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    High-content screen for modifiers of Niemann-Pick Type C disease in patient cells.
    Hum Mol Genet 2018 Apr 12. Epub 2018 Apr 12.
    Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA, phone: 858-646-3100, fax: 858-646-3192.
    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. Read More

    Attenuation of the Niemann-Pick type C2 disease phenotype by intracisternal administration of an AAVrh.10 vector expressing Npc2.
    Exp Neurol 2018 Apr 12. Epub 2018 Apr 12.
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, United States. Electronic address:
    Niemann-Pick type C2 (NPC2) disease is a rare, neurodegenerative disorder caused by mutations in the NPC2 gene, leading to lysosomal accumulation of unesterified cholesterol and other lipids. It is characterized by hepatosplenomegaly, liver dysfunction and severe neurological manifestations, resulting in early death. There is no effective therapy for NPC2 disease. Read More

    Identification Of Unusual Oxysterols And Bile acids With 7-Oxo Or 3β,5α,6β-Trihydroxy Functions In Human Plasma By Charge-Tagging Mass Spectrometry With Multistage Fragmentation.
    J Lipid Res 2018 Apr 6. Epub 2018 Apr 6.
    Swansea University, United Kingdom.
    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. Read More

    Consensus clinical management guidelines for Niemann-Pick disease type C.
    Orphanet J Rare Dis 2018 Apr 6;13(1):50. Epub 2018 Apr 6.
    Mayo 1290 Clinic Department of Pediatric and Adolescent Medicine, Minnesota, USA.
    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. Read More

    Microglia Activation in Niemann-Pick Disease, type C1 is Amendableto Therapeutic Intervention.
    Hum Mol Genet 2018 Mar 30. Epub 2018 Mar 30.
    Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20879.
    Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 is associated with neuroinflammation; however, attempts to therapeutically target neuroinflammation in NPC1 have had mixed success. We show here that NPC1 neuroinflammation is characterized by an atypical microglia activation phenotype. Read More

    Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann-Pick-Disease Type C1.
    Int J Mol Sci 2018 Mar 24;19(4). Epub 2018 Mar 24.
    Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany.
    Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Read More

    Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts.
    Chem Phys Lipids 2018 Mar 23;213:48-61. Epub 2018 Mar 23.
    Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, DK-5230 Odense M, Denmark. Electronic address:
    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. Read More

    Butyrate from pectin fermentation inhibits intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E-deficient mice.
    J Nutr Biochem 2018 Feb 27;56:175-182. Epub 2018 Feb 27.
    Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong Province 510080, PR China; Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province 510080, PR China. Electronic address:
    Short-chain fatty acids (SCFAs), the major products of dietary fiber fermentation by intestinal microflora, exert beneficial effects on pathogenesis of multiple metabolic diseases. The aim of this study was to determine whether SCFAs from fermentation of pectin (PE), a soluble dietary fiber, prevent the development of atherosclerosis in apolipoprotein E-deficient (apoE) mice. Male apoE mice (8-week-old) were fed a high-fat, high-cholesterol diet (HCD; 21% wt/wt fat, 0. Read More

    Large-scale computational drug repositioning to find treatments for rare diseases.
    NPJ Syst Biol Appl 2018 13;4:13. Epub 2018 Mar 13.
    1Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803 USA.
    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. Read More

    Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders.
    J Inherit Metab Dis 2018 Mar 19. Epub 2018 Mar 19.
    Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron cedex, France.
    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. Read More

    Long-term therapy with miglustat and cognitive decline in the adult form of Niemann-Pick disease type C: a case report.
    Neurol Sci 2018 Mar 13. Epub 2018 Mar 13.
    Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy.
    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. Read More

    Predicting the Binding Mode of 2-Hydroxypropyl-β-cyclodextrin to Cholesterol by Means of the MD Simulation and the 3D-RISM-KH Theory.
    J Phys Chem B 2018 Mar 19. Epub 2018 Mar 19.
    Toyota Physical and Chemical Research Institute , 41-1, Yokomichi , Nagakute , Aichi 480-1192 , Japan.
    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 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 simulation and a statistical mechanics theory of liquids, or the three-dimensional reference interaction site model theory with Kovalenko-Hirata closure relation. Read More

