Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro" Medical School, Bari,Italy.
    Background: Cholesterol cholelithiasis is a multifactorial hepatobiliary disease.

    Methods: Interactions between genetic and environmental factors play a critical role in biliary cholesterol homeostasis and its imbalance enhances cholelithogenesis.

    Results: In patients developing symptoms or complications of gallstone disease, laparoscopic cholecystectomy is recommended for treatment of gallstones. Read More

    Synthesis of multi-lactose-appended β-cyclodextrin and its cholesterol-lowering effects in Niemann-Pick type C disease-like HepG2 cells.
    Beilstein J Org Chem 2017 3;13:10-18. Epub 2017 Jan 3.
    Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
    Niemann-Pick type C (NPC) disease, characterized by intracellular accumulation of unesterified cholesterol and other lipids owing to defects in two proteins NPC1 and NPC2, causes neurodegeneration and other fatal neurovisceral symptoms. Currently, treatment of NPC involves the use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD is effective in the treatment of hepatosplenomegaly in NPC disease, albeit at a very high dose. Read More

    Ezetimibe reduces cholesterol content and NF-kappaB activation in liver but not in intestinal tissue in guinea pigs.
    J Inflamm (Lond) 2017 2;14. Epub 2017 Feb 2.
    0000 0004 1936 973Xgrid.5252.0Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany.
    Background: Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. Read More

    New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease.
    Sci Rep 2017 Feb 7;7:41931. Epub 2017 Feb 7.
    Department of Genetics, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
    Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. Read More

    Types A and B Niemann-Pick disease.
    Mol Genet Metab 2017 Jan - Feb;120(1-2):27-33. Epub 2016 Dec 16.
    Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
    The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Read More

    Early experience with compassionate use of 2 hydroxypropyl-beta-cyclodextrin for Niemann-Pick type C disease: review of initial published cases.
    Neurol Sci 2017 Feb 2. Epub 2017 Feb 2.
    Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain.
    Niemann-Pick type C (NP-C) is a rare neurodegenerative disorder. Management is mainly supportive and symptomatic. The investigational use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) showed a promising role in treating NP-C, although efficacy and safety have not been established. Read More

    Trifunctional lipid probes for comprehensive studies of single lipid species in living cells.
    Proc Natl Acad Sci U S A 2017 Feb 2;114(7):1566-1571. Epub 2017 Feb 2.
    Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany;
    Lipid-mediated signaling events regulate many cellular processes. Investigations of the complex underlying mechanisms are difficult because several different methods need to be used under varying conditions. Here we introduce multifunctional lipid derivatives to study lipid metabolism, lipid-protein interactions, and intracellular lipid localization with a single tool per target lipid. Read More

    Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels.
    Mol Aspects Med 2017 Jan 31. Epub 2017 Jan 31.
    Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia.
    Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focuses on the adenosine-mediated regulation of lipid availability in the cell and in the systemic circulation as well in humans and animal models. Therefore, adenosine, mainly by acting on A1R, inhibits lipolysis activity, leading to reduction of the circulating fatty acid levels. Read More

    Evolution of structural neuroimaging biomarkers in a series of adult patients with Niemann-Pick type C under treatment.
    Orphanet J Rare Dis 2017 Feb 2;12(1):22. Epub 2017 Feb 2.
    Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
    Background: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by a wide clinical spectrum and non-specific conventional magnetic resonance imaging (MRI) signs. As substrate reduction therapy with miglustat is now used in almost all patients, its efficacy and the course of the disease are sometimes difficult to evaluate. Neuroimaging biomarkers could prove useful in this matter. Read More

    A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency.
    Sci Rep 2017 Jan 30;7:41408. Epub 2017 Jan 30.
    Laboratory for Membrane Trafficking, VIB Center for Brain &Disease Research, KU Leuven, Department of Neurosciences, Leuven, Belgium.
    Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. Read More

