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    Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience.
    J Pediatr 2017 Jul 17. Epub 2017 Jul 17.
    Newborn Screening Laboratory, Illinois Department of Public Health, Chicago, IL; Division of Laboratory Services, Tennessee Department of Health, Nashville, TN.
    Objectives: To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois.

    Study Design: Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago.

    Results: The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p. Read More

    The role of macrophages in interstitial lung diseases: Number 3 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.
    Eur Respir Rev 2017 Sep 19;26(145). Epub 2017 Jul 19.
    Unit of Pathologic Anatomy, Azienda ULSS 13, Hospital of Dolo, Dolo, Italy.
    The finding of collections of macrophages/histiocytes in lung biopsy and bronchoalveolar lavage is relatively common in routine practice. This morphological feature in itself is pathological, but the exact clinical significance and underlying disease should be evaluated together with clinical data, functional respiratory and laboratory tests and imaging studies.Morphological characteristics of macrophages and their distribution along the different pulmonary structures should be examined carefully by pathologists. Read More

    Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat.
    JIMD Rep 2017 Jul 15. Epub 2017 Jul 15.
    Neuropsychiatry Unit, Royal Melbourne Hospital, Melbourne, VIC, Australia.
    Niemann-Pick disease type C (NPC) is a rare neurometabolic disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment currently available is miglustat, an iminosugar that inhibits the accumulation of lipid metabolites in neurons and other cells. This longitudinal diffusion tensor imaging (DTI) study examined how the rate of white matter change differed between treated and non-treated adult-onset NPC patient groups. Read More

    Modulating cancer cell survival by targeting intracellular cholesterol transport.
    Br J Cancer 2017 Jul 11. Epub 2017 Jul 11.
    Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
    Background: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis. Read More

    Patient With Niemann-Pick Type C Presenting With a Jaw Mass Characterized With Lymph Node Involvement by Niemann-Pick Cells.
    J Pediatr Hematol Oncol 2017 Jul 7. Epub 2017 Jul 7.
    *Division of Pediatric Metabolism and Nutrition †Department of Pathology ‡Division of Pediatric Haematology and Oncology, Gazi University Hospital, Ankara, Turkey.
    Niemann-Pick type C disease (NPC) is an autosomal recessive disorder resulting in accumulation of unesterified lysosomal cholesterol. An 8-year-old girl with NPC disease had a painless, rigid, and fixed mass measuring 3 cm in diameter located on the left angular region of mandibula. The mass biopsy showed lipid-laden phagocytic cells infiltrating the lymph node consistent with Niemann-Pick cells. Read More

    Overview of immune abnormalities in lysosomal storage disorders.
    Immunol Lett 2017 Aug 4;188:79-85. Epub 2017 Jul 4.
    Centro Italiano Macula, Rome, Italy.
    The critical relevance of the lysosomal compartment for normal cellular function can be proved by numbering the clinical phenotypes that arise in lysosomal storage disorders (LSDs), a group of around 70 different monogenic autosomal or X-linked syndromes, caused by specific lysosomal enzyme deficiencies: all LSDs are characterized by progressive accumulation of heterogeneous biologic materials in the lysosomes of various parts of the body such as viscera, skeleton, skin, heart, and central nervous system. At least a fraction of LSDs has been associated with mixed abnormalities involving the immune system, while some patients with LSDs may result more prone to autoimmune phenomena. A large production of proinflammatory cytokines has been observed in Gaucher and Fabry diseases, and wide different autoantibody production has been also reported in both. Read More

    Expanded carrier screening for monogenic disorders: Where are we now?
    Prenat Diagn 2017 Jul 6. Epub 2017 Jul 6.
    Centre for Biomedical Ethics and Law, Department of Public Health and Primary Care, University of Leuven, Belgium.
    Background: Expanded carrier screening (ECS), which can identify carriers of a large number of recessive disorders in the general population, has grown in popularity and is now widely accessible to prospective parents. This article presents a comprehensive overview of the characteristics of currently available ECS tests.