    The formation of giant plasma membrane vesicles enable new insights into the regulation of cholesterol efflux.
    Exp Cell Res 2018 Apr 6;365(2):194-207. Epub 2018 Mar 6.
    Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556-0369, USA. Electronic address:
    Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease. 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. Read More

    Niemann-Pick type C2 protein supplementation in experimental non-alcoholic fatty liver disease.
    PLoS One 2018 9;13(3):e0192728. Epub 2018 Mar 9.
    Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Background And Aims: Hepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model. Read More

    Live-cell imaging of new polyene sterols for improved analysis of intracellular cholesterol transport.
    J Microsc 2018 Mar 8. Epub 2018 Mar 8.
    Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark.
    Analysis of intracellular cholesterol transport by fluorescence microscopy requires suitable fluorescent analogues of cholesterol. Most existing cholesterol analogues contain lipophilic dyes which can compromise the sterol properties in membranes. An alternative strategy is to introduce additional double bonds into the sterol ring system resulting in intrinsic fluorescence, while at the same time keeping the cholesterol-like properties of the analogues. Read More

    Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC.
    F1000Res 2018 15;7:194. Epub 2018 Feb 15.
    Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa, 11, 25123 Brescia BS, Italy.
    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. Read More

    Tolerance of chronic HDACi treatment for neurological, visceral and lung Niemann-Pick Type C disease in mice.
    Sci Rep 2018 Mar 1;8(1):3875. Epub 2018 Mar 1.
    Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN, 46556, USA.
    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. Read More

    Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules.
    Chem Pharm Bull (Tokyo) 2018 ;66(3):207-216
    Graduate School of Pharmaceutical Sciences, Kumamoto University.
    Supramolecular chemistry is an extremely useful and important domain for understanding pharmaceutical sciences because various physiological reactions and drug activities are based on supramolecular chemistry. However, it is not a major domain in the pharmaceutical field. In this review, we propose a new concept in pharmaceutical sciences termed "supramolecular pharmaceutical sciences," which combines pharmaceutical sciences and supramolecular chemistry. Read More

    The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma.
    J Cancer 2018 1;9(3):556-563. Epub 2018 Jan 1.
    The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
    Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Read More

    Niemann-Pick Disease, Type C1 Gene Expression in PBMCs is Associated with Interleukin 10 Serum Concentration: a Case-Control Study.
    Clin Lab 2018 Jan;64(1):17-24
    Background: Recent studies showed that atherosclerosis is a lysosomal storage disease (LSD) and Niemann-Pick disease type C1 (NPC1) is the most important protein of the lysosomal membrane that is involved in the removal of FC from lysosomes. Whereas several in vitro and in vivo studies have described the crosstalk between lysosomal cholesterol accumulation and increased inflammation, there is no study addressing the correlation between NPC1 gene expression and an anti-inflammatory cytokine, interleukin 10 (IL-10) serum concentration in atherosclerotic patients.

    Methods: IL-10 and 25-hydroxyvitamin D serum concentrations were quantified by enzyme-linked immunosorbent assay (ELISA) in atherosclerotic patients (n = 40) and a control group (n = 40). Read More

    Metabolic causes of nonimmune hydrops fetalis: A next-generation sequencing panel as a first-line investigation.
    Clin Chim Acta 2018 Jun 22;481:1-8. Epub 2018 Feb 22.
    Department of Metabolic Biochemistry, Rouen University Hospital, Rouen 76000, France; Normandie Univ, UNIROUEN, CHU Rouen, INSERM U1245, 76000 Rouen, France. Electronic address:
    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. Read More

    Niemann-Pick C2 Proteins: A New Function for an Old Family.
    Front Physiol 2018 31;9:52. Epub 2018 Jan 31.
    State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.
    Niemann-Pick proteins type C2 (NPC2) are carriers of cholesterol in vertebrates, with a single member in each species. The high sequence conservation between mammals and across vertebrates is related to their common function. In contrast, NPC2 proteins in arthropods have undergone extensive duplication and differentiation, probably under environmental pressure, and are likely to have different functions. Read More

