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Mol Genet Metab 2020 Jun 24. Epub 2020 Jun 24.

Clinical Development, Sanofi Genzyme, Cambridge, MA, United States of America.

The liver is a major site of lipoprotein synthesis and metabolism. Liver manifestations of chronic visceral ASMD include hepatomegaly, fibrosis, elevated liver enzymes and a pro-atherogenic lipid profile. Measurements of sphingomyelin (SM) levels in liver biopsies and lyso-SM in plasma were used as pharmacodynamic biomarkers. Read More

Ann Biol Clin (Paris) 2020 Jul 2. Epub 2020 Jul 2.

Laboratoire d'hématologie, Groupe Hospitalier de la région Mulhouse Sud Alsace, Mulhouse, France.

Mol Genet Metab 2020 Jun 24. Epub 2020 Jun 24.

Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Acid sphingomyelinase deficiency (ASMD) also known as Niemann-Pick disease, is a rare lysosomal storage disorder with a diverse disease spectrum that includes slowly progressive, chronic visceral (type B) and neurovisceral forms (intermediate type A/B), in addition to infantile, rapidly progressive fatal neurovisceral disease (type A).

Purpose And Methods: We review the published evidence on the relevance of splenomegaly and reduced lung diffusion capacity to the clinical burden of chronic forms of ASMD. Targeted literature searches were conducted to identify relevant ASMD and non-ASMD studies for associations between diffusing capacity of the lungs for carbon monoxide (DL) and splenomegaly, with clinical parameters and outcome measures. Read More

Development 2020 Jul 1. Epub 2020 Jul 1.

Department of Molecular & Cellular Biosciences, Rowan University, Glassboro, NJ, USA

Little is known about the effects of NPC1 deficiency in brain development and if they contribute to neurodegeneration in Niemann-Pick Type C disease. Since cerebellar Purkinje cells die early and to a higher extent in NPC, here we analyzed the effect of NPC1 deficiency in microglia and climbing fiber synaptic refinement during cerebellar postnatal development using the mouse. Our analysis revealed that NPC1 deficiency leads to early phenotypic changes in microglia that are not associated with an innate immune response. Read More

Neurotox Res 2020 Jun 30. Epub 2020 Jun 30.

Center for Hearing and Deafness, 137 Cary Hall, University at Buffalo, Buffalo, NY, 14214, USA.

2-Hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol chelator, is being used to treat diseases associated with abnormal cholesterol metabolism such as Niemann-Pick C1 (NPC1). However, the high doses of HPβCD needed to slow disease progression may cause hearing loss. Previous studies in mice have suggested that HPβCD ototoxicity results from selective outer hair cell (OHC) damage. Read More

Int J Mol Sci 2020 Jun 24;21(12). Epub 2020 Jun 24.

Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany.

Niemann-Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Read More

J Neurol 2020 Jun 26. Epub 2020 Jun 26.

Neurology Department, Reference Center for Lysosomal Diseases, Neurogenetics and Metabolism Unit, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75013, Paris, France.

Late-onset Niemann-Pick type C (NP-C) is a rare, underdiagnosed lysosomal disease with neurological manifestations. A specific treatment, miglustat, can stabilize the disease if given early. Recently, three plasma screening biomarkers (PSBs) were developed [cholestane3β,5α,6βtriol (C-triol), 7-ketocholesterol (7-KC), and lysosphingomyelin-509 (LSM-509)], allowing a simpler and quite robust screening of patients suitable for genetic testing. Read More

Biol Pharm Bull 2020 Jun 25. Epub 2020 Jun 25.

Faculty of Pharmaceutical Sciences, Tohoku University.