    Methods: To identify relevant ECS providers, we employed a multi-step approach, which included online searching, review of the recent literature, and consultations with researchers familiar with the current landscape of ECS. Read More

    Early Hippocampal i-LTP and LOX-1 Overexpression Induced by Anoxia: A Potential Role in Neurodegeneration in NPC Mouse Model.
    Int J Mol Sci 2017 Jul 5;18(7). Epub 2017 Jul 5.
    Department of Medical System, University of Rome Tor Vergata, Rome 00133, Italy.
    Niemann-Pick type C disease (NPCD) is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endo-lysosomal compartment of cells. In the central nervous system, hypoxic insults could result in low-density lipoprotein (LDL) oxidation and Lectin-like oxidized LDL receptor-1 (LOX-1) induction, leading to a pathological hippocampal response, namely, ischemic long-term potentiation (i-LTP). These events may correlate with the progressive neural loss observed in NPCD. Read More

    Decreased calcium flux in Niemann-Pick type C1 patient-specific iPSC-derived neurons due to higher amount of calcium-impermeable AMPA receptors.
    Mol Cell Neurosci 2017 Jun 27;83:27-36. Epub 2017 Jun 27.
    Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, D-18147 Rostock, Germany. Electronic address:
    Niemann-Pick disease type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene, resulting mainly in the accumulation of cholesterol and the ganglioside GM2. Recently, we described accumulations of these lipids in neuronal differentiated cells derived from NPC1 patient-specific induced pluripotent stem cells (iPSCs). As these lipids are essential for proper cell membrane composition, we were interested in the expression and function of voltage-gated ion channels and excitatory AMPA receptors (AMPARs) in neurons derived from three patient-specific iPSC lines. Read More

    ICAM-1 targeting, intracellular trafficking, and functional activity of polymer nanocarriers coated with a fibrinogen-derived peptide for lysosomal enzyme replacement.
    J Drug Target 2017 Jul 14:1-10. Epub 2017 Jul 14.
    b Institute for Bioscience & Biotechnology Research , University of Maryland , College Park , MD , USA.
    Enzyme replacement is a viable treatment for diseases caused by genetic deficiency of lysosomal enzymes. However, suboptimal access of enzymes to target sites limits this strategy. Polymer nanocarriers (NCs) coated with antibody against intercellular adhesion molecule 1 (ICAM-1), a protein overexpressed on most cells under disease states, enhanced biodistribution and lysosomal delivery of these therapeutics. Read More

    Cognition and anatomy of adult Niemann-Pick disease type C: Insights for the Alzheimer field.
    Cogn Neuropsychol 2017 Jun 30:1-14. Epub 2017 Jun 30.
    a Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques , CHU de Québec , Quebec City , Quebec , Canada.
    Niemann-Pick disease type C (NPC) is a rare lysosomal storage disorder causing an intracellular lipid trafficking defect and varying damage to the spleen, liver, and central nervous system. The adult form, representing approximately 20% of the cases, is associated with progressive cognitive decline. Intriguingly, brains of adult NPC patients exhibit neurofibrillary tangles, a characteristic hallmark of Alzheimer's disease (AD). Read More

    The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes.
    Cell Rep 2017 Jun;19(13):2823-2835
    Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China. Electronic address:
    Proper intracellular cholesterol trafficking is critical for cellular function. Two lysosome-resident proteins, NPC1 and NPC2, mediate the egress of low-density lipoprotein-derived cholesterol from lysosomes. However, other proteins involved in this process remain largely unknown. Read More

    Analytical Characterization of Methyl-β-Cyclodextrin for Pharmacological Activity to Reduce Lysosomal Cholesterol Accumulation in Niemann-Pick Disease Type C1 Cells.
    Assay Drug Dev Technol 2017 May/Jun;15(4):154-166
    1 National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda, Maryland.
    Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Read More

    Impact of the Niemann-Pick c1 Gene Mutation on the Total Cellular Glycomics of CHO Cells.
    J Proteome Res 2017 Jul 3. Epub 2017 Jul 3.
    Graduate School of Advanced Life Science, Hokkaido University , Sapporo 001-0021, Japan.
    Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, and the majority of cases are caused by mutations in the NPC1 gene. In this study, we clarified how a single gene mutation in the NPC1 gene impacts the cellular glycome by analyzing the total glycomic expression profile of Chinese hamster ovary cell mutants defective in the Npc1 gene (Npc1 KO CHO cells). A number of glycomic alterations were identified, including increased expression of lactosylceramide, GM1, GM2, GD1, various neolacto-series glycosphingolipids, and sialyl-T (O-glycan), which was found to be the major sialylated protein-bound glycan, as well as various N-glycans, which were commonly both fucosylated and sialylated. Read More

    Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments.
    FEBS J 2017 Jun 19. Epub 2017 Jun 19.
    Izmir International Biomedicine and Genome Institute (iBG-izmir), Dokuz Eylul University, Izmir, Turkey.
    While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Read More

    Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK.
    Autophagy 2017 Jun 14. Epub 2017 Jun 14.
    a National Center for Advancing Translational Sciences (NCATS), NIH , Bethesda , MD 20892 , USA.
    The drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease, type C (NPC) and has been advanced to human clinical trials. However, its mechanism of action for reducing cholesterol accumulation in NPC cells is uncertain and its molecular target is unknown. We found that methyl-β-cyclodextrin (MβCD), a potent analog of HPβCD, restored impaired macroautophagy/autophagy flux in Niemann-Pick disease, type C1 (NPC1) cells. Read More

    N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV.
    Neurobiol Dis 2017 Sep 10;105:257-270. Epub 2017 Jun 10.
    Dominick P. Purpura Dept. of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:
    Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Read More

    Enhanced Delivery and Effects of Acid Sphingomyelinase by ICAM-1-Targeted Nanocarriers in Type B Niemann-Pick Disease Mice.
    Mol Ther 2017 Jul 9;25(7):1686-1696. Epub 2017 Jun 9.
    Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, MD 20742, USA; Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA. Electronic address:
    Acid sphingomyelinase deficiency in type B Niemann-Pick disease leads to lysosomal sphingomyelin storage, principally affecting lungs, liver, and spleen. Infused recombinant enzyme is beneficial, yet its delivery to the lungs is limited and requires higher dosing than liver and spleen, leading to potentially adverse reactions. Previous studies showed increased enzyme pulmonary uptake by nanocarriers targeted to ICAM-1, a protein overexpressed during inflammation. Read More

    Imipramine Inhibits Chikungunya Virus Replication in Human Skin Fibroblasts through Interference with Intracellular Cholesterol Trafficking.
    Sci Rep 2017 Jun 9;7(1):3145. Epub 2017 Jun 9.
    Laboratoire MIVEGEC, UMR 224 IRD/CNRS/UM1, Montpellier cedex 5, 34394, France.
    Chikungunya virus (CHIKV) is an emerging arbovirus of the Togaviridae family that poses a present worldwide threat to human in the absence of any licensed vaccine or antiviral treatment to control viral infection. Here, we show that compounds interfering with intracellular cholesterol transport have the capacity to inhibit CHIKV replication in human skin fibroblasts, a major viral entry site in the human host. Pretreatment of these cells with the class II cationic amphiphilic compound U18666A, or treatment with the FDA-approved antidepressant drug imipramine resulted in a near total inhibition of viral replication and production at the highest concentration used without any cytotoxic effects. Read More

    Induced pluripotent stem cell models of lysosomal storage disorders.
    Dis Model Mech 2017 Jun;10(6):691-704
    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models. Read More

    Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole.
    Elife 2017 Jun 7;6. Epub 2017 Jun 7.
    Department of Molecular Cell Biology and Anatomy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
    Niemann-Pick type C is a storage disease caused by dysfunction of NPC proteins, which transport cholesterol from the lumen of lysosomes to the limiting membrane of that compartment. Using freeze fracture electron microscopy, we show here that the yeast NPC orthologs, Ncr1p and Npc2p, are essential for formation and expansion of raft-like domains in the vacuolar (lysosome) membrane, both in stationary phase and in acute nitrogen starvation. Moreover, the expanded raft-like domains engulf lipid droplets by a microautophagic mechanism. Read More

    Miglustat therapy in a case of early-infantile Niemann-Pick type C.
    Brain Dev 2017 Jun 3. Epub 2017 Jun 3.
    Department of Pediatrics, Jichi Medical University, Tochigi, Japan. Electronic address:
    Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPC1 or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Read More

    Ocular findings in patients with cholestatic disorders of infancy: A single-centre experience.
    Arab J Gastroenterol 2017 Jun 3;18(2):108-113. Epub 2017 Jun 3.
    Faculty of Pharmacy, Misr International University, Cairo, Egypt.
    Background And Study Aims: Neonatal cholestasis can be associated with ocular findings that might aid in its diagnosis, e.g., Alagille syndrome (AGS) and Niemann Pick disease (NPD). Read More

    Niemann-Pick type C as a cause of progressive intellectual and neurological deterioration in childhood.
    Dev Med Child Neurol 2017 Jun 2. Epub 2017 Jun 2.
    PIND Research Group, Addenbrooke's Hospital, Cambridge, UK.
    Aim: To describe the cases of Niemann-Pick type C (NP-C) disease in a United Kingdom epidemiological study of progressive intellectual and neurological deterioration in childhood.