    Duodenal Niemann-Pick C1-like 1 expression was negatively correlated with liver X receptor expression in nonalcoholic fatty liver disease.
    Korean J Intern Med 2018 Feb 23. Epub 2018 Feb 23.
    College of Pharmacy, The Catholic University of Korea, Bucheon, Korea.
    Background/aims: Intestinal cholesterol absorption includes intestinal Niemann-Pick C1-like 1 (NPC1L1) and is an important target pathway in nonalcoholic fatty liver disease (NAFLD). We investigated the expression of NPC1L1 and its correlation with liver X receptor (LXR) expression in peripheral mononuclear (PMN) cells in patients with NAFLD.

    Methods: We evaluated intestinal expression of NPC1L1 in 25 NAFLD patients and 28 healthy controls. Read More

    Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice.
    Sci Rep 2018 Feb 20;8(1):3318. Epub 2018 Feb 20.
    Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, D-18147, Rostock, Germany.
    Niemann-Pick disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease. NPC1-patients suffer, amongst others, from ataxia, based on a loss of cerebellar Purkinje cells (PCs). Impaired expression/function of excitatory amino acid transporters (EAATs) are suspected of contributing to PC-degeneration in hereditary spinocerebellar ataxias (SCAs). Read More

    Systematic review of psychiatric signs in Niemann-Pick disease type C.
    World J Biol Psychiatry 2018 Mar 12:1-13. Epub 2018 Mar 12.
    e Royal Melbourne Hospital , Melbourne , Australia.
    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; and (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.

    Results: Of 152 identified publications 40 were included after screening that contained useable data from 58 NPC patients (mean [SD] age at diagnosis of NPC 27. Read More

    Probable Diagnosis of a Patient with Niemann-Pick Disease Type C: Managing Pitfalls of Exome Sequencing.
    JIMD Rep 2018 Feb 17. Epub 2018 Feb 17.
    Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
    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. Read More

    The erythrocyte osmotic resistance test as screening tool for cholesterol-related lysosomal storage diseases.
    Clin Chim Acta 2018 May 13;480:161-165. Epub 2018 Feb 13.
    Instituto de Investigación Sanitaria Aragón (IIS Aragón) GIIS-012, Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza 50009, Spain; Fundación para el Estudio y la Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), Zaragoza 50009, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) U-752, Zaragoza 50009, Spain.
    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. Read More

    Secondary Hemophagocytic Syndrome Associated with COG6 Gene Defect: Report and Review.
    JIMD Rep 2018 Feb 15. Epub 2018 Feb 15.
    King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.
    Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease that is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. Clinically, it is characterized by prolonged fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. It can be classified as primary if it is due to a genetic defect, or secondary if it is due to a different etiology such as severe infection, immune deficiency syndrome, rheumatological disorder, malignancy, and inborn errors of metabolism such as galactosemia, multiple sulfatase deficiency, lysinuric protein intolerance, Gaucher disease, Niemann-Pick disease, Wolman disease, propionic acidemia, methylmalonic acidemia, biotinidase deficiency, cobalamin C defect, galactosialidosis, Pearson syndrome, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Read More

    Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update.
    Neurol Clin Pract 2017 Dec;7(6):499-511
    Mayo Clinic (MCP), Rochester, MN; UCL Great Ormond Street Institute of Child Health (PC, PG), London, UK; Great Ormond Street Hospital (PG), London, UK; Département de Neurologie (MA), Hôpital de Hautepierre, CHU de Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (MA), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch; Fédération de Médecine Translationnelle de Strasbourg (FMTS) (MA), Université de Strasbourg, France; Institute of Medical Genetics and Applied Genomics (PB), University Hospital of Tübingen; Centogene AG (PB), Rostock, Germany; Universitaire de Psychiatrie de l'Enfant et de l'Adolescent (OB), CHU de Nantes, France; Regional Coordinator Centre for Rare Diseases (AD), University Hospital Santa Maria della Misericordia, Udine, Italy; Division of Metabolism, Bambino Gesù Children's Hospital (CD-V), Rome, Italy; Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie der Universität Regensburg am Bezirksklinikum (H-HK), Regensburg, Germany; Hospices Civils de Lyon-Centre de Biologie et Pathologie Est (PL), Bron, France; University of São Paulo (HCFMRP-USP) (CML), Ribeirão Preto, SP, Brazil; Department of Medicine (DSO), Washington University, St Louis, MO; Child Development Centre (AP), Addenbrooke's Hospital, Cambridge, UK; University of Zaragoza (MP), IIS Aragon, Spain; Department of Neurology and German Center for Vertigo and Balance Disorders (MS), University Hospital Munich, Germany; Laboratoire Gillet-Mérieux (MTV), Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France; Department of Neuropsychiatry (MW), Royal Melbourne Hospital & University of Melbourne, Australia; and Universitätsklinikum Münster (TM), Germany.
    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. Read More