Early diagnosis of Niemann-Pick diseases (NPDs) is important for better prognosis of such diseases. N-Palmitoyl-O-phosphocholine-serine (PPCS) is a new NPD biomarker possessing high sensitivity, and with its combination with sphingosylphosphocholine (SPC) it may be possible to distinguish NPD-C from NPD-A/B. In this study, a rapid liquid chromatography/tandem mass spectrometry (LC/MS/MS) method (method 1) and a validated LC/MS/MS analysis (method 2) of PPCS and SPC were developed, and we have proposed a diagnostic screening strategy for NPDs using a combination of serum PPCS and SPC concentrations. Read More

Curr Opin Cell Biol 2020 Jun 21;65:103-111. Epub 2020 Jun 21.

Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Cholesterol is an essential component of mammalian membranes, and its homeostasis is strictly regulated, with imbalances causing atherosclerosis, Niemann Pick disease, and familial hypercholesterolemia. Cellular cholesterol supply is mediated by LDL-cholesterol import and de novo cholesterol biosynthesis, and both pathways are adjusted to cellular demand by the cholesterol-sensitive SREBP2 transcription factor. Cholesterol homeostasis is modulated by a wide variety of metabolic pathways and the ubiquitination machinery, in particular E3 ubiquitin ligases. Read More

Cerebellum 2020 Jun 22. Epub 2020 Jun 22.

Division of Neurology, Department of Clinical Medicine, Universidade Federal do Ceará, Fortaleza, Brazil.

Niemann-Pick type C (NPC) is a rare autosomal recessive disorder characterized by storage of unesterified glycolipids and cholesterol in lysosome. NPC's clinical presentation is highly heterogeneous, depending on the time of onset. It encompasses visceral, neurological, and/or psychiatric manifestations. Read More

Dysphagia 2020 Jun 19. Epub 2020 Jun 19.

Centre for Neuroscience of Speech, The University of Melbourne, 550 Swanston Street, Parkville, Melbourne, VIC, 3010, Australia.

Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disease, characterized by progressive psychiatric and neurological deficits. Neurological symptoms include cognitive decline and dysphagia. Aspiration pneumonia secondary to dysphagia is a leading cause of death in NPC. Read More

J Diabetes Metab Disord 2020 Jun 22;19(1):415-422. Epub 2020 Apr 22.

Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran.

Purpose: The intestine has substantial role in cholesterol homeostasis due to the presence of various cholesterol transporters and gut microbiota. spp. are important members of gut microbiota that employ outer membrane vesicles (OMVs) to interact with host. Read More

Cell 2020 Jun 11. Epub 2020 Jun 11.

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that reveal the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane (TM) domain of NPC1. At pH 8. Read More

J Cell Mol Med 2020 Jun 15. Epub 2020 Jun 15.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

Neurite outgrowth inhibitor-B (Nogo-B) is a membrane protein which is extensively expressed in multiple organs, especially in endothelial cells and vascular smooth muscle cells of blood vessels and belongs to the reticulon protein family. Notably, its specific receptor, Nogo-B receptor (NgBR), encoded by NUS1, has been implicated in many crucial cellular processes, such as cholesterol trafficking, lipid metabolism, dolichol synthesis, protein N-glycosylation, vascular remodelling, angiogenesis, tumorigenesis and neurodevelopment. In recent years, accumulating studies have demonstrated the statistically significant changes of NgBR expression levels in human diseases, including Niemann-Pick type C disease, fatty liver, congenital disorders of glycosylation, persistent pulmonary hypertension of the newborn, invasive ductal breast carcinoma, malignant melanoma, non-small cell lung carcinoma, paediatric epilepsy and Parkinson's disease. Read More

Am J Forensic Med Pathol 2020 Jun 12. Epub 2020 Jun 12.

From the Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.

The rupture of spleen is common in clinical and forensic practice. Trauma is the most common cause of splenic rupture. Although rare, traumatic splenic rupture may occur in these individuals with asymptomatic underlying disease, and clinical and forensic pathologists may neglect the disease and diagnose only the traumatic splenic rupture. Read More

Biochim Biophys Acta Mol Basis Dis 2020 Jun 6;1866(10):165875. Epub 2020 Jun 6.

Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address:

Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Read More

Curr Opin Neurol 2020 Jun 8. Epub 2020 Jun 8.

Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute (KDAH).

Purpose Of Review: The aim of this article is to review recent developments in the areas of the disease features and treatment of Wilson disease, and survey disorders that share its pathophysiology or clinical symptoms.

Recent Findings: Knowledge of the clinical spectrum of Wilson disease has expanded with recognition of patients who present in atypical age groups - patients with very early onset (<5 years) and those in whom symptoms present in mid-to-late adulthood. A disease phenotype with dominant psychiatric features and increased risk of cardiac problems and various sleep disorders have been identified. Read More

J Virol 2020 Jun 3. Epub 2020 Jun 3.

Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada

Ebola virus (EBOV) entry requires internalization into host cells and extensive trafficking through the endolysosomal network in order to reach late endosomal/lysosomal compartments that contain triggering factors for viral membrane fusion. These triggering factors include low-pH activated cellular cathepsin proteases, which cleave the EBOV glycoprotein (GP) to expose the binding domain of the filoviral receptor, Niemann-Pick C1 (NPC1). Here, we report that trafficking of EBOV to NPC1 requires expression of the homotypic fusion and protein sorting (HOPS) tethering complex as well as its regulator, UV radiation resistance associated gene (UVRAG). Read More

Life Sci Alliance 2020 Jul 2;3(7). Epub 2020 Jun 2.

Department of Pharmacology, University of Oxford, Oxford, UK

Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the or genes. Mutations in the gene lead to the majority of clinical cases (95%); however, the function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann-Pick C-related protein 1 (Ncr1). Read More

J Genet 2020 ;99

Oasi Research Institute - IRCCS, 94018 Troina, Italy.

Niemann-Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the (in 95% of cases) or (in ~5% of cases) genes, inherited in an autosomal recessive manner. We report the case of a 38-year-old woman with learning disorder from her first year of schooling, and could notice slow progressed cognitive impairment, social withdrawal, apathy, handwriting alterations, deterioration of language skills and dysphagia. Brain magnetic resonance imaging showed severe cerebellar atrophy, hypoplasia of the corpus callosum, asymmetric lateral ventricular enlargement, and severe enlargement of frontal and parietal subarachnoid spaces. Read More

J Pathol 2020 May 29. Epub 2020 May 29.

Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands.

Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. Read More

Sci Rep 2020 May 26;10(1):8663. Epub 2020 May 26.

Department of Microbiology, Immunology, and Physiology, Meharry Medical College, Nashville, TN, 37208, USA.

Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 and NPC2 genes that result in an accumulation of cholesterol in lysosomes. The majority of children with NPC die in adolescence. Currently, no FDA-approved therapies exist for NPC and the mechanisms of NPC disease are not fully understood. Read More

J Lipid Res 2020 07 26;61(7):972-982. Epub 2020 May 26.

School of Biological Sciences and Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Read More

Int J Pharm 2020 Jun 16;584:119440. Epub 2020 May 16.

Departamento de Bioquímica y Biología Molecular-A, Facultad de Biología, Universidad de Murcia - Regional Campus of International Excellence "Campus Mare Nostrum", E-30100 Murcia, Spain. Electronic address:

Niemann Pick disease Type C (NPC) is a recessive rare disease caused by the mutation on NPC1 and/or NPC2 genes changing the processing of the Low-density proteins (LDL) resulting in an accumulation of lipids in the cells. Until today there is not a cure, the current treatment is based on palliative affairs to reduce the symptoms and prevent its appearance. Among all the treatments proposed the use of cyclodextrins (CDs), nanocarriers which can complex cholesterol, is one of the most useful alternatives. Read More

Front Microbiol 2020 30;11:612. Epub 2020 Apr 30.

Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Influenza A virus (IAV) is a major human respiratory pathogen causing annual epidemics as well as periodic pandemics. A complete understanding of the virus pathogenesis and host factors involved in the viral lifecycle is crucial for developing novel therapeutic approaches. Sphingomyelin (SM) is the most abundant membrane sphingolipid. Read More

Neuroimage 2020 Aug 15;217:116894. Epub 2020 May 15.