    Method: Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015.

    Results: Fifty-three NP-C patients were identified: 29 females, 24 males. Read More

    Rapid whole genome sequencing identifies a novel homozygous NPC1 variant associated with Niemann-Pick Type C1 Disease in a 7 week old male with cholestasis.
    Cold Spring Harb Mol Case Stud 2017 May 26. Epub 2017 May 26.
    Rady Children's Institute for Genomic Medicine;
    Niemann-Pick Type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in NPC1. While characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction due to intrahepatocyte lipid accumulation. Read More

    ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.
    Brain 2017 Jun;140(6):1595-1610
    Department of Clinical Neurosciences, Institute of Neurology, Royal Free Campus, University College London, NW3 2PF, UK.
    Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Read More

    Quantitative magnetic resonance imaging of brain atrophy in a mouse model of Niemann-Pick type C disease.
    PLoS One 2017 24;12(5):e0178179. Epub 2017 May 24.
    Biomedical Engineering Program, University of Arizona, Tucson, Arizona, United States of America.
    In vivo magnetic resonance imaging (MRI) was used to investigate regional and global brain atrophy in the neurodegenerative Niemann Pick Type C1 (NPC1) disease mouse model. Imaging experiments were conducted with the most commonly studied mouse model of NPC1 disease at early and late disease states. High-resolution in vivo images were acquired at early and late stages of the disease and analyzed with atlas-based registration to obtain measurements of twenty brain region volumes. Read More

    Deviant lysosomal Ca(2+) signalling in neurodegeneration. An introduction.
    Messenger (Los Angel) 2016 Jun;5(1-2):24-29
    Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT.
    Lysosomes are key acidic Ca(2+) stores. The principle Ca(2+)-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca(2+) store content. Read More

    Afr J Infect Dis 2016 1;10(2):69-88. Epub 2016 May 1.
    Epidemiology, Molecular Virology, and Special Pathogens Research, Department of Microbiology, Adekunle Ajasin University, P.M.B. 001, Akungba Akoko, Ondo state, Nigeria.
    Background: Owing to the extreme virulence and case fatality rate of ebola virus disease (EVD), there had been so much furore, panic and public health emergency about the possible pandemic from the recent West African outbreak of the disease, with attendant handful research, both in the past and most recently. The magnitude of the epidemic of ebola virus disease has prompted global interest and urgency in the discovery of measures to mitigate the impact of the disease. Researchers in the academia and the industry were pressured to only focus on the development of effective and safe ebola virus vaccines, without consideration of the other aspects to this virus, which may influence the success or otherwise of a potential vaccine. Read More

    Cataplexy and Its Mimics: Clinical Recognition and Management.
    Curr Treat Options Neurol 2017 Jun;19(6):23
    Sleep Medicine Center Kempenhaeghe, P.O. Box 61, , 5590 AB, Heeze, The Netherlands.
    Opinion Statement: This review describes the diagnosis and management of cataplexy: attacks of bilateral loss of muscle tone, triggered by emotions and with preserved consciousness. Although cataplexy is rare, its recognition is important as in most cases, it leads to a diagnosis of narcolepsy, a disorder that still takes a median of 9 years to be diagnosed. The expression of cataplexy varies widely, from partial episodes affecting only the neck muscles to generalized attacks leading to falls. Read More

    Linking mitochondrial dysfunction to neurodegeneration in lysosomal storage diseases.
    J Inherit Metab Dis 2017 May 5. Epub 2017 May 5.
    Department of Neurology, Harvard Medical School, Boston Children's Hospital, 3 Blackfan Circle, CLS 14060, Boston, MA, 02115, USA.
    Lysosomal storage diseases (LSD) are inborn errors of metabolism resulting in multisystem disease. Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD. Available treatments fail to prevent or correct neurologic symptoms and decline. Read More

    Novel NPC1 mutations with different segregation in two related Greek patients with Niemann-Pick type C disease: molecular study in the extended pedigree and clinical correlations.
    BMC Med Genet 2017 May 4;18(1):51. Epub 2017 May 4.
    Third Department of Pediatrics, Athens University Medical School, University General Hospital "Attikon", 1 Rimini Str, 12464 -Haidari, Athens, Greece.
    Background: Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse.