    TDP-43 post-translational modifications in health and disease.
    Expert Opin Ther Targets 2018 Mar 20;22(3):279-293. Epub 2018 Feb 20.
    a Department of Molecular Pathology , International Centre for Genetic Engineering and Biotechnology (ICGEB) , Trieste , Italy.
    Introduction: 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. Read More

    Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-β-Cyclodextrin.
    Pediatr Neurol 2018 Mar 8;80:24-34. Epub 2018 Jan 8.
    Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois; Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois.
    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 2.5 to three years in humans with Niemann-Pick disease, type C, were evaluated. Read More

    A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened.
    J Appl Genet 2018 May 6;59(2):187-191. Epub 2018 Feb 6.
    Department of Pediatrics, University of Arizona College of Medicine, Tucson, AZ, USA.
    We have tested the efficacy of hydroxypropyl-beta-cyclodextrin (HPBCD) delivered by the nasal route in the mouse model of juvenile Niemann-Pick C1 disease (NPC1), as pulmonary disease has not responded to systemic therapy with this drug. Since mice have no gag reflex, coating of the nasal cavity, with possible access to the brain, would be followed by delivery of HPBCD to the lung. While foamy macrophages, containing stored cholesterol, were found in the Npc1 homozygous mice, a marked inflammatory response was found with inhaled HPBCD, both in mutant and wild-type animals. Read More

    Lovastatin promotes myelin formation in NPC1 mutant oligodendrocytes.
    J Neurol Sci 2018 Mar 12;386:56-63. Epub 2018 Jan 12.
    Albrecht-Kossel-Institute for Neuroregeneration, School of Medicine University of Rostock, Gehlsheimer Strasse 20, 18147 Rostock, Germany; Centre for Transdisciplinary Neuroscience Rostock, School of Medicine University of Rostock, Gehlsheimer Strasse 20, 18147 Rostock, Germany. Electronic address:
    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. Furthermore, in in vitro oligodendrocyte cultivation, NPC1 oligodendrocytes showed less response to the stimulation of neuron-conditioned medium (CdM), indicating a defect of oligodendrocyte per se. Read More

    The role of Purkinje cell-derived VEGF in cerebellar astrogliosis in Niemann-Pick type C mice.
    BMB Rep 2018 Feb;51(2):79-84
    Stem Cell Neuroplasticity Research Group, Kyungpook National University, Daegu 41566; Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea.
    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. Read More

    [Clinical features and gene mutation analysis of patients with Niemann-Pick disease type C].
    Zhonghua Yi Xue Za Zhi 2018 Jan;98(4):284-288
    Department of Pediatric, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
    To analyze the clinical manifestations, therapeutic efficacy, prognosis and characteristics of NPC1 mutation in Chinese patients with Niemann-Pick disease type C(NPC). Ten unrelated Chinese NPC patients were diagnosed by NPC1 mutation analysis from July 2013 to February 2017 in Beijing Tian Tan Hospital of Capital Medical University. Clinical data of 10 cases were analyzed retrospectively which included clinical manifestations, laboratory results and NPC1 gene mutation features, and a series of follow-up were carried out about therapeutic efficacy and prognosis. Read More