Skirball Institute of Biomolecular Medicine and Department of Radiology, New York University School of Medicine, New York, NY, USA; Biomedical Imaging & Technology Graduate Program, New York University School of Medicine, USA. Electronic address:

Niemann-Pick Type C (NPC) is a rare genetic disorder characterized by progressive cell death in various tissues, particularly in the cerebellar Purkinje cells, with no known cure. Mouse models for human NPC have been generated and characterized histologically, behaviorally, and using longitudinal magnetic resonance imaging (MRI). Previous imaging studies revealed significant brain volume differences between mutant and wild-type animals, but stopped short of making volumetric comparisons of the cerebellar sub-regions. Read More

Elife 2020 May 15;9. Epub 2020 May 15.

Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.

Transport of LDL-derived cholesterol from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary cholesterol. We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domain dynamics in cholesterol transport. Using a sensitive method to monitor lysosomal cholesterol efflux, we found that NPC1's N-terminal domain need not release from the rest of the protein for efficient cholesterol export. Read More

Cells 2020 May 7;9(5). Epub 2020 May 7.

Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain.

We recently identified elevated annexin A6 (AnxA6) protein levels in Niemann-Pick-type C1 (NPC1) mutant cells. In these cells, AnxA6 depletion rescued the cholesterol accumulation associated with NPC1 deficiency. Here, we demonstrate that elevated AnxA6 protein levels in NPC1 mutants or upon pharmacological NPC1 inhibition, using U18666A, were not due to upregulated AnxA6 mRNA expression, but caused by defects in AnxA6 protein degradation. Read More

J Control Release 2020 May 7;324:181-193. Epub 2020 May 7.

Institute for Bioscience and Biotechnology Research (IBBR) and Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742-4450, USA; Institute for Bioengineering of Catalonia (IBEC) of the Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain; Institution of Catalonia for Research and Advanced Studies (ICREA), Barcelona 08910, Spain. Electronic address:

The interaction of drug delivery systems with tissues is key for their application. An example is drug carriers targeted to endothelial barriers, which can be transported to intra-endothelial compartments (lysosomes) or transcellularly released at the tissue side (transcytosis). Although carrier targeting valency influences this process, the mechanism is unknown. Read More

J Biotechnol 2020 Jul 6;318:20-30. Epub 2020 May 6.

Molecular Pathology, International Institute for Genetic Engineering and Biotechnology, Trieste, Italy. Electronic address:

Niemann-Pick type C (NPC) is an autosomal recessive lysosomal storage disorder due to mutations in NPC1 (95 % cases) or NPC2 genes, encoding NPC1 and NPC2 proteins, respectively. Both NPC1 and NPC2 proteins are involved in transport of intracellular cholesterol and their alteration leads to the accumulation of unesterified cholesterol and other lipids within the lysosomes. The disease is characterized by visceral, neurological and psychiatric symptoms. Read More

J Biol Chem 2020 Jul 8;295(27):9121-9133. Epub 2020 May 8.

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. Read More

BMC Med Genet 2020 05 6;21(1):94. Epub 2020 May 6.

Internal Medicine Department, Hospital General Universitario Gregorio Marañón, Calle Dr. Esquerdo 46, 28007, Madrid, Spain.

Background: Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by deficient activity of acid sphingomyelinase.

Case Presentation: We present a case of NPD type B with a unique compound heterozygosity for SMPD1 (NM_000543.4:c. Read More

J Lipid Res 2020 Jul 5;61(7):1004-1013. Epub 2020 May 5.

Department of Chemistry, University of Illinois at Chicago, Chicago, IL

Niemann-Pick disease type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Read More

Neurobiol Aging 2020 Sep 8;93:143.e1-143.e4. Epub 2020 Apr 8.

Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address:

Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Read More

J Clin Med 2020 May 2;9(5). Epub 2020 May 2.

Department of Metabolic Biochemistry, Rouen University Hospital, 76000 Rouen, France.

: Fabry disease (FD) is an X-linked progressive lysosomal disease (LD) due to glycosphingolipid metabolism impairment. Currently, plasmatic globotriaosylsphingosine (LysoGb3) is used for disease diagnosis and monitoring. However, this biomarker is inconstantly increased in mild forms and in some female patients. Read More

Curr Med Chem 2020 May 4. Epub 2020 May 4.

Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001. China.

Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum cholesterol is currently the most important strategy in reducing CHD. In humans, the serum cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the key molecules in the three pathways is an important strategy in lowering serum lipids. Read More

FASEB J 2020 06 5;34(6):7253-7264. Epub 2020 May 5.

Lipoprotein Metabolism Section, Translational Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Read More

J Biol Chem 2020 Jun 30;295(23):8017-8035. Epub 2020 Apr 30.

Department of Molecular Medicine, Scripps Research, La Jolla, California, USA

Niemann-Pick type C (NPC) disease is primarily caused by mutations in the gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. The most prevalent disease-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking from the endoplasmic reticulum to the LE/Ly compartments. We now show that the FDA-approved histone deacetylase inhibitor (HDACi) valproic acid (VPA) corrects the folding and trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis, an effect that is largely driven by a reduction in HDAC7 expression. Read More

Clin Chim Acta 2020 Aug 27;507:181-186. Epub 2020 Apr 27.

Division of Metabolism, Bambino Gesù Children Hospital and Research Institute, Rome, Italy.

Background: Infantile cholestasis (IC) is defined as an impairment of bile production or flow occurring in the first months of life. The diagnostic approach in IC is challenging since the differential diagnosis is broad.

Methods: We retrospectively evaluated 91 cholestatic infants referred to our department from 2014 to 2019. Read More

Neurodegener Dis Manag 2020 Apr 30;10(2):73-80. Epub 2020 Apr 30.

Neurology Section, Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, 65. 28009, Madrid, España.

Niemann-Pick type C (NP-C) disease is a neurovisceral atypical lysosomal lipid storage disorder with a poor prognosis. We present the 5-year neuropsychological follow-up of a patient with juvenile onset NP-C, spanning the pre-diagnostic stage to the period after treatment with miglustat (Actelion Pharmaceuticals Inc., CA, US). Read More

Paediatr Anaesth 2020 Apr 29. Epub 2020 Apr 29.

Department of Neurology, Rush University, Chicago, USA.

Background: Niemann-Pick disease type C is an autosomal-recessive, lysosomal storage disorder with variable age of onset and a heterogeneous clinical presentation that includes neurological, psychiatric, and visceral findings. Serial intrathecal injections of 2-hydroxypropyl-beta-cyclodextrin are being evaluated as a treatment modality for Niemann-Pick disease type C with a subset of patients requiring anesthesia for this procedure.

Aims: The aim of this study was to evaluate the safety of anesthesia provided for patients undergoing intrathecal injection of 2-hydroxypropyl-beta-cyclodextrin. Read More

Vet Pathol 2020 Jul 29;57(4):559-564. Epub 2020 Apr 29.

The University of Tokyo, Tokyo, Japan.

A 4-month-old female mixed-breed cat showed gait disturbance and eventual dysstasia with intention tremor and died at 14 months of age. Postmortem histological analysis revealed degeneration of neuronal cells, alveolar epithelial cells, hepatocytes, and renal tubular epithelial cells. Infiltration of macrophages was observed in the nervous system and visceral organs. Read More

Pathol Int 2020 Apr 27. Epub 2020 Apr 27.

Division of Neuropathology, Faculty of Medicine, Tottori University, Tottori, Japan.