    Rare Loss-of-function Variants in NPC1 Predispose to Human Obesity.
    Diabetes 2017 Jan 27. Epub 2017 Jan 27.
    Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    Some evidence has indicated a role of NPC1 for obesity traits. However, whether the loss-of-function mutations in NPC1 cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous NPC1 mutations on adiposity. Read More

    Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal β-glucocerebrosidase GBA1.
    J Lipid Res 2017 Jan 26. Epub 2017 Jan 26.
    University of Bonn, Germany
    Glucosylceramide is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B and C. The regulatory roles of lipids on the hydrolysis of membrane bound glucosylceramide by glucocerebrosidase GBA1 was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of Sap C. Read More

    Association between the rs1805081 polymorphism of Niemann-Pick type C1 gene and cardiovascular disease in a sample of an Iranian population.
    Biomed Rep 2017 Jan 7;6(1):83-88. Epub 2016 Nov 7.
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran; Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan 9816743175, Iran.
    The aim of the present study was to investigate the association between a genetic variation, A+644G, in the Niemann-Pick type C1 (NPC1) gene and the risk of cardiovascular disease (CVD) in a Southeast Iranian population. A total of 320 individuals, including 200 patients with CVD and 120 healthy individuals, were involved in the present study. The polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism method. Read More

    The Spectrum of Niemann-Pick Type C Disease in Greece.
    JIMD Rep 2017 Jan 20. Epub 2017 Jan 20.
    Department Enzymology and Cellular Function, Institute of Child Health, Athens, 11527, Greece.
    Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. Read More

    Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K.
    J Atheroscler Thromb 2017 Jan 17. Epub 2017 Jan 17.
    Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo.
    Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. Read More

    Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature.
    BMC Med Genet 2017 Jan 17;18(1). Epub 2017 Jan 17.
    FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380 015, India.
    Background: Niemann-Pick disease type C (NPC) is an inherited metabolic disorder; due to defect in cellular cholesterol trafficking. It is clinically a heterogeneous disease with variable age of onset with multiple organ systems being involved. NPC1 gene is involved in 95% cases where as remaining ~5% cases are linked with NPC2 gene. Read More

    Preliminary Results on Long-Term Potentiation-Like Cortical Plasticity and Cholinergic Dysfunction After Miglustat Treatment in Niemann-Pick Disease Type C.
    JIMD Rep 2017 Jan 17. Epub 2017 Jan 17.
    Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Piazzale Spedali Civili 1, Brescia, Italy.
    Niemann-Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder, which manifests clinically with a wide range of neurological signs and symptoms. We assessed multiple neurological, neuropsychological and neurophysiological biomarkers using a transcranial magnetic stimulation (TMS) multi-paradigm approach in two patients with NPC carrying a homozygous mutation in the NPC1 gene, and in two heterozygous family members.We assessed short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity with a paired associative stimulation (PAS) protocol. Read More

    Cholesterolomics: An update.
    Anal Biochem 2017 Jan 10. Epub 2017 Jan 10.
    Swansea University Medical School, Singleton Park, Swansea SA2 8PP, UK. Electronic address:
    Cholesterolomics can be regarded as the identification and quantification of cholesterol, its precursors post squalene, and metabolites of cholesterol and of its precursors, in a biological sample. These molecules include 1,25-dihydroxyvitamin D3, steroid hormones and bile acids and intermediates in their respective biosynthetic pathways. In this short article we will concentrate our attention on intermediates in bile acid biosynthesis pathways, in particular oxysterols and cholestenoic acids. Read More

    FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts.
    FASEB J 2017 Jan 12. Epub 2017 Jan 12.
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
    Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 or NPC2 with decreased functions leading to lysosomal accumulation of cholesterol and sphingolipids. FTY720/fingolimod, used for treatment of multiple sclerosis, is phosphorylated by nuclear sphingosine kinase 2 and its active phosphorylated form (FTY720-P) is an inhibitor of class I histone deacetylases. In this study, administration of clinically relevant doses of FTY720 to mice increased expression of NPC1 and -2 in brain and liver and decreased cholesterol in an SphK2-dependent manner. Read More

    Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice.
    Hum Mol Genet 2017 Jan 5. Epub 2017 Jan 5.
    Nathan Kline Institute, Orangeburg, NY; Dept. of
    2-hydroxypropyl-β-cyclodextrin (CYCLO), a modifier of cholesterol efflux from cellular membrane and endo-lysosomal compartments, reduces lysosomal lipid accumulations and has therapeutic effects in animal models of Niemann-Pick disease type C and several other neurodegenerative states. Here, we investigated CYCLO effects on autophagy in wild-type mice and TgCRND8 mice - an Alzheimer's Disease (AD) model exhibiting β-amyloidosis, neuronal autophagy deficits leading to protein and lipid accumulation within greatly enlarged autolysosomes. A 14-day intracerebroventricular administration of CYCLO to 8 month old TgCRND8 mice that exhibit moderately advanced neuropathology markedly diminished the sizes of enlarged autolysosomes and lowered their content of GM2 ganglioside and Aβ-immunoreactivity without detectably altering amyloid precursor protein processing or extracellular Aβ/β-amyloid burden. Read More

    Intracardiac injection of AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse Niemann-Pick type C disease.
    J Lipid Res 2017 Jan 4. Epub 2017 Jan 4.
    Wuhan University, China
    Niemann-Pick type C (NPC) disease is a fatal, inherited neurodegenerative disorder caused by loss-of-function mutations in the NPC1 or NPC2 gene. There is no effective way to treat NPC disease. In this study, we used adeno-associated virus (AAV) serotype 9 to deliver a functional NPC1 gene systemically into NPC1-/- mice at postnatal day 4 (P4). Read More

    Cholesterol crystallisation in human atherosclerosis is triggered in smooth muscle cells during the transition from fatty streak to fibroatheroma.
    J Pathol 2016 Dec 31. Epub 2016 Dec 31.
    Univ Paris Diderot, Sorbonne Paris Cité, Laboratory for Vascular Translational Science, Inserm Unit 1148, Paris, France.
    Recent studies have shown that in addition to being major constituents of the atheromatous core, solid cholesterol crystals (CCs) promote atherosclerotic lesion development and rupture by causing mechanical damage and exerting cytotoxic and pro-inflammatory effects. These findings suggest that targeting CCs might represent a therapeutic strategy for plaque stabilisation. However, little is known about how cholesterol crystallisation is initiated in human atherothrombotic disease. Read More

    Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat.
    J Biol Chem 2016 Dec 28. Epub 2016 Dec 28.
    Columbia University Medical Center, United States;
    Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no FDA-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Read More

    PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.
    Int J Technol Assess Health Care 2016 Jan 28;32(6):393-399. Epub 2016 Dec 28.
    The Hospital for Sick Children.
    Objectives: To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II).

    Methods: Researchers and HTA experts who responded to an email invitation participated in a telephone interview. Read More

    The Potential of Cyclodextrins as Novel Active Pharmaceutical Ingredients: A Short Overview.
    Molecules 2016 Dec 25;22(1). Epub 2016 Dec 25.
    Drug Transport and Delivery Research Group, Department of Pharmacy, University of Tromsø, The Arctic University of Norway, 9019 Tromsø, Norway.
    Cyclodextrins (CDs) are cyclic oligosaccharides of natural origin that were discovered more than 100 years ago. The peculiar cone-like conformation of the sugar ring, expressing a lipophilic cavity and a hydrophilic external surface, allows these substances to spontaneously complex poorly soluble compounds in an aqueous environment. For more than 50 years, these substances have found applicability in the pharmaceutical and food industries as solubilizing agents for poorly soluble chemical entities. Read More

    Effect of lysosomotropic molecules on cellular homeostasis.
    Pharmacol Res 2017 Mar 23;117:177-184. Epub 2016 Dec 23.
    Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Penn State Hershey Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; The Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States. Electronic address:
    Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. Read More

    Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.
    Wellcome Open Res 2016 Nov 18;1:18. Epub 2016 Nov 18.
    Department of Pharmacology, University of Oxford, Oxford, UK.
    Background: Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Read More

    Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases.
    Molecules 2016 Dec 20;21(12). Epub 2016 Dec 20.
    Laboratoire de la barrière hémato-encéphalique (LBHE), University Artois, EA 2465, Lens, F-62300, France.
    Cardiovascular diseases, like atherosclerosis, and neurodegenerative diseases affecting the central nervous system (CNS) are closely linked to alterations of cholesterol metabolism. Therefore, innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potential. However, these approaches need to take into account the existence of biological barriers such as intestinal and blood-brain barriers which participate in the organ homeostasis and are major defense systems against xenobiotics. Read More

    Triazoles inhibit cholesterol export from lysosomes by binding to NPC1.
    Proc Natl Acad Sci U S A 2017 Jan 19;114(1):89-94. Epub 2016 Dec 19.
    Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
    Niemann-Pick C1 (NPC1), a membrane protein of lysosomes, is required for the export of cholesterol derived from receptor-mediated endocytosis of LDL. Lysosomal cholesterol export is reportedly inhibited by itraconazole, a triazole that is used as an antifungal drug [Xu et al. (2010) Proc Natl Acad Sci USA 107:4764-4769]. Read More

    Differences in Niemann-Pick disease Type C symptomatology observed in patients of different ages.
    Mol Genet Metab 2016 Dec 7. Epub 2016 Dec 7.
    Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
    Background: Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression is more pronounced in patients with early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. Read More

    The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking.
    Biochem Biophys Res Commun 2017 Jan 9;482(4):1367-1374. Epub 2016 Dec 9.
    Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, 34134, Republic of Korea. Electronic address:
    Neuronal growth regulator 1 (NEGR1) is a newly identified raft-associated protein, which has recently been spotlighted as a new locus related to human obesity. Niemann-Pick disease Type C2 (NPC2) protein functions as a key player in the intracellular cholesterol trafficking, and its defect is linked to a fatal human neurodegenerative disease, NPC. In this study, we identified that NEGR1 interacts with NPC2 and increases its protein stability. Read More

    Lysosomal Storage Disorders in Nonimmune Hydrops Fetalis (NIHF): An Indian Experience.
    JIMD Rep 2016 Dec 8. Epub 2016 Dec 8.
    FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, Satellite, Ahmedabad, 380 015, India.
    Lysosomal storage disorders (LSD) are rare inherited neurovisceral inborn errors of metabolism which may present as nonimmune hydrops fetalis (NIHF) during pregnancy. Although causes of NIHF are highly diverse, LSDs are one of the underlying causes of NIHF. The aim of this study was to elucidate most frequent causes of LSDs presenting as NIHF in Indian population. Read More

    Facial Dystonia with Facial Grimacing and Vertical Gaze Palsy with "Round the Houses" Sign in a 29-Year-Old Woman.
    Neuroophthalmology 2016 Feb 19;40(1):31-34. Epub 2016 Jan 19.
    Department of Neurology, St. Pau's Hospital , Barcelona, Spain.
    A 29-year-old woman developed progressive dysarthria and coordination problems from the age of 15. Examination showed dysarthria, facial dystonia, bibrachial dystonia, hyperreflexia, ataxia, and emotional incontinence. Downward supranuclear gaze palsy was prominent with a "Round the Houses" sign. Read More

    Diversity of glycosphingolipid GM2 and cholesterol accumulation in NPC1 patient-specific iPSC-derived neurons.
    Brain Res 2017 Feb 5;1657:52-61. Epub 2016 Dec 5.
    Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, 18147 Rostock, Germany. Electronic address:
    Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. On the cellular level NPC1 mutations lead to an accumulation of cholesterol and gangliosides. As a thorough analysis of the severely affected neuronal cells is unfeasible in NPC1 patients, we recently described the cellular phenotype of neuronal cells derived from NPC1 patient iPSCs carrying the compound heterozygous mutation c. Read More