    Niemann-Pick Disease Type C Associated with Fuchs Heterochromic Iridocyclitis.
    Adv Biomed Res 2017 28;6:168. Epub 2017 Dec 28.
    Department of Ophthalmology, Eye Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran.
    In this study, we report a 26-year-old female case of Niemann-Pick disease type C in association with Fuchs heterochromic iridocyclitis who was admitted with the complaint of ocular pain and redness following trauma. She had mild inflammatory signs and also vertical ocular motility limitations. Read More

    Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency.
    Orphanet J Rare Dis 2018 Jan 27;13(1):24. Epub 2018 Jan 27.
    Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132, Genoa, Italy.
    Background: Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Read More

    Alpha galactosidase A activity in Parkinson's disease.
    Neurobiol Dis 2018 Apr 2;112:85-90. Epub 2018 Feb 2.
    Translational Sciences, Sanofi R&D, Framingham, MA, USA.
    Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Read More

    N-glycome of the Lysosomal Glycocalyx is Altered in Niemann-Pick Type C Disease (NPC) Model Cells.
    Mol Cell Proteomics 2018 Apr 24;17(4):631-642. Epub 2018 Jan 24.
    From the ‡Laboratory for Neurodegenerative Disease Research, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia;
    Increasing evidence implicates lysosomal dysfunction in the pathogenesis of neurodegenerative diseases, including the rare inherited lysosomal storage disorders (LSDs) and the most common neurodegenerative diseases, such as Alzheimer's and Parkinson's disease (AD and PD). Although the triggers of the lysosomal impairment may involve the accumulated macromolecules or dysfunction of the lysosomal enzymes, the role of the lysosomal glycocalyx in the lysosomal (dys)function has not been studied. The goal of this work was to analyze whether there are changes in the lysosomal glycocalyx in a cellular model of a LSD Niemann-Pick type C disease (NPC). Read More

    [Niemann-Pick type C disease in a child].
    Zh Nevrol Psikhiatr Im S S Korsakova 2017 ;117(11. Vyp. 2):62-66
    Research Centre of Medical Genetics, Russian Academy of Sciences, Moscow, Russia.
    The authors consider a clinical case of Niemann-Pick disease type C, an orphan hereditary autosomal recessive neurodegenerative disease belonging to the group of lysosomal storage disease, in an 11-year female patient with the late infantile form of the disease. The combination of psychomotor retardation, polymorphic neurological symptoms and physical changes in the form of isolated splenomegaly suggested the diagnosis of Niemann-Pick type C disease. DNA testing was carried out using direct automated sequencing. Read More

    Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases.
    Orphanet J Rare Dis 2018 Jan 22;13(1):18. Epub 2018 Jan 22.
    Niemann-Pick UK, Suite 2, Vermont House, Concord, Washington, Tyne and Wear, NE37 2SQ, UK.
    Background: Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Read More

    Gastrointestinal Tract Pathology in a BALB/c Niemann-Pick Disease Type C1 Null Mouse Model.
    Dig Dis Sci 2018 Apr 22;63(4):870-880. Epub 2018 Jan 22.
    Department of Health and Human Services, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, 20892, USA.
    Background: Niemann-Pick disease, type C (NPC) is a rare lysosomal storage disorder characterized by progressive neurodegeneration, splenomegaly, hepatomegaly, and early death. NPC is caused by mutations in either the NPC1 or NPC2 gene. Impaired NPC function leads to defective intracellular transport of unesterified cholesterol and its accumulation in late endosomes and lysosomes. Read More

    Assessment of Neurodegeneration in Type C Niemann-Pick Disease by IDEAL-IQ.
    Korean J Radiol 2018 Jan-Feb;19(1):93-100. Epub 2018 Jan 2.
    Department of Radiology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
    Objective: To noninvasively assess the neurodegenerative changes in the brain of patients with Niemann-Pick type C (NPC) disease by measuring the lesion tissue with the iterative decomposition of water and fat with echo asymmetry and least square estimation-iron quantification (IDEAL-IQ).