Niemann-Pick disease type C (NPC) is a neurovisceral lipid-storage disease. Although NPC patients show lipid storage in anterior horn cells of the spinal cord, little information is available regarding the electron microscopic analyses of the morphologies of intra-endosomal lipid like-materials in the anterior horn cells of NPC patients. In this study, we elucidated the intra-endosomal ultrastructures in spinal anterior horn cells in an NPC patient, as well as in mutant BALB/c NPC1 mice with a retroposon insertion in the NPC1 gene. Read More

J Pediatr Genet 2020 Jun 2;9(2):87-92. Epub 2020 Jan 2.

Department of Paediatrics, Genetic Clinic, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

Lysosomal storage disorders (LSDs) are relatively common slow progressive inborn error of metabolism encountered by clinicians. This work intends to highlight the more common LSDs, their clinical presentation, outcome, and mutation (wherever feasible) collected from the genetic clinic at tertiary care center in Eastern Uttar Pradesh. The data for analysis were collected retrospectively from genetic records from a follow-up clinic. Read More

Orphanet J Rare Dis 2020 Apr 25;15(1):104. Epub 2020 Apr 25.

Institut Pediatric Hospital Sant Joan, Hospital Sant Joan de Déu, Passeig de Sant Joan de Deu, 2, 08950, Esplugues de Llobregat, Barcelona, Spain.

Background: Niemann-Pick disease Type C (NP-C) is a rare, progressive neurodegenerative disorder characterized by progressive neurodegeneration and premature death. We report data at closure of the NPC Registry that describes the natural history, disease course and treatment experience of NP-C patients in a real-world setting.

Methods: The NPC Registry was a prospective observational cohort study that ran between September 2009 and October 2017. Read More

Int J Mol Sci 2020 Apr 22;21(8). Epub 2020 Apr 22.

Department of Physical and Theoretical Chemistry, Technische Universität Berlin, 10623 Berlin, Germany.

The Niemann-Pick C1 (NPC1) protein is the main protein involved in NPC disease, a fatal lysosomal lipid storage disease. NPC1, containing 1278 amino acids, is comprised of three lumenal domains (N-terminal, middle lumenal, C-terminal) and a transmembrane (TM) domain that contains a five helix bundle referred to as the sterol-sensing domain (SSD). The exact purpose of the SSD is not known, but it is believed that the SSD may bind cholesterol, either as a part of the lipid trafficking pathway or as part of a signaling mechanism. Read More

Am J Physiol Heart Circ Physiol 2020 06 24;318(6):H1474-H1486. Epub 2020 Apr 24.

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio.

The gut microbe-derived metabolite trimethylamine--oxide (TMAO) has recently been linked to cardiovascular disease (CVD) pathogenesis, prompting the development of therapeutic strategies to reduce TMAO. Previous work has shown that experimental alteration of circulating TMAO levels via dietary alterations or inhibition of the host TMAO producing enzyme flavin containing monooxygenase 3 (FMO3) is associated with reorganization of host cholesterol and bile acid metabolism in mice. In this work, we set out to understand whether recently developed nonlethal gut microbe-targeting small molecule choline trimethylamine (TMA) lyase inhibitors also alter host cholesterol and bile acid metabolism. Read More

J Inherit Metab Dis 2020 Apr 23. Epub 2020 Apr 23.

Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.

Miglustat has been indicated for the treatment of Niemann-Pick disease type C (NP-C) since 2009. The aim of this observational study was to assess the effect of miglustat on long-term survival of patients with NP-C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Read More

Indian J Pathol Microbiol 2020 Apr-Jun;63(2):312-314

Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Sea-blue histiocytes in bone marrow can be associated with a number of conditions and have indeed often been reported in Niemann-Pick diseases, mostly in Niemann-Pick type B, but also Niemann-Pick type C. Rarely, it was reported to be related to a progressive neurological condition. In this work, early bone marrow aspirations in a boy following the discovery of hepatosplenomegaly at 1 month of age and later isolated splenomegaly did not reveal abnormal cells (which is not uncommon). Read More