    Niemann-Pick disease, type C and Roscoe Brady.
    Mol Genet Metab 2017 Jan - Feb;120(1-2):34-37. Epub 2016 Nov 29.
    Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York, NY, United States. Electronic address:
    The Niemann-Pick family of diseases was poorly understood until Roscoe Brady and his colleagues began their investigations in the 1960s. Following Brady's discovery of the defect in acid sphingomyelinase in Niemann-Pick disease, types A and B, Peter Pentchev, a senior scientist in the group, launched a series of investigations of an unusual lipid storage disease in a spontaneous mouse model. These led initially to identification of the cholesterol trafficking defect in the mouse, and then in human Niemann-Pick disease, type C (NPC). Read More

    Amelioration of non-alcoholic fatty liver disease with NPC1L1-targeted IgY or n-3 polyunsaturated fatty acids in mice.
    Metabolism 2017 Jan 11;66:32-44. Epub 2016 Oct 11.
    CHA Cancer Prevention Research Center, CHA Bio Complex, CHA University, Seongnam, Gyunggi-do, 13488, Republic of Korea; Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Gyunggi-do, 13496, Republic of Korea. Electronic address:
    Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk for progression to hepatocellular carcinoma in addition to comorbidities such as cardiovascular and serious metabolic diseases; however, the current therapeutic options are limited. Based on our previous report that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can significantly ameliorate high fat diet (HFD)-induced NAFLD, we explored the therapeutic efficacy of n-3 PUFAs and N-IgY, which is a chicken egg yolk-derived IgY specific for the Niemann-Pick C1-Like 1 (NPC1L1) cholesterol transporter, on NAFLD in mice. We generated N-IgY and confirmed its efficient cholesterol transport-blocking activity in HepG2 and Caco-2 cells, which was comparable to the effect of ezetimibe (EZM). Read More

    Fostering collaborative research for rare genetic disease: the example of niemann-pick type C disease.
    Orphanet J Rare Dis 2016 Dec 1;11(1):161. Epub 2016 Dec 1.
    Diabetic Cardiovascular Disease Center, Washington University School of Medicine, Box 8086, 660 S. Euclid Ave, St. Louis, MO, 63110, USA.
    Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Read More

    Loss of Cathepsin B and L Leads to Lysosomal Dysfunction, NPC-Like Cholesterol Sequestration and Accumulation of the Key Alzheimer's Proteins.
    PLoS One 2016 30;11(11):e0167428. Epub 2016 Nov 30.
    Division of Molecular Medicine, Rudjer Boskovic Institute, Croatia.
    Proper function of lysosomes is particularly important in neurons, as they cannot dilute accumulated toxic molecules and aggregates by cell division. Thus, impairment of lysosomal function plays an important role in neuronal degeneration and in the pathogenesis of numerous neurodegenerative diseases. In this work we analyzed how inhibition and/or loss of the major lysosomal proteases, the cysteine cathepsins B and L (CtsB/L), affects lysosomal function, cholesterol metabolism and degradation of the key Alzheimer's disease (AD) proteins. Read More

    Genome sequencing in a case of Niemann-Pick type C.
    Cold Spring Harb Mol Case Stud 2016 Nov;2(6):a001222
    Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
    Adult-onset Niemann-Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical ("variant" level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Read More

    Identification of Two Sulfated Cholesterol Metabolites Found in the Urine of a Patient with Niemann-Pick Disease Type C as Novel Candidate Diagnostic Markers.
    Mass Spectrom (Tokyo) 2016 25;5(2):S0053. Epub 2016 Nov 25.
    Department of Pharmaceutical Sciences, Tohoku University Hospital.
    In the urine of a Niemann-Pick disease type C (NPC) patient, we have identified three characteristic intense peaks that have not been observed in the urine of a 3β-hydroxysteroid-Δ(5)-C27-steroid dehydrogenase deficiency patient or a healthy infant and adult. Based on accurate masses of the protonated molecules, we focused on two of them as candidate NPC diagnostic markers. Two synthesized authentic preparations agreed with the two compounds found in NPC patient urine in regard to both chromatographic behavior and accurate masses of the deprotonated molecules. Read More

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