    Materials And Methods: Routine brain MRI, IDEAL-IQ and H-proton magnetic resonance spectroscopy (H-MRS, served as control) were performed on 12 patients with type C Niemann-Pick disease (4 males and 8 females; age range, 15-61 years; mean age, 36 years) and 20 healthy subjects (10 males and 10 females; age range, 20-65 years; mean age, 38 years). The regions with lesion and the normal appearing regions (NARs) of patients were measured and analyzed based on the fat/water signal intensity on IDEAL-IQ and the lipid peak on H-MRS. Read More

    LC3 Immunostaining in the Inferior Olivary Nuclei of Cats With Niemann-Pick Disease Type C1 Is Associated With Patterned Purkinje Cell Loss.
    J Neuropathol Exp Neurol 2018 Mar;77(3):229-245
    Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    The feline model of Niemann-Pick disease, type C1 (NPC1) recapitulates the clinical, neuropathological, and biochemical abnormalities present in children with NPC1. The hallmarks of disease are the lysosomal storage of unesterified cholesterol and multiple sphingolipids in neurons, and the spatial and temporal distribution of Purkinje cell death. In feline NPC1 brain, microtubule-associated protein 1 light chain 3 (LC3) accumulations, indicating autophagosomes, were found within axons and presynaptic terminals. Read More

    Niemann-Pick disease type B: HRCT assessment of pulmonary involvement.
    J Bras Pneumol 2017 Nov-Dec;43(6):451-455
    . Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil.
    Objective: To analyze HRCT findings in patients with Niemann-Pick disease (NPD) type B, in order to determine the frequency of HRCT patterns and their distribution in the lung parenchyma, as well as the most common clinical characteristics.

    Methods: We studied 13 patients (3 males and 10 females) aged 5 to 56 years. HRCT images were independently evaluated by two observers, and disagreements were resolved by consensus. Read More

    The Extending Spectrum of NPC1-Related Human Disorders: From Niemann-Pick C1 Disease to Obesity.
    Endocr Rev 2018 Apr;39(2):192-220
    Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
    The Niemann-Pick type C1 (NPC1) protein regulates the transport of cholesterol and fatty acids from late endosomes/lysosomes and has a central role in maintaining lipid homeostasis. NPC1 loss-of-function mutations in humans cause NPC1 disease, a rare autosomal-recessive lipid-storage disorder characterized by progressive and lethal neurodegeneration, as well as liver and lung failure, due to cholesterol infiltration. In humans, genome-wide association studies and post-genome-wide association studies highlight the implication of common variants in NPC1 in adult-onset obesity, body fat mass, and type 2 diabetes. Read More

    Fourier Transform Infrared Microscopy Enables Guidance of Automated Mass Spectrometry Imaging to Predefined Tissue Morphologies.
    Sci Rep 2018 Jan 10;8(1):313. Epub 2018 Jan 10.
    Center for Applied Research in Applied Biomedical Mass Spectrometry (ABIMAS), Mannheim University of Applied Sciences, Paul-Wittsack Str. 10, 68163, Mannheim, Germany.
    Multimodal imaging combines complementary platforms for spatially resolved tissue analysis that are poised for application in life science and personalized medicine. Unlike established clinical in vivo multimodality imaging, automated workflows for in-depth multimodal molecular ex vivo tissue analysis that combine the speed and ease of spectroscopic imaging with molecular details provided by mass spectrometry imaging (MSI) are lagging behind. Here, we present an integrated approach that utilizes non-destructive Fourier transform infrared (FTIR) microscopy and matrix assisted laser desorption/ionization (MALDI) MSI for analysing single-slide tissue specimen. Read More

    Subcellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases.
    Nano Lett 2018 Feb 17;18(2):1351-1359. Epub 2018 Jan 17.
    Department of Physics, ‡Department of Chemistry, and §Grossman Institute of Neuroscience, Quantitative Biology and Human Behavior, University of Chicago , Chicago, Illinois 60637, United States.
    We describe a new method to measure viscosity within subcellular organelles of a living cell using nanorheology. We demonstrate proof of concept by measuring viscosity in lysosomes in multiple cell types and disease models. The lysosome is an organelle responsible for the breakdown of complex biomolecules. Read More

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