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    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

    THE STRENGTHS, WEAKNESSES, OPPORTUNITIES, AND THREATS (SWOTs) ANALYSES OF THE EBOLA VIRUS - PAPER RETRACTED.
    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 Apr 22. 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 Apr 3. Epub 2017 Apr 3.
    Department of Psychology, Section of Neuroscience Section and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 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 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 Apr 2. Epub 2017 Apr 2.
    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

    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

    Changes to cholesterol trafficking in macrophages by Leishmania parasites infection.
    Microbiologyopen 2017 Mar 27. Epub 2017 Mar 27.
    Mycotic and Parasitic Agents and Mycobacteria, Department of Infectious Diseases, Robert Koch-Institute, Berlin, Germany.
    Leishmania spp. are protozoan parasites that are transmitted by sandfly vectors during blood sucking to vertebrate hosts and cause a spectrum of diseases called leishmaniases. It has been demonstrated that host cholesterol plays an important role during Leishmania infection. Read More

    Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex.
    Science 2017 Mar;355(6331):1306-1311
    Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
    The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Read More

    Primary cilium alterations and expression changes of Patched1 proteins in niemann-pick type C disease.
    J Cell Physiol 2017 Mar 23. Epub 2017 Mar 23.
    Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
    Niemann-Pick type C disease (NPC) is a disorder characterized by abnormal intracellular accumulation of unesterified cholesterol and glycolipids. Two distinct disease-causing genes have been isolated, NPC1 and NPC2. The NPC1 protein is involved in the sorting and recycling of cholesterol and glycosphingolipids in the late endosomal/lysosomal system. Read More

    Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe.
    Biochem Pharmacol 2017 Jul 18;135:116-125. Epub 2017 Mar 18.
    Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States. Electronic address:
    Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman disease and cholesteryl ester storage disease (CESD). Read More

    N-terminal domain of the cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) is essential for α-tocopherol transport.
    Biochem Biophys Res Commun 2017 Apr 16;486(2):476-480. Epub 2017 Mar 16.
    Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 985-1 Sanzo, Higashimura-cho, Fukuyama, Hiroshima 729-0292, Japan.
    Both cholesterol and α-tocopherol are essential lipophilic nutrients for humans and animals. Although cholesterol in excess causes severe problems such as coronary heart disease, it is a necessary component of cell membranes and is the precursor for the biosynthesis of steroid hormones and bile acids. Niemann-Pick C1-like 1 (NPC1L1) is a cholesterol transporter that is highly expressed in the small intestine and liver in humans and plays an important role in cholesterol homeostasis. Read More

    Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.
    Mol Genet Metab 2017 May 9;121(1):16-21. Epub 2017 Mar 9.
    Department of Genetics, Hospital Central Sur de Alta Especialidad, PEMEX, Mexico City, Mexico; Facultad Mexicana de Medicina, Universidad La Salle, Mexico City, Mexico. Electronic address:
    Objective: To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services).

    Study Design: Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. Read More

    Oligo(ethylene glycol)-modified β-cyclodextrin-based polyrotaxanes for simultaneously modulating solubility and cellular internalization efficiency.
    J Biomater Sci Polym Ed 2017 Mar 16:1-16. Epub 2017 Mar 16.
    a Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering , Tokyo Medical and Dental University , Tokyo , Japan.
    We developed stimuli-labile polyrotaxanes (PRXs) composed of β-cyclodextrin (β-CD), Pluronic as an axle polymer, and acid-cleavable N-triphenylmethyl groups as bulky stopper molecules, and found that the PRXs are potent therapeutics for Niemann-Pick type C disease, because the PRX can effectively reduce intracellular cholesterol through the intracellular release of threaded β-CDs. In general, the PRXs need to be chemically modified with hydrophilic functional groups because PRXs are not soluble in aqueous media. Herein, four series of oligo(ethylene glycol)s (OEGs) with different ethylene glycol repeating unit (2 or 3) and chemical structure of OEG terminal (hydroxy or methoxy) were modified onto the threaded β-CDs in PRX. Read More

    The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.
    Curr Med Res Opin 2017 May 2;33(5):877-890. Epub 2017 Mar 2.
    ac Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
    Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. Read More

    Rare disease heralded by pulmonary manifestations: Avoiding pitfalls of an "asthma" label.
    J Postgrad Med 2017 Apr-Jun;63(2):122-127
    Department of Pathology, Seth G.S. Medical College and KEM Hospital, Mumbai, Maharashtra, India.
    Pulmonary manifestations are seldom recognized as symptoms of storage disorders. The report describes the diagnostic journey in a 30-month-old male infant, born of a third-degree consanguineous marriage referred to our institute as severe persistent asthma. History revealed that the child had progressively worsening breathlessness and persistent dry cough not associated with fever but accompanied by weight loss. Read More

    Relationship between HSP90a, NPC2 and L-PGDS proteins to boar semen freezability.
    J Anim Sci Biotechnol 2017 1;8:21. Epub 2017 Mar 1.
    Universidad de Caldas, Faculty of Agricultural Sciences, A.A. 275, Manizales, Caldas Colombia.
    Background: The purpose of this study was to determine the association of three proteins involved in sperm function on the freezability of porcine semen: the heat shock protein 90 alpha (HSP90a), the Niemann-Pick disease type C2 protein (NPC2), and lipocalin-type prostaglandin D synthase (L-PGDS). Six adult boars (each boar was ejaculated three times, 18 in total) were classified by freezability based on the percentage of functionally competent sperm. The male semen with highest freezability (MHF) and the male semen with lowest freezability (MLF) were centrifuged immediately after collection to separate seminal plasma and spermatozoa to make four possible combinations of these two components and to incubate them for 3 h, adjusting the temperature to 17 °C, to freeze them afterwards. Read More

    Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca(2+) storage.
    Sci Rep 2017 Mar 6;7:43575. Epub 2017 Mar 6.
    Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
    Sphingosine-1-phosphate (S1P) lyase irreversibly cleaves S1P, thereby catalysing the ultimate step of sphingolipid degradation. We show here that embryonic fibroblasts from S1P lyase-deficient mice (Sgpl1(-/-)-MEFs), in which S1P and sphingosine accumulate, have features of Niemann-Pick disease type C (NPC) cells. In the presence of serum, overall cholesterol content was elevated in Sgpl1(-/-)-MEFs, due to upregulation of the LDL receptor and enhanced cholesterol uptake. Read More

    Quantitation of plasmatic lysosphingomyelin and lysosphingomyelin-509 for differential screening of Niemann-Pick A/B and C diseases.
    Anal Biochem 2017 May 1;525:73-77. Epub 2017 Mar 1.
    Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
    Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Read More

    Precision Medicine in Cats: Novel Niemann-Pick Type C1 Diagnosed by Whole-Genome Sequencing.
    J Vet Intern Med 2017 Mar 24;31(2):539-544. 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 Niemann-Pick C1 mutant cells.
    J Lipid Res 2017 Apr 13;58(4):695-708. Epub 2017 Feb 13.
    Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065; and Department of Chemical Physiology and Cell and Molecular Biology,
    Niemann-Pick C (NPC) disease 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.
    Institute 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 May 2;38(5):727-743. 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

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