    Methods: The study population consisted of two Greek NPC patients and their extended pedigree. Read More

    Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein.
    Bioorg Med Chem Lett 2017 Jun 22;27(12):2781-2787. Epub 2017 Apr 22.
    Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; RIKEN, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan. Electronic address:
    Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Read More

    Functional characterization of a Niemann-Pick type C2 protein in the parasitoid wasp Microplitis mediator.
    Insect Sci 2017 Apr 29. Epub 2017 Apr 29.
    State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
    Niemann-Pick type C2 (NPC2) is a type of small soluble protein involved in lipid metabolism and triglyceride accumulation in vertebrates and arthropods. Recent studies have determined that NPC2 also participates in chemical communication of arthropods. In this work, two novel NPC2 proteins (MmedNPC2a and MmedNPC2b) in Microplitis mediator were identified. Read More

    Prenatal Diagnosis of Lysosomal Storage Disorders Using Chorionic Villi.
    Methods Mol Biol 2017 ;1594:265-291
    Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.
    Prenatal enzymatic diagnosis for an array of lysosomal storage disorders (LSDs) can be performed accurately, provided that a confirmed diagnosis by biochemical/molecular study in the index case is available and a strict defined protocol, specific to each individual disorder is followed. The present chapter describes the protocols for reliable and accurate prenatal enzymatic diagnoses by fluorometric and spectrophotometric methods of lysosomal storage disorders: Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandhoff, GM1, Mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy, and Batten diseases using uncultured chorionic villi samples. The biological reference intervals for enzyme levels in normal and affected fetuses are given for interpretation of prenatal results. Read More

    Quantitative Co-Localization and Pattern Analysis of Endo-Lysosomal Cargo in Subcellular Image Cytometry and Validation on Synthetic Image Sets.
    Methods Mol Biol 2017 ;1594:93-128
    Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark.
    Late endosomes and lysosomes (LE/LYSs) play a central role in trafficking of endocytic cargo, secretion of exosomes, and hydrolysis of ingested proteins and lipids. Failure in such processes can lead to lysosomal storage disorders in which a particular metabolite accumulates within LE/LYSs. Analysis of endocytic trafficking relies heavily on quantitative fluorescence microscopy, but evaluation of the huge image data sets is challenging and demands computer-assisted statistical tools. Read More

    Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease.
    Sci Rep 2017 Apr 28;7:46737. Epub 2017 Apr 28.
    Department of Chemistry, Purdue University, Multi-disciplinary Cancer Research Facility, 1203 W, State Street, West Lafayette, Indiana 47907, United States.
    Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as a potential NPC therapeutic by extending lifetime in NPC mice, delaying neurodegeneration, and decreasing visceral and neurological cholesterol burden. Read More

    Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult.
    Front Neurol 2017 4;8:108. Epub 2017 Apr 4.
    Department of Neurology, University Hospital Freiburg, Freiburg im Breisgau, Germany.
    Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). Read More

    Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1.
    PLoS One 2017 17;12(4):e0175478. Epub 2017 Apr 17.
    Vtesse, Inc., Gaithersburg, MD, United States of America.
    2-Hydroxypropyl-beta-cyclodextrin (HPβCD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HPβCD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. Read More

    Dataset in support of the generation of Niemann-Pick disease Type C1 patient-specific iPS cell lines carrying the novel NPC1 mutation c.1180T>C or the prevalent c.3182T>C mutation - Analysis of pluripotency and neuronal differentiation.
    Data Brief 2017 Jun 2;12:123-131. Epub 2017 Apr 2.
    Albrecht-Kossel-Institute for Neuroregeneration (AKos), University Medicine Rostock, Gehlsheimer Straße 20, 18147 Rostock, Germany.
    Data presented in this article demonstrate the generation and characterization of two novel Niemann-Pick disease Type C1 (NPC1) patient-specific induced pluripotent stem cell (iPSC) lines, related to the research article Trilck et al. (Diversity of Glycosphingolipid GM2 and Cholesterol Accumulation in NPC1 Patient-Specific iPSC-Derived Neurons; Brain Res.; 2017; 1657:52-61. Read More

    The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection.
    PLoS Negl Trop Dis 2017 Apr 12;11(4):e0005540. Epub 2017 Apr 12.
    Department of Cell Biology, University of Virginia, Charlottesville, Virginia, United States of America.
    Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase involved in endosome maturation that emerged from a haploid genetic screen as being required for Ebola virus (EBOV) infection. Here we analyzed the effects of apilimod, a PIKfyve inhibitor that was reported to be well tolerated in humans in phase 2 clinical trials, for its effects on entry and infection of EBOV and Marburg virus (MARV). We first found that apilimod blocks infections by EBOV and MARV in Huh 7, Vero E6 and primary human macrophage cells, with notable potency in the macrophages (IC50, 10 nM). Read More

    Niemann-Pick type C disease - the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment.
    BJPsych Bull 2017 Apr;41(2):109-114
    The Mark Holland Metabolic Unit, Salford Royal Foundation NHS Trust, Manchester, UK.
    Niemann-Pick type C (NP-C) disease is a rare neurodegenerative lysosomal storage disorder. It is highly heterogeneous, and there is limited awareness of a substantial subgroup that has an attenuated adolescent/adult-onset disease. In these patients psychiatric features, often a psychosis, may dominate the initial impression, although often there is an associated ataxia and cognitive impairment. Read More

    Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C.
    Neuropathology 2017 Apr 7. Epub 2017 Apr 7.
    Department of Developmental Medical Sciences, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
    Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. Read More

    Direct administration of 2-Hydroxypropyl-Beta-Cyclodextrin into guinea pig cochleae: Effects on physiological and histological measurements.
    PLoS One 2017 6;12(4):e0175236. Epub 2017 Apr 6.
    Washington University School of Medicine Department of Otolaryngology Saint Louis, Missouri, United States of America.
    2-Hydroxypropyl-Beta-Cyclodextrin (HPβCD) can be used to treat Niemann-Pick type C disease, Alzheimer's disease, and atherosclerosis. But, a consequence is that HPβCD can cause hearing loss. HPβCD was recently found to be toxic to outer hair cells (OHCs) in the organ of Corti. Read More

    Increased Regenerative Capacity of the Olfactory Epithelium in Niemann-Pick Disease Type C1.
    Int J Mol Sci 2017 Apr 6;18(4). Epub 2017 Apr 6.
    Institute of Anatomy, University of Rostock, 18057 Rostock, Germany.
    Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Read More

    Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease.
    Hum Mol Genet 2017 Jun;26(12):2277-2289
    Department of Psychology, Section of Neuroscience and Center for Research in Neurobiology 'Daniel Bovet', Sapienza University of Rome, 00185 Rome, Italy.
    The Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder due to mutations in the NPC1 gene, encoding a transmembrane protein related to the Sonic hedgehog (Shh) receptor, Patched, and involved in intracellular trafficking of cholesterol. We have recently found that the proliferation of cerebellar granule neuron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh expression. This finding prompted us to analyze the formation of the primary cilium, a non-motile organelle that is specialized for Shh signal transduction and responsible, when defective, for several human genetic disorders. Read More

    Tau aggregates: Where, When, Why and What consequences?
    Neuropathol Appl Neurobiol 2017 Mar 30. Epub 2017 Mar 30.
    C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA 02114, USA.
    Neuropathologists have been aware of neurofibrillary tangles for more than a century following their description as part of Alois Alzheimer's initial report. Since those early days, our understanding of the relationship of this particular type of cellular inclusion associated with neurodegeneration has continually broadened. Textbooks, now a partially antiquated concept, commonly list a range of disorders as being associated with tangles -NDASH- including typical neurodegenerative diseases (Alzheimer disease [AD], forms of frontotemporal lobar degenerations [FTLD-tau], progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], primary aged related tauopathy [PART]), secondary degenerative diseases such as chronic traumatic encephalopathy, metabolic disease (Niemann-Pick disease type C) and infections (SSPE). Read More

    Investigational therapies for hypercholesterolemia.
    Expert Opin Investig Drugs 2017 May 13;26(5):603-617. Epub 2017 Apr 13.
    a Diabetes Institute of Ireland , Beacon Clinic and Trinity College , Dublin 2 , Ireland.
    Introduction: Cardiovascular morbidity and mortality are of increasing concern, not only to patients but also to the health care profession and service providers. The preventative benefit of treatment of dyslipidaemia is unquestioned but there is a large, so far unmet need to improve clinical outcome. There are exciting new discoveries of targets that may translate into improved clinical outcome. Read